1．Successful Mental Health Aging: Results From a Longitudinal Study of Older Australian Men. [article]  

American Journal of Geriatric Psychiatry   2006，14(2)：27-35

Abstract: Objective: The authors investigated the associations of medical and lifestyle factors with the mental health of men in their 80s., Methods: This was a prospective study of a community-representative cohort of older men. Successful mental health aging was defined as reaching age 80 years with Mini-Mental State Examination score (MMSE) of 24 or more and Geriatric Depression Scale-15 items (GDS-15) score of 5 or less., Results: Of 601 men followed for 4.8 years, 76.0% enjoyed successful mental health aging. Successful mental health aging was inversely associated with age (hazard ratio [HR] = 0.87; 95% confidence interval [CI]: 0.81-0.94), non-English-speaking background (HR = 0.42; 95% CI: 0.21-0.85), and the consumption of full-cream milk (HR = 0.63; 95% CI: 0.45-0.89), and directly associated with high school or university education (HR = 1.92; 95% CI: 1.34-2.75) and vigorous (HR = 1.89; 95% CI: 1.17-3.05) and nonvigorous physical activity (HR = 1.50; 95% CI: 1.05-2.14). Marital status, smoking and alcohol use, weekly consumption of meat or fish, and a medical history of hypercholesterolemia, hypertension, diabetes, myocardial infarction, and stroke were not associated with mental health outcomes in men aged 80 years or over., Conclusion: Three in four men who reach age 80 years undergo successful mental health aging. Factors associated with successful mental health aging include education and lifestyle behaviors such as physical activity. Lifestyle modification by means of increasing physical activity and reducing saturated fat intake may prove to be a safe, inexpensive, and readily available strategy to help maximize the successful mental health aging of the population., Copyright (C) 2006 American Association for Geriatric Psychiatry

2．Thrombin and Prothrombin Are Expressed by Neurons and Glial Cells and Accumulate in Neurofibrillary Tangles in Alzheimer Disease Brain.[article]

Journal of Neuropathology & Experimental Neurology  2006，65(1)：19-25

Abstract: Thrombin is a serine protease that is generated by proteolytic cleavage of its precursor, prothrombin. We previously showed that thrombin proteolyses the microtubule-associated protein tau and that phosphorylation of tau inhibits this process. To characterize further the role of thrombin in the brain, we investigated prothrombin and thrombin expression in cultured brain cells and in brains of control, Alzheimer disease (AD) and parkinsonism-dementia complex of Guam (PDCG). We show by reverse transcriptase-polymerase chain reaction that prothrombin mRNA is expressed in brain tissues, neuroblastoma cells, and cultured human astrocytes, oligodendrocytes, and microglial cells. We also show by immunohistochemistry that the proteins prothrombin and thrombin are present in brain using specific monoclonal and polyclonal antibodies for both proteins. All antibodies stained residual serum in blood vessels, as well as normal pyramidal neurons and their processes, and some astrocytes. Additionally, in AD and PDCG cases, all antibodies stained extra- and intracellular neurofibrillary tangles (NFTs), senile plaques, and reactive microglial cells. The ubiquitous expression of prothrombin and thrombin in brain cells suggests that thrombin plays an important physiological role in normal brain. The accumulation of thrombin and prothrombin in NFTs supports the hypothesis that thrombin may be involved in tau proteolysis and that failure to metabolize tau may lead to its aggregation in neurodegenerative diseases., (C) 2006 American Association of Neuropathologists, Inc

3．A Prion Disease-Possible Gerstmann-Straussler-Scheinker Disease: A Case Report. [report]

Journal of Computer Assisted Tomography 2006，30(1)：135-9

Abstract: Summary: A 50-year-old patient with a 6-month history of progressive cognitive and motor disability is presented. There were no myoclonic jerks on examination and no periodic sharp waves by electroencephalography. Imaging showed high signal on T2-weighted scans in the basal ganglia and posterior limbs of the internal capsules, with no restricted diffusion and parenchymal volume loss. A brain biopsy was performed. Western blot analysis revealed a protease-resistant prion protein fragment (PrP7-8), the molecular hallmark of Gerstmann-Straussler-Scheinker disease., (C) 2006 Lippincott Williams & Wilkins, Inc.

4．Inclusion-body myositis: A myodegenerative conformational disorder associated with A[beta], protein misfolding, and proteasome inhibition. [article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.  2006,66(2)：S39-S48

Abstract: mdash;: Sporadic inclusion-body myositis (s-IBM), the most common muscle disease of older persons, is of unknown cause and there is no successful treatment. We summarize our most recent findings, which provide a better understanding of the steps in the pathogenetic cascade. We suggest that s-IBM is primarily a myodegenerative disease. Intriguing are the phenotypic similarities between s-IBM muscle fibers and the brains of Alzheimer disease, the most common neurodegenerative disease of older persons. In s-IBM, abnormal accumulation of the amyloid-[beta] (A[beta]) precursor protein and its proteolytic fragment, A[beta], associated with the aging intracellular milieu of the muscle fiber, appear to be key upstream pathogenic events. We propose that the identified abnormal accumulation, misfolding, and aggregation of proteins, perhaps provoked by the aging milieu and aggravated by the oxidative stress, lead to the s-IBM-specific vacuolar degeneration and atrophy of muscle fibers., (C)2006AAN Enterprises, Inc.

5．Apolipoprotein e genotype and age-related myelin breakdown in healthy individuals: implications for cognitive decline and dementia. [article]

Arch Gen Psychiatry  2006,63(1),63-72

Abstract: CONTEXT: Apolipoprotein E (APOE) genotype is the most influential Alzheimer disease (AD) risk factor after advanced age. The APOE4 alleles decrease and the APOE2 alleles increase age at onset of AD. Human and nonhuman primate data suggest that in midlife, the structural integrity of myelin sheaths begins breaking down, with an accelerating age-related trajectory most evident in the brain's later-myelinating association regions. This may result in a progressive "disconnection" of widely distributed neural networks that may underlie the age risk factor for AD. OBJECTIVE: To assess, using magnetic resonance imaging, whether the shift in age at onset of AD observed with the APOE genotype is associated with the trajectory of age-related myelin breakdown. DESIGN: Cross-sectional. SETTING: Metropolitan university medical center. PARTICIPANTS: Healthy individuals (N = 104) aged 55 to 75 years who underwent genotyping for APOE. MAIN OUTCOME MEASURES: Calculated transverse relaxation rates, an indirect measure of white matter structural integrity, for late-myelinating frontal lobe white matter (Fwm) and early- and later-myelinating regions of the corpus callosum, the splenium (Swm) and the genu (Gwm). RESULTS: The presence of the protective APOE2 allele was associated with significantly higher relaxation rates in Fwm and Gwm but not in Swm. Furthermore, APOE status impacted the trajectory of age-related myelin breakdown in late-myelinating regions (Fwm and Gwm) but not in Swm. In Fwm and Gwm, APOE4+ individuals had a steeper slope of decline in relaxation rates with age than APOE2+ individuals; those with APOE3/3 alleles had an intermediate slope. CONCLUSIONS: In later-myelinating regions, the severity and rate of myelin breakdown in healthy older individuals are associated with APOE status and support the hypothesis that this process may contribute to age at onset of AD. Combining APOE status with noninvasive measures of myelin breakdown may be useful in assessing treatment strategies for the primary prevention of AD.

6．Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment. [article]

Arch Neurol  2006,63(1)：97-101

Abstract: OBJECTIVE: To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions. DESIGN: A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure. SETTING: Referral dementia clinic.Subjects Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions. MAIN OUTCOME MEASURES: Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes. RESULTS: The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD. CONCLUSION: These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.

Author Address: Author Affiliations: Alzheimer's Disease Research Center and Departments of Psychiatry, Neurology, Psychology, and Radiology, University of Pittsburgh, Pittsburgh, Pa.

7．Population-based case-control study of cognitive function in essential tremor. [article]

Neurology   2006，66(1)：69-74

Abstract: Objectives: To determine whether patients with essential tremor (ET) have cognitive deficits when compared with controls and whether the types of cognitive deficits reported previously are also found in this large sampling of patients with ET., Methods: A total of 232 patients with ET and 696 matched controls age 65 years or older (median 75 years) living in central Spain (the Neurologic Diseases in Central Spain study) underwent a neuropsychological assessment, including tests of global cognitive performance, frontal executive function, verbal fluency, and memory. Subjects also were asked whether they had forgetfulness., Results: Fifty-six patients with ET were previously undiagnosed; only 14 (6%) were taking medication for tremor. Adjusted for age, gender, education, premorbid intelligence, medications, and depressive symptoms, cases performed less well on most neuropsychological tests and especially tests of global cognitive performance (37-item Mini-Mental State Examination = 27.0 +/- 6.7 in cases vs 28.9 +/- 5.9 in controls, p < 0.001) and frontal executive function (Trail Making Test number of errors = 8.7 +/- 11.0 in cases vs 3.8 +/- 7.6 in controls, p < 0.001). Forgetfulness was reported in 117 (50.4%) patients with ET vs 300 (43.1%) controls (p = 0.05)., Conclusions: In a population-based sample of largely untreated patients with essential tremor, cases performed more poorly on formal neuropsychological testing than did their counterparts without tremor. A complaint of forgetfulness was also marginally more common in patients with essential tremor., (C)2006AAN Enterprises, Inc.

8．Expression of Vascular Endothelial Growth Factor and Its Receptors in the Central Nervous System in Amyotrophic Lateral Sclerosis. [Article]

Journal of Neuropathology & Experimental Neurology    2006，65（1）：26-36

Abstract: Vascular endothelial growth factor (VEGF) prolongs survival in the mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis (ALS), whereas dysregulation of VEGF through deletion of its hypoxia-regulatory element causes motor neuron degeneration in mice. We investigated the expression of VEGF and its major agonist receptors in the normal central nervous system and in patients with ALS. Immunohistochemistry demonstrated similar expression patterns of VEGF and VEGF receptor 2 (VEGFR2) in the spinal cord with finely punctate staining of the neuropil and strong expression in anterior horn cells (AHCs). Granular staining on the surface of some AHCs, similar to that seen with synaptic markers, suggested synaptic labeling. VEGFR2 staining was reduced in the neuropil of ALS cases (p = 0.018) associated with a reduction of synaptophysin but not SNAP25 expression. A greater proportion of AHCs in ALS cases showed low expression of VEGF (p = 0.006) and VEGFR2 (p = 0.009) compared with controls. Expression of VEGF and VEGFR2 was confirmed by Western blotting and quantitative reverse transcriptase-polymerase chain reaction (QPCR). The similar expression patterns of VEGF and VEGFR2 suggests autocrine/paracrine effects on spinal motor neurons, and the reduction in their expression seen in ALS cases would support the hypothesis that, as in mouse models of the disease, reduced VEGF signaling may play a role in the pathogenesis of ALS., (C) 2006 American Association of Neuropathologists, Inc

9．Central acute D2 stimulation worsens bladder function in patients with mild Parkinson's disease

Journal of Urology   2006，175（1）：202-6

Abstract: Purpose: The different roles of D1 and D2 dopamine receptors in LUT behavior have been demonstrated in animal studies. In particular D2 selective agonists and D1 selective antagonists seem to produce a reduction of the bladder capacity in conscious rats. This finding has never been confirmed in human studies. Thus, in this study we investigated the role of D1 and D2 agonists/antagonists on LUT behavior in patients with PD. Materials and Methods: A total of 87 patients with mild PD were evaluated. Patients were evaluated with urodynamic studies (cystometry followed by a pressure flow study with perineal floor electromyography) performed in off status and after oral administration of 250 mg of LD. In 70 patients a third urodynamic evaluation was conducted in one of the following conditions: after simultaneous administration of 250 mg oral LD and 60 or 120 mg oral domperidone (D2 peripheral antagonist); after simultaneous administration of 250 mg oral LD and 25, 50 or 150 mg intramuscular L-sulpiride (D2 central and peripheral antagonist). Several urodynamic parameters were evaluated and results obtained in different conditions compared. Results: LD alone worsened detrusor overactivity: in particular, a reduction of first urinary sensation, involuntary detrusor contraction threshold (reflex volume) and bladder capacity was observed. L-sulpiride (central and peripheral D2 antagonist) coadministration counteracted the worsening in a dose dependent manner. Domperidone (peripheral D2 antagonist) coadministration failed to determine the same counteraction. Conclusions: According to our results, a central acute D2 stimulation seems to be responsible of a reduction of bladder capacity with worsening of detrusor overactivity in patients with mild PD.

10．Treatment and prevention of the amyloidoses: Can the lessons learned be applied to sporadic inclusion-body myositis? [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.   2006，66（2）：S110-S113

Abstract: mdash;: The amyloid fibril represents a final common pathologic pathway for a variety of human proteins, all of which have a propensity to misfold. Each seems to require a predisposing event to realize its fibrillogenic potential. It may be mutation, inappropriate or incomplete cleavage, overproduction, or the availability of a template for misfolding. Therapies have been based on decreasing the stimulus (inflammation in the case of AA) reducing the number of producing cells (AL) and a variety of approaches to removing the extracellular aggregates. Sporadic inclusion-body myositis (sIBM), while physically resembling the extracellular amyloidoses, is an intracellular disease, hence imposes the additional requirement of developing a therapy that can access and function inside the affected or potentially affected, cell. Current approaches to the treatment of other forms of amyloidosis are discussed in the context of their applicability, or lack thereof, to sIBM., (C)2006AAN Enterprises, Inc.

11．Demographic Factors Influence Cognitive Recovery After Shunt for Normal-Pressure Hydrocephalus. [Article]

Neurologist     2006，12（1）：39-42

Abstract: Background: Several studies have reported that ventriculoperitoneal shunt insertion for treatment of normal-pressure hydrocephalus results in improvement of gait and, less frequently, improvement of cognition. We sought to identify the demographic factors associated with cognitive improvement after shunt insertion to improve assessment of prognosis for cognitive gains with treatment., Review Summary: We report cognitive testing before and after ventriculoperitoneal shunt insertion in 36 patients with normal pressure hydrocephalus, who previously had improvement of any clinical symptom-gait, urinary incontinence, cognition-after a diagnostic trial of continuous cerebrospinal fluid drainage., Conclusions: One third of patients met our definition of good cognitive improvement: improvement by at least 25% on at least half of the cognitive tests administered. There was a significant negative linear relationship between age and probability of good cognitive improvement. Additionally, the degree of cognitive improvement was found to be greater in women than men (P = 0.002). Age was found to be a better predictor of improvement on memory tests, while sex was a better predictor of improvement on nonmemory tests after shunt insertion., (C) 2006 Lippincott Williams & Wilkins, Inc.

12．Conventional protein kinase C isoforms mediate neuroprotection induced by phorbol ester and estrogen

Journal of Neurochemistry    2006，96（1）：204-217

Abstract: Rapid signal transduction pathways play a prominent role in mediating neuroprotective actions of estrogen in the CNS. We have previously shown that estrogen-induced neuroprotection of primary cerebrocortical neurons from beta-amyloid peptide (A beta) toxicity depends on activation of protein kinase C (PKC). PKC activation with phorbol-12-myristate-13-acetate (PMA) also provides neuroprotection in this paradigm. Because the PKC family includes several isoforms that have opposing roles in regulating cell survival, we sought to identify which PKC isoforms contribute to neuroprotection induced by PMA and estrogen. We detected protein expression of multiple PKC isoforms in primary neuron cultures, including conventional (alpha, beta I, beta II), novel (delta, epsilon, theta) and atypical (zeta, iota/lambda) PKC. Using a panel of isoform-specific peptide inhibitors and activators, we find that novel and atypical PKC isoforms do not participate in the mechanism of either PMA or estrogen neuroprotection. In contrast, a selective peptide activator of conventional PKC isoforms provides dose-dependent neuroprotection against A beta toxicity. In addition, peptide inhibitors of conventional, beta I, or beta II PKC isoforms significantly reduce protection afforded by PMA or 17 beta-estradiol. Taken together, these data provide evidence that conventional PKC isoforms mediate phorbol ester and estrogen neuroprotection of cultured neurons challenged by A beta toxicity.

13．Hyperphosphorylation of JNK-interacting Protein 1, a Protein Associated with Alzheimer Disease

Mol Cell Proteomics  2006，5（1）：97-113

Abstract: The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein (MAP) kinases are activated by pleiotropic signals including environmental stresses, growth factors, and hormones. JNK-interacting protein 1 (JIP1) is a scaffold protein that assembles and facilitates the activation of the mixed lineage kinase-dependent JNK module and also establishes an interaction with beta-amyloid precursor protein that has been partially characterized. Here we show that, similarly to other proteins involved in various neurological diseases, JIP1 becomes hyperphosphorylated following activation of stress-activated and MAP kinases. By immobilized metal affinity chromatography and a combined microcapillary LC/MALDI-TOF/ESI-ion trap mass spectrometry approach, we identified 35 sites of mitotic phosphorylation within JIP1, among which eight were present within (Ser/Thr)-Pro sequence. This motif is modified by various kinases in aggregates of the microtubule-associated protein tau, which generates typical intraneuronal lesions occurring in Alzheimer disease. Most of the post-translational modifications found were located within the JNK, MAP kinase kinase, and RAC-alpha Ser/Thr protein kinase binding regions; no modifications occurred in protein Src homology 3 and phosphotyrosine interaction domains, which are essential for binding to kinesin, beta-amyloid precursor protein, and MAP kinase kinase kinase. Protein phosphorylation is known to affect stability and protein-protein interactions. Thus, the findings that JIP1 is extensively phosphorylated after activation of stress-activated and MAP kinases indicate that these signaling pathways might modulate JIP1 signaling by regulating its stability and association with some, but not all, interacting proteins.

14．Use of hippocampal and amygdalar volumes on magnetic resonance imaging to predict dementia in cognitively intact elderly people

Arch Gen Psychiatry    2006，63（1）：57-62

Abstract: CONTEXT: The recent focus on the development of preventive interventions for Alzheimer disease has fueled the search for biomarkers of presymptomatic disease. Patients with Alzheimer disease and mild cognitive impairment have marked atrophy of the hippocampus and amygdala compared with healthy elderly people. Whether atrophy of these structures is also present in persons without cognitive impairment who later develop dementia is unknown. OBJECTIVE: To assess whether volumetric assessment of the hippocampus and amygdala using magnetic resonance imaging (MRI) predicts dementia in elderly people without cognitive impairment. DESIGN: Longitudinal cohort study. SETTING: A general community in the Netherlands. PARTICIPANTS: Five hundred eleven persons, aged 60 to 90 years, free of dementia at baseline were followed up during 3043 person-years (mean per person, 6.0 years). We performed volumetric assessment of the hippocampus and amygdala, obtained information about daily memory problems, and performed extensive neuropsychological testing in all study participants.Main Outcome Measure Dementia, as assessed by repeated neuropsychological screening and monitoring of medical records. RESULTS: Thirty-five persons developed dementia (26 with Alzheimer disease). Hippocampal and amygdalar volumes were strongly associated with the risk of dementia; the age-, sex-, and education-adjusted hazard ratio per 1-SD decrease in volume was 3.0 (95% confidence interval, 2.0-4.6) for the hippocampus and 2.1 (95% confidence interval, 1.5-2.9) for the amygdala. The hazard ratios associated with atrophy were similar in persons without memory complaints or low cognitive function at baseline. Compared with those remaining free of dementia, baseline brain volumes were 17% smaller in persons who received a clinical diagnosis of dementia within 2 to 3 years after MRI and still 5% smaller in those whose conditions were diagnosed 6 years after MRI. CONCLUSION: Atrophy of the hippocampus and amygdala on MRI in cognitively intact elderly people predicts dementia during a 6-year follow-up.

15．When Blue Turns Gray: Postwarranty Performance. [Miscellaneous]

American Journal of Geriatric Psychiatry     2006，14（1）：21-26

Abstract: Objective: The objective of this study was to review the lifestyle and expectations of a group of 86- to 87-year-old Yale College graduates at the time of their 65th reunion and to compare the results with equivalent data from the general public., Methods: A five-page questionnaire was sent to the 263 living survivors of the Yale College class of 1939 at the time of their 65th reunion., Results: One hundred fifty-one replies were received, some only partially completed. Median survival was 79 years. Among the more interesting results was a wide discrepancy (optimism) between the perceived quality of life and that which one would anticipate from the many physical disabilities of the study group., Conclusion: This is by nature a self-selected group of male octogenarians, but their lifestyle and medical disabilities fit with the general population; their attitude toward being elderly is remarkably positive, and their personal and civic performance continues beyond expectations., Copyright (C) 2006 American Association for Geriatric Psychiatry

16．Polymorphisms in the PON gene cluster are associated with Alzheimer disease

Hum Mol Genet    2006，15（1）：77-85

Abstract: Paraoxonase is an arylesterase enzyme that is expressed in the liver and found in the circulation in association with apoA1 and the high-density lipoprotein, and prevents the accumulation of oxidized lipids in low-density lipoproteins in vitro. Common polymorphisms in genes encoding paraoxonase are established risk factors in a variety of vascular disorders including coronary artery disease and carotid artery stenosis, but their association with Alzheimer disease (AD) is controversial. We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD. Eight SNPs were associated with AD in the African American families (0.0001</=P</=0.04) and two SNPs were associated with AD in Caucasian families (0.01</=P</=0.04). Of note, the pattern of association for the PON1 promoter SNP -161[C/T] was the same in both ethnic groups (P=0.006). Haplotype analysis using sliding windows revealed 11 contiguous SNP combinations spanning the three PON genes with significant global test scores (0.006</=P</=0.04) in the two ethnic groups combined. The most significantly associated haplotype comprised SNPs in the region spanning the -161[C/T] SNP (P=0.00009). Our results demonstrate association between AD and variants in the PON gene cluster in Caucasians and African Americans.

17．Hallucinations in Parkinson disease in the prelevodopa era

Neurology    2006，66（1）93-8

Abstract: Whether chronic hallucinations belong to the natural history of untreated Parkinson disease (PD) remains undetermined. For early authors such as Gowers or Charcot and his followers, hallucinations that occurred in the course of PD either accompanied the final phase of the disease or reflected comorbidities. However, a few authors observed that hallucinations could occur in PD patients with severe depression, confusion, or dementia. Interest in hallucinations with parkinsonism increased with the outbreak of von Economo encephalitis, as they were more frequent than in PD, provoking new pathophysiologic questions. Later studies on mental symptoms in parkinsonism were often based on series that pooled patients with PD and postencephalitic syndromes, confounding a clear analysis. It remains difficult to estimate the prevalence of hallucinations in the natural course of PD before the introduction of levodopa therapy. The lack of prospective studies, the wide early use of anticholinergics and ergots compounds, and the absence of dementia with Lewy bodies in the nosology of the time are further limitations. Even with these limitations, historical descriptions of PD from the prelevodopa era suggest that hallucinations may be part of PD itself, especially in the context of late dementia, depression, or nonspecific encephalopathy.

18．Microtubule-associated Protein MAP1A, MAP1B, and MAP2 Proteolysis during Soluble Amyloid {beta}-Peptide-induced Neuronal Apoptosis: SYNERGISTIC INVOLVEMENT OF CALPAIN AND CASPASE-3

J Biol Chem    2006，281（1）：229-40

Abstract: A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid beta-peptide (Abeta) may be the proximate effectors of neuronal injuries and death in the early stages of Alzheimer disease. However, the molecular mechanisms associated with neuronal apoptosis induced by soluble Abeta remain to be elucidated. We recently demonstrated the involvement of an early reactive oxygen species-dependent perturbation of the microtubule network (Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pincon-Raymond, M., Olivier, J.-L., Chambaz, J., and Pillot, T. (2003) J. Biol. Chem. 278, 3437-3445). Because microtubule-associated proteins (MAPs) are responsible for the polymerization, stabilization, and dynamics of the microtubule network, we investigated whether MAPs might represent the intracellular targets that would enable us to explain the microtubule perturbation involved in soluble Abeta-mediated neuronal apoptosis. The data presented here show that soluble Abeta oligomers induce a time-dependent degradation of MAP1A, MAP1B, and MAP2 involving a perturbation of Ca(2+) homeostasis with subsequent calpain activation that, on its own, is sufficient to induce the proteolysis of isoforms MAP2a, MAP2b, and MAP2c. In contrast, MAP1A and MAP1B sequential proteolysis results from the Abeta-mediated activation of caspase-3 and calpain. The prevention of MAP1A, MAP1B, and MAP2 proteolysis by antioxidants highlights the early reactive oxygen species generation in the perturbation of the microtubule network induced by soluble Abeta. These data clearly demonstrate the impact of cytoskeletal perturbations on soluble Abeta-mediated cell death and support the notion of microtubule-stabilizing agents as effective Alzheimer disease drugs.

19．A perspective on sporadic inclusion-body myositis: The role of aging and inflammatory processes. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.    2006，66（2）：S1-S6

Abstract: mdash;: Sporadic inclusion-body myositis (sIBM) is an age-related condition manifested after midlife. This review points out salient features of sIBM that are shared with normal aging in muscle and with inflammatory changes in vascular atheromas and senile plaques of Alzheimer disease (AD). The amyloid precursor protein (APP) and derived Abeta peptides are found in both AD and sIBM. Because transgenic expression of human APP induces sIBM like changes, it is of potential interest that an inducer of APP, IL-1, increases during aging in mouse muscle. Because various subsets of the usual aging changes in aging brain, muscle, and vessels can be attenuated in rodents by caloric intake and possibly in humans by drugs with anti-inflammatory and anticoagulant activities, this study suggests that diet and inflammation may be useful experimental variations in exploring the pathogenesis of sIBM., (C)2006AAN Enterprises, Inc.

20．Parkinson's disease and other basal ganglia or movement disorders in a large nationwide cohort of Swedish welders. [Article]

Occupational & Environmental Medicine   2006，63（2）：135-140

Abstract: Introduction: Although it has been hypothesised that metal welding and flame cutting are associated with an increased risk for Parkinson's disease due to manganese released in the welding fume, few rigorous cohort studies have evaluated this risk., Methods: The authors examined the relation between employment as a welder and all basal ganglia and movement disorders (ICD-10, G20-26) in Sweden using nationwide and population based registers. All men recorded as welders or flame cutters (n = 49 488) in the 1960 or 1970 Swedish National Census were identified and their rates of specific basal ganglia and movement disorders between 1964 and 2003 were compared with those in an age and geographical area matched general population comparison cohort of gainfully employed men (n = 489 572)., Results: The overall rate for basal ganglia and movement disorders combined was similar for the welders and flame cutters compared with the general population (adjusted rate ratio (aRR) = 0.91 (95% CI 0.81 to 1.01). Similarly, the rate ratio for PD was 0.89 (95% CI 0.79 to 0.99). Adjusted rate ratios for other individual basal ganglia and movement disorders were also not significantly increased or decreased. Further analyses of Parkinson's disease by attained age, time period of follow up, geographical area of residency, and educational level revealed no significant differences between the welders and the general population. Rates for Parkinson's disease among welders in shipyards, where exposures to welding fumes are higher, were also similar to the general population (aRR = 0.95; 95% CI 0.70 to 1.28)., Conclusion: This nationwide record linkage study offers no support for a relation between welding and Parkinson's disease or any other specific basal ganglia and movement disorders., (C) 2006 BMJ Publishing Group Ltd

21．Midlife pulse pressure and incidence of dementia: the Honolulu-Asia Aging Study

Stroke    2006，37（1）：33-7

Abstract: BACKGROUND AND PURPOSE: Previous studies have shown that midlife systolic blood pressure (SBP) predicts late-life cognitive decline and incident dementia. This study explores whether this association is attributable to the pulsatile, ie, pulse pressure (PP), or the nonpulsatile component of blood pressure (BP). METHODS: Data are from the Honolulu-Asia Aging Study, a community-based study of Japanese American men. Midlife BP was measured in 1971 to 1974 and dementia assessment was conducted in late-life. The 2505 men who were dementia free in 1991 and had complete follow-up data were re-examined for incident dementia in 1994 to 1996 and 1997 to 1999. Their age ranged from 71 to 93 years. Survival analysis with age as the time scale was performed to estimate the risk (hazard ratio [HR] and 95% CI) for incident dementia associated with mid- and late-life tertiles of PP and mean arterial BP, as well as SBP and diastolic BP categories. RESULTS: Over a mean of 5.1 years of follow-up, 189 cases (7.5%) of incident Alzheimer disease or vascular dementia were identified. After adjustment for cerebrovascular risk factors, dementia was significantly associated with SBP (HR 1.77; 95% CI, 1.10 to 2.84, for SBP > or =140 mm Hg compared with SBP <120 mm Hg), but not with PP tertiles. Limiting the analysis to those never treated with antihypertensives, high levels of all 4 BP components were significantly associated with dementia. In models with 2 BP components, only SBP remained significant in both the total sample and the never-treated subgroup (HR 2.29; 95% CI, 1.23 to 4.25, for SBP > or =140 mm Hg in total sample), whereas PP was not significantly associated with the risk for dementia. CONCLUSIONS: Midlife PP is not independently associated with dementia incidence. Midlife SBP is the strongest BP component predicting incident dementia.

22．Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue

J Biol Chem    2006，281（1）：5-8

Abstract: The creatine/phosphocreatine system, regulated by creatine kinase, plays an important role in maintaining energy balance in the brain. Energy metabolism and the function of creatine kinase are known to be affected in Alzheimer diseased brain and in cells exposed to the beta-amyloid peptide. We used infrared microspectroscopy to examine hippocampal, cortical, and caudal tissue from 21-89-week-old transgenic mice expressing doubly mutant (K670N/M671L and V717F) amyloid precursor protein and displaying robust pathology from an early age. Microcrystalline deposits of creatine, suggestive of perturbed energetic status, were detected by infrared microspectroscopy in all animals with advanced plaque pathology. Relatively large creatine deposits were also found in hippocampal sections from post-mortem Alzheimer diseased human brain, compared with hippocampus from non-demented brain. We therefore speculate that this molecule is a marker of the disease process.

23．Ezrin Immunoreactivity Reveals Specific Astrocyte Activation in Cerebral HIV. [Article]

Journal of Neuropathology & Experimental Neurology    2006，65（1）：87-96

Abstract: The actin-binding protein ezrin is associated with cellular shape changes, motility, tumor invasion, and lymphocyte activation. We have earlier shown that ezrin immunoreactivity (IR) is faintly present in normal astrocytes but increased in malignant human astrogliomas. We studied the role of ezrin in astrocyte activation, applying immunostaining on serial paraffin sections from human autopsied brain tissues (51 cases). Cerebral HIV infection was chosen as a model displaying consistent exemplary astrocyte activation. Semiquantitative ezrin-IR was compared with the common glial markers GFAP, ferritin, and HLA-DR in relation to clinical and morphologic criteria of HIV encephalopathy. In all cases with HIV infection, GFAP-, HLA-DR-, and ferritin-IR were elevated in comparison to normal brain tissues. In contrast, high ezrin-IR in HIV infection strictly correlated with additional HIV encephalopathy. HIV encephalopathy with particularly high ezrin-IR was correlated with neuronal apoptosis (TUNEL). Combined ezrin-IR and GFAP-IR thus reveals 2 distinct states of astrocytic activation. Normal ezrin-IR, when paralleled by upregulated GFAP, reflects astroglial activation not associated with neuronal apoptosis. High ezrin-IR indicates specific astrocyte stressors related to cellular damage within the central nervous system. Ezrin-IR might also provide a diagnostic tool for the classification of HIV encephalopathy., (C) 2006 American Association of Neuropathologists, Inc

24．Neurovascular coupling in the normal brain and in hypertension, stroke, and Alzheimer disease

J Appl Physiol     2006，100（1）：328-35

Abstract: The brain is critically dependent on a continuous supply of blood to function. Therefore, the cerebral vasculature is endowed with neurovascular control mechanisms that assure that the blood supply of the brain is commensurate to the energy needs of its cellular constituents. The regulation of cerebral blood flow (CBF) during brain activity involves the coordinated interaction of neurons, glia, and vascular cells. Thus, whereas neurons and glia generate the signals initiating the vasodilation, endothelial cells, pericytes, and smooth muscle cells act in concert to transduce these signals into carefully orchestrated vascular changes that lead to CBF increases focused to the activated area and temporally linked to the period of activation. Neurovascular coupling is disrupted in pathological conditions, such as hypertension, Alzheimer disease, and ischemic stroke. Consequently, CBF is no longer matched to the metabolic requirements of the tissue. This cerebrovascular dysregulation is mediated in large part by the deleterious action of reactive oxygen species on cerebral blood vessels. A major source of cerebral vascular radicals in models of hypertension and Alzheimer disease is the enzyme NADPH oxidase. These findings, collectively, highlight the importance of neurovascular coupling to the health of the normal brain and suggest a therapeutic target for improving brain function in pathologies associated with cerebrovascular dysfunction.

25．Common structure and toxic function of amyloid oligomers implies a common mechanism of pathogenesis. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.    2006，66（2）：S74-S78

Abstract: mdash;: Recent findings indicate that soluble amyloid oligomers may represent the primary pathologic species in degenerative diseases. These amyloid oligomers share common structural features and the ability to permeabilize membranes, suggesting that they also share a common primary mechanism of pathogenesis. Membrane permeabilization by amyloid oligomers may initiate a common group of downstream pathologic processes, including intracellular calcium dyshomeostasis, production of reactive oxygen species, altered signaling pathways, and mitochondrial dysfunction that represent key effectors of cellular dysfunction and cell death in amyloid-associated degenerative disease, such as sporadic inclusion-body myositis.,

26．Gain-of-function haplotypes in the vesicular monoamine transporter promoter are protective for Parkinson disease in women

Hum Mol Genet    2006，15（2）：299-305

Abstract: The vesicular monoamine transporter can protect against toxins that induce an acute parkinsonian syndrome. It has been hypothesized that cytoplasmic dopamine has subacute toxic effects in Parkinson Disease (PD) leading to neuronal death and clinical symptoms. Regulatory polymorphisms in the brain form of the vesicular monoamine transporter (VMAT2) which affect its quantitative expression might therefore serve as genetic risk factors for PD. We have screened the promoter region of the gene for VMAT2 (SLC18A2) and identified several novel polymorphisms that form discrete haplotypes. We have tested the common halpotypes in SLC18A2 for functional effects in reporter gene assays and found that there are several gain-of-function haplotypes that display significantly increased transcriptional activity from the reference element. These gain-of-function haplotypes were tested for association with PD and found to confer a protective effect that was selective for females. This finding is consistent with the prediction that increased sequestration of dopamine in secretory vesicles by VMAT2 is protective for PD.

27．The Parkinson disease causing LRRK2 mutation I2020T is associated with increased kinase activity

Journal: Hum Mol Genet    2006，15（2）：223-32

Abstract: Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been recently identified in families with autosomal dominant late-onset Parkinson disease (PD). The LRRK2 protein consists of multiple domains and belongs to the Roco family, a novel group of the Ras/GTPase superfamily. Besides the GTPase (Roc) domain, it contains a predicted kinase domain, with homology to MAP kinase kinase kinases. Using cell fractionation and immunofluorescence microscopy, we show that LRRK2 is localized in the cytoplasm and is associated with cellular membrane structures. The purified LRRK2 protein demonstrates autokinase activity. The disease-associated I2020T mutant shows a significant increase in autophosphorylation of approximately 40% in comparison to wild-type protein in vitro. This suggests that the pathology of PD caused by the I2020T mutation is associated with an increase rather than a loss in LRRK2 kinase activity.

28．Operative techniques and morbidity with subthalamic nucleus deep brain stimulation in 100 consecutive patients with advanced Parkinson's disease

J Neurol Neurosurg Psychiatry    2006，77（1）：12-7

Abstract: OBJECTIVE: Subthalamic nucleus (STN) stimulation for patients with medically refractory Parkinson disease (PD) is expanding. Reported experience has provided some indication of techniques, efficacy, and morbidity, but few centres have reported more than 50 patients. To expand this knowledge, we reviewed our experience with a large series of consecutive patients. METHODS: From March 1999 to September 2003, 191 subthalamic stimulator devices (19 unilateral) were implanted in 100 patients with PD at New York Presbyterian Hospital/Columbia University Medical Center. Sixteen patients had undergone a prior surgery for PD (pallidotomy, thalamotomy, or fetal transplant). Microelectrode guided implantations were performed using techniques similar to those described previously. Electrode implantation occurred 1-2 weeks before outpatient pulse generator implantation. RESULTS: Reductions of dyskinesias and off severity/duration were similar to prior published reports. Morbidity included: 7 device infections (3.7%), 1 cerebral infarct, 1 intracerebral haematoma, 1 subdural haematoma, 1 air embolism, 2 wound haematomas requiring drainage (1.0%), 2 skin erosions over implanted hardware (1.0%), 3 periprocedural seizures (1.6%), 6 brain electrode revisions (3.1%), postoperative confusion in 13 patients (6.8%), and 16 battery failures (8.4%). Of the 100 patients, there were no surgical deaths or permanent new neurological deficits. The average hospital stay for all 100 patients was 3.1 days. CONCLUSION: Subthalamic stimulator implantation in a large consecutive series of patients with PD produced significant clinical improvement without mortality or major neurological morbidity. Morbidity primarily involved device infections and hardware/wound revisions.

Author Address: Departments of Neurological Surgery and Neurology, Columbia College of Physicians and Surgeons, New York, NY, USA. rrg2@columbia.edu

29．A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease

American Journal of Human Genetics    2006，78（1）：78-88

Abstract: Strong evidence of linkage to late-onset Alzheimer disease ( LOAD) has been observed on chromosome 10, which implicates a wide region and at least one disease-susceptibility locus. Although significant associations with several biological candidate genes on chromosome 10 have been reported, these findings have not been consistently replicated, and they remain controversial. We performed a chromosome 10-specific association study with 1,412 genebased single-nucleotide polymorphisms ( SNPs), to identify susceptibility genes for developing LOAD. The scan included SNPs in 677 of 1,270 known or predicted genes; each gene contained one or more markers, about half (48%) of which represented putative functional mutations. In general, the initial testing was performed in a white case-control sample from the St. Louis area, with 419 LOAD cases and 377 age-matched controls. Markers that showed significant association in the exploratory analysis were followed up in several other white case-control sample sets to confirm the initial association. Of the 1,397 markers tested in the exploratory sample, 69 reached significance (P < .05). Five of these markers replicated at P < .05 in the validation sample sets. One marker, rs498055, located in a gene homologous to RPS3A ( LOC439999), was significantly associated with Alzheimer disease in four of six case-control series, with an allelic P value of .0001 for a meta-analysis of all six samples. One of the case-control samples with significant association to rs498055 was derived from the linkage sample (P = .0165). These results indicate that variants in the RPS3A homologue are associated with LOAD and implicate this gene, adjacent genes, or other functional variants ( e. g., noncoding RNAs) in the pathogenesis of this disorder.

30．Plasma beta-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy

Neurology     2006，66（1）：23-9

Abstract: BACKGROUND: Microvascular brain injury, typically measured by extent of white matter hyperintensity (WMH) on MRI, is an important contributor to cognitive impairment in the elderly. Recent studies suggest a role for circulating beta-amyloid peptide in microvascular dysfunction and white matter disease. METHODS: The authors performed a cross-sectional study of clinical, biochemical, and genetic factors associated with WMH in 54 subjects with Alzheimer disease (AD) or mild cognitive impairment (AD/MCI) and an independent group of 42 subjects with cerebral amyloid angiopathy (CAA). Extent of WMH was determined by computer-assisted volumetric measurement normalized to intracranial size (nWMH). Biochemical measurements included plasma concentrations of the 40- and 42-amino acid species of beta-amyloid (Abeta40 and Abeta42) detected by specific enzyme-linked immunosorbent assays. RESULTS: Plasma Abeta40 concentrations were associated with nWMH in both groups (correlation coefficient = 0.48 in AD/MCI, 0.42 in CAA, p < or = 0.005). Plasma Abeta40 remained independently associated with nWMH after adjustment for potential confounders among age, hypertension, diabetes, homocysteine, creatinine, folate, vitamin B12, and APOE genotype. The presence of lacunar infarctions was also associated with increased Abeta40 in both groups. nWMH was greater in CAA (19.8 cm3) than AD (11.1 cm3) or MCI (10.0 cm3; p < 0.05 for both comparisons). CONCLUSIONS: Plasma beta-amyloid 40 concentration is independently associated with extent of white matter hyperintensity in subjects with Alzheimer disease, mild cognitive impairment, or cerebral amyloid angiopathy. If confirmed in longitudinal studies, these data would suggest circulating beta-amyloid peptide as a novel biomarker or risk factor for microvascular damage in these common diseases of the elderly.

31．Evaluation of extracranial blood flow in Parkinson disease

Neurosci Lett    2006，391（3）：131-5

Abstract: Decreased cerebral flow velocities in Parkinsonian patients were reported previously. Because of the limited data on vascular changes in Parkinson disease (PD), which may have a vascular etiology, we aimed to disclose any possible cerebral hemodynamic alteration in Parkinsonian patients. We prospectively evaluated 28 non-demented, idiopathic parkinsonian patients and 19 age and sex matched controls with Doppler sonography. Flow volumes, peak systolic flow velocities, and cross-sectional areas of vertebral and internal carotid arteries (ICA) were measured and compared between patients and controls. Correlation of patient age and disease duration with Doppler parameters was observed; and each Doppler parameter of patients within each Hoehn-Yahr scale was compared. There was no significant difference of measured parameters between groups. No correlation was found between disease duration and age with flow volume, cross-sectional area or peak systolic velocity. Hoehn-Yahr scale was not found having significant relation with Doppler parameters. Values of vertebral, internal carotid and cerebral blood flow volumes (CBF), peak systolic velocities, and cross-sectional areas were not significantly different between Parkinsonian patients and age and sex matched controls. Although regional blood flow decreases may be seen as reported previously, Parkinson disease is not associated with a flow volume or velocity alteration of extracranial cerebral arteries.

Author Address: Afyon Kocatepe University, Faculty of Medicine, Department of Radiology, Mavi Hastane, 03120 Afyon, Turkey. dralpay@yahoo.com

32．Amyloid double trouble

Nat Genet    2006，38（1）：11-2

Abstract: A new study shows that some cases of early-onset Alzheimer disease result from duplications of the APP locus, which encodes the amyloid beta precursor protein. This finding fulfills a 20-year-old prediction that genetic variability in APP expression could lead to disease and provides further, perhaps definitive, evidence for the amyloid hypothesis of the disorder.

Author Address: John Hardy is at the Laboratory of Neurogenetics, National Institute on Aging, Porter Neuroscience Building, 35 Convent Drive, Bethesda, Maryland 20892, USA. hardyj@mail.nih.gov.

33. Deficiency of disulfide bonds facilitating fibrillogenesis of endostatin

J Biol Chem    2006，281（2）：1048-57

Abstract: Endostatin is an endogenous inhibitor of tumor angiogenesis and tumor growth. It has two pairs of disulfide bonds in a unique nested pattern, which play a key role in its native conformation, stability, and activity. Here, we constructed a disulfide-deficient variant of endostatin, endo-all-Ala, to examine the effects of the two disulfide bonds on fibrillogenesis of endostatin under nondenaturing conditions. Based on thioflavin T fluorescence, atomic force microscopy, far-UV circular dichroism, and Fourier transform infrared spectroscopy, we found that endo-all-Ala, which has a higher alpha-helical content compared with wild type, is prone to forming fibrils in a pH-dependent manner. Subsequently, more hydrophobic patches with a lower stability of endo-all-Ala were observed when compared with wild type, which possibly contributes to the propensity of amyloid formation of endo-all-Ala. To our surprise, the significant increase of the alpha-helical content in endostatin induced by trifluoroethanol can also facilitate fibril formation. In addition, the cytotoxicity of fibrillar aggregates of endo-all-Ala, which were generated at different stages of the fibril formation process, was evaluated by cell viability assay. The results indicate that the cytotoxicity is not due to the fibrils but rather due to the granular aggregates of endo-all-Ala. Moreover, endostatin was interestingly found to be reduced by glutathione at physiological concentrations. Our present work not only elucidates the correlation between the existence of disulfide bonds and the fibril formation of endostatin but also may provide some insights into the structural and functional basis of endostatin in Alzheimer disease brains.

34. Apolipoprotein E and Alzheimer disease. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.     2006，66（2）：S79-S85

Abstract: mdash;: Apolipoprotein (apo) E, a multifunctional protein with central roles in lipid metabolism and neurobiology, has three common isoforms (apoE2, apoE3, and apoE4) with different effects on lipid homeostasis and neurobiology. Unlike apoE3, the most common isoform, apoE4, is associated with increased risk of developing Alzheimer disease (AD) and other neurodegenerative disorders. Although the mechanisms underlying apoE4's action in AD pathogenesis are still poorly understood, emerging data strongly suggest that apoE4 contributes to this disease by interacting with different factors through various pathways. Thus, multiple molecular and cellular mechanisms should be considered when anti-AD drugs are developed based on apoE studies., (C)2006AAN Enterprises, Inc.

University of California, San Francisco, CA.

35. A systematic review of neurotransmitter deficits and treatments in frontotemporal dementia. [Review]

Neurology    2006，66（1）：17-22

Abstract: Objective: To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD)., Methods: The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD., Results: Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD., Conclusions: Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner., (C)2006AAN Enterprises, Inc.

36. Upregulation of Protease-Activated Receptor-1 in Astrocytes in Parkinson Disease: Astrocyte-Mediated Neuroprotection Through Increased Levels of Glutathione Peroxidase. [Article]

Journal of Neuropathology & Experimental Neurology    2006，65（1）：66-77

Abstract: In the present study, we investigated the expression of protease-activated receptors (PARs), receptors for thrombin, in substantia nigra pars compacta (SNpc) of Parkinson disease (PD) brains and cultures of human neurons, astrocytes, oligodendrocytes, and microglia as determined by immunocytochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR). Expression of PAR-1 was demonstrated only in glial fibrillary acidic protein-positive astrocytes in SNpc, and the number of astrocytes expressing PAR-1 increased in SNpc of PD as compared with nonneurologic control brain. Immunoreactivity for thrombin and prothrombin was stronger in astrocytes and the vessel walls in SNpc of PD brains. PAR-1 was expressed in human astrocytes and neurons, but not in oligodendrocytes or microglia as determined by RT-PCR. We investigated thrombin-mediated activation of human astrocytes. Thrombin treatment activates human astrocytes and induces morphologic change and a marked increase in proliferation of astrocytes. Increased expression of glial cell line-derived growth factor and glutathione peroxidase (GPx) but no change in the expression of nerve growth factor and inflammatory cytokines/chemokine (IL-1[beta], IL-6, IL-8, MCP-1) was found in thrombin/PAR-activated astrocytes. Next, we studied the neuroprotective effect exerted by thrombin-activated astrocytes in human cerebral neuron x human neuroblastoma hybrid neurons. Although thrombin showed neurotoxicity against human hybrid neurons in a dose-dependent manner, the conditioned media derived from thrombin-pretreated astrocyte cultures promoted the survival of human hybrid neurons. The protective effect was completely inhibited with a GPx inhibitor, mercaptosuccinic acid, indicating that GPx released from thrombin/PAR-activated astrocytes is responsible for neuroprotection of hybrid neurons against thrombin cytotoxicity. The present study suggests that the increased expression of PAR-1 in astrocytes in SNpc of PD brain is the restorative move taken by the brain to provide neuroprotection against neuronal degeneration and cell death of dopaminergic neurons caused by noxious insults during the progression of PD pathology., (C) 2006 American Association of Neuropathologists, Inc

37. Age-dependent increase of clusterin in the human pituitary gland

Leg Med (Tokyo)    2006，8（1）：28-33

Abstract: Clusterin is a glycoprotein known to play various physiological roles including complement activity, amyloid binding activity in Alzheimer disease, as well as binding with heat shock proteins and abnormal prions. The present study immunohistochemically investigated the expression of clusterin in the human pituitary gland in subjects of 10-88 years of age (n=173). Causes of death were blunt injury (n=35), sharp injury (n=15), poisoning (n=11), drowning (n=14), fire fatalities (n=28), asphyxiation (n=15), hypothermia (n=7), hyperthermia (n=3), and natural diseases (n=45). Clusterin was detected in mixed cell follicles and the anterior lobar parenchymal cells. The area occupied by cells positive for clusterin were measured, and the ratio to the whole area of the anterior lobe (% clusterin-positive cell area) was estimated. There was a good correlation between the age of the subjects in years and the % clusterin-positive cell area in the anterior lobe of the pituitary gland (r=0.736, P<0.01). Relationships between % clusterin-positive cell and gender, cause of death, and survival time were insignificant. These findings indicate an age-dependent accumulation of clusterin in the pituitary gland, which may be related to the aging of endocrine systems.

Author Address: Department of Legal Medicine, Osaka City University Medical School, Asahi-machi 1-4-3, Abeno, Osaka 545-8585, Japan.

38. Protein composition of the intranuclear inclusions of FXTAS. [Article]

Brain    2006，129（1）：256-271

Abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by premutation expansions (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. The pathologic hallmark of FXTAS is the ubiquitin-positive intranuclear inclusion found in neurons and astrocytes in broad distribution throughout the brain. The pathogenesis of FXTAS is likely to involve an RNA toxic gain-of-function mechanism, and the FMR1 mRNA has recently been identified within the inclusions. However, little is known about the proteins that mediate the abnormal cellular response to the expanded CGG repeat allele. As one approach to identify the protein mediators, we have endeavoured to define the protein complement of the inclusion itself. Fluorescence-activated flow-based methods have been developed for the efficient purification of inclusions from the post-mortem brain tissue of FXTAS patients. Mass spectrometric analysis of the entire protein complement of the isolated inclusions, combined with immunohistochemical analysis of both isolated nuclei and tissue sections, has been used to identify inclusion-associated proteins. More than 20 inclusion-associated proteins have been identified on the basis of combined immunohistochemical and mass spectrometric analysis, including a number of neurofilaments and lamin A/C. There is no dominant protein species in the inclusions, and ubiquitinated proteins represent only a minor component; thus, inclusion formation is not likely to reflect a breakdown in proteasomal degradation of nuclear proteins. The list of proteins includes at least two RNA binding proteins, heterogeneous nuclear ribonucleoprotein A2 and muscle blind-like protein 1, which are possible mediators of the RNA gain-of-function in FXTAS., (C) Guarantors of Brain 2006. Published by Oxford University Press. All righs reserved.

39. Central and Extrapontine Myelinolysis: Then[horizontal ellipsis]and Now. [Review]

Journal of Neuropathology & Experimental Neurology      2006，65（1）：1-11

Abstract: In this review, we emphasize neuropathologic and neurobehavioral aspects of central pontine and extrapontine myelinolysis (CPM/EPM), also known as the osmotic demyelination syndrome. The literature is reviewed from the time of the initial report in 1959 and from key developments that have occurred more recently. Particular consideration is given to pathogenic mechanisms as revealed by recent animal studies. The role of white matter pathology in neurobehavioral dysfunction is also considered. The "then" and "now" of CPM and EPM tell 2 different stories. Yet, in many respects, this expansion of information over the past nearly 50 years simply represents a continuum, as well as recognition, of the vast gaps that still persist in our understanding of this disorder., (C) 2006 American Association of Neuropathologists, Inc

40. A region-of-interest template for three-dimensional stereotactic surface projection images: Initial application to the analysis of Alzheimer's disease and mild cognitive impairment. [Article]

Nuclear Medicine Communications    2006，27（1）：37-44

Abstract: Objective: To construct a region-of-interest (ROI) template for Z-score images of three-dimensional stereotactic surface projections (3-D SSP) and to assess whether the ROI template can be a useful tool for evaluation of brain perfusion abnormalities of neurological disorders., Materials and methods: We constructed the ROI template for Z-score images of 3-D SSP based on the standardized magnetic resonance imaging data of 10 healthy volunteers. We assigned a total of 26 ROIs to Z-score images and superimposed it on Z-score images constructed from the brain perfusion SPECT data of 15 patients with Alzheimer's disease and 10 patients with mild cognitive impairment (MCI) who developed Alzheimer's disease within the following 2 years. We then obtained the mean Z-scores of each ROI and examined them to determine whether the hypoperfusion typical of Alzheimer's disease had been demonstrated quantitatively. We also visually inspected the Z-score image of each patient in both groups to determine whether the areas with the highest Z-scores were demonstrated within the ROIs of regions typical of Alzheimer's disease., Results: In the patients with Alzheimer's disease, our ROI template quantitatively demonstrated hypoperfusion in regions typical of the disease and the Z-scores were very high. In the MCI patients, the mean Z-scores of the ROI in the posterior cingulated gyrus were the highest among all regions. Visual inspection of the Z-score images of each patient in both groups confirmed that the areas with the highest Z-scores were demonstrated within the ROIs in regions typical of Alzheimer's disease in all cases., Conclusion: Use of 3-D SSP methods and our ROI template enables automated quantitative evaluation of brain function images over the entire brain surface. In addition, the ROI template may facilitate visual interpretation of functional images of individual patients with neurological disorders., (C) 2006 Lippincott Williams & Wilkins, Inc.

41. Familial Parkinson Mutant {alpha}-Synuclein Causes Dopamine Neuron Dysfunction in Transgenic Caenorhabditis elegans

J Biol Chem     2006，281（1）：334-340

Abstract: Mutations in alpha-synuclein gene cause familial form of Parkinson disease, and deposition of wild-type alpha-synuclein as Lewy bodies occurs as a hallmark lesion of sporadic Parkinson disease and dementia with Lewy bodies, implicating alpha-synuclein in the pathogenesis of Parkinson disease and related neurodegenerative diseases. Dopamine neurons in substantia nigra are the major site of neurodegeneration associated with alpha-synuclein deposition in Parkinson disease. Here we establish transgenic Caenorhabditis elegans (TG worms) that overexpresses wild-type or familial Parkinson mutant human alpha-synuclein in dopamine neurons. The TG worms exhibit accumulation of alpha-synuclein in the cell bodies and neurites of dopamine neurons, and EGFP labeling of dendrites is often diminished in TG worms expressing familial Parkinson disease-linked A30P or A53T mutant alpha-synuclein, without overt loss of neuronal cell bodies. Notably, TG worms expressing A30P or A53T mutant alpha-synuclein show failure in modulation of locomotory rate in response to food, which has been attributed to the function of dopamine neurons. This behavioral abnormality was accompanied by a reduction in neuronal dopamine content and was treatable by administration of dopamine. These phenotypes were not seen upon expression of beta-synuclein. The present TG worms exhibit dopamine neuron-specific dysfunction caused by accumulation of alpha-synuclein, which would be relevant to the genetic and compound screenings aiming at the elucidation of pathological cascade and therapeutic strategies for Parkinson disease.

42. Genetics of Vascular Cognitive Impairment: The Opportunity and the Challenges. [Review]

Stroke     2006，37（1）：248-255

Abstract: Background and Purpose-: This review considers the current state of knowledge of genetic factors underlying vascular cognitive impairment (VCI)., Summary of Review-: We argue here that genes conferring susceptibility to VCI must be of 2 nonmutually exclusive classes: (1) genes that confer susceptibility to cerebrovascular disease, and (2) genes that determine brain tissue responses to cerebrovascular disease (ie, render parenchymal tissue more or less susceptible to injury or able to repair itself after injury). Although some progress has been made in identifying genes of the first class, little has been done to explore genes of the second class. Evidence for the existence of such genes is presented. We discuss the advantages and disadvantages of different forms of cerebrovascular disease for studying these genes, and different study designs that might be used., Conclusion-: The most critical challenge for genetic studies of VCI is to identify quantifiable phenotypes that can be reliably and effectively determined in large samples of subjects., (C) 2006 American Heart Association, Inc.

43. Infratentorial Abnormalities in Vascular Dementia. [Article]

Stroke     2006，37（1）：105-110

Abstract: Background and Purpose-: Infratentorial abnormalities may cause cognitive deficits, but current research criteria for vascular dementia (VaD) do not consider them. Our purposes were to determine the prevalence of infratentorial abnormalities in VaD, their relation with supratentorial abnormalities, and whether they are relevant to cognition., Methods-: We examined 182 patients (120 men, mean age=73 years, SD=8) with probable VaD at inclusion into a multicenter clinical trial. MRI scans were evaluated for infratentorial vascular abnormalities, midbrain atrophy, cerebellar atrophy, basilar artery diameter and tortuosity, and supratentorial abnormalities. Cognitive testing included the mini-mental state examination (MMSE) and the vascular dementia assessment scale (VaDAS-cog)., Results-: One hundred forty-one (77.5%) patients had infratentorial abnormalities: 119 (65.4%) had focal infratentorial vascular lesions, 65 (35.7%) had diffuse pontine vascular abnormalities hyperintense on T2-weighted images, 20 (11.0%) had midbrain atrophy, and 16 (8.8%) had cerebellar atrophy. Significant correlations were found between number of infratentorial vascular lesions and basilar artery diameter (rs=0.26;P<0.0001), infratentorial and basal ganglia (including thalamus) vascular abnormalities (rs=0.30;P<0.0001), as well as between midbrain atrophy and global supratentorial atrophy (rs=0.27;P<0.0001). Infratentorial vascular abnormalities and cerebellar atrophy were not significantly associated with cognitive impairment. Patients with midbrain atrophy performed worse on cognitive tests than those without midbrain atrophy. After correction for sex, age, education, supratentorial abnormalities, and center, midbrain atrophy remained significantly associated with lower MMSE scores (P<0.05)., Conclusions-: Infratentorial abnormalities often occur in patients with VaD, but only midbrain atrophy was found to be relevant to cognition., (C) 2006 American Heart Association, Inc.

44. Anti-Abeta(42)- and anti-Abeta(40)-specific mAbs attenuate amyloid deposition in an Alzheimer disease mouse model

J Clin Invest     2006，116（1）：193-201

Abstract: Accumulation and aggregation of amyloid beta peptide 1-42 (Abeta(42)) in the brain has been hypothesized as triggering a pathological cascade that causes Alzheimer disease (AD). To determine whether selective targeting of Abeta(42) versus Abeta(40) or total Abeta is an effective way to prevent or treat AD, we compared the effects of passive immunization with an anti-Abeta(42) mAb, an anti-Abeta(40) mAb, and multiple Abeta(1-16) mAbs. We established in vivo binding selectivity of the anti-Abeta(42) and anti-Abeta(40) mAbs using novel TgBRI-Abeta mice. We then conducted a prevention study in which the anti-Abeta mAbs were administered to young Tg2576 mice, which have no significant Abeta deposition, and therapeutic studies in which mAbs were administered to Tg2576 or CRND8 mice with modest levels of preexisting Abeta deposits. Anti-Abeta(42), anti-Abeta(40), and anti-Abeta(1-16) mAbs attenuated plaque deposition in the prevention study. In contrast, anti-Abeta(42) and anti-Abeta(40) mAbs were less effective in attenuating Abeta deposition in the therapeutic studies and were not effective in clearing diffuse plaques following direct injection into the cortex. These data suggest that selective targeting of Abeta(42) or Abeta(40) may be an effective strategy to prevent amyloid deposition, but may have limited benefit in a therapeutic setting.

45. Viral-mediated temporally controlled dopamine production in a rat model of Parkinson disease

Mol Ther    2006，13（1）：160-6

Abstract: Regulation of gene expression is necessary to avoid possible adverse effects of gene therapy due to excess synthesis of transgene products. To reduce transgene expression, we developed a viral vector-mediated somatic regulation system using inducible Cre recombinase. A recombinant adeno-associated virus (AAV) vector expressing Cre recombinase fused to a mutated ligand-binding domain of the estrogen receptor alpha (CreER(T2)) was delivered along with AAV vectors expressing dopamine-synthesizing enzymes to rats of a Parkinson disease model. Treatment with 4-hydroxytamoxifen, a synthetic estrogen receptor modulator, activated Cre recombinase within the transduced neurons and induced selective excision of the tyrosine hydroxylase (TH) coding sequence flanked by loxP sites, leading to a reduction in transgene-mediated dopamine synthesis. Using this strategy, aromatic l-amino acid decarboxylase (AADC) activity was retained so that l-3,4-dihydroxyphenylalanine (l-dopa), a substrate for AADC, could be converted to dopamine in the striatum and the therapeutic effects of l-dopa preserved, even after reduction of TH expression in the case of dopamine overproduction. Our data demonstrate that viral vector-mediated inducible Cre recombinase can serve as an in vivo molecular switch, allowing spatial and temporal control of transgene expression, thereby potentially increasing the safety of gene therapy.

46. Hormone therapy, timing of initiation, and cognition in women aged older than 60 years: the REMEMBER pilot study. [Article]

Menopause     2006，13（1）：28-36

Abstract: Objective: The aim of this pilot study was to assess any trends related to the timing of initiation, and duration, of hormone therapy (HT) use on cognitive function to facilitate the design and power calculations for a future large cohort study entitled Research into Memory, Brain function and Estrogen Replacement (REMEMBER)., Design: A total of 428 women aged older than 60 years were recruited from a computer-generated random selection of Adelaide households. Demographic and lifestyle characteristics, and HT use history were recorded and confirmed. The Center for Epidemiological Studies-Depression score was used to assess mood. Cognitive tests were administered measuring global cognition (Mini-Mental State Examination), attention and concentration (Trail Making Test Parts A and B), verbal learning and memory (Consortium to Establish a Registry for Alzheimer's Disease [CERAD] word list immediate and delayed recall), and verbal expression (letter fluency [FAS], category fluency [Animals], and the Boston Naming Test [short form]). Analyses were adjusted for age, education, mood, body mass index, smoking, alcohol intake, and history of cerebrovascular disease. HT use was defined as the use of systemic HT for at least 1 year. Early initiation of HT use was defined as commencement of HT before age 56 years for women with a uterus and ovaries, or within 5 years of a hysterectomy and bilateral oophorectomy. Late initiation of HT use was defined as HT commencing after these times., Results: Early initiators of HT performed better than late initiators on the Mini-Mental State Examination (P = 0.04) and were faster than never users on the Trail Making Test Part A (P = 0.02). Women aged 70-79 years who initiated HT early performed better on the FAS test than never users (P = 0.0008). Late initiators performed worse than never users on the Mini-Mental State Examination (P = 0.09), and on the FAS test in the 60-69 year (P = 0.06) and 80 years and older (P = 0.095) age groups. However, late initiators performed better than never users on the FAS test in the 70-79 year age group (P = 0.015). HT users of less than 11 years (P = 0.09), HT users of more than 11 years (P = 0.04), and estrogen-only users (P = 0.024) performed faster than never users on the Trail Making Test Part A. Combined estrogen plus progestin users performed better than never users on the Boston Naming Test short form (P = 0.07)., Conclusions: For some cognitive domains, early initiation of HT from around menopause may be beneficial, and initiation of HT in late menopause may be detrimental. The timing of the initiation of HT seems critical. To fully test these hypotheses and to further examine these trends by route and type of HT regimen in this population, a study size of 2,500 women would be required., (C)2006The North American Menopause Society

47. Neuropathologic Substrate of Mild Cognitive Impairment

Arch Neurol     2006，63（1）：38-46

Abstract: OBJECTIVE: To define the neuropathologic findings in amnestic mild cognitive impairment (MCI) and early Alzheimer disease (EAD). METHODS: The mean numbers of diffuse plaques, neuritic plaques (NPs), and neurofibrillary tangles (NFTs) in 4 neocortical regions and 4 ventromedial temporal lobe regions were counted in 10 patients with amnestic MCI and compared with the mean numbers in 23 normal control subjects and 10 patients with EAD, and then were compared with memory performance. All of the controls and patients were followed longitudinally. RESULTS: Patients with MCI showed no significant difference (P>.05) in the number of diffuse plaques from that in normal controls or patients with EAD. In patients with MCI, the number of NPs was significantly elevated in all 4 neocortical regions and amygdala compared with controls (P<.01 to <.001). There were no significant differences (P>.05) in the number of NPs between MCI and EAD cerebral cortex, but significant increases were present for NPs in EAD amygdala and subiculum compared with MCI (P<.01). In patients with MCI compared with controls, the only significant increase in NFTs in the neocortex was in the parietal lobe. However, the number of NFTs was significantly elevated in MCI in all 4 ventromedial temporal lobe structures compared with controls (P<.01 to <.001). In comparing MCI with EAD, there were significant increases in NFTs in EAD in frontal and temporal lobes, amygdala, and subiculum (P<.01). The numbers of NPs and NFTs were significantly elevated in all of the neocortical regions and ventromedial temporal lobe regions in patients with EAD compared with controls (P<.001). Memory function was significantly correlated with NFTs in CA1 of the hippocampus (P<.01) and the entorhinal cortex (P<.05). CONCLUSIONS: In patients with amnestic MCI who were followed longitudinally, the early changes of Alzheimer disease were present. The NFTs were slightly more prominent than beta-amyloid peptide deposition in the progression from normal to MCI to EAD. Ventromedial temporal lobe NFTs probably represent the substrate for memory decline in MCI. From a neuropathologic perspective, it appears that amnestic MCI is, in reality, EAD.

Author Address: Author Affiliations: Alzheimer's Disease Center, Sanders-Brown Center on Aging, and Departments of Neurology, Pathology, Statistics and Public Health, and Physiology, University of Kentucky, Lexington.

48. Developing therapeutics for the diseases of protein misfolding. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.     2006,66(2):S118-S122

Abstract: mdash;: Our current structural and biologic understanding of the misfolding diseases has restricted the development of therapies that target these diseases at a molecular level. The prion diseases are illustrative of this group of misfolding disorders and provide a model system for therapeutic intervention. Strategies to inhibit the replication and accumulation of the prion protein are being developed and have entered animal and clinical studies. Due to the underlying molecular basis of this disease class, many of the therapeutic approaches used to target prion misfolding have parallels in other misfolding diseases., (C)2006AAN Enterprises, Inc.

49.Immunotherapeutic relief from persistent infections and amyloid disorders. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.    2006,66(2): S59-S64

Abstract: mdash;: Persistent infections and amyloid disorders afflict a significant number of people worldwide. It would appear at first glance that the treatment of these afflictions should be entirely unrelated; however, in both cases components of the adaptive immune system have been harnessed in an attempt to provide some therapeutic relief. Given that the ability of a pathogen to establish persistence often depends in part on a shortcoming of the adaptive immune response, it seems logical to devise immunotherapies with the intention of supplementing (or replacing) the insufficient immunologic element. A case in point is an intervention referred as immunocytotherapy, which relies upon the adoptive transfer of pathogen-specific T lymphocytes into a persistently infected host. Remarkably, the adoptively transferred T lymphocytes not only have the capacity to clear the persistent infection, but can also provide the recipient with protection against subsequent rechallenge (i.e., immunologic memory). Treatment of amyloid disorders (e.g., Alzheimer disease, sporadic inclusion-body myositis) with a similar therapeutic approach is complicated by the fact that the aberrant protein accumulations are self-derived. Focusing the adaptive response on these aberrant self-proteins has the potential to result in autoimmune pathology. This review critically evaluates the importance of immunotherapeutic approaches for the treatment of persistent infections and amyloid disorders, and attempts to delineate the interventions that are most likely to succeed in an exceedingly complex disorder such as sporadic inclusion-body myositis., (C)2006AAN Enterprises, Inc.

50. Cognitive Functioning as a Predictor of Functional Disability in Later Life. [Article]

American Journal of Geriatric Psychiatry      2006,14(1): 36-42

Abstract: Objective: The contribution of cognitive functioning on multiple levels of functional disability and mortality over two years as well as individual activities of daily living (ADLs) and instrumental activities of daily living (IADLs) tasks, in a sample of older U.S. adults was examined., Methods: A total of 4,077 U.S. adults (1,493 males and 2,584 females) aged >=70 years (mean = 76.35 years) from the Second Longitudinal Study of Aging (1997/1998-1999/2000) were examined using an adapted Telephone Interview of Cognitive Status (TICS), ADLs, and IADLs., Results: Multivariate logistic regression investigated cognition as a predictor of five mutually exclusive levels of functional disability. People with the lowest level of cognition had greater odds of mortality at follow-up (adjusted odds ratio [AOR] = 2.86, 95% confidence interval [CI] = 1.94-4.20), ADL and IADL disability (AOR = 1.58, 95% CI = 1.15-2.16), ADL disability (AOR = 1.83, 95% CI = 1.27-2.64), or IADL disability (AOR = 1.22, 95% CI = 0.86-1.71) than those who were disability-free. Cognitive functioning was not predictive of individual ADL tasks but was predictive of the IADL tasks of preparing meals, shopping for groceries, managing money, telephone use, light housework, and medications but not heavy housework., Conclusion: Persons with lower levels of cognitive functioning were more likely to die or become disabled than those with higher levels of cognition. Changes in cognitive functioning might serve as an early indicator of neurologic and medical factors., Copyright (C) 2006 American Association for Geriatric Psychiatry

51. Retrospective Analysis of Diabetes Risk in Elderly Patients With Dementia in Olanzapine Clinical Trials. [Article]

American Journal of Geriatric Psychiatry    2006,14(1): 62-70

Abstract: Objective: The objective of this study was to evaluate the association of established risk factors for treatment-emergent diabetes (TED) among patients over 65 years of age with dementia who received treatment with olanzapine., Methods: This was a post hoc analysis of data pooled from seven olanzapine clinical trials, which included patients over 65 years of age with dementia. The association of established risk factors for TED was evaluated using categorical and time-to-event analysis. TED was defined as two casual (fasting or nonfasting) glucose values >=200 mg/dL at any time after baseline or one casual glucose value >=200 mg/dL at the final visit, initiation of antidiabetic medication, or new clinical diagnosis of diabetes., Results: Elderly patients subsequently identified with TED (N = 29, 2.1%) had similar baseline body mass indices (24 kg/m2) and were similar in age (82 versus 80 years) to those who did not have TED. Cox proportional hazards model identified only elevated casual glucose (>=140 mg/dL) measure at baseline to be significantly associated with the development of TED (hazard ratio [HR] = 11.2, p <0.0001) in this elderly cohort. Other clinical risk factors, like body mass index >=25 (HR = 0.86), 7% weight gain (HR = 2.26), and antipsychotic treatment (HR = 1.36) were not significant., Conclusion: In elderly patients with dementia enrolled in olanzapine clinical trials, an elevated casual glucose (>=140 mg/dL) at baseline was the only risk factor significantly associated with subsequent development of TED. Risk of diabetes in these studies was not significantly associated with antipsychotic treatment group assignment., Copyright (C) 2006 American Association for Geriatric Psychiatry

52. Correlates of Self-Rated Successful Aging Among Community-Dwelling Older Adults. [Article]

American Journal of Geriatric Psychiatry     2006,14(1)43-51

Abstract: Objective: There is no consensus on how to define successful aging. The authors sought to determine the correlates of self-rated successful aging as well as its correspondence with major researcher-defined criteria., Methods: Participants were 205 community-dwelling adults over age 60. A questionnaire survey asked the participants to rate their own degree of successful aging and inquired about demographic characteristics, medical history, activity levels, resilience, daily functioning, and health-related quality of life (Medical Outcomes study 36-item Short-Form [MOS-SF-36]). Participants' subjective ratings of successful aging were contrasted with sets of researcher-defined criteria, and correlates of subjectively rated successful aging were examined., Results: Ninety-two percent of the participants rated themselves as aging successfully. A majority of them also met other research criteria for successful aging such as independent living, mastery/growth, and positive adaptation but not those requiring an absence of chronic medical illness or physical disability. Higher SF-36 scores as compared with a published sample indirectly corroborated participants' subjectively rated successful aging. Subjective ratings of successful aging were significantly correlated with higher scores on health-related quality of life as well as resilience, greater activity, and number of close friends but not with several demographic characteristics., Conclusion: Most community-dwelling older adults viewed themselves as aging successfully despite having chronic physical illnesses and some disability. Longitudinal studies of the reliability and validity of subjective ratings of successful aging are warranted., Copyright (C) 2006 American Association for Geriatric Psychiatry

53. Brain and brawn: Parallels in oxidative strength. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.    2006,66(2): S97-S101

Abstract: mdash;: Neuronal oxidative stress occurs early in the progression of Alzheimer disease (AD), significantly before the development of the pathologic hallmarks, neurofibrillary tangles, and senile plaques. Study of Down syndrome, cases with autosomal dominant mutation, and sporadic AD all suggest amyloid-[beta] deposition and hyperphosphorylated [tau] function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. Amyloid-[beta] and [tau] hyperphosphorylation also define vulnerable muscle cells in sporadic inclusion-body myositis (s-IBM). The role of the structural changes of s-IBM, as in AD, remains to be determined but may mark a critical response yielding a novel balance in oxidant homeostasis., (C)2006AAN Enterprises, Inc.

54. Behavioral Alterations and Vascular Dementia. [Article]

Neurologist    2006,12(1):43-47

Abstract: Background: Vascular dementia is one of the most frequent forms of dementia, where behavioral and cognitive symptoms coexist. Negative signs, such as apathy, abulia, opposition, and agnosia, are badly tolerated and dramatically experienced by caregivers, even worse than the other signs of cognitive decline., Review Summary: We have studied 120 subjects affected by subcortical vascular dementia (group A) and 120 subjects suffering from multiinfarct dementia (group B) for 24 months. The main outcomes of the study were the global performance, the global behavioral symptoms, the caregiver stress, the depression status, and the insight in their clinical situation., Conclusions: Group A manifested a reduction of depression, agitation and suicidal ideation during follow-up, with a constant tendency to refer somatic pain, to exhibit anxiety, and an evident increase in apathy, cognitive abulia, social withdrawal, and loss of insight. On the contrary, group B showed a constant tendency to manifest depression, somatic pain, anxiety, agitation, cognitive abulia, social withdrawal, and suicide ideations; they manifested a decrease of apathy and an increase in delusions, hallucinations, craving for food, and loss of insight and awareness. Their behavioral alterations were stronger than those exhibited by group A, and that was reflected by an increment of caregivers' burden score. Even from a behavioral perspective, multiinfarct dementia is not the same as subcortical vascular dementia. This opinion must be taken into account to find more suitable and tailored therapy to specific pathologies and not to a single, generic entity., (C) 2006 Lippincott Williams & Wilkins, Inc.

55. The Effect of Small Doses of Botulinum Toxin A on Neck-Shoulder Myofascial Pain Syndrome: A Double-Blind, Randomized, and Controlled Crossover Trial. [Article]

Clinical Journal of Pain     2006,22(1): 90-96

Abstract: Objectives: Myofascial pain syndrome is a common cause of muscular pain in the shoulder-neck region. Injections of large amounts of botulinum toxin A have been found to be beneficial for the alleviation of myofascial pain, but large doses of this toxin may cause paresis of the muscle and other adverse events. The aim of this work was to determine the effect of small doses (5 U) of botulinum toxin A (BTA) injected directly into the painful trigger points of the muscles, using a double-blind crossover technique., Methods: On the basis of the empirical criteria proposed for diagnosis of myofascial pain syndrome, 31 patients suffering from myofascial pain in the neck-shoulder region were studied. The patients received either botulinum toxin A or physiological saline injections on 2 occasions 4 weeks apart. The total dose varied from 15 to 35 U of botulinum toxin A [28 +/- 6 U (mean +/- SD)]. The follow-up measurements were carried out at 4 weeks after each treatment. Neck pain and result of treatment were assessed with questionnaires. The pressure pain threshold was determined using a dolorimeter., Results: Neck pain values decreased from 4.3 +/- 2.4 to 3.3 +/- 2.0 after saline injections and from 4.1 +/- 2.1 to 3.3 +/- 2.2 after botulinum toxin A. The pressure pain threshold values increased from 5.2 +/- 1.6 to 5.9 +/- 1.5 and from 5.7 +/- 1.6 to 5.9 +/- 1.6 after injections with saline and botulinum toxin A, respectively. No statistically significant changes in the neck pain and pressure pain threshold values occurred between the botulinum toxin A and saline groups. After the first injections, the subjective result of treatment was significantly (P = 0.008) in favor of botulinum toxin A, and after the second injections, the subjective result was better for saline, but the difference was not statistically significant (P = 0.098). There was no significant difference in the prevalence of side effects between saline and botulinum toxin A., Conclusions: Our study shows that there was no difference between the effect of small doses of botulinum toxin A and those of physiological saline in the treatment of myofascial pain syndrome., (C) 2006 Lippincott Williams & Wilkins, Inc.

56. The Solvent Protection of Alzheimer Amyloid-{beta}-(1-42) Fibrils as Determined by Solution NMR Spectroscopy

J Biol Chem    2006,28(1):477-83

Abstract: Alzheimer disease is a neurodegenerative disorder that is tightly linked to the self-assembly and amyloid formation of the 39-43-residue-long amyloid-beta (Abeta) peptide. Considerable evidence suggests a correlation between Alzheimer disease development and the longer variants of the peptide, Abeta-(1-42/43). Currently, a molecular understanding for this behavior is lacking. In the present study, we have investigated the hydrogen/deuterium exchange of Abeta-(1-42) fibrils under physiological conditions, using solution NMR spectroscopy. The obtained residue-specific and quantitative map of the solvent protection within the Abeta-(1-42) fibril shows that there are two protected core regions, Glu(11)-Gly(25) and Lys(28)-Ala(42), and that the residues in between, Ser(26) and Asn(27), as well as those in the N terminus, Asp(1)-Tyr(10), are solvent-accessible. This result reveals considerable discrepancies when compared with a previous investigation on Abeta-(1-40) fibrils and suggests that the additional residues in Abeta-(1-42), Ile(41) and Ala(42), significantly increase the solvent protection and stability of the C-terminal region Lys(28)-Ala(42). Consequently, our findings provide a molecular explanation for the increased amyloidogenicity and toxicity of Abeta-(1-42) compared with shorter Abeta variants found in vivo.

Author Address: Umea Centre for Molecular Pathogenesis, Umea University, SE-901 87 Umea, Sweden and Department of Biochemistry, Umea University, SE-901 87 Umea, Sweden.

57. Cell transplantation for patients with Parkinson's disease

Handb Exp Pharmacol    2006,174:361-88

Abstract: This chapter focuses on cell replacement therapies in Parkinson's disease (PD) and describes experimental data leading to clinical trials, as well as the methodology and efficacy of grafts of human embryonic nigral tissue in patients with PD. It also highlights some of the clinical problems the procedure presents and considers future alternative sources of donor tissue, including various forms of stem cells.

58. RNA interference as potential therapy for neurodegenerative disease: Applications to inclusion-body myositis? [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.   2006,66(2): S114-S117

Abstract: mdash;: The discovery of RNA interference (RNAi) has led to powerful new approaches to silence targeted genes in a sequence-specific manner. The potential therapeutic application of RNAi to neurologic disease is highlighted by the recent success of several laboratories in suppressing the expression of neurodegenerative disease genes in transgenic mouse models. Here I discuss potential applications of RNAi to inclusion-body myositis (IBM) after first reviewing its application more generally to neurologic disease. The clearest application of RNAi to IBM is as a research tool to identify critical target genes that contribute to pathogenesis. Provided that proximal pathogenic targets are identified, RNAi could surface as a potential therapeutic strategy to modulate their expression., (C)2006AAN Enterprises, Inc.

59. Response to 4-month treatment with reboxetine in Parkinson's disease patients with a major depressive episode

Gen Hosp Psychiatry    2006,28(1): 59-64

Abstract: OBJECTIVE: The aim of this study is to evaluate response to reboxetine in a 4-month follow-up study on depression in Parkinson's disease (PD), and to assess its tolerability profile. METHODS: A prospective 4-month follow-up study was performed in 17 PD patients with a major depressive episode. The intensity of depressive symptoms was evaluated mainly with the Hamilton Rating Scale for Depression (HAM-D), and PD was assessed with the Unified Parkinson Disease Rating Scale (UPDRS). RESULTS: Reboxetine causes a progressive decrease in depressive symptoms in PD patients; the initial score of 16.76 (2.68) on HAM-D decreased to 5.85 (2.42) at 4 months (P<.002). Mean UPDRS scores did not show a statistically significant increase: 18.18 (2.6) at the beginning and 18.25 (2.4) at the end of the follow-up period (P=.8). CONCLUSIONS: Reboxetine, as first choice treatment for major depressive episodes in PD patients, seems to be effective in progressively improving depressive symptoms over the first 4 months of treatment until complete remission. Reboxetine does not seem to increase PD symptoms, whereas patients' quality of life improves.

60. Coated-platelets retain amyloid precursor protein on their surface

Platelets    2006,17(1): 56-60

Abstract: Coated-Platelets are a subset of platelets produced by dual-agonist activation with collagen plus thrombin and are characterized by strong retention of several procoagulant, alpha-granule proteins on the cell surface. In this report we demonstrate that coated-platelets also retain full-length amyloid precursor protein (APP) on their surface in contrast to the cleavage of APP in platelets activated with a single agonist. In addition, western blot analysis indicated that APP is derivatized during coated-platelet synthesis. We subsequently measured coated-platelet production in patients with Alzheimer's disease (AD). Twenty-two AD patients showed a wide distribution of coated-platelet values; however the least impaired AD patients produced coated-platelets at a level significantly above that of aged controls (41.0 +/- 9.9 vs. 28.7 +/- 11.4%; mean +/- 1SD; p = 0.017). These findings suggest that coated-platelets may be a model of aberrant APP processing in early AD patients.

Notes: ISI Document Delivery No.: 988FU

61. Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease

Neurology    2006,66(1): 49-55

Abstract: BACKGROUND: Little is known about Alzheimer disease at advanced ages, although its incidence continues to increase at least through the ninth decade of life. OBJECTIVE: To examine the effects of age on the relationship between clinical dementia severity and neuropathologic hallmarks in a large sample spanning the full age range. METHODS: The authors assessed 81 subjects during life for dementia severity, and examined their brains. They analyzed plaque and tangle burden, as well as the activities of the cholinergic marker enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), in relation to age at death and the clinical severity of dementia. RESULTS: Dementia severity was strongly related to plaque and tangle burden in relatively young patients (aged < 75 years), but this correlation diminished with age and disappeared in the ninth decade of life. Among the oldest patients studied, there was no difference in plaque and tangle load between the mild and severe dementia cases. This interaction (p < 0.0001 for plaque density) was not observed for the cholinergic markers ChAT and AChE. CONCLUSION: The nature or expression of Alzheimer disease may be different in severely demented older patients, who have equal cholinergic deficits but significantly lower plaque and tangle burden. If confirmed in a prospective study, these findings have diagnostic and therapeutic implications.

Author Address: Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA. isak.prohovnik@mssm.edu

62. Dissociation of neuropathology from severity of dementia in late-onset Alzheimer disease. [Article]

Neurology     2006,66(1): 49-55

Abstract: Background: Little is known about Alzheimer disease at advanced ages, although its incidence continues to increase at least through the ninth decade of life., Objective: To examine the effects of age on the relationship between clinical dementia severity and neuropathologic hallmarks in a large sample spanning the full age range., Methods: The authors assessed 81 subjects during life for dementia severity, and examined their brains. They analyzed plaque and tangle burden, as well as the activities of the cholinergic marker enzymes acetylcholinesterase (AChE) and choline acetyltransferase (ChAT), in relation to age at death and the clinical severity of dementia., Results: Dementia severity was strongly related to plaque and tangle burden in relatively young patients (aged <75 years), but this correlation diminished with age and disappeared in the ninth decade of life. Among the oldest patients studied, there was no difference in plaque and tangle load between the mild and severe dementia cases. This interaction (p < 0.0001 for plaque density) was not observed for the cholinergic markers ChAT and AChE., Conclusion: The nature or expression of Alzheimer disease may be different in severely demented older patients, who have equal cholinergic deficits but significantly lower plaque and tangle burden. If confirmed in a prospective study, these findings have diagnostic and therapeutic implications., (C)2006AAN Enterprises, Inc.

63. Adaptive Task Prioritization in Aging: Selective Resource Allocation to Postural Control Is Preserved in Alzheimer Disease. [Article]

American Journal of Geriatric Psychiatry    2006,14(1): 52-61

Abstract: Objective: With age, the performance of multiple tasks decreases, a pattern exaggerated in Alzheimer disease (AD). At the same time, recent research, based on adaptive theories of healthy aging, indicates a preference of older adults to allocate resources toward tasks of higher immediate value (e.g., postural control). This study investigated whether such models also hold for pathologic cognitive aging., Method: Using a dual-task paradigm, the authors combined a working memory with a postural control task under easy and difficult conditions in patients with AD, older adults, older adults low on performance on a cognitive marker test, and young adults (N = 40). Participants repeatedly performed a cognitive and a postural control task both simultaneously and in isolation over the course of eight sessions., Results: Consistent with earlier studies on divided attention in age and AD, the authors found large dual-task performance decrements with age and more so in AD. When not challenged, patients with AD showed large performance decrements under dual-task conditions in both postural control and working memory. With increasing difficulty in the postural control task, however, older adults, and more so patients with AD, maintained a high level of functioning in postural control, as compared with working memory., Conclusion: The findings indicate that the theory of selective optimization with compensation extends to pathologic aging and have broad implications for models of dual-task performance and executive control in aging and AD., Copyright (C) 2006 American Association for Geriatric Psychiatry

64. A Comparison of Underlying Cause and Multiple Causes of Death: US Vital Statistics, 2000-2001. [Report]

Epidemiology     2006,17(1): 100-103

Abstract: Background: Mortality statistics can be compiled using underlying cause-of-death data or multiple cause-of-death data, which include other contributing causes of death., Methods: For the leading causes of death in the United States during 2000-2001, we compared underlying and multiple cause-of-death statistics., Results: For some conditions, little difference was observed between the 2 estimates. For other conditions, up to 10 times more deaths were identified from multiple-cause data than from underlying-cause data. The 10 leading causes of death differed when using the 2 types of data., Conclusions: Whenever possible, underlying and multiple cause-of-death statistics should both be presented. Analyses that use only the underlying cause of death ignore additional information that is readily available from multiple-cause data, and the more limited data may underestimate the importance of several leading causes of death., (C) 2006 Lippincott Williams & Wilkins, Inc.

65. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease

Arch Neurol    2006,63(1): 49-54

Abstract: BACKGROUND: This study is an extension of a 28-week, randomized, double-blind, placebo-controlled study of memantine in 252 patients with moderate to severe Alzheimer disease. OBJECTIVE: To evaluate long-term memantine treatment in moderate to severe Alzheimer disease.Design, Setting, and Patients Open-label, 24-week extension trial. Raters remained blind to the patients' initial study treatment. Patients (n = 175) were enrolled from the previous double-blind study in an outpatient setting.Intervention Twenty mg of memantine was given daily. MAIN OUTCOME MEASURES: Efficacy assessments from the double-blind study were continued and safety parameters were monitored. RESULTS: Patients who switched to memantine treatment from their previous placebo therapy experienced a significant benefit in all main efficacy assessments (functional, global, and cognitive) relative to their mean rate of decline with placebo treatment during the double-blind period (P<.05). The completion rate for the extension phase of the study was high (78%) and the favorable adverse event profile for memantine therapy was similar to that seen in the double-blind study. CONCLUSION: These results extend previous findings that demonstrated the efficacy and safety of memantine in the treatment of patients with moderate to severe Alzheimer disease.

66. Young-Onset Dementia: A Practical Approach to Diagnosis. [Article]

Neurologist     2006,12(1): 2-13

Abstract: Background: Young-onset dementia is best defined as dementia presenting at age less than 65 years. And, while cognitive impairment in the elderly is dominated by dementia of the Alzheimer type, young-onset dementia has a vast differential diagnosis., Review Summary: This article reviews an extensive differential diagnosis for young-onset dementia by utilizing different clues in the historical records and laboratory findings to aid with diagnosis. Laboratory testing should be completed in at least 2 stages. In the first stage, referred to as the first "wave," we suggest more routine testing, particularly for treatable causes of dementia. The second "wave," which we also outline, emphasizes more esoteric testing that may require referral to a tertiary care medical facility. The manuscript is divided into 2 parts, with part 1 focusing on clues from the historical data, while part 2 focuses on laboratory abnormalities., Conclusion: Unlike dementia presenting in the elderly, the differential diagnosis in young-onset dementia is vast. A thorough historical review of the symptoms, with special emphasis on the pattern of cognitive impairment, temporal profile of the disease, detailed family history, and extensive but coordinated laboratory and ancillary testing, may yield subtle clues to the diagnosis., (C) 2006 Lippincott Williams & Wilkins, Inc.Minnesota.

67. Familial Alzheimer disease in Latinos: interaction between APOE, stroke, and estrogen replacement

Neurology    2006,66(1)：35-40

Abstract: BACKGROUND: Factors that modify risk related to APOE variants have been examined primarily in unrelated patients and controls, but seldom in family-based studies. Stroke, vascular risk factors, estrogen replacement therapy (ERT), head injury (HI), and smoking have been reported to influence risk of sporadic but not familial Alzheimer disease (AD). OBJECTIVES: To examine the potential relationship between these risk factors and APOE, the authors used a family study design in a population in which the APOE-epsilon4 variant is strongly associated with risk of AD. METHODS: Latino families primarily from the Caribbean Islands in which two or more living relatives had dementia were identified in the New York City metropolitan area, the Dominican Republic, and Puerto Rico. A total of 1,498 participants from 350 families underwent a clinical interview, medical and neurologic examinations, neuropsychological testing, and APOE genotyping. Diagnosis was made by consensus using research criteria for AD. RESULTS: APOE-epsilon4 was associated with a nearly twofold increased risk of AD. A history of stroke was also associated with a fourfold increased risk. A statistical interaction between APOE-epsilon4 and stroke was observed. Women with an APOE-epsilon4 who took ERT did not have an increased risk of AD, but in women with a history of stroke ERT was a deleterious effect modifier. CONCLUSIONS: APOE-epsilon4 and stroke independently increase risk of familial Alzheimer disease (AD) among Latinos, and may interact to further increase AD risk. Among women, the risk of AD associated with APOE-epsilon4 may be attenuated by a history of ERT.

68. Kinetics of cerebral amyloid angiopathy progression in a transgenic mouse model of Alzheimer disease

J Neurosci    2006，26（2）：365-71

Abstract: Cerebral amyloid angiopathy (CAA), the deposition of cerebrovascular beta-amyloid (Abeta) in the walls of arterial vessels, has been implicated in hemorrhagic stroke and is present in most cases of Alzheimer disease. Previous studies of the progression of CAA in humans and animal models have been limited to the comparison of pathological tissue from different brains at single time points. Our objective was to visualize in real time the initiation and progression of CAA in Tg2576 mice by multiphoton microscopy through cranial windows. Affected vessels were labeled by methoxy-X04, a fluorescent dye that selectively binds cerebrovascular beta-amyloid and plaques. With serial imaging sessions spaced at weekly intervals, we were able to observe the earliest appearance of CAA in leptomeningeal arteries as multifocal deposits of band-like Abeta. Over subsequent imaging sessions, we were able to identify growth of these deposits (propagation), as well as appearance of new bands (additional initiation events). Statistical modeling of the data suggested that as the extent of CAA progressed in this vascular bed, there was increased prevalence of propagation over initiation. During the early phases of CAA development, the overall pathology burden progressed at a rate of 0.35% of total available vessel area per day (95% confidence interval, 0.3-0.4%). The consistent rate of disease progression implies that this model is amenable to investigations of therapeutic interventions.

69. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy

Nature Genetics    2006，38（1）：24-26

Abstract: We report duplication of the APP locus on chromosome 21 in five families with autosomal dominant early-onset Alzheimer disease (ADEOAD) and cerebral amyloid angiopathy (CAA). Among these families, the duplicated segments had a minimal size ranging from 0.58 to 6.37 Mb. Brains from individuals with APP duplication showed abundant parenchymal and vascular deposits of amyloid-beta peptides. Duplication of the APP locus, resulting in accumulation of amyloid-beta peptides, causes ADEOAD with CAA.

70. Amyloid in neurosurgical and neurological practice

J Clin Neurosci    2006

Abstract: The amyloidoses are a diverse group of diseases characterized by the deposition of specific proteins with distinct affinity to the dye Congo red, collectively called amyloid. The amyloidogenic proteins have acquired an abnormal, highly ordered, beta-pleated sheet configuration with a propensity to self-aggregate. The amyloid may be distributed in different organs with a remarkable diversity. Two broad categories of amyloidoses are recognised: The systemic (consisting of the primary or light chain form, the secondary or reactive form and the familial or hereditary form) and the localised that target specific organs. A tropism of amyloid proteins to the neural tissue produces certain patterns of central nervous system diseases: cerebral amyloid angiopathy, a substrate of spontaneous intracerebral haemorrhage; mature neuritic plaques found in Alzheimer disease and a subset of prion diseases; a topographically restricted accumulation of extracellular proteins giving rise to tumour-mimicking masses, the amyloidomas; and finally, spinal extradural amyloid collections that occasionally are found in the context of rheumatoid arthritis. In this review article we present original illustrative cases of amyloid diseases of the central nervous system that may be encountered in neurosurgical and neurological practice. Molecular aspects and clinical management problems are discussed.

71. Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats

Mol Ther    2006，13（1）：167-74

Abstract: Recombinant AAV vectors containing a dimerizer-inducible system of transcriptional activation provide a strategy for control of therapeutic gene expression in the CNS. Here we explored this system for regulated expression of human aromatic l-amino acid decarboxylase (hAADC) in a rodent model of Parkinson disease. Expression of hAADC, the enzyme that converts l-dopa to dopamine, was dependent on reconstitution of a functional transcription factor (TF) by the dimerizer rapamycin. Two vectors, AAV-CMV-TF and AAV-Z12-hAADC, were infused into striata of 6-OHDA-lesioned rats. Rapamycin-induced increases in expression of hAADC repeatedly produced robust rotational behavior in response to low doses of l-dopa. Seven weeks after vector infusion, AADC expression in brain was quantitated by both stereology and Western blot analysis following the final rapamycin treatment. While a low level of hAADC was observed in rats that were not induced with rapamycin, this basal expression was not significant enough to elicit a rotational response to l-dopa. This study demonstrated a robust behavioral response of parkinsonian rats to regulated hAADC expression. Recombinant AAV vectors controlled by rapamycin or its analogs show promise as candidates for CNS therapies in which regulation of the transgene is desired.

72. Case Study: Delirium in an Adolescent Girl With Human Immunodeficiency Virus-Associated Dementia. [Article]

Journal of the American Academy of Child & Adolescent Psychiatry    2006，45（1）：104-108

Abstract: Delirium and human immunodeficiency virus (HIV)-associated dementia are well recognized neuropsychiatric consequences of HIV infection in adults. Almost nothing is known regarding the management of delirium in HIV-infected children and adolescents. HIV-related progressive encephalopathy is thought to represent the pediatric form of HIV-associated dementia; however, this condition occurs in HIV-infected infants and preschool children and is rapidly followed by death. This report describes the identification and treatment of apparent HIV-associated dementia complicated by delirium in an adolescent girl., Copyright 2006 (C) American Academy of Child and Adolescent Psychiatry

73. Anesthesia for Minimally Invasive Cranial and Spinal Surgery. [Review]

Journal of Neurosurgical Anesthesiology    2006，18（1）：47-56

Abstract: The field of minimally invasive neurosurgery has evolved rapidly in its indications and applications over the last few years. New, less invasive techniques with low morbidity and virtually no mortality are replacing conventional neurosurgical procedures. Providing anesthesia for these procedures differs in many ways from conventional neurosurgical operations. Anesthesiologists are faced with the perioperative requirements and risks of newly developed procedures. This review calls attention to the anesthetic issues in various minimally invasive neurosurgical procedures for cranial and spinal indications. Among the procedures specifically discussed are endoscopic third ventriculostomy, endoscopic transsphenoidal hypophysectomy, endoscopic strip craniectomy, deep brain stimulation, video-assisted thorascopic surgery, vertebroplasty and kyphoplasty, cervical discectomy and foraminectomy, and laparoscopically assisted lumbar spine surgery., (C) 2006 Lippincott Williams & Wilkins, Inc.

74. Deregulation of cdk5 in Hippocampal Sclerosis. [Article]

Journal of Neuropathology & Experimental Neurology   2006，65（1）：55-66

Abstract: Hippocampal sclerosis (HS) is the most common cause of chronic medically refractory epilepsy in adults. Histologically, HS is characterized by segmental neuronal loss and gliosis. Although neuronal loss is important to the pathophysiology of HS, the molecular mechanisms underlying the neuronal loss remain uncertain. Recently, it has been appreciated that proteins important in neurodevelopment may also have a role in neurodegeneration. Cyclin-dependent kinase 5 (cdk5), known to be crucial in development of the normal cerebral cortex, has now been shown as pivotal in several cell death paradigms, including apoptosis and necrosis. Deregulation of cdk5 by p25 causes hyperphosphorylation of tau and may contribute to pathology in several neurodegenerative conditions. Furthermore, it has been shown that after transient forebrain ischemia, cdk5 causes specific death of CA1 neurons in the rat hippocampus by direct phosphorylation of the NR2A subunit of the NMDA receptor and subsequent excitotoxicity. Because apoptosis, necrosis, and excitotoxicity are all thought to contribute to neuronal loss in HS, we hypothesized that abnormalities of the cdk5 pathway would accompany this disorder. Surgically resected cases of HS with adjacent histologically normal lateral temporal cortex were examined for cdk5 and its activator p35/p25. We consistently found increased immunoreactivity for p35/p25 in surviving neurons within areas of neuronal loss compared with areas where neurons were preserved. Western blots showed the ratio of p25 to p35 to be greater in diseased hippocampi than in the adjacent histologically normal temporal lobe. Histone-based kinase assays demonstrated increased activity of the p25-cdk5 complex in HS compared with the temporal lobe despite neuronal loss in the hippocampal samples. Our results suggest that p25 is pathologically increased in HS and that deregulation of cdk5 by p25 might contribute to neuronal death in this condition., (C) 2006 American Association of Neuropathologists, Inc

75. The Lifetime Risk of Stroke. Estimates From the Framingham Study

Stroke  2006

Abstract: BACKGROUND AND PURPOSE: The lifetime risk (LTR) of stroke has not been reported for the United States population; such data would assist public education and health planning. METHODS: Framingham Original cohort participants (n=4897) who were stroke- and dementia-free at 55 years of age were followed biennially for up to 51 years (115 146 person years). We estimated the sex-specific 10-, 20-, and 30-year risks and LTR of developing a stroke by baseline age and blood pressure (BP) and compared it with the risk of developing Alzheimer disease (AD). RESULTS: A total of 875 participants (522 women) developed a first-ever stroke; 749 (448 women) had an ischemic stroke. LTR of stroke was high and remained similar at ages 55, 65, and 75 years, approximating 1 in 5 for women and 1 in 6 for men. Participants with a normal BP (<120/80 mm Hg) had approximately half the LTR of stroke compared with those with high BP (>/=140/90 mm Hg). The LTR of AD at age 65 (292 participants; 211 women) approximated 1 in 5 for women and 1 in 10 for men. The LTR of developing either stroke or dementia approximated 1 in 3 in both sexes. CONCLUSIONS: The LTR of stroke in middle-aged adults is 1 in 6 or more, which is equal to or greater than the LTR of AD. Women had a higher risk because of longer life expectancy. BP is a significant determinant of the LTR of stroke, and promotion of normal BP levels in the community might be expected to substantially reduce this risk.

Author Address: From the Departments of Neurology and Preventive Medicine, School of Medicine, and the Department of Biostatistics, School of Public Health, Boston University, Massachusetts.

76. Relation of blood pressure to risk of incident Alzheimer's disease and change in global cognitive function in older persons

Neuroepidemiology    2006，26（1）：30-36

Abstract: Purpose: To examine the relation of systolic and diastolic blood pressure to incident Alzheimer's disease (AD) and rate of cognitive change. Methods: Longitudinal cohort study with annual clinical evaluations. At baseline, blood pressure was measured, apolipoprotein E (APOE) genotyping was performed, and medications were reviewed. Results: 824 older Catholic clergy members without baseline dementia were recruited from across the United States. During a mean of about 6 years of observation, 151 persons developed AD. In a proportional hazards model adjusted for age, sex and education, neither systolic (relative risk = 0.995; 95% CI: 0.986, 1.004, p = 0.249) nor diastolic (relative risk = 1.000; 95% CI: 0.985, 1.015, p = 0.975) blood pressure was related to AD incidence. In mixed effects models, neither systolic nor diastolic blood pressure was related to level or to annual rate of change on a global measure of cognition. These results did not change in subsequent models that accounted for the use of medications with antihypertensive properties or for the possession of an APOE epsilon 4 allele. Conclusions: In a cohort of older persons with a majority taking medications with antihypertensive properties, we did not find a relationship between blood pressure and risk of AD or cognitive decline. Copyright (C) 2006 S. Karger AG, Basel.

77. Nuclear Pore Complex Proteins in Alzheimer Disease. [Article]

Journal of Neuropathology & Experimental Neurology     2006，65（1）：45-54

Abstract: Ultrastructural studies of neurofibrillary tangles in Alzheimer disease (AD) have demonstrated a close relationship between nuclear pores and the cytoplasmic paired helical filaments comprising the tangles, as well as nuclear irregularity in many tangle-bearing neurons; nuclear pore aggregation has been observed in nearby neurons. These observations prompted examination of the nuclear pore complex (NPC) and proteins critical to nucleocytoplasmic transport in neurons with and without tangles in AD and control cases. Light microscopic study of hippocampus and neocortex in AD and controls revealed that all nuclei were labeled by antibodies to NPC proteins, including the central transporter nucleoporin Nup62. Nucleoporin and tau label revealed significantly more nuclear irregularity in AD, often associated with neurofibrillary tangles. Double label of Nup62 with apoptotic markers (TUNEL and active caspase-3) and a cell-cycle protein (cyclin B1) revealed no clear relationship of nuclear irregularity to apoptosis or cell-cycle protein expression. However, cytoplasmic accumulation of nuclear transport factor 2 (NTF2), a protein that transports cargo from the cytoplasm into the nucleus, was observed in a subset of hippocampal neurons with and without tangles in AD but not control cases. Further investigation of the NPC and nucleocytoplasmic transport in AD is warranted., (C) 2006 American Association of Neuropathologists, Inc

78. Scanning cysteine mutagenesis analysis of abeta-(1-40) amyloid fibrils

J Biol Chem    2006，281（2）：993-1000

Abstract: We describe here the use of cysteine substitution mutants in the Alzheimer disease amyloid plaque peptide Abeta-(1-40) to probe amyloid fibril structure and stabilization. In one approach, amyloid fibrils were grown from Cys mutant peptides under reducing conditions and then challenged with an alkylating agent to probe solvent accessibility of different residues in the fibril. In another approach, monomeric Cys mutants, either in the thiol form or modified with iodoacetic acid or methyl iodide, were grown into amyloid fibrils, and the equilibrium position at the end of the amyloid formation reaction was quantified by determining the concentration of monomeric Abeta. The DeltaG values of fibril elongation obtained were then compared in order to provide information on the environment of each residue side chain in the fibril. In general, Cys residues in the N and C termini of Abeta-(1-40) were not only accessible to alkylation in the fibril state but also, when modified in the monomeric state, did not greatly impact fibril stability; these observations were consistent with previous indications that these portions of the peptide are not part of the amyloid core. In contrast, residues 16-19 and 31-34 were not only uniformly inaccessible to alkylation in the fibril state, but their modification with the negatively charged carboxymethyl group in monomeric Abeta also destabilized fibril elongation, confirming other data showing that these segments are likely packed into a hydrophobic amyloid core. Residues 20, 30, and 35, flanking these implicated beta-sandwich regions, are accessible to alkylation in the fibril indicating a location in solvent exposed structure.

79. Polychlorinated biphenyls and neurodegenerative disease mortality in an occupational cohort

Epidemiology    2006，17（1）：8-13

Abstract: BACKGROUND: Production of polychlorinated biphenyls (PCBs) ended in the United States in the 1970s, but PCBs persist in the environment and are detectable in the blood of approximately 80% of Americans over age 50. PCBs decrease dopamine levels in rats and monkeys. Loss of dopamine is the hallmark of Parkinson disease, a neurodegenerative disease. There are no epidemiologic studies of PCBs and neurodegenerative disease. METHODS: We conducted a retrospective mortality study of 17,321 PCB-exposed workers to determine whether mortality from Parkinson disease, dementia, and amyotrophic lateral sclerosis was elevated compared with the U.S. population. All workers had a least 90 days employment in 1 of 3 electrical capacitor plants using PCBs from the 1940s to the 1970s. PCB serum levels from a sample of these workers in the 1970s were approximately 10 times the level of community controls. RESULTS: We found no overall excess of Parkinson disease, amyotrophic lateral sclerosis, or dementia in the PCB-exposed cohort (standardized mortality ratios [SMRs]-1.40, 1.11, and 1.26, respectively, and number of deaths-14, 10, and 28 respectively). However, sex-specific analyses revealed that women had an excess of amyotrophic lateral sclerosis (SMR-2.26; 95% confidence interval [CI] = 1.08-4.15; 10 deaths). Furthermore, among highly exposed women (defined by a job-exposure matrix), we found an excess of Parkinson disease (SMR-2.95; 95% CI = 1.08-6.42; 6 deaths) and dementia (SMR-2.04; 95% CI = 1.12-3.43; 14 deaths). CONCLUSIONS: Our data are limited due to small numbers and reliance on mortality rather than incidence data, but are suggestive of an effect of PCBs on neurodegenerative disease for women. The literature does not offer an explanation for why women would be more affected than men by PCB exposure for these outcomes.

80. Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes

Neurobiol Aging    2006，27（1）：1-9

Abstract: In this study we surveyed a total of 218 cerebrospinal fluid (CSF) samples from patients with different neurological diseases including Alzheimer disease, non-Alzheimer forms of dementia, other neurodegenerative diseases without dementia and normal controls to quantitate by capture ELISA the concentrations of the immunoglobulin superfamily adhesion molecules L1 and NCAM, and characterized by immunoblot analysis the molecular forms of L1 and NCAM. We found a significant increase of L1 and a strong tendency for increase of the soluble fragments of NCAM in the CSF of Alzheimer patients compared to the normal control group. The proteolytic fragments of L1, but not NCAM were also elevated in patients with vascular dementia and dementia of mixed type. Higher L1 concentrations were observed irrespective of age and gender. NCAM concentrations were independent of gender, but positively correlated with age and, surprisingly, also with incidence of multiple sclerosis. Thus, there was an influence of Alzheimer and non-Alzheimer dementias and neurodegeneration on L1, whereas age and neurodegeneration influenced NCAM concentrations. These observations point to an abnormal processing and/or shedding of L1 and NCAM in dementia-related neurodegeneration and age, respectively, reflecting changes in adhesion molecule-related cell interactions.

Author Address: Zentrum fur Molekulare Neurobiologie, Universitat Hamburg, Martinistr. 52, D 20246 Hamburg, Germany.

81. Immunization in familial amyloidotic polyneuropathy: counteracting deposition by immunization with a Y78F TTR mutant

Laboratory Investigation    2006，86（1）: 23-31

Abstract: The mechanism of amyloid formation in familial amyloidotic polyneuropathy (FAP), a hereditary disorder associated with mutant transthyretin (TTR), is still unknown. It is generally believed that altered conformations exposing cryptic regions are intermediary steps in this mechanism. A TTR mutant-Y78F ( transthyretin mutant with phenylalanine replacing tyrosine at position 78)-designed to destabilize the native structure has been shown to expose a cryptic epitope recognized by a monoclonal antibody that reacts only with highly amyloidogenic mutants presenting the amyloid fold or with amyloid fibrils. To test whether TTR deposition in FAP can be counteracted by antibodies for cryptic epitopes, we immunized with TTR Y78F, transgenic mice carrying the most common FAP-associated TTR mutant-V30M ( transthyretin mutant with methionine replacing valine at position 30)-at selected ages that present normally with either nonfibrillar or TTR amyloid deposition. Compared to age-matched control nonimmunized mice, Y78F-immunized mice had a significant reduction in TTR deposition usually found in this strain, in particular in stomach and intestine; by contrast, animals immunized with V30M did not show differences in deposition in comparison with nonimmunized mice. Immunohistochemical analyses of tissues revealed that immunization with Y78F lead to infiltration by lymphocytes and macrophages at common deposition sites, but not in tissues such as liver, choroid plexus, and Langerhans islets, in which TTR is produced. These results suggest that Y78F induced production of an antibody that reacts specifically with deposits and leads to an immune response effective in removing/preventing TTR deposition. Therefore, TTR immunization with selected TTR mutants has potential application in immune therapy for FAP.

82. Dementia patients caregivers quality of life: the PIXEL study

Int J Geriatr Psychiatry    2006,21(1):50-6

Abstract: BACKGROUND: Alzheimer's disease and related syndromes have heavy social and human consequences for the patient and his family. Beyond the neuropsychiatric effects of specific therapies for dementia, one of today's challenges is the quality of life for both patients and their informal caregivers. OBJECTIVES: This survey tends to determine parameters influencing caregivers' quality of life, and its possible link with patients' quality of life. METHODS: A scale measuring caregivers' quality of life, developed from data from previous PIXEL studies was used. It is a questionnaire composed of 20 items. The scale was related to the socio-demographic data of both patients and their main caregivers, to the ADRQL scale (Alzheimer Disease Related Quality Life) of Rabins for the QoL of dementia patients, to the patients medical and therapeutic data, specially a neuropsychological inventory: Folstein's cognition test, Cornell's depression scale, the fast battery of frontal assessment, Katz's dependence index, Cummings' neuropsychiatric inventory for behavioral and psychological symptoms of dementia and to a physician evaluation of caregiver's depression. RESULTS: One hundred patients diagnosed with dementia who live at home with their principal caregivers were recruited for this survey. Patients were 80.2 +/- 6.8 years old and caregivers were 65.7 +/- 12.8 years old. The caregivers' quality of life was correlated to the quality of life of the patients they cared for, the importance of behavioral disorders, and the duration of dementia evolution. Women caregivers had a worse quality of life and were more depressive than men. DISCUSSION: Caregivers' and patients' quality of life are related and both share a community of distress. Copyright (c) 2005 John Wiley & Sons, Ltd.

83. Frameshift proteins in autosomal dominant forms of Alzheimer disease and other tauopathies. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.   2006,66(2): S86-S92

Abstract: mdash;: Frameshift (+1) proteins such as APP+1 and UBB+1 accumulate in sporadic cases of Alzheimer disease (AD) and in older subjects with Down syndrome (DS). We investigated whether these proteins also accumulate at an early stage of neuropathogenesis in young DS individuals without neuropathology and in early-onset familial forms of AD (FAD), as well as in other tauopathies, such as Pick disease (PiD) or progressive supranuclear palsy (PSP). APP+1 is present in many neurons and beaded neurites in very young cases of DS, which suggests that it is axonally transported. In older DS patients (>37 years), a mixed pattern of APP+1 immunoreactivity was observed in healthy looking neurons and neurites, dystrophic neurites, in association with neuritic plaques, as well as neurofibrillary tangles. UBB+1 immunoreactivity was exclusively present in AD type of neuropathology. A similar pattern of APP+1 and UBB+1 immunoreactivity was also observed for FAD and much less explicit in nondemented controls after the age of 51 years. Furthermore, we observed accumulation of +1 proteins in other types of tauopathies, such as PiD, frontotemporal dementia, PSP and argyrophylic grain disease. These data suggest that accumulation of +1 proteins contributes to the early stages of dementia and plays a pathogenic role in a number of diseases that involve the accumulation of tau., (C)2006AAN Enterprises, Inc.

84. Anesthesia for Functional Neurosurgery: Review of Complications. [Report]

Journal of Neurosurgical Anesthesiology     2006,18(1): 64-67

Abstract: The use of functional stereotactic neurosurgery is increasing for treatment of patients with movement disorders and other chronic illnesses. The anesthetic considerations include the influence of the anesthetic agents on the microelectrode recordings and stimulation testing of an awake patient. The purpose of this study was to review the anesthetic management and incidences of intraoperative complications during functional neurosurgery in our institution. One hundred seventy-eight patients underwent an ablative procedure (n = 6) or the insertion of deep brain stimulator (n = 172) under monitored anesthesia care for movement disorders (n = 124), chronic pain (n = 20), and other procedures (n = 34). Local anesthetic was used for head frame pin sites and burr holes. No sedation/analgesia was administered to 57 (32%) patients. One patient required conscious sedation and another general anesthesia for the entire procedure. The remainder received small increments (mean +/- SD) of propofol (113 +/- 73 mg), midazolam (1.6 +/- 0.8 mg), and/or fentanyl (93 +/- 55 [mu]g). Intraoperative complications that occurred in 16% of the patients included seizures (n = 8), change in neurologic status (n = 5), airway obstruction (n = 2), and hypertension (n = 7). Functional neurosurgery can be performed with minimal anesthesia in many patients. Awareness and vigilance can improve the identification and early treatment of intraoperative complications such as seizures, loss of airway, and changes in the neurologic status., (C) 2006 Lippincott Williams & Wilkins, Inc.

85. Amyloidogenic processing of [beta]-amyloid precursor protein in intracellular compartments. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.   2006,66(2)：S69-S73

Abstract: mdash;: Trafficking and proteolytic processing of amyloid precursor protein (APP) have been the focus of numerous investigations in the past two decades, since the identification of A[beta] as the principal component of brain senile plaques and the cloning of APP cDNA. Tremendous progress has been made in the recent past toward the characterization of [beta]- and [gamma]-secretases. Here, we review the salient features of Alzheimer disease amyloidogenesis, and discuss the current knowledge on APP trafficking and amyloidogenic processing of APP in intracellular membrane compartments and microdomains., (C)2006AAN Enterprises, Inc.

86. Role of melatonin in Alzheimer-like neurodegeneration

Acta Pharmacol Sin     2006，27（1）：41-9

Abstract: Alzheimer disease (AD), an age-related neurodegenerative disorder with progressive loss of memory and deterioration of comprehensive cognition, is characterized by extracellular senile plaques of aggregated beta-amyloid (Abeta), and intracellular neurofibrillary tangles that contain hyperphosphorylated tau protein. Recent studies showed that melatonin, an indoleamine secreted by the pineal gland, may play an important role in aging and AD as an antioxidant and neuroprotector. Melatonin decreases during aging and patients with AD have a more profound reduction in this hormone. Data from clinical trials indicate that melatonin supplementation improves sleep, ameliorates sundowning, and slows down the progression of cognitive impairment in Alzheimer patients. Melatonin efficiently protects neuronal cells from Abeta-mediated toxicity via antioxidant and anti-amyloid properties: it not only inhibits Abeta generation, but also arrests the formation of amyloid fibrils by a structure-dependent interaction with Abeta. Our recent studies have demonstrated that melatonin efficiently attenuates Alzheimer-like tau hyperphosphorylation. Although the exact mechanism is still not fully understood, a direct regulatory influence of melatonin on the activities of protein kinases and protein phosphatases is proposed. Additionally, melatonin also plays a role in protecting cholinergic neurons and in anti-inflammation. Here, the neuroprotective effects of melatonin and the underlying mechanisms by which it exerts its effects are reviewed. The capacity of melatonin to prevent or ameliorate tau and Abeta pathology further enhances its potential in the prevention or treatment of AD.

87. Effects of ginseng saponins on beta-amyloid-induced amnesia in rats

Journal of Ethnopharmacology     2006，103（1）：103-106

Abstract: We have previously demonstrated that ginseng saponins (GS) can reverse the inhibitory effect of beta-amyloid on acetylcholine (ACh) release in the hippocampal slices. The present study was carried out to examine whether GS has any beneficial effects against amnesia induced by beta-amyloid peptides in vivo. Intracerebroventricular injection of 50 mu g, but not 10 mu g, beta-amyloid fragment(25-35) markedly impaired the performance of rats in avoiding a shock prod, confirming the amnesiac effect of beta-amyloid. Chronically treating the rats with GS (orally, 5 days before icv beta-amyloid injection and 7 days afterward) resulted in a dose-related improvement against beta-amyloid-induced amnesia; a significant reversion was observed at the highest GS dose (80 mg/kg/day). Post-treatment analysis on K+-evoked [H-3]-ACh release from the hippocampal slices showed that beta-amyloid-treatment significantly reduced ACh release from that of the control group. However, pre-treatment with GS completely protected the animal against beta-amyloid-induced reduction of hippocampal ACh release. In contrast, treating the animals with the same optimal dose of GS and duration but only after icv beta-amyloid injection was found to be ineffective in obliterating beta-amyloid's amnesiac effect. Taken together, these observations indicated that GS pre-treatment can functionally prevent the beta-amyloid-induced memory loss possibly by minimizing the inhibitory effect of beta-amyloid on hippocampal cholinergic transmission. (c) 2005 Published by Elsevier Ireland Ltd.

88. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine

Acta Pharmacol Sin     2006，27（1）:1-26

Abstract: Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase(AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, beta-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.

Author Address: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.

89. Patterns of atrophy in pathologically confirmed FTLD with and without motor neuron degeneration. [Miscellaneous Article]

Neurology     2006,66(1)：102-104

Abstract: mdash;: The authors used voxel-based morphometry to compare the patterns of brain atrophy in two variants of pathologically confirmed frontotemporal lobar degeneration (FTLD): FTLD with motor neuron disease (FTLD-MND) and FTLD with ubiquitin-only-immunoreactive neuronal changes (FTLD-U). Patterns of atrophy were distinct and different from each other. A localized pattern of frontal lobe atrophy was found in FTLD-MND with a more widespread pattern of atrophy affecting the frontal and temporal lobes in FTLD-U., (C)2006AAN Enterprises, Inc.

90. The Neuropathology of Alzheimer Disease in African American and White Individuals

Arch Neurol    2006，63（1）：87-90

Abstract: BACKGROUND: Data from neuropathologic studies of the frequency of Alzheimer disease (AD) among African American persons conflict as to whether the neuropathologic phenotype of AD is identical in African American and white persons. OBJECTIVES: To examine clinical and neuropathologic phenotypes of AD in African American individuals and to compare AD and vascular burdens between African American and white persons.Design, Setting, and Patients Ten African American decedents who underwent brain autopsy at the Washington University Alzheimer's Disease Research Center were matched for age, sex, and Clinical Dementia Rating with 10 white decedents between January 1, 1990, and January 1, 2000. The presence and degree of neurofibrillary tangles, senile plaques, Lewy bodies, cerebral infarcts, and cerebral amyloid angiopathy were determined. RESULTS: All 20 individuals had a neuropathologic diagnosis of AD. There were no group differences in the presence or number of infarcts, plaques, tangles, Lewy bodies, or amyloid angiopathy. CONCLUSION: In this small sample, we found no substantive differences in the neuropathology of AD among African American and white individuals.

91. Striatal deafferentation increases dopaminergic neurogenesis in the adult olfactory bulb

Exp Neurol     2006，197（1）：113-21

Abstract: Dopaminergic loss is known to be one of the major hallmarks of Parkinson disease (PD). In addition to its function as a neurotransmitter, dopamine plays significant roles in developmental and adult neurogenesis. Both dopaminergic deafferentation and stimulation modulate proliferation in the subventricular zone (SVZ)/olfactory bulb system as well as in the hippocampus. Here, we study the impact of 6-hydroxydopamine (6-OHDA) lesions to the medial forebrain bundle on proliferation and neuronal differentiation of newly generated cells in the SVZ/olfactory bulb axis in adult rats. Proliferation in the SVZ decreased significantly after dopaminergic deafferentation. However, the number of neural progenitor cells expressing the proneuronal cell fate determinant Pax-6 increased in the SVZ. Survival and quantitative cell fate analysis of newly generated cells revealed that 6-OHDA lesions induced opposite effects in the two different regions of neurogenesis in the olfactory bulb: a transient decrease in the granule cell layer contrasts to a sustained increase of newly generated neurons in the glomerular layer. These data point towards a shift in the ratio of newly generated interneurons in the olfactory bulb layers. Dopaminergic neurogenesis in the glomerular layer tripled after lesioning and consistent with this finding, the total number of tyrosine hydroxylase (TH)-positive cells increased. Thus, loss of dopaminergic input to the SVZ led to a distinct cell fate decision towards stimulation of dopaminergic neurogenesis in the olfactory bulb glomerular layer. This study supports the accumulating evidence that neurotransmitters play a crucial role in determining survival and differentiation of newly generated neurons.

92. The unfolded protein response: A stress signaling pathway critical for health and disease. [Article]

Neurology Inclusion body myositis: Clinical and pathologic aspects, and basic research potentially relevant to treatment.    2006，66（2）：S102-S109

Abstract: mdash;: The endoplasmic reticulum (ER) is an intracellular organelle consisting of a membranous labyrinth network that extends throughout the cytoplasm of the cell and is contiguous with the nuclear envelope. In all eukaryotic cells, the ER is the site where folding and assembly occurs for proteins destined to the extracellular space, plasma membrane, and the exo/endocytic compartments. The ER is exquisitely sensitive to alterations in homeostasis, and provides stringent quality control systems to ensure that only correctly folded proteins transit to the Golgi and unfolded or misfolded proteins are retained and ultimately degraded. A number of biochemical and physiologic stimuli, such as perturbation in calcium homeostasis or redox status, elevated secretory protein synthesis, expression of misfolded proteins, sugar/glucose deprivation, altered glycosylation, and overloading of cholesterol can disrupt ER homeostasis, impose stress to the ER, and subsequently lead to accumulation of unfolded or misfolded proteins in the ER lumen. The ER has evolved highly specific signaling pathways called the unfolded protein response (UPR) to cope with the accumulation of unfolded or misfolded proteins. Recent discoveries of the mechanisms of ER stress signaling have led to major new insights into the diverse cellular and physiologic processes that are regulated by the UPR. This review summarizes the complex regulation of UPR signaling and its relevance to human physiology and disease., (C)2006AAN Enterprises, Inc.