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AbstractOBJECTIVE: To examine the longitudinal relationship between poor physical performance and risk of dementia in non-demented oldest-old.BACKGROUND: We have previously reported a strong, dose-dependent cross-sectional relationship between poor physical performance and odds of dementia, where poorer physical performance was associated with increased odds of prevalent dementia.DESIGN/METHODS: The 90+ Study is a population based investigation of dementia in people aged 90 and older. 594 participants from The 90+ Study were included in this study. Physical performance measures (5 chair-stands, 10-second balance, 4-m walk and handgrip) were scored from 0-4 (0= unable to perform, 4= best performance). The outcome was dementia, diagnosed by applying DSM-IV criteria. Hazard Ratios (HR) for dementia in relation to physical performance were estimated by Cox Regression after adjustment for age and gender.RESULTS: At baseline, all participants were non-demented (normal: 57%, cognitively impaired non-demented: 43%), mostly women (69%) with an average age of 93.3 (range 90.0-103.0) years. The average length of follow-up was 2.6 (range 0.1-9.0) years. Poor physical performance in all measures was significantly associated with increased risk of incident dementia. HR for every unit decrease in physical performance score were 1.18 for 5 chair-stands, 1.27 for balance, 1.35 for 4-m walk, 1.17 for handgrip (all p

In a previous study of hippocampal neurons in aging and AD [Lancet 344 (1994) 769], we demonstrated that the loss of neurons in the CA1 region was disease-specific and not related to aging. In the present study, we examined for loss of hippocampal neurons in preclinical AD, a period during which there are abundant amyloid deposits in the brain but no evidence of cognitive decline. We examined the postmortem brains of 33 subjects from the Baltimore Longitudinal Study of Aging and the Johns Hopkins Alzheimer's Disease Research Center. Using unbiased stereology, we estimated the total number of neurons in the granule cell layer, hilus, CA3-2, CA1, and subiculum of AD (n = 14) preclinical AD (n = 8), and age-matched control subjects (n = 11). The results from the present study confirm our previous finding of significant neuronal losses in the CA1 (48%), hilus (14%), and subiculum (24%) in AD [Lancet 344 (1994) 769]. However, we did not observe a significant loss of neurons in CA1 or any of the other subdivisions of the hippocampus in preclinical AD.

Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson's disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in α-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in α-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated α-synuclein-mediated DA neurodegeneration and α-synuclein aggregation, whereas Aldh1a1 -null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium-, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against α-synuclein- mediated DA neurodegeneration but did not rescue α-synuclein-induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic α-synuclein oligomers., Introduction Parkinson's disease (PD), the most common degenerative movement disorder, is pathologically characterized by a preferential loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the [...]

The definitive Alzheimer's disease (AD) diagnosis requires postmortem confirmation of neuropathological hallmarks-amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The advent of radiotracers for amyloid imaging presents an opportunity to investigate amyloid deposition in vivo. The C-Pittsburgh compound-B (PiB)-PET ligand remains the most widely studied to date; however, regional variations in C-PiB binding and the extent of agreement with neuropathological assessment have not been thoroughly investigated. Sojkova and colleagues [] reported variable agreement between CERAD-based neuropathologic diagnosis of AD lesions and mean cortical PiB, suggesting the need for a more direct quantification of regional Aβ in relation to in vivo imaging. In the present study, we extend these findings by examining the correspondence among regional C-PiB load, region-matched quantitative immunohistological assessments of Aβ and NFTs, and brain atrophy (MRI) in six older Baltimore Longitudinal Study of Aging participants who came to autopsy (imaging-autopsy interval range 0.2-2.4 years). The total number of Aβ plaques (6E10) and NFTs (PHF1) in paraffin sections from hippocampus, orbito-frontal cortex, anterior and posterior cingulate gyrus, precuneus and cerebellum was quantified using a technique guided by unbiased stereological principles. We report a general agreement between the regional measures of amyloid obtained via stereological assessment and imaging, with significant relationships evident for the anterior ( r = 0.83; p = 0.04) and posterior ( r = 0.94; p = 0.005) cingulate gyri, and the precuneus ( r = 0.94; p = 0.005). No associations were observed between C-PiB load and NFT count for any of the regions examined ( p > 0.2 in all regions), or between regional Aβ or NFT counts and corresponding brain volumes. The strong associations of PiB retention with region-matched, quantitative analyses of Aβ in postmortem tissue offer support for the validity of C-PiB-PET imaging as a method for evaluation of plaque burden in vivo. [ABSTRACT FROM AUTHOR]

Although the pathogenesis of Alzheimer's disease (AD) is not fully understood, growing evidence indicates that the deposition of β-amyloid (Aβ) and the local reactions of various cell types to this protein play major roles in the development of the disease. Immunization with the Aβ 1-42 peptide has been reported to decrease Aβ deposits in the brains of mutant amyloid precursor protein (APP/V717F) transgenic (tg) mice (Schenk et al. Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:173–177). We have replicated this finding in APPswe/PS1ΔE9 tg mice, which also develop Aβ deposits in the brain. The immunized animals developed high titers of antibodies against Aβ 1-42 in serum, and Aβ deposits in the brains were significantly reduced. Using surface-enhanced laser desorption/ionization (SELDI) mass spectrometry and ProteinChip[sup ®] technology, we detected trends toward increased soluble Aβ peptide in the brain and a decrease in assayable Aβ peptide in the serum of immunized compared with control animals. This last finding raises the possibility that anti-Aβ antibodies in the periphery sequester Aβ peptides or target them for degradation and in this way contribute to the enhanced Aβ clearance from the brain in immunized animals. [ABSTRACT FROM AUTHOR]

We measured cell bodies, nuclei, and nucleoli in anterior cingulate (AC) and posterior cingulate (PC) gyri in 9 subjects with asymptomatic Alzheimer's disease from the Baltimore Longitudinal Study of Aging (BLSA). Asymptomatic AD is characterized by AD pathology in the brain of normal subjects. We examined three other group: 9 old controls (OC), 9 with MCI (MCI) and 8 with AD dementia (AD). Volumes were estimated using unbiased stereology. Results show a significant increase of the nuclei in AC and of the nucleoli both in AC and PC. We observed atrophy of AC cell bodies in MCI and AD, but not in PC. The hypertrophy of the neuronal nuclei and nucleoli may reflect a reactive process that allows the brain of ASYMAD subjects to function normally despite the presence of AD lesions, or represent the earliest stages of neurodegeneration. In MCI and AD, we found significant atrophy of neuronal cell body in AC, but not in PC. Compared to the changes in AC, the lack of nuclear enlargement and body atrophy in PC suggests that this region is involved later in the course of the disease or is less vulnerable to it. [ABSTRACT FROM AUTHOR]

Subpopulations of dopaminergic (DA) neurons within the substantia nigra pars compacta (SNpc) display a differential vulnerability to loss in Parkinson's disease (PD); however, it is not clear why these subsets are preferentially selected in PD-associated neurodegeneration. In rodent SNpc, DA neurons can be divided into two subpopulations based on the expression of aldehyde dehydrogenase 1 (ALDH1A1). Here, we have shown that, in α-synuclein transgenic mice, a murine model of PD-related disease, DA neurodegeneration occurs mainly in a dorsomedial ALDH1A1-negative subpopulation that is also prone to cytotoxic aggregation of α-synuclein. Notably, the topographic ALDH1A1 pattern observed in α-synuclein transgenic mice was conserved in human SNpc. Postmortem evaluation of brains of patients with PD revealed a severe reduction of ALDH1A1 expression and neurodegeneration in the ventral ALDH1A1-positive DA subpopulations. ALDH1A1 expression was also suppressed in α-synuclein transgenic mice. Deletion of Aldh1a1 exacerbated α-synuclein-mediated DA neurodegeneration and α-synuclein aggregation, whereas Aldh1a1-null and control DA neurons were comparably susceptible to 1-methyl-4-phenylpyridinium-, glutamate-, or camptothecin-induced cell death. ALDH1A1 overexpression appeared to preferentially protect against a-synuclein-mediated DA neurodegeneration but did not rescue α-synuclein-induced loss of cortical neurons. Together, our findings suggest that ALDH1A1 protects subpopulations of SNpc DA neurons by preventing the accumulation of dopamine aldehyde intermediates and formation of cytotoxic α-synuclein oligomers. [ABSTRACT FROM AUTHOR]

Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration., (2009 Elsevier Inc. All rights reserved.)

Immunization with amyloid-beta (Abeta) prevents the deposition of Abeta in the brain and memory deficits in transgenic mouse models of Alzheimer's disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of Abeta vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an Abeta vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1-9 aa of Abeta protein repetitively on the viral capsid surface (Abeta-VLP). This Abeta peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with Abeta-VLP were well tolerated and induced high-titer autoAb against Abeta, that inhibited effectively assembly of Abeta(1-42) peptides into neurotoxic fibrils in vitro. Following Abeta-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced Abeta deposits in the brain and increased numbers of activated microglia. Furthermore, Abeta-VLP vaccinated mice also showed increased levels of Abeta in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the Abeta-VLP vaccine induces an effective humoral immune response to Abeta and may thus form a basis to develop a safe and efficient immunotherapy for human AD.