Neuropsychological Profile of Parkin Mutation Carriers with and without Parkinson Disease: The CORE-PD Study.

The cognitive profile of early onset Parkinson's disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers. EOPD probands and their first-degree relatives who did not have Parkinson's disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N = 43) and without (N = 52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD. No significant differences in neuropsychological test performance were found between parkin carrier and noncarrier probands. Performance also did not differ between EOPD noncarriers and carrier subgroups (i.e., heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives. Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to noncarriers. The cognitive functioning of parkin carriers over time warrants further study.

A pilot study of gene/gene and gene/environment interactions in Alzheimer disease.

BACKGROUND: Although some genes associated with increased risk of Alzheimer Disease (AD) have been identified, few data exist related to gene/gene and gene/environment risk of AD. The purpose of this pilot study was to explore gene/gene and gene/environment associations in AD and to obtain data for sample size estimates for larger, more definitive studies of AD. METHODS: The effect of gene/gene and gene/environment interaction related to late onset Alzheimer Disease (LOAD) was investigated in 153 subjects with LOAD and 302 gender matched controls enrolled in the Personalized Medicine Research Project, a population-based bio-repository. Genetic risk factors examined included APOE, ACE, OLR1,and CYP46 genes, and environmental factors included smoking, total cholesterol, LDL, HDL, triglycerides, C-reactive protein, blood pressure, statin use, and body mass index. RESULTS: The mean age of the cases was 78.2 years and the mean age of the controls was 87.2 years. APOE4 was significantly associated with LOAD (OR=3.55, 95%CL=1.70, 7.45). Cases were significantly more likely to have ever smoked cigarettes during their life (49.3% versus 38.4%, p=0.03). The highest recorded blood pressure and pulse pressure measurements were significantly higher in the controls than the cases (all P<0.005). Although not statistically significant in this pilot study, the relationship of the following factors was associated in opposite directions with LOAD based on the presence of an APOE4 allele: obesity at the age of 50, ACE, OLR1, and CYP46. CONCLUSIONS: These pilot data suggest that gene/gene and gene/environment interactions may be important in LOAD, with APOE, a known risk factor for LOAD, affecting the relationship of ACE and OLR1 to LOAD. Replication with a larger sample size and in other racial/ethnic groups is warranted and the allele and risk factor frequencies will assist in choosing an appropriate sample size for a definitive study.

Alzheimer's disease or other dementia and medical care utilization.

PURPOSE: Recent findings on medical care utilization among people with Alzheimer's disease (AD) or other dementia (OD) are conflicting. A population-based case-control study was designed to determine if patients with clinically diagnosed AD or OD have different medical care utilization patterns before and after diagnosis compared to age-matched controls. METHODS: All community dwelling incident cases of AD (n = 240) or OD (n = 208) diagnosed between July 1, 1992 and June 30, 1997, and age-matched controls (n = 363) living in an enumerated population, were included. Medical care services, defined by Physicians' Current Procedural Terminology Codes, were assessed the year prior to diagnosis and up to five years after diagnosis of AD/OD. RESULTS: Prior to diagnosis, AD/OD cases had a significantly greater age-adjusted average number of medical services per year, 33 and 29, respectively, compared to 20 for controls (p = 0.0001 and p = 0.0002, respectively). These differences were significant after adjusting for age, gender, follow-back time, comorbidities, and insurance status. After diagnosis, AD/OD cases still had significantly greater age-adjusted average number of medical services per year (34 services and 37 services, respectively) compared to controls with 27 services (p = 0.0064 and p = 0.0006, respectively). After adjusting for confounding variables (particularly comorbid conditions), these differences were no longer significant. CONCLUSIONS: This research demonstrates that higher medical care utilization by patients with AD/OD after diagnosis is not due to dementia per se, but explained by their poorer physical health compared to controls. Greater utilization prior to diagnosis of AD/OD is most likely due to the search for a diagnosis for the person developing dementia.

Predictors of nursing home admission and/or death in incident Alzheimer's disease and other dementia cases compared to controls: a population-based study.

This research elucidates the risk of institutional care and/or death of patients with Alzheimer's disease (AD) or other dementia (OD) compared with noncases. Community dwelling incident cases of AD (n = 240) or OD (n = 208) and age-matched noncases (n = 363) living in an enumerated population were included. The adjusted hazard ratio (HR) of being admitted to a nursing home compared with controls was 5.44 (95% confidence interval, CI: 3.68,8.05) for AD cases and 5.08 (95% CI: 3.38, 7.63) for OD cases. The adjusted RR of death compared to controls was 1.90 (95% CI: 1.36, 2.65) for AD cases and 2.27 (95% CI: 1.62, 3.18) for OD cases. This is the only population-based study in the U.S. documenting that AD/OD increases the risk of death independent of comorbid conditions. AD/OD patients have more comorbidities and are at greater risk of entering a nursing home than to die during the follow-up, compared with those without these diagnoses.

Cognitive and motor function in long-duration PARKIN-associated Parkinson disease.

IMPORTANCE: Data on the long-term cognitive outcomes of patients with PARKIN-associated Parkinson disease (PD) are unknown but may be useful when counseling these patients. OBJECTIVE: Among patients with early-onset PD of long duration, we assessed cognitive and motor performances, comparing homozygotes and compound heterozygotes who carry 2 PARKIN mutations with noncarriers. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of 44 participants at 17 different movement disorder centers who were in the Consortium on Risk for Early-Onset PD study with a duration of PD greater than the median duration (>14 years): 4 homozygotes and 17 compound heterozygotes (hereafter referred to as carriers) and 23 noncarriers. MAIN OUTCOMES AND MEASURES: Unified Parkinson Disease Rating Scale Part III (UPDRS-III) and Clinical Dementia Rating scores and neuropsychological performance. Linear regression models were applied to assess the association between PARKIN mutation status and cognitive domain scores and UPDRS-III scores. Models were adjusted for age, education, disease duration, language, and levodopa equivalent daily dose. RESULTS: Carriers had an earlier age at onset of PD (P < .001) and were younger (P = .004) at time of examination than noncarriers. They performed better than noncarriers on the Mini-Mental State Examination (P = .010) and were more likely to receive lower scores on the Clinical Dementia Rating (P = .003). In multivariate analyses, carriers performed better than noncarriers on the UPDRS-III (P = .02) and on tests of attention (P = .03), memory (P = .03), and visuospatial (P = .02) cognitive domains. CONCLUSIONS AND RELEVANCE: In cross-sectional analyses, carriers demonstrated better cognitive and motor performance than did noncarriers with long disease duration, suggesting slower disease progression. A longitudinal follow-up study is required to confirm these findings.

Predictors of parkin mutations in early-onset Parkinson disease: the consortium on risk for early-onset Parkinson disease study.

BACKGROUND: Mutations in the parkin gene are the most common genetic cause of early-onset Parkinson disease (PD). Results from a multicenter study of patients with PD systematically sampled by age at onset have not been reported to date. OBJECTIVE: To determine risk factors associated with carrying parkin mutations. DESIGN: Cross-sectional observational study. SETTING: Thirteen movement disorders centers. PARTICIPANTS: A total of 956 patients with early-onset PD, defined as age at onset younger than 51 years. MAIN OUTCOME MEASURES: Presence of heterozygous, homozygous, or compound heterozygous parkin mutations. RESULTS: Using a previously validated interview, 14.7% of patients reported a family history of PD in a first-degree relative. Sixty-four patients (6.7%) had parkin mutations (3.9% heterozygous, 0.6% homozygous, and 2.2% compound heterozygous). Copy number variation was present in 52.3% of mutation carriers (31.6% of heterozygous, 83.3% of homozygous, and 81.0% of compound heterozygous). Deletions in exons 3 and 4 and 255delA were common among Hispanics (specifically Puerto Ricans). Younger age at onset (<40 years) (odds ratio [OR], 5.0; 95% confidence interval [CI], 2.8-8.8; P = .001), Hispanic race/ethnicity (OR compared with white non-Hispanic race/ethnicity, 2.7; 95% CI, 1.3-5.7; P = .009), and family history of PD in a first-degree relative (OR compared with noncarriers, 2.8; 95% CI, 1.5-5.3; P = .002) were associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous). Hispanic race/ethnicity was associated with carrying a heterozygous mutation (OR compared with white non-Hispanic race/ethnicity, 2.8; 95% CI, 1.1-7.2; P = .03) after adjustment for covariates. CONCLUSIONS: Age at onset, Hispanic race/ethnicity, and family history of PD are associated with carrying any parkin mutation (heterozygous, homozygous, or compound heterozygous) and heterozygous mutations alone. The increased odds of carrying a parkin mutation among Hispanics warrants further study.

Self-report of cognitive impairment and mini-mental state examination performance in PRKN, LRRK2, and GBA carriers with early onset Parkinson's disease.

While little is known about risk factors for cognitive impairment in early onset Parkinson disease (EOPD), postmortem studies have shown an association between dementia with Lewy bodies (DLB) and glucocerebrosidase (GBA) mutation. We compared Mini-Mental State Examination (MMSE) performance and self-reported cognitive impairment in 699 EOPD participants genotyped for mutations in parkin (PRKN), leucine-rich repeat kinase-2 (LRRK2), and GBA. Logistic regression was used to assess the association between reported cognitive impairment and MMSE score, as well as between GBA group membership and self-reported impairment and MMSE. GBA carriers reported more impairment, but MMSE performance did not differ among genetic groups. Detailed neuropsychological testing is required to explore the association between cognitive impairment and GBA mutations.

Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease.

OBJECTIVE: To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. DESIGN: Cross-sectional observational study. SETTING: Thirteen movement disorders centers. PARTICIPANTS: Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. MAIN OUTCOME MEASURES: LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. RESULTS: Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). CONCLUSION: Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.