PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-5 (5)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
Document Types
1.  Ataxin-2 repeat-length variation and neurodegeneration 
Human Molecular Genetics  2011;20(16):3207-3212.
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
doi:10.1093/hmg/ddr227
PMCID: PMC3140823  PMID: 21610160
2.  Clinical Characterization of a Kindred with a Novel Twelve Octapeptide Repeat Insertion in the Prion Protein Gene 
Archives of Neurology  2011;68(9):1165-1170.
Objective
To report the clinical, electroencephalographic, and neuroradiologic findings in a kindred with a novel insertion in the prion protein gene (PRNP).
Design
Clinical description of a kindred.
Setting
Mayo Clinic Alzheimer’s Disease Research Center (Rochester).
Subjects
Two pathologically-confirmed cases and their relatives.
Main outcome measures
Clinical features, electroencephalographic patterns, magnetic resonance imaging abnormalities, genetic analyses and neuropathological features.
Results
The proband presented with clinical and neuroimaging features of atypical frontotemporal dementia (FTD) and ataxia. Generalized tonic-clonic seizures developed later in her course, and electroencephalography revealed spike and wave discharges but no periodic sharp wave complexes. Her affected sister and father also exhibited FTD-like features, and both experienced generalized tonic-clonic seizures and gait ataxia late in their course. Genetic analyses in the proband identified a novel defect in PRNP with one mutated allele carrying a 288 base pair insertion (BPI) consisting of 12 octapeptide repeats. Neuropathologic examination of the sister and proband revealed PrP-positive plaques and widespread tau-positive tangles.
Conclusion
This kindred has a unique combination of clinical and neuropathologic features associated with the largest BPI identified to date in PRNP, and underscores the need to consider familial prion disease in the differential diagnosis of a familial FTD-like syndrome.
doi:10.1001/archneurol.2011.187
PMCID: PMC3326586  PMID: 21911696
frontotemporal dementia; FTD; nonfluent aphasia; Gerstmann–Straüssler–Scheinker syndrome (GSS); Creutzfeldt-Jakob disease (CJD); prion; PRNP
3.  Longitudinal Growth Modeling of Cognitive Aging and the APOE e4 Effect 
The New England journal of medicine  2009;361(3):255-263.
Objective
Age-related cognitive decline trajectories were compared in apolipoprotein E (APOE) e4 homozygotes (HMZ), heterozygotes (HTZ), and noncarriers (NC) in the absence of mild cognitive impairment (MCI) and Alzheimer’s dementia (AD).
Background
At how young an age memory decline diverges from that of noncarriers in healthy people with elevated genetic risk for late-onset AD due to APOE e4 is unknown.
Methods
Cognitively normal participants age 21-97 years were recruited with local ads, grouped using an APOE e4 enrichment paradigm, and had longitudinal neuropsychological testing. Anyone who developed MCI or dementia during followup was excluded. Acceleration of the rates of decline for predetermined cognitive measures were compared between APOE e4/4 HMZ, e3/4 HTZ, and e4 NC using a mixed model for longitudinal change with age.
Results
79 e4 HMZ, 238 HTZ and 498 NC were included. APOE e4 carriers were younger (mean 58.0 vs 61.4 years, p<0.001) and had more years of followup (5.3 v 4.7 years, p=0.01), with equivalent education (15.4 years) and gender (69% women). With accelerating declines beginning prior to age 60 in e4 carriers, longitudinal decline in memory in e4 carriers accelerated more than in NC (p=0.0253) with a possible e4 gene-dose effect (p=0.0231) in which longitudinal decline in e4 HMZ accelerated more than in NC (p=0.0087). Weaker similar effects were also found on a visuospatial and general mental status measure.
Conclusions
Age-related memory decline in APOE e4 carriers diverges from NC prior to age 60 and appears most severe in HMZ despite ongoing normal clinical status.
doi:10.1056/NEJMoa0809437
PMCID: PMC2928998  PMID: 19605830
4.  Assessment of Patient and Caregiver Experiences of Dementia-Related Symptoms: Development of the Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire 
Background
To provide preliminary validation data on a self- or informant-report multidimensional questionnaire of symptoms associated with neurodegenerative disorders.
Methods
Participants from 2 trials (n = 125), the Arizona APOE Cohort and the Arizona Alzheimer's Disease Center, completed the Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS) and other related measures.
Results
Measures of central tendency are provided for the sample as a whole and by cognitive status. Internal consistency of the MANS is excellent (α = 0.98). Factor analysis suggests 4 factors. Correlational analyses support the construct validity of the MANS with moderate to high (r = 0.54–0.87) correlations between the MANS and measures of mood, cognition and daily functioning.
Conclusion
Results provide initial support for the MANS as a brief measure that is a reliable and valid indicator of cognitive, personality, functional and motor symptoms potentially related to neurodegenerative etiologies. Further research with the MANS is warranted.
doi:10.1159/000203890
PMCID: PMC2743176  PMID: 19246911
Multidimensional questionnaire; Neurodegenerative disorders; Validation
5.  Assessment of Patient and Caregiver Experiences of Dementia-Related Symptoms: Development of the Multidimensional Assessment of Neurodegenerative Symptoms Questionnaire (MANS) 
Background
To provide preliminary validation data on a self- or informant-report multidimensional questionnaire of symptoms associated with neurodegenerative disorders.
Methods
Participants from two trials (N = 125), the Arizona APOE Cohort and the Arizona Alzheimer’s Disease Center (ADC) completed the MANS and other related measures.
Results
Measures of central tendency are provided for the sample as a whole and by cognitive status. Internal consistency of the MANS is excellent (alpha = .98). Factor analysis suggests four factors. Correlational analyses support the construct validity of the MANS with moderate to high (r = 0.54 – 0.87) correlations between the MANS and measures of mood, cognition, and daily functioning.
Conclusion
Results provide initial support for the MANS as a brief measure that is a reliable and valid indicator of cognitive, personality, functional, and motor symptoms potentially related to neurodegenerative etiologies. Further research with the MANS is warranted.
doi:10.1159/000203890
PMCID: PMC2743176  PMID: 19246911
Multidimensional questionnaire; neurodegenerative disorders; symptoms; validation

Results 1-5 (5)