Comparative study of Parkinson's disease and leucine-rich repeat kinase 2 p.G2019S parkinsonism.

Parkinson disease is a progressive neurodegenerative disease for which leucine-rich repeat kinase 2 (LRRK2 carriers) p.G2019S confers substantial genotypic and population attributable risk. With informed consent, we have recruited clinical data from 778 patients from Tunisia (of which 266 have LRRK2 parkinsonism) and 580 unaffected subjects. Motor, autonomic, and cognitive assessments in idiopathic Parkinson disease and LRRK2 patients were compared with regression models. The age-associated cumulative incidence of LRRK2 parkinsonism was also estimated using case-control and family-based designs. LRRK2 parkinsonism patients had slightly less gastrointestinal dysfunction and rapid eye movement sleep disorder. Overall, disease penetrance in LRRK2 carriers was 80% by 70 years but women become affected a median 5 years younger than men. Idiopathic Parkinson disease patients with younger age at diagnosis have slower disease progression. However, age at diagnoses does not predict progression in LRRK2 parkinsonism. LRRK2 p.G2019S mutation is a useful aid to diagnosis and modifiers of disease in LRRK2 parkinsonism may aid in developing therapeutic targets.

STX6 rs1411478 is not associated with increased risk of Parkinson's disease.

A variant in Syntaxin 6 (a soluble N-ethylmaleimide-sensitive factor attachment protein receptor STX6) (rs1411478) has been shown to be associated with progressive supranuclear palsy (PSP). Although Parkinson's disease (PD) and PSP are distinct neurodegenerative diseases, they share some clinical and genetic features. In this study, we evaluated STX6 genetic variability in PD susceptibility in ethnically matched case-control series from Canada, Norway, Taiwan and Tunisia and we evaluated the presence of pathogenic mutations within families. No pathogenic mutations were found in STX6. Similarly, statistical analysis of rs1411478 failed to identify differences in genotype or allelic frequencies between cases and controls. Our results do not support a role for STX6 in PD.

Outcomes of cognitively impaired not demented at 2 years in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.

BACKGROUND: People who are cognitively impaired not demented (CIND) can be at an increased risk for developing dementia, but little is known about the natural history of CIND in clinical settings. METHOD: We examined the 2-year outcome of CIND subjects in the Canadian Cohort Study of Cognitive Impairment and Related Dementias.CIND was diagnosed when at least one positive item was endorsed on the DSM-III-R dementia criteria, but not all criteria were met. CIND was further subclassified as: pre-Alzheimer's disease (pre-AD), vascular cognitive impairment (VCI-ND), non-AD degenerative, psychiatric, other neurologic, other medical conditions, mixed disorders and no etiology identified (not otherwise specified [NOS]). RESULT: Of 146 CIND patients with 2-year follow-up data available, 49 (34%) progressed to dementia, while 20 (14%) recovered to not cognitively impaired (NCI). Progressors were significantly older than stable CIND and reverters (p < 0.0001; mean age = 71.1, 64.3, and 59.1, respectively), and there were significantly (p = 0.001) more ApoE epsilon4 carriers among progressors (67%) than stable CIND (29%) and reverters (12%). Pre-AD CIND and VCI-ND had the highest rate of conversion to dementia (41.0 and 40.0%, respectively), while psychiatric CIND and CIND NOS had highest rate of recovery to NCI (20.0 and 30.0%, respectively). All conversions in pre-AD CIND were to 'probable AD'. CONCLUSION: CIND consists of a heterogeneous group of disorders that can be classified syndromically. Many subclassess - not just those with pre-AD CIND - are at high risk of progression to dementia, usually to Alzheimer's disease.