Do risk factors for Alzheimer's disease predict dementia in Parkinson's disease? An exploratory study

The extent to which concomitant Alzheimer's disease (AD) is etiologically related to the development of dementia in Parkinson's disease (PD) remains controversial. We explored the association of four risk factors associated with AD, including head injury, smoking, hypertension, and diabetes mellitus, with incident dementia in PD. A cohort of 180 nondemented PD patients from the Washington Heights community in northern Manhattan, New York, completed a risk factor questionnaire at baseline and was followed annually with neurological and neuropsychological evaluations. The association of baseline variables with incident dementia was analyzed by using Cox proportional hazards models. All analyses controlled for age at baseline, gender, years of education, duration of PD, and total Unified Parkinson's Disease Rating Scale (UPDRS) motor score at baseline. Of 180 patients (mean age, 71.0 +/- 10.3 years), 52 (29%) became demented during a mean follow-up period of 3.6 +/- 2.2 years. Head injury risk ratio ([RR] 0.9; 95% confidence interval [CI], 0.4-2.2; P = 0.9), hypertension (RR, 0.7; 95% CI, 0.4-1.4, P = 0.3), and diabetes mellitus (RR, 0.8; 95% CI, 0.3-2.3; P = 0.7) were not significantly associated with incident dementia in the Cox models. Patients who reported having ever smoked were at increased risk for the development of dementia compared with nonsmokers (RR, 2.0; 95% CI, 1.0-3.9; P = 0.05). Current smoking was significantly associated with incident dementia (RR, 4.5; 95% CI, 1.2-16.4; P = 0.02), whereas past smoking approached significance (RR, 1.9; 95% CI, 0.9-3.7; P = 0.07). Although an inverse association between smoking and PD has been reported in several studies, our study showed a positive association between smoking and dementia in the setting of PD. The association of smoking with incident dementia in PD deserves further study.     

Presence of an APOE4 allele results in significantly earlier onset of Parkinson's disease and a higher risk with dementia.

The epsilon4 allele of the apolipoprotein E gene (APOE4) has been consistently associated with a greater risk of Alzheimer's disease (AD) as well as an earlier onset of AD. It is possible that APOE4 may also play a role in the etiology of other neurodegenerative disorders, such as Parkinson's disease (PD). APOE genotype, age of onset, disease duration, smoking history, and dementia status were collected for families with PD, yielding 324 Caucasian families with complete information. Logistic regression employing one individual per family and including age of onset and disease duration as covariates demonstrated a significantly increased risk of dementia for those individuals having inherited at least one epsilon4 allele (OR=3.37; P=0.002). Survival analyses also demonstrated a significantly earlier age of onset for those subjects with at least one epsilon4 allele (59.7 years) as compared with those homozygous for the more common epsilon3 allele (62.4 years; P=0.009). Thus, consistent with previous studies, we find evidence that the presence of an epsilon4 allele results in significantly earlier onset of PD and a greater likelihood of dementia. It appears the similarities between PD and AD may be due to an overlap in the diseases' genetic etiology.     

Risk and incidence of dementia in a cohort of older subjects with Parkinson's disease in the United Kingdom.

To determine the incidence and possible risk factors for dementia in patients with clinically probable Parkinson's disease (PD), a cohort (n = 86) of nondemented patients over 65 years of age with PD fulfilling the PD Brain Bank clinical diagnostic criteria were determined from community records. A similarly aged group of control subjects (n = 102) were recruited from the same area. Both groups were assessed at baseline and approximately 4 years later for cognition, mood, and motor function (PD patients only). The presence and severity of cognitive impairments was based on subject and informant interview, neuropsychological assessment based on the Cambridge Cognitive Examination (CAMCOG) and the application of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). At 4 years, 51 (59%) of the PD and 72 (71%) of the control cohort were available for reassessment. Of the PD cohort, 18 (35.3%) had developed dementia and 5 (9.4%) had evidence of mild cognitive impairments. In the control group, 5 (7%) had developed dementia. The incidence of dementia per 1,000 person-years in the PD cohort was 107.1 (95% confidence interval [CI], 59.9-159.8) and in the control group was 17.9 (95% CI, 5.8-31.9). The relative risk of patients developing dementia was 5.1 times that of the controls (95% CI, 2.1-12.5). Increasing age, later age of onset of PD, longer duration of PD symptoms, the presence of hallucinations, and impairment of memory and language function were all predictive factors for the development of dementia (P < 0.05). Dementia was also found to be a significant predictor for institutional placement in the PD group. Compared with similarly aged controls, patients with clinically probable PD have a fivefold-increased risk of developing dementia. This finding has significant implications for successful clinical management of this condition.     

Onset of dementia is associated with age at menopause in women with Down's syndrome

Women with Down's syndrome experience early onset of both menopause and Alzheimer's disease. This timing provides an opportunity to examine the influence of endogenous estrogen deficiency, indicated by age at menopause, on risk of Alzheimer's disease. A community-based sample of 163 postmenopausal women with Down's syndrome, 40 to 60 years of age, was ascertained through the New York State Developmental Disability service system. Information from cognitive assessments, medical record review, neurological evaluation, and caregiver interviews was used to establish ages for onset of menopause and dementia. We used survival and multivariate regression analyses to determine the relation of age at menopause to age at onset of Alzheimer's disease, adjusting for age, level of mental retardation, body mass index, and history of hypothyroidism or depression. Women with early onset of menopause (46 years or younger) had earlier onset and increased risk of Alzheimer's disease (AD) compared with women with onset of menopause after 46 years (rate ratio, 2.7; 95% confidence interval [CI], 1.2-5.9). Demented women had higher mean serum sex hormone binding globulin levels than nondemented women (86.4 vs 56.6 nmol/L, p = 0.02), but similar levels of total estradiol, suggesting that bioavailable estradiol, rather than total estradiol, is associated with dementia. Our findings support the hypothesis that reductions in estrogens after menopause contribute to the cascade of pathological processes leading to AD.     

NOS2A and the modulating effect of cigarette smoking in Parkinson's disease

OBJECTIVE: Inducible nitric oxide synthase, a protein product of NOS2A, generates nitric oxide as a defense mechanism, but excessive levels threaten cellular survival. NOS2A is a candidate gene for Parkinson's disease (PD) that potentially interacts with cigarette smoking. We examined NOS2A for association with PD risk and age at onset (AAO) and for interaction with smoking. METHODS: We genotyped 13 NOS2A single nucleotide polymorphisms (SNPs) in 466 singleton families and in a validation set of 286 multiplex families. We tested allelic and haplotypic association using the association in the presence of linkage test, genotypic associations using the genotype pedigree disequilibrium test, AAO effects using the quantitative transmission disequilibrium test, and interactions using generalized estimating equations. RESULTS: Among the pooled earliest onset families, rs2255929 and rs1060826 generated significant allelic (p = 0.000059 and 0.0062, respectively) and genotypic (p = 0.0039 and 0.0014, respectively) associations with risk and AAO (p = 0.00070 and 0.0073, respectively); the two-SNP haplotype generated even stronger association with PD (p = 0.000013). Significant interactions with smoking (p = 0.0015 for rs 2255929 and p < 0.0001 for rs 1060826) were detected in a subset of the families; smoking was inversely associated with PD among risk allele noncarriers, but significance diminished among carriers. INTERPRETATION: Our findings support NOS2A as a genetic risk factor in PD, potentially by influencing AAO and by modifying the inverse association between PD and smoking.     

S18Y polymorphism in the UCH-L1 gene and Parkinson's disease: evidence for an age-dependent relationship.

We studied the relationship between Parkinson's disease (PD) and the S18Y polymorphism in the UCH-L1 gene and the effect on this relationship of age at onset, smoking, and pesticides. Patients requested free health coverage for PD to the Mutualité Sociale Agricole (MSA), the French health insurance organization for people whose work is related to agriculture. Controls requested reimbursement of health expenses to the MSA. A maximum of three controls were matched to each case. Analyses included participants with both parents born in Europe. There were no differences in S18Y genotypes between patients (n = 209; 67% SS, 32% SY, 1% YY) and controls (n = 488; 66% SS, 30% SY, 4% YY). The relationship between PD and S18Y was modified by age at onset (P = 0.03). The Y allele was inversely associated with PD for patients with onset before 61 years (odds ratio [OR] = 0.53; 95% confidence interval [CI], 0.29-0.99); there was no association for older patients (62-68 years: OR = 1.21; 95% CI, 0.67-2.20; >68 years: OR = 1.24; 95% CI, 0.67-2.31). Among patients, Y carriers had a later onset than noncarriers (P = 0.04). These findings were not modified or confounded by smoking and pesticides. In this community-based case-control study, carriers of the Y allele were at decreased risk of developing PD at a young age, independently of pesticides and smoking.     

Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies

BACKGROUND: A previous cross sectional study found over-representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD). AIMS: (1) To examine rates of cognitive and motor decline over two years in PD (n=40), PDD (n=42) and DLB (n=41) subjects, compared with age matched controls (n=41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype. RESULTS: Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non-demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE -4.5 and -3.9, respectively), compared with PD (-0.2) and controls (-0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (chi2=6.7, Fisher's exact test p<0.05). CONCLUSION: A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.     

Risk factors for dementia, depression and psychosis in long-standing Parkinson's disease

Summary. Objectives. To study the relationships between clinical features of Parkinson's disease (PD) and the development of dementia, depression or psychosis in patients with long-standing disease. Background. The natural history of dementia and depression in PD, and its relation to psychosis in long standing PD, are unclear. Method. 172 consecutive patients (99 men and 73 women, mean age at symptoms onset 58.3 ± 13.2 years) with 5 years or more of PD (mean symptom duration of 11.8 ± 5.6 years) were studied. Clinical data were collected during the last office visit through physical examination, detailed history, review of patient charts and outside documents. Dementia and depression were diagnosed according to DSM-IV criteria, while psychosis was diagnosed if hallucinations or delusions were present. Chi-square and t tests were used to compare the patient characteristics among those with vs. those without mental complications of the disease at different disease stages. Logistic regression was used for the comparison of associations between the presence of dementia or depression (dependent variable) and age at onset of PD, duration of PD and disease staging (explanatory variables). Results. The study population consisted of 45 patients at Hoehn & Yahr (H&Y) stage ≤2.5 (26%), 104 patients at stage 3 (60.5%) and 23 patients at H&Y stage 4–5 (13.5%). Sixty one patients (36%) had dementia, 55 patients had depression (33%) and 50 patients (27%) had psychosis. Dementia and depression were significantly associated with disease severity as reflected in the H&Y scale (P = 0.0003, Z = 3.59; P = 0.006, Z = 3.22, respectively). These associations were significant also for the older age of PD onset (≥59 years n = 89) subgroup (p = 0.001, Z = 3.2 for dementia and p = 0.02, Z = 2.9 for depression), but not for younger onset cases (<59 years n = 83). Dementia was significantly associated with older age of PD onset (β = 0.04, p = 0.009) while depression was inversely associated with age of PD onset (β = −0.04, p = 0.02). The presence of dementia was also significantly associated with depression (β = 1.49, p = 0.0006). Dementia and depression were found to be independent explanatory variables for the development of psychosis (logistic regression, odds ratio (OR) = 26.0, p < 0.0001; OR = 10.2, p < 0.0001, respectively). In patients with younger age of PD onset, depression more than dementia was strongly correlated with the appearance of psychosis. Conclusion. Dementia in PD was related to older age of symptoms onset and old age. Depression was associated with dementia or early age of PD onset. Depression seemed to contribute to the appearance of psychosis even more than dementia, especially in patients with younger age of symptoms onset. Received January 28, 1999; accepted June 30, 1999     

Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study

BACKGROUND: Few longitudinal studies of dementia in Parkinson disease (PD) have been reported, and the proportion of patients with PD who eventually develop dementia is unknown. OBJECTIVE: To examine the 8-year prevalence, characteristics, and risk factors of dementia in patients with PD. METHODS: Patients were recruited from an epidemiological study of PD in the county of Rogaland, Norway, using explicit criteria for PD. Subjects with cognitive impairment at disease onset were excluded. A semistructured caregiver-based interview, cognitive rating scales, and neuropsychological tests were used to diagnose dementia according to criteria from the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition at baseline and 4 and 8 years later. A population-based sample of 3295 subjects in the municipality of Odense, Denmark, was used as a comparison group and examined at baseline and after 2 and 5 years. RESULTS: We included 224 patients with PD (116 women). At baseline, 51 patients (26%) had dementia. Fifty-five patients died, and 10 refused follow-up without their dementia status known. Forty-three and 28 new cases of dementia were identified at the 4- and 8-year evaluations, respectively. The 4-year prevalence of dementia in PD was nearly 3 times higher than in the non-PD group. The 8-year prevalence in PD was 78.2% (95% confidence interval [CI], 71.1-84.0). Risk factors for dementia were hallucinations before baseline (odds ratio [OR] = 3.1; 95% CI, 1.6-6.2) and akinetic-dominant or mixed tremor/akinetic PD (OR = 3.3; 95% CI, 1.2-8.5). CONCLUSIONS: More than three quarters of this representative PD cohort developed dementia during the 8-year study period. Early hallucinations and akinetic-dominant PD were associated with an increased risk of dementia.     

Motor impairment in PD: relationship to incident dementia and age

OBJECTIVE: To analyze the relationship of specific motor impairment in idiopathic PD to incident dementia. BACKGROUND: The total Unified PD Rating Scale (UPDRS) motor score at baseline has been associated with an increased risk of developing dementia in PD. METHODS: A cohort of 214 nondemented community-dwelling patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of baseline motor impairment with incident dementia was analyzed using Cox proportional hazards models. Facial expression, tremor, rigidity, and bradykinesia were analyzed as part of subscore A (indicative of dopaminergic deficiency); speech and axial impairment were analyzed as part of subscore B (indicative of predominantly nondopaminergic deficiency). The correlation between the six motor domains and age was also analyzed. RESULTS: Of 173 patients followed for at least 1 year, 50 became demented according to the Diagnostic and Statistical Manual of Mental Disorders, revised 3rd edition (DSM III-R) criteria (mean follow-up, 3.6 +/- 2. 2 years). When both subscores A and B were entered into the Cox model, subscore B was associated with incident dementia (relative risk = 1.19; 95% CI, 1.09 to 1.30; p = 0.0001), in addition to gender, age, and education, whereas subscore A was not (relative risk = 1.03; 95% CI, 0.99 to 1.07; p = 0.19). Of the six motor domains, speech and bradykinesia were associated with incident dementia (p < 0.05), and axial impairment approached significance (p = 0.06). Only axial impairment was correlated with age (correlation coefficient = 0.32; p < 0.001). CONCLUSION: The findings suggest that motor impairment mediated predominantly by nondopaminergic systems is associated with incident dementia in PD. Axial impairment may be the result of a combined effect of the disease and the aging process.     

A population-based investigation of Parkinson's disease with and without dementia. Relationship to age and gender.

Because the prevalence of idiopathic Parkinson's disease (PD) with or without dementia remains controversial, we initiated a population-based investigation in the Washington Heights-Inwood section of New York, NY, so that nearly complete case ascertainment could be achieved. A "registry" was developed for the study, and we advertised in periodicals and on radio and television. Subjects, or their records, were examined by experienced neurologists, and most underwent a battery of neuropsychological tests specifically designed for assessment in this community. All data were reviewed by a team of clinicians to achieve a consensus diagnosis. The crude prevalence of idiopathic PD, with and without dementia, was 99.4 per 100,000, increasing from 2.3 per 100,000 for those younger than 50 years to 1144.9 per 100,000 for those aged 80 years and older. The crude prevalence for PD with dementia alone was 41.1 per 100,000 and also increased with age from zero for those younger than 50 years to 787.1 per 100,000 for those aged 80 years and older. Prevalence ratios were comparable with those of other published population-based studies in similar settings. After standardization, men had PD with and without dementia more frequently than did women. The major difference between patients with and without dementia was a later estimated age at onset of motor manifestations. We conclude that PD is a frequent disorder in the elderly population that affects men and whites more frequently than women and nonwhites. Moreover, dementia in patients with PD is more frequent than previously recognized and is strongly related to the age at onset of motor manifestations.     

Smoking and cognitive function in Parkinson's disease.

The risk of dementia among Parkinson's disease (PD) patients is greatly elevated compared to controls, yet little is known about determinants of cognitive function among PD patients. We assessed the relation between cigarette smoking prior to disease onset and later cognitive function among PD patients (n = 286) and age- and sex-matched controls (n = 1144) participating in the Nurses' Health Study and Health Professionals Follow-up Study. Both groups completed telephone-administered assessments of cognitive function. We used linear regression to calculate mean differences in cognitive test scores across smoking categories, adjusted for age, education, sex, age at onset of PD, and years since diagnosis. PD patients scored significantly worse on all tests than their matched controls. In analyses only among PD cases, but not among controls, current smokers at PD onset scored worse than never smokers on the Telephone Interview for Cognitive Status (difference = -0.82, 95% CI: -1.33, -0.30, P = 0.002) as well as on a global score combining results of all tests (difference = -0.36, 95% CI: -0.72, 0.01, P = 0.06). This difference was equivalent to the difference in global score observed among controls approximately 10 years apart in age. Analyses of pack-years of smoking prior to disease onset gave similar results. These findings, nested in prospective cohort studies, suggest that cigarette smoking prior to disease onset is associated with worse cognitive function in PD.     

Risk of cognitive impairment or dementia in relatives of patients with Parkinson disease

BACKGROUND: The evidence for increased risk of dementia in relatives of patients with Parkinson disease (PD) remains conflicting. OBJECTIVE: To study the risk of cognitive impairment or dementia in first-degree relatives of patients with PD. Design, Setting, and PARTICIPANTS: We conducted a historical cohort study of 1019 first-degree relatives of 162 patients with PD and of 858 relatives of 147 matched controls representative of the population of Olmsted County, Minnesota. In addition, we studied 2716 first-degree relatives of 411 patients with PD referred to Mayo Clinic. MAIN OUTCOME MEASURES: We administered via telephone a cognitive test directly to relatives or a dementia questionnaire to proxies. For relatives reported by proxies to have dementia, we obtained copies of their medical records to confirm the diagnosis. We also obtained dementia information from a medical records-linkage system. RESULTS: In the overall population-based sample, the risk of cognitive impairment or dementia was increased in relatives of patients with PD compared with relatives of controls (hazard ratio, 1.37; 95% confidence interval, 1.03-1.81; P = .03) and was particularly increased in relatives of patients with onset of PD at age 66 years or younger (youngest tertile; hazard ratio, 1.73; 95% confidence interval, 1.21-2.46; P = .003). The findings were consistent in several sensitivity analyses. In the referral-based sample, the risk of cognitive impairment or dementia in relatives increased with younger age at onset of PD but did not vary by other clinical characteristics. CONCLUSION: Cognitive impairment or dementia may share familial susceptibility factors with PD (genetic or nongenetic).     

Memory and executive function impairment predict dementia in Parkinson's disease.

We analyzed the association of neuropsychological test impairment at baseline with the development of dementia in idiopathic Parkinson's disease (PD) patients. A cohort of nondemented PD patients from northern Manhattan, NY was followed annually with neurological and neuropsychological evaluations. The neuropsychological battery included tests of verbal and nonverbal memory, orientation, visuospatial ability, language, and abstract reasoning. The association of baseline neuropsychological tests scores with incident dementia was analyzed using Cox proportional hazards models. The analysis controlled for age, gender, education, duration of PD, and the total Unified Parkinson's Disease Rating Scale motor score at baseline. Forty-five out of 164 patients (27%) became demented during a mean follow-up of 3.7 +/- 2.3 years. Four neuropsychological test scores were significantly associated with incident dementia in the Cox model: total immediate recall (RR: 0.92, 95% CI: 0.87-0.97, P = 0.001) and delayed recall (RR: 0.73, 95% CI: 0.59-0.91, P = 0.005) of the Selective Reminding Test (SRT), letter fluency (RR: 0.87, 95% CI: 0.77-0.99, P = 0.03), and Identities and Oddities of the Mattis Dementia Rating Scale (RR: 0.85, 95% CI: 0.73-0.98, P = 0.03). When the analysis was performed excluding patients with a clinical dementia rating of 0.5 (questionable dementia) at baseline evaluation, total immediate recall and delayed recall were still predictive of dementia in PD. Our results indicate that impairment in verbal memory and executive function are associated with the development of dementia in patients with PD.     

The association of incident dementia with mortality in PD

OBJECTIVE: To evaluate the association of incident dementia with mortality in a cohort of patients with idiopathic PD who were nondemented at baseline evaluation, controlling for extrapyramidal sign (EPS) severity at each study visit. BACKGROUND: The development of dementia has been associated with reduced survival in PD. Because EPS severity is associated with both dementia and mortality in PD, the association of dementia with mortality may be confounded by disease severity. METHODS: A cohort of patients with PD was followed annually with neurologic and neuropsychological evaluations. The association of incident dementia and the total Unified PD Rating Scale (UPDRS) motor score with mortality in PD was examined using Cox proportional hazards models with time-dependent covariates. All analyses were adjusted for age at baseline, sex, years of education, ethnicity, and duration of PD. RESULTS: Of 180 PD patients, 41 (22.8%) died during a mean follow-up period of 3.9 +/- 2.2 years. Among those who died during the study period, 48.8% (20 of 41) became demented during follow-up, as compared to 23.0% (32 of 139) of those who remained alive. Both incident dementia (RR: 2.2, 95% CI: 1.1 to 4.5, p = 0.04) and the total UPDRS motor score at each study visit (RR: 1.04, 95% CI: 1.02 to 1.07, p = 0.001) were associated with mortality in PD when included in the same Cox model. CONCLUSIONS: Incident dementia has an independent effect on mortality when controlling for EPS severity. The development of dementia is associated with a twofold increased mortality risk in PD.     

Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects

OBJECTIVE: The authors conducted a prospective study of neurodegenerative and vascular dementia in Belgium. Strict diagnostic inclusion criteria were used to include well defined patients and controls. The results of apolipoprotein E (APOE) genotype effect on risk and clinical characteristics are presented. METHODS: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12). RESULTS: The APOE allele frequencies of this Belgian control population (epsilon 2: 6.9%; epsilon 3: 76.2%; epsilon 4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE epsilon 4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE epsilon 3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE epsilon 2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE epsilon 4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of epsilon 4 alleles in MCI and mixed dementia patients. CONCLUSIONS: This study confirmed the risk association between APOE epsilon 4 and AD. The observation that APOE epsilon 4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE epsilon 4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.     

Risk of dementia in Parkinson's disease: a community-based, prospective study

OBJECTIVE: To calculate the incidence of and determine possible risk factors for dementia in PD. BACKGROUND: Dementia has important clinical consequences for patients with PD and their caregivers, but the incidence is unknown. METHODS: A population-based cohort of nondemented patients with PD (n = 171) from the county of Rogaland, Norway, was assessed at baseline and 4.2 years later with a comprehensive evaluation of motor, cognitive, and neuropsychiatric symptoms. The diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSM-III-R) criteria, based on interview of the patient and a caregiver, cognitive rating scales, and neuropsychologic tests. A representative sample of 3,062 nondemented elderly subjects without PD served as control group. RESULTS: Forty-three patients with PD were demented at follow-up evaluation, equivalent to an incidence rate of 95.3 per 1,000 person-years (95% CI, 68.2 to 122.0). The risk for the development of dementia in patients with PD relative to the control subjects after adjusting for age, sex, and education was 5.9 (95% CI, 3.9 to 9.1). Predictive factors at baseline for dementia in PD in addition to age were Hoehn & Yahr score >2 (OR, 3.4; 95% CI, 1.3 to 8.6) and Mini-Mental State Examination score < 29 (OR, 3.3; 95% CI, 1.3 to 8.2). CONCLUSIONS: Patients with PD have an almost sixfold increased risk for becoming demented compared with subjects without PD.     

Influence of leisure activity on the incidence of Alzheimer's disease.

OBJECTIVE: To determine whether leisure activities modify the risk for incident dementia. BACKGROUND: Although high educational and occupational attainments have been associated with reduced risk of incident dementia, the relation between leisure activities and dementia risk has not been adequately investigated. METHODS: A total of 1,772 nondemented individuals aged 65 years or older, living in northern Manhattan, New York, were identified and followed longitudinally in a community-based cohort incidence study. Subjects' leisure activities at baseline were assessed, annual examinations with the same standardized neurologic and neuropsychological measures were performed for up to 7 years (mean 2.9 years), and incident dementia was assessed as the main outcome measure. Cox proportional hazards models, adjusting for age, ethnic group, education, and occupation, were used to estimate the relative risk (RR) of incident dementia associated with high leisure activities. RESULTS: Of the 1,772 subjects, 207 became demented. The risk of dementia was decreased in subjects with high leisure activities (RR, 0.62; 95% CI 0.46 to 0.83). The association of high leisure with decreased RR of incident dementia was present even when baseline cognitive performance, health limitations interfering with desired leisure activities, cerebrovascular disease, and depression were considered. CONCLUSIONS: The data suggest that engagement in leisure activities may reduce the risk of incident dementia, possibly by providing a reserve that delays the onset of clinical manifestations of the disease.     

Association of alpha-synuclein Rep1 polymorphism and Parkinson's disease: influence of Rep1 on age at onset.

The alpha-synuclein Rep1 polymorphism was studied in patients and controls in an ethnic Greek population. There was an association of allele 2 with risk of Parkinson's disease (PD; adjusted odd ratio = 3.25; 95% CI = 1.80-5.87). Survival analyses (Cox proportional hazards models) were employed to explore the influence of genotypes on age at onset of PD. Age at onset of carriers of at least one Rep1 allele 2 was earlier (3.6 years) compared to noncarriers (adjusted hazard ratio = 2.21; 95% CI = 1.58-3.10). Kaplan-Meier analysis also supported a dosage effect of Rep1 allele 2 on age at onset. For Rep1 allele 1, there was neither association with risk of PD nor influence on age at onset. This is the first study showing an influence of Rep1 polymorphism on age at onset of PD.     

Fall-related brain injuries and the risk of dementia in elderly people: a population-based study.

Severe head injury in early adulthood may increase the risk of dementia in older age, but it is not known whether head injury in later life also increases the risk of dementia. A representative sample (82%) of persons aged 70 years or older with a Mini-Mental State Examination (MMSE) test score of > or =26 (n = 325) were followed-up for 9 years to record all their fall-related head injuries resulting in traumatic brain injury (TBI). At the end of the follow-up period, 152 persons (81% of the surviving population) were examined for clinical dementia, according to DSM-IV criteria. Eight persons sustained a TBI and 34 developed dementia. Brain injury was associated with younger age at detection of dementia even when adjusted for sex and educational status (low educational status significantly associated with dementia); age-specific hazard ratio (95% confidence interval) 2.80 (1.35-5.81). In a population scoring > or =28 points in the baseline MMSE an apolipoprotein E (ApoE) epsilon4 phenotype was also associated with younger age at the time of detecting dementia; 3.56 (1.35-9.34), and the effect of brain injury and ApoE epsilon4 phenotype was synergistic; 7.68 (2.32-25.3). We conclude that fall-related TBI predicts earlier onset of dementia and the effect is especially high amongst subjects who carry the ApoE epsilon4 allele.