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Objective: To identify potential genetic modifiers contributing to the phenotypic variability that is detected in patients with repeat expansions in chromosome 9 open reading frame 72 ( C9ORF72 ), we investigated the frequency of these expansions in a cohort of 334 subjects previously found to carry mutations in genes known to be associated with a spectrum of neurodegenerative diseases. Methods: A 2-step protocol, with a fluorescent PCR and a repeat-primed PCR, was used to determine the presence of hexanucleotide expansions in C9ORF72 . For one double mutant, we performed Southern blots to assess expansion sizes, and immunohistochemistry to characterize neuropathology. Results: We detected C9ORF72 repeat expansions in 4 of 334 subjects (1.2% [or 1.8% of 217 families]). All these subjects had behavioral phenotypes and also harbored well-known pathogenic mutations in either progranulin ( GRN : p.C466LfsX46, p.R493X, p.C31LfsX35) or microtubule-associated protein tau ( MAPT : p.P301L). Southern blotting of one double mutant with a p.C466LfsX46 GRN mutation demonstrated a long repeat expansion in brain (>3,000 repeats), and immunohistochemistry showed mixed neuropathology with characteristics of both C9ORF72 expansions and GRN mutations. Conclusions: Our findings indicate that co-occurrence of 2 evidently pathogenic mutations could contribute to the pleiotropy that is detected in patients with C9ORF72 repeat expansions. These findings suggest that patients with known mutations should not be excluded from further studies, and that genetic counselors should be aware of this phenomenon when advising patients and their family members.

Objective: The present study characterizes the relationship between report of stroke symptoms (SS) or TIA and incident cognitive impairment in the large biracial cohort of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Methods: The REGARDS Study is a population-based, biracial, longitudinal cohort study that has enrolled 30,239 participants from the United States. Exclusion of those with baseline cognitive impairment, stroke before enrollment, or incomplete data resulted in a sample size of 23,830. Participants reported SS/TIA on the Questionnaire for Verifying Stroke-free Status at baseline and every 6 months during follow-up. Incident cognitive impairment was detected using the Six-item Screener, which was administered annually. Results: Logistic regression found significant association between report of SS/TIA and subsequent incident cognitive impairment. Among white participants, the odds ratio for incident cognitive impairment was 2.08 (95% confidence interval: 1.81, 2.39) for those reporting at least one SS/TIA compared with those reporting no SS/TIA. Among black participants, the odds ratio was 1.66 (95% confidence interval: 1.45, 1.89) using the same modeling. The magnitude of impact was largest among those with fewer traditional stroke risk factors, particularly among white participants. Conclusions: Report of SS/TIA showed a strong association with incident cognitive impairment and supports the use of the Questionnaire for Verifying Stroke-free Status as a quick, low-cost instrument to screen for people at increased risk of cognitive decline.

The dopamine agonists ropinirole and pramipexole exhibit highly specific affinity for the cerebral dopamine D3 receptor. Use of these medications in Parkinson’s disease has been complicated by the emergence of pathologic behavioral patterns such as hypersexuality, pathologic gambling, excessive hobbying, and other circumscribed obsessive-compulsive disorders of impulse control in people having no history of such disorders. These behavioral changes typically remit following discontinuation of the medication, further demonstrating a causal relationship. Expression of the D3 receptor is particularly rich within the limbic system, where it plays an important role in modulating the physiologic and emotional experience of novelty, reward, and risk assessment. Converging neuroanatomical, physiological, and behavioral science data suggest the high D3 affinity of these medications as the basis for these behavioral changes. These observations suggest the D3 receptor as a therapeutic target for obsessive-compulsive disorder and substance abuse, and improved understanding of D3 receptor function may aid drug design of future atypical antipsychotics.

Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from I to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer's disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateratized topography of degeneration across all affected individuals. (C) 2007 Elsevier Inc. All rights reserved.