Pooled analysis of tobacco use and risk of Parkinson disease

CONTEXT: Epidemiologic studies have reported that cigarette smoking is inversely associated with Parkinson disease (PD). However, questions remain regarding the effect of age at smoking onset, time since quitting, and race/ethnicity that have not been addressed due to sample size constraints. This comprehensive assessment of the apparent reduced risk of PD associated with smoking may provide important leads for treatment and prevention. OBJECTIVE: To determine whether race/ethnicity, sex, education, age at diagnosis, and type of tobacco modify the observed effects of smoking on PD. DESIGN, SETTING, AND PARTICIPANTS: We conducted the first ever pooled analysis of PD combining individual-level data from 8 US case-control and 3 cohort studies (Nurses' Health Study, Health Professionals Follow-Up Study, and Honolulu-Asia Aging Study) conducted between 1960 and 2004. Case-control studies provided data for 2328 PD cases and 4113 controls matched by age, sex, and ethnicity; cohort studies contributed 488 cases and 4880 controls selected from age- and sex-matched risk sets. MAIN OUTCOME MEASURE: Incident PD. RESULTS: We confirmed inverse associations between PD and smoking and found these to be generally stronger in current compared with former smokers; the associations were stronger in cohort than in case-control studies. We observed inverse trends with pack-years smoked at every age at onset except the very elderly (>75 years of age), and the reduction of risk lessened with years since quitting smoking. The risk reductions we observed for white and Asian patients were not seen in Hispanic and African American patients. We also found an inverse association both for smoking cigars and/or pipes and for chewing tobacco in male subjects. CONCLUSIONS: Our data support a dose-dependent reduction of PD risk associated with cigarette smoking and potentially with other types of tobacco use. Importantly, effects seemed not to be influenced by sex or education. Differences observed by race and age at diagnosis warrant further study.     

Survival of Parkinson's disease patients in a large prospective cohort of male health professionals.

Parkinson's disease (PD) patients have higher mortality than individuals without PD. However, most of the previous studies were based on prevalent cases and few examined the potential effects of duration and smoking on the survival of PD patients. We compared the survival experience of 288 men with incident PD diagnosed between 1986 and 2000 with that of 51,012 men free of PD in the Health Professionals Follow-up Study. As of January 2002, 92 deaths occurred among PD cases and 8,485 among men without PD. After controlling for age, men with PD had 60% higher mortality than those without PD (95% CI: 1.3-2.0). PD mortality was strongly related to disease duration: compared with men without PD, the age-adjusted relative risk for PD patients was 1.1 during the first 5 years from diagnosis, 2.3 from 5 to 10 years, and 3.5 after 10 years (P < 0.0001 for trend). As expected, cigarette smoking was strongly and positively associated with total mortality among men free of PD (comparing >30 pack-years vs. never smokers, relative risk, 2.0; P < 0.0001 for trend), but this association was not observed among PD patients (RR: 1.0; P = 0.95 for trend). This study confirms that PD patients have a higher mortality than individuals without PD and that the excess mortality increases with disease duration. However, smoking seems to impose little additional risk among PD patients in this large cohort of health professionals.     

A case-control study on cigarette,alcohol, and coffee consumption preceding Parkinson's disease

OBJECTIVE: To investigate the association between cigarette smoking, alcohol drinking, coffee consumption and Parkinson's disease (PD). METHODS: We selected subjects affected by idiopathic PD, with a Mini-Mental State Examination of > or =24, and controls matched 1 to 1 with cases by age (+/- 2 years) and sex. Controls were randomly selected from the resident list of the same municipality of residence of the cases. We assessed cigarette smoking, alcohol drinking, and coffee consumption preceding the onset of PD or the corresponding time for controls using a structured questionnaire, which also evaluated the duration and dose of exposure. Using conditional logistic regression analysis, we calculated adjusted OR and 95% CI. RESULTS: We interviewed 150 PD patients and 150 matched controls. Cigarette smoking (ever vs. never smokers OR = 0.66, 95% CI = 0.41-1.05, p = 0.08) did not show a statistically significant association with PD. We observed an inverse association between alcohol drinking (ever vs. never OR = 0.61, 95% CI = 0.39-0.97, p = 0.037) and coffee consumption (ever vs. never OR = 0.16, 95% CI 0.05-0.46, p = 0.0001) and PD. These associations remained significant after adjustment for other covariates: OR for ever vs. never alcohol consumption was 0.62 (95% CI = 0.43-0.89, p = 0.009) and that for coffee drinking 0.19 (95% CI = 0.07-0.52, p = 0.001). Heavy coffee consumption confirmed the inverse association between coffee and PD (more than 81 cup/year vs. none: OR = 0.20, 95% CI = 0.08-0.47, p < or = 0.0001). CONCLUSIONS: Consistent with previous studies, our results suggest an inverse association between coffee drinking, alcohol consumption and PD. The multiple inverse association observed may indicate a complex interaction between genetic and environmental factors.     

Cigarette smoking and Parkinson's disease: a case-control study in a population characterized by a high prevalence of pesticide exposure.

Epidemiological studies have been consistent in showing that cigarette smoking is inversely associated with Parkinson's disease (PD), whereas pesticide use is positively associated with PD. However, the relationship between PD and cigarette smoking remains poorly understood. Our objective was to study the relationship between cigarette smoking and PD in a population characterized by a high prevalence of pesticide exposure. This case-control study was carried out among subjects enrolled in the Mutualite Sociale Agricole, the French health insurance organization for workers connected to the agricultural world. We included 247 cases and 676 controls matched on age, sex, and region of residency. Information on smoking was obtained through in-person interviews. Pesticide exposure was assessed using a case-by-case expert evaluation procedure. We found an inverse relationship between ever cigarette smoking and PD (odds ratio [OR] = 0.6; 95% confidence interval [CI] = 0.4-0.9). The strength of this association increased with the number of pack-years. This relationship was present even when smoking was considered as long as 40 years before PD onset. An inverse association was also present among subjects professionally exposed to pesticides (OR = 0.5; 95% CI = 0.3-0.8) and was independent of the duration of exposure among men. We confirm the inverse association between cigarette smoking and PD in a population characterized by a high prevalence of professional pesticide exposure. The relationship between PD and cigarette smoking was not significantly modified or confounded by exposure to pesticides.     

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.     

Cigarette smoking in Parkinson's disease: Influence on disease progression

Previous studies have shown an inverse association between smoking and the prevalence of Parkinson's disease (PD), suggesting that smoking may induce a biological protection against nigral neuronal damage. In 1993, we examined the frequency of cigarette smokers among 239 patients with PD and two control groups. In addition, the progression of parkinsonism and other clinical features were followed prospectively in smoking and nonsmoking PD patients over an 8‐year period. Mortality in the two PD groups was also examined. We found a 50% higher prevalence of smokers in the control groups than in patients with PD. In contrast, during the follow‐up period, there were no significant differences in progression of parkinsonism, cognitive impairment, and mood in smoking and nonsmoking patients with PD. Mortality was also similar in the two groups. The lack of influence on disease progression may indicate that cigarette smoking does not have a major neuroprotective effect in patients with already diagnosed PD. © 2004 Movement Disorder Society     

Cognitive status of young and older cigarette smokers: data from the international brain database.

Previous studies that have examined the impact of cigarette smoking on cognition have revealed mixed results; some studies report no impact and others report detrimental effects, especially in older individuals. Few studies, however, have examined the effects of cigarette smoking on both young and old healthy individuals using highly robust and standardized methods of cognitive assessment. This study draws on an international database to contrast cognitive differences between younger and older individuals who regularly smoke cigarettes and non-smokers. Data were sampled from 1000 highly screened healthy individuals free of medical or psychiatric health complications. A cohort of 62 regular smokers (n = 45 < 45 years of age; n = 1745 years) with a Fagerstrom nicotine dependency score of 1 or more were identified and matched to a cohort of 62 healthy nonsmokers (n = 43 < 45 years; n = 1945 years) on demographic variables and estimated intelligence. Performances on cognitive measures of attention, reaction time, cognitive flexibility, psychomotor speed, and memory were considered for analysis. As a group, smokers performed more poorly than nonsmokers on one measure of executive function. A significant age and smoking status interaction was identified with older smokers performing more poorly than older nonsmokers and younger smokers on a measure of long-delayed recall of new information. Cigarette smoking is associated with isolated and subtle cognitive difficulties among very healthy individuals.     

The effect of apolipoprotein E epsilon4 in the relationships of smoking and drinking to cognitive function

OBJECTIVES: To investigate the joint effect of the apolipoprotein E epsilon4 (APOE epsilon4), smoking and drinking on cognitive performance in a population-based longitudinal study of elderly men. DESIGN AND SETTING: The NHLBI Twin Study, a longitudinal cardiovascular study of World War II, white, male veterans. PARTICIPANTS: A total of 589 male participants in the third cardiovascular examination of this panel and aged 59-69 when assessed for cognitive function. OUTCOME MEASURES: Cognitive function assessed by the Mini-Mental State Examination, the Digit Symbol Substitution Test, the Benton Visual Retention Test, APOE epsilon4 allele frequency and cardiovascular disease (CVD) health status. RESULTS: For the sample as a whole, after adjustment for age, education and CVD, smoking was significantly associated with poor cognitive function (odds ratio (OR) = 2.0, 95% confidence interval (CI) 1.2-3.2, in current smokers compared with never smokers), whereas light drinking (one or fewer drinks per day) showed a protective effect (OR = 0.6, 95% CI 0.4-0.9 compared with abstainers). Stratification by APOE epsilon4 indicated that the protective effect of light drinking was stronger and the harmful effect of smoking was weaker among APOE epsilon4 carriers than among noncarriers. CONCLUSIONS: These data suggest a possible mediating effect of the APOE epsilon4 allele in the relation of smoking and drinking to cognitive function in the elderly.     

The association of self-reported sleep duration, difficulty sleeping, and snoring with cognitive function in older women

We examined the association of sleep duration, snoring, and difficulty sleeping with cognitive function in a cohort of community-dwelling women. Women (n = 1844), aged 70 to 81 years at initial cognitive interview in 2000, are members of the Nurses' Health Study cohort. Women completed six tests of cognitive function encompassing general cognition, verbal memory, category fluency, and attention. We repeated the assessment 2 years later. We used linear regression models to obtain multivariate-adjusted mean differences in initial test performance, and in cognitive decline over time, across categories of sleep duration (< or =5,6,7,8,9+ hours/night), frequency of snoring (never, occasionally, regularly), and sleep difficulties (rarely/never, occasionally, regularly). In analyses of initial test performance, women sleeping < or =5 hours/night scored worse than women sleeping 7 hours/night (mean difference on global score combining all cognitive tests = 0.15 standard units, 95% CI: -0.28, -0.02). Women who regularly had difficulty falling or staying asleep scored 0.11 units lower on the global score (95% CI: -0.22, 0.01) compared with those who rarely had difficulty sleeping. These differences were equivalent to the mean differences in score observed between participants who were 4 to 5 years apart in age. We found no associations with snoring or with any of the sleep variables and cognitive decline over 2 years. Associations between sleep patterns and initial cognitive function may be clinically relevant given that diminished cognition is a risk factor for dementia. However, the lack of an association with prospective cognitive decline warrants further investigation.     

Environmental factors and Parkinson's disease: a case-control study in the Tuscany region of Italy

To date the aetiology of Parkinson's disease (PD) is unknown although both genetic susceptibility and environmental factors appear to play an important role in the development of the disease. Recent data have also indicated that chronic exposure to a common pesticide can reproduce the neurochemical, behavioral and neuropathological features of PD. The epidemiological studies previously carried on the prevalence of PD in population exposed to environmental factors have produced controversial results, probably because of different trial design and different analysis methods. A case–control retrospective study was conducted in a well-defined geographic area in Tuscany—Italy with the aim to identify environmental factors possibly related to PD. No significant difference between PD patients and control subjects was observed in time spent in rural or industrial residence, in well water drinking and in the exposure to herbicides and pesticides. A significant difference between patients with PD and controls was reported for cigarette smoking, controls resulting more likely cigarette smokers in comparison with PD patients. The present findings support the view of a protective effect of cigarette smoking and do not show any significant association between environmental factors and the risk of development of PD.     

Cigarette smoking and the incidence of Parkinson's disease in two prospective studies.

An inverse association between cigarette smoking and idiopathic Parkinson's disease has been reported in several retrospective studies, but prospective evidence is available only for men. We assessed the association between the incidence of Parkinson's disease and smoking in two large prospective cohort studies comprising men and women. New cases of Parkinson's disease were identified in the Nurses' Health Study for 1976-1996, and in the Health Professionals Follow-up Study for 1986-1996. Smoking history was assessed at baseline and updated on subsequent biennial questionnaires. In women, the age-adjusted rate ratios (95% confidence intervals) for Parkinson's disease relative to never-smokers were 0.7 (0.5, 1.0) for past smokers, and 0.4 (0.2, 0.7) for current smokers. In men, the age-adjusted rate ratios for Parkinson's disease relative to never-smokers were 0.5 (0.4, 0.7) for past smokers, and 0.3 (0.1, 0.8) for current smokers. In both cohorts, the strength of the association decreased with time since quitting (among past smokers), increased with number of cigarettes per day (among current smokers), and increased with pack-years of smoking. These prospective findings confirm that an inverse association between smoking and the incidence of Parkinson's disease exists in both men and women.     

Prospective study of phobic anxiety and risk of Parkinson's disease.

Anxiety disorders are common in Parkinson's disease (PD). However, the risk of PD among people with anxiety has not been examined in a prospective cohort study. We examined this relation prospectively within the Health Professionals Follow-Up Study, a cohort of US male health professionals. In 1988, anxiety was assessed using the Crown-Crisp phobic anxiety index in 35,815 men without PD, stroke, or cancer at baseline. There were 189 incident cases of PD during 12 years of follow-up. After adjusting for age, smoking, and caffeine intake, the relative risk of PD among men with the highest level of anxiety (Crown-Crisp index scores of 4 and above) was 1.5 (95% CI = 1.0-2.1; P-trend = 0.01) compared to men with the lowest level of anxiety. This positive association persisted after excluding cases of PD with onset in the first 2 years of follow-up. Use of anxiolytic medication was also associated with an elevated risk of PD (RR= 1.6; 95% CI = 0.9-3.1), but adjusting for this potential confounder did not materially affect the association between anxiety and risk of PD. Our results suggest that anxiety is a risk factor for PD. Whether this association is causal or the result of shared underlying biology remains a question.     

Dose-dependent protective effect of coffee, tea, and smoking in Parkinson's disease: a study in ethnic Chinese

INTRODUCTION: Few studies have examined the relationship of coffee and tea in Parkinson's disease (PD). The potential protective effect of coffee intake and risk of PD has not been studied in a Chinese population. There is a high prevalence of caffeine takers among Chinese in our population. OBJECTIVE: We undertook a case control study to examine the relationship between coffee and tea drinking, cigarette smoking, and other enviromental factors and risk of PD among ethnic Chinese in our population. METHODS AND RESULTS: 300 PD and 500 population controls were initially screened. Two hundred case control pairs matched for age, gender, and race were finally included in the analysis. Univariate analysis revealed significant association of PD with coffee drinking (p<0.0005), tea drinking (p=0.019), alcohol drinking (p=0.001), cigarette smoking (p<0.0005), and exposure to heavy metals (p=0.006). Conditional logistic regression analysis demonstrated that amount of coffee drunk (OR 0.787, 95%CI 0.664-0.932, p=0.006), amount of tea drunk (OR 0.724, 95%CI 0.559-0.937, p=0.014), number of cigarettes smoked (OR 0.384, 95%CI 0.204-0.722, p=0.003), history of heavy metal and toxin exposure (OR 11.837, 95%CI 1.075-130.366, p=0.044), and heart disease (OR 5.518, 95%CI 1.377-22.116, p=0.016) to be significant factors associated with PD. One unit of coffee and tea (3 cups/day for 10 years) would lead to a 22% and 28% risk reduction of PD. One unit of cigarette smoke (3 packs/day for 10 years) reduced the risk of PD by 62%. CONCLUSIONS: We demonstrated a dose-dependent protective effect of PD in coffee and tea drinkers and smokers in an ethnic Chinese population. A history of exposure to heavy metals increased the risk of PD, supporting the multifactorial etiologies of the disease.     

A registry-based, case–control investigation of Parkinson''s disease with and without cognitive impairment

In approximately 40% of the patients, Parkinson's disease (PD) is complicated by cognitive impairment. The objective of this study was to evaluate the impact of cognitive impairment on disease severity and motor function in idiopathic PD patients. Forty-one PD patients with cognitive impairment (PD-CI) (Mini-Mental State Examination < or =24) and 41 PD patients without cognitive impairment (PD-Control) matched for age at onset and duration of the disease were examined using the Unified Parkinson's Disease Rating Scale (UPDRS). PD patients with cognitive impairment had overall poorer motor function, worse rigidity (both axial and limb) and bradykinesia, as well as worse performance in activities of daily living compared with matched PD patients without cognitive impairment. This could either be attributed to a direct effect of cognitive impairment on parkinsonian symptoms or to decreased compliance of patients during clinical examination. PD patients should be routinely and carefully screened for dementia and caregivers should be aware of the effect of dementia on PD.     

The quality of life in Parkinson's disease.

The objective of this study was to examine the quality of life in patients with Parkinson's disease (PD) in a community-based sample (n = 228 patients) using a Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) as a measure. Associations to the variables age, age at onset, duration, clinical stage (Hoehn and Yahr), depression (Zung), and dementia (MMSE) were studied. Women scored significantly lower on five of the eight dimensions of SF-36. Depression, as measured in this study, was more common among parkinsonian women than men. Depression was the factor that was associated most significantly with the experienced quality of life, according to SF-36. With physical functioning, only the clinical stage had a more significant association than depression. To improve the quality of life in patients with PD, it is necessary to make every effort to recognize and relieve the depression of patients with PD.     

Side and type of motor symptom influence cognition in Parkinson's disease.

It is well known that many patients with Parkinson's disease experience neuropsychological decline. However, the nature and extent of mental status change varies widely, with some patients showing mild or no cognitive impairments and others exhibiting frank dementia. Research has shown that several clinical disease parameters may differentially correlate with patterns of neuropsychological dysfunction. The present study examined side and type of motor symptom at disease onset and their relationship to cognition in idiopathic Parkinson's disease (PD). We identified 58 patients who initially presented with one of the following symptom profiles: right-side tremor onset (RSO-T; n = 15), right-side bradykinesia/rigidity onset (n = 12), left-side tremor onset (n = 19), and left-side bradykinesia/rigidity onset (n = 12). There were no differences between groups in disease duration, overall mental status, education, or depression severity. We administered a battery of neuropsychological measures to the four PD subgroups and a group of matched control subjects (n = 40). MANCOVAs controlling for age revealed patients with RSO-T performed significantly better than the other three PD subgroups across the entire neuropsychological battery. Further, the RSO-T subgroup performed comparably to controls. In contrast, the other three PD subgroups showed widespread cognitive deficits. These findings suggest an intricate relationship between motor symptom and side of disease onset and it is the combination of these factors that may influence the disease course and extent of cognitive deterioration. Furthermore, patients who develop tremor on the right side of their body represent a distinct subgroup of PD patients who exhibit relative sparing of cognitive function.     

Poor metabolization of n-hexane in Parkinson's disease

Although genomic screening studies have identified several genes associated with Parkinson's disease (PD), there is evidence that environmental factors are also involved in the pathogenesis of the disease and that hydrocarbon-solvents may be one of them. The genetic component is less evident in late-onset PD. To assess whether age and PD may affect the catabolism of the hydrocarbon n-hexane, a two-part study was performed. In the first part the urinary levels of its main metabolites, 2,5-hexanedione and 2,5-dimethylpyrroles, were measured in 108 patients and 108 healthy controls, matched by age and sex. Metabolite urinary excretion was significantly reduced in PD patients as compared with controls and was inversely related to age in both groups. In the second part the same comparison was made between 24 non-smoking and 10 smoking patients, matched to controls, after smoking of a hydrocarbon-rich cigarette. In these subjects also n-hexane and 2,5-hexanedione blood levels were measured. There was no appreciable difference in n-hexane blood levels between patients and controls in non-smokers, whereas there was a significant increase in patients over controls in smokers (p < 0.01). 2,5-hexanedione blood levels were significantly lower in patients than in healthy controls, both in non-smokers and in smokers, but the reduction was more pronounced in smokers (−46.3 % versus −10.7 %). The same was true for 2,5-hexanedione and 2,5-dimethylpyrrole urinary levels. This study suggests that aging and PD may be associated with a reduction in the capacity to eliminate the hydrocarbon n-hexane. This metabolic alteration may play a role in the pathogenesis of PD. Received: 18 March 2002, Received in revised form: 9 October 2002, Accepted: 29 November 2002 Funding: Fondazione Grigioni per il Morbo di Parkinson Associazione Italiana Parkinsoniani. Correspondence to Gianni Pezzoli     

Gender difference in the interaction of smoking and monoamine oxidase B intron 13 genotype in Parkinson's disease

We tested for gender-specific interactions between smoking and genetic polymorphisms of monoamine oxidase B (MAO-B) intron 13 (G or A allele), monoamine oxidase A (MAO-A) EcoRV (Yor N allele), and dopamine D2 recepor (DRD2) Taq1B (B1 or B2 allele) in a case-control study of 186 incident idiopathic Parkinson's disease (PD) cases and 296 age- and gender-matched controls. The odds ratios (ORs) for PD risk for ever smokers versus never smokers were 0.27 (95% CI: 0.13-0.58) for men of genotype G, and 1.26 (0.60-2.63) for men of genotype A (interaction chi2 = 8.14, P = 0.004). In contrast, for women, the OR for ever smokers versus never smokers were 0.62 (95% CI: 0.25-1.34) and 0.64 (95% CI: 0.18-2.21) for women of genotype GG/GA and AA, respectively (interaction chi2 = 0.001, P = 0.975). No interactions were detected between smoking and either MAO-A EcoRV or DRD2 Taq1B genotypes. These results suggest that a strong gender difference exists with respect to the modifying effect of MAO-B genotype on the smoking association with PD.     

A 2-year follow-up study of cigarette smoking and risk of dementia

The report focused on investigating the relationship between cigarette smoking and dementia in elderly people through prospective studies. We did a 2-year follow-up study of elderly people. A total of 2820 participants aged 60 years old and over from six communities of Chongqing agreed to take part. Dementia was diagnosed with MMSE (Mini-Mental State Examination) and DSM-III-R (Diagnostic and Statistical Manual of Mental Disorders). Participants were classified as never smokers, past smokers, and current smokers. During follow-up, we recorded incident cases of dementia. The association of smoking and dementia was investigated using proportional hazards regression analysis. A total of 121 incident cases of dementia were detected, of which 84 (69%) were Alzheimer's disease, 17 (14%) were vascular dementia, and 21(17%) were other dementia. Compared with never smokers, current smokers had an increased risk of Alzheimer's disease (RR = 2.72; 95% CI = 1.63-5.42) and vascular dementia (RR = 1.98; 95% CI = 1.53-3.12) adjusting for age, sex, education, blood pressure, and alcohol intake. Compared with light smokers, the adjusted risk of Alzheimer's disease was significantly increased among smokers with a medium level of exposure (RR = 2.56; 95% CI = 1.65-5.52), with an even higher risk of Alzheimer's disease in the heavy smoking group (RR = 3.03; 95% CI = 1.25-4.02). Smoking was associated with the risk of dementia. This study suggests that both smoking status and amount is associated with dementia.