Alzheimer's disease with and without coexisting Parkinson's disease changes

Gearing, Maria; Schneider, Julia; Rebeck, G. William; Hyman, B. T.; Mirra, Suzanne S.

doi:10.1212/wnl.45.11.1985

Cited by 60 publications

(32 citation statements)

References 2 publications

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“…These findings are congru- ent with prior imaging studies 13 and are within range of cortical ␤-amyloid deposition seen in postmortem case studies in cognitively normal, mildly cognitively impaired, and patients with Alzheimer disease. [33][34][35] Our findings also demonstrate that the relationship between cognitive decline and the amount of cortical ␤-amyloid deposition is variable because we see studies with positive findings in all of our experimental groups (normal, EMCI, LMCI, and AD) and they are compatible with prior pathologic studies. 36 The degree of cortical ␤-amyloid deposition could have prognostic importance because recent studies have demonstrated that cognitively normal, mild cognitively impaired, and subjects with Alzheimer disease who have PET scans positive for amyloid demonstrate greater cognitive and global deterioration during an 18-month 37 and 3-year 38 follow-up than subjects with scans with negative findings.…”

Section: 712supporting

confidence: 86%

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation

Nayate

Dubroff

Schmitt

et al. 2015

American Journal of Neuroradiology

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Section: 712supporting

confidence: 86%

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation

Nayate

Dubroff

Schmitt

et al. 2015

American Journal of Neuroradiology

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“…The diagnosis of AD was established using CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria (9). ApoE genotypes (Table I) were determined for all subjects as previously described (10).…”

Section: Methodsmentioning

confidence: 99%

Oxidative Modifications and Down-regulation of Ubiquitin Carboxyl-terminal Hydrolase L1 Associated with Idiopathic Parkinson's and Alzheimer's Diseases

Choi

Levey

Weintraub

et al. 2004

Journal of Biological Chemistry

525

372

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Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common neurodegenerative diseases that occur either in relatively rare, familial forms or in common, sporadic forms. The genetic defects underlying several monogenic familial forms of AD and PD have recently been identified, however, the causes of other AD and PD cases, particularly sporadic cases, remain unclear. To gain insights into the pathogenic mechanisms involved in AD and PD, we used a proteomic approach to identify proteins with altered expression levels and/or oxidative modifications in idiopathic AD and PD brains. Here, we report that the protein level of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), a neuronal de-ubiquitinating enzyme whose mutation has been linked to an early-onset familial PD, is down-regulated in idiopathic PD as well as AD brains. By using a combination of two-dimensional gel electrophoresis and mass spectrometry, we have identified three human brain UCH-L1 isoforms, a full-length form and two amino-terminally truncated forms. Our proteomic analyses reveal that the full-length UCH-L1 is a major target of oxidative damage in AD and PD brains, which is extensively modified by carbonyl formation, methionine oxidation, and cysteine oxidation. Furthermore, immunohistochemical studies show that prominent UCH-L1 immunostaining is associated with neurofibrillary tangles and that the level of soluble UCH-L1 protein is inversely proportional to the number of tangles in AD brains. Together, these results provide evidence supporting a direct link between oxidative damage to the neuronal ubiquitination/de-ubiquitination machinery and the pathogenesis of sporadic AD and PD.Alzheimer's disease (AD) 1 and Parkinson's disease (PD) are the two most common neurodegenerative disorders in humans, however, the causes of AD and PD, particularly the sporadic cases, remain unclear. A prominent feature of AD and PD as well as other neurodegenerative diseases is the accumulation of insoluble proteinaceous deposits, such as senile plaques and neurofibrillary tangles in AD and Lewy bodies in PD (1). Although these deposits have different protein compositions, they all contain ubiquitin and ubiquitinated proteins (2). Interestingly, mutations in two enzymes of the ubiquitination/de-ubiquitination system, parkin and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), have been identified as causative genetic defects for certain familial forms of PD (3). In familial AD patients, an aberrant form of ubiquitin resulting from a ϩ1 frameshift mutation in the ubiquitin-B gene has been detected (4). Moreover, impaired proteasome function has been reported in idiopathic AD and PD brains (2). Collectively, these different lines of evidence support a role for dysfunction of the ubiquitinproteasome pathway in the pathogenesis of AD and PD.Oxidative stress is another important factor that has been implicated in the pathogenesis of a number of age-related neurodegenerative diseases, including AD and PD (5, 6). Both AD and PD have been associated wit...

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“…The diagnosis of AD was established using Consortium to Establish a Registry for Alzheimer Disease (CERAD) criteria (13). ApoE genotypes (Table I) were determined for all subjects as described previously (14).…”

Section: Methodsmentioning

confidence: 99%

Oxidative Modifications and Aggregation of Cu,Zn-Superoxide Dismutase Associated with Alzheimer and Parkinson Diseases

Choi

Rees

Weintraub

et al. 2005

Journal of Biological Chemistry

268

196

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Although oxidative stress has been strongly implicated in the pathogenesis of Alzheimer disease (AD) and Parkinson disease (PD), the identities of specific protein targets of oxidative damage remain largely unknown. Here, we report that Cu,Zn-superoxide dismutase (SOD1), a key antioxidant enzyme whose mutations have been linked to autosomal dominant neurodegenerative disorder familial amyotrophic lateral sclerosis (ALS), is a major target of oxidative damage in AD and PD brains. By using a combination of twodimensional gel electrophoresis, immunoblot analysis, and mass spectrometry, we have identified four human brain SOD1 isoforms with pI values of 6.3, 6.0, 5.7, and 5.0, respectively. Of these, the SOD1 pI 6.0 isoform is oxidatively modified by carbonylation, and the pI 5.0 isoform is selectively accumulated in AD and PD. Moreover, Cys-146, a cysteine residue of SOD1 that is mutated in familial ALS, is oxidized to cysteic acid in AD and PD brains. Quantitative Western blot analyses demonstrate that the total level of SOD1 isoforms is significantly increased in both AD and PD. Furthermore, immunohistochemical and double fluorescence labeling studies reveal that SOD1 forms proteinaceous aggregates that are associated with amyloid senile plaques and neurofibrillary tangles in AD brains. These findings implicate, for the first time, the involvement of oxidative damage to SOD1 in the pathogenesis of sporadic AD and PD. This work suggests that AD, PD, and ALS may share a common or overlapping pathogenic mechanism(s) that could potentially be targeted by similar therapeutic strategies.

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Alzheimer's disease with and without coexisting Parkinson's disease changes

Cited by 60 publications

References 2 publications

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation

Use of Standardized Uptake Value Ratios Decreases Interreader Variability of [18F] Florbetapir PET Brain Scan Interpretation

Oxidative Modifications and Down-regulation of Ubiquitin Carboxyl-terminal Hydrolase L1 Associated with Idiopathic Parkinson's and Alzheimer's Diseases

Oxidative Modifications and Aggregation of Cu,Zn-Superoxide Dismutase Associated with Alzheimer and Parkinson Diseases

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