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.     

Clinical diagnostic criteria for dementia associated with Parkinson's disease.

Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.     

Associations between family history of Parkinson's disease and dementia and risk of dementia in Parkinson's disease: A community-based, longitudinal study.

Dementia is common in patients with Parkinson's disease (PDD). The etiology of PDD is still unclear, but exciting advances have been made in discovering pathogenetic components in Parkinson's disease (PD), implicating the role of genetic factors. It is, however, still controversial whether genetic factors also contribute to the development of dementia in PD. Thus, we investigated the association between development of dementia and a positive family history of PD or dementia in a community-based study of PD in Rogaland County, Norway (n = 219). The patients were followed prospectively with neurological and neuropsychological assessments. Dementia was more common in patients with a strong family association of PD (first-degree relatives > second-degree relatives > no family history; P < 0.05). However, time to dementia did not differ between the two groups. No associations between dementia in PD and familial occurrence of dementia could be shown. Further studies with larger samples are needed to explore a possible relationship between a family history of PD and development of dementia in PD and its potential pathogenetic mechanisms.     

Long-term cognitive profile and incidence of dementia after STN-DBS in Parkinson's disease.

An effect of subthalamic nucleus deep brain stimulation (STN-DBS) on cognition has been suspected but long-term observations are lacking. The aim of this study was to evaluate the long-term cognitive profile and the incidence of dementia in a cohort of Parkinson's disease (PD) patients treated by STN-DBS. 57 consecutive patients were prospectively assessed by the mean of a neuropsychological battery over 3 years after surgery. Dementia (DSM-IV) and UPDRS I to IV were recorded. 24.5% of patients converted to dementia over 3 years (incidence of 89 of 1,000 per year). This group of patients cognitively continuously worsened over 3 years up to fulfilling dementia criteria (PDD). The rest of the cohort remained cognitively stable (PD) over the whole follow-up. Preoperative differences between PDD and PD included older age (69.2 +/- 5.8 years; 62.6 +/- 8 years), presence of hallucinations and poorer executive score (10.1 +/- 5.9; 5.5 +/- 4.4). The incidence of dementia over 3 years after STN-DBS is similar to the one reported in medically treated patients. The PDD presented preoperative risk factors of developing dementia similar to those described in medically treated patients. These observations suggest dementia being secondary to the natural evolution of PD rather than a direct effect of STN-DBS.     

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.     

A review of studies describing the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia

OBJECTIVE: To review the literature relating to the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia (PDD). METHOD: MEDLINE (1966--December 2004), PsychINFO (1972--December 2004), EMBASE (1980--December 2004), CINHAL (1982--December 2004), and the Cochrane Collaboration were searched in December 2004. RESULTS: Three controlled trials and seven open studies were identified. Efficacy was assessed in three key domains: cognitive, neuropsychiatric and parkinsonian symptoms. CONCLUSION: Cholinesterase inhibitors have a moderate effect against cognitive symptoms. There is no clear evidence of a noticeable clinical effect against neuropsychiatric symptoms. Tolerability including exacerbation of motor symptoms--in particular tremor--may limit the utility of cholinesterase inhibitors.     

Subtypes of mild cognitive impairment in Parkinson's disease: progression to dementia.

The aim of this study was to establish the rate of progression from mild cognitive impairment (MCI) to dementia in patients with Parkinson's disease (PD). PD patients without dementia were recruited in 1997 from an ongoing prospective epidemiological study. The assessment included neurological and psychiatric examinations, a clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria for dementia, and a battery of neuropsychological tests. PD was diagnosed according to established criteria, dementia was diagnosed according to the DSM-III-R criteria, and subtypes of MCI were classified according to modified Petersen's criteria. Seventy-two nondemented PD patients were included. A total of 34 were cognitively intact, whereas 38 were diagnosed with MCI (amnestic, n = 6; single nonmemory domain, n = 17; multiple domains slightly impaired, n = 15). Fifty-nine patients (82%) completed follow-up examination 4 years later, and 18 (62%) of the patients with MCI and 6 (20%) of the cognitively intact PD patients were demented (P = 0.001). Single domain nonmemory MCI and multiple domains slightly impaired MCI were associated with later development of dementia (P = 0.003; P = 0.04), whereas amnestic MCI subtype was not (P = 0.76). We conclude that patients with PD and MCI had a higher risk of developing dementia than cognitively intact PD patients, suggesting that MCI in PD is an early manifestation of dementia. However, these findings should be interpreted with caution due to the relatively small number of subjects included in this study.     

PDD-5S: A useful screening tool for Parkinson's disease dementia

IntroductionParkinson's disease dementia (PDD) contributes to poor quality of life and increases the mortality risk. Early detection and diagnosis of PDD are essential for clinical care.MethodsWe recruited patients with idiopathic Parkinson's disease (PD), who underwent clinical assessments and neuropsychological tests, at 12 teaching hospitals in Taiwan. Probable PDD was diagnosed according to the Movement Disorder Society Task Force clinical criteria. Using binary logistic regression, we selected significant items from an original 30-item informant questionnaire. We utilized these items, along with a simple cognitive test, to discriminate between PDD and nondemented PD (PD-ND).ResultsAmong the 265 PD patients (156 men, 109 women, mean age 71.9 ± 9.1 years), 102 and 163 patients were diagnosed with probable PDD and PD-ND, respectively. The mean education of participants was 8.8 ± 5.3 years, and the mean disease duration was 5.5 ± 5.4 years. When the patients fulfilled either of the following criteria: (1) a score ≥ 3 for the five endorsed screening questions, (2) a score of 1–2 for the five above screening questions combined with a score ≤ 10 items for category verbal fluency, the sensitivity and specificity of the PDD screening tool were 80.4% and 80.4%, respectively. The area under the receiver operating characteristic curve (AUC) was 0.804. We tested this screening tool in another 137 unrelated PD patients and the sensitivity, specificity, and AUC were 77.4%, 96.4%, and 0.869, respectively.ConclusionThe “PDD-5S” is a brief and useful screening tool for PDD.     

Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson's disease course

Mutations in the glucocerebrosidase gene are associated with Parkinson's disease and Lewy body dementia. However, whether these alterations have any effect on the clinical course of Parkinson's disease is not clear. The glucocerebrosidase coding region was fully sequenced in 225 Parkinson's disease patients, 17 pathologically confirmed Lewy body dementia patients, and 186 controls from Spain. Twenty-two Parkinson's disease patients (9.8%) and 2 Lewy body dementia patients (11.8%) carried mutations in the glucocerebrosidase gene, compared with only 1 control (0.5%); P = .016 and P = .021 for Parkinson's disease and Lewy body dementia, respectively. The N370S and the L444P mutations represented 50% of the alterations. Two novel variants, L144V and S488T, and 7 previously described alterations were also found. Alterations in glucocerebrosidase were associated with a significant risk of dementia during the clinical course of Parkinson's disease (age at onset, years of evolution, and sex-adjusted odds ratio, 5.8; P = .001). Mutation carriers did not show worse motor symptoms, had good response to L-dopa, and tended to present the intermediate parkinsonian phenotype. Our findings suggest that mutations in the glucocerebrosidase gene not only increase the risk of both Parkinson's disease and Lewy body dementia but also strongly influence the course of Parkinson's disease with respect to the appearance of dementia.     

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.     

Association between amantadine and the onset of dementia in Parkinson's disease.

The objective of this study is to compare the occurrence of dementia among Parkinson's disease (PD) patients treated with amantadine (AM group) with those never exposed to it (NoAM group). PD dementia shares neuroanatomical and biochemical similarities with Alzheimer's disease (AD). Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist has been shown to be beneficial in AD. Memantine is a dimethyl derivative of amantadine, which also possesses NMDA receptor blocking properties. We hypothesized that amantadine could have a beneficial effect on the occurrence of PD dementia. PD patients attending the Movement Disorders Clinics in Hillel Yaffe, Asaf Harofe Medical Centers (Israel) and Pisa (Italy) were included. Taking the onset of dementia as the endpoint, survival curves for AM and NoAM patients were estimated by the Kaplan-Meier method. The study population consisted of 593 patients (age, 69.5 +/- 9.9 years; PD duration, 9.2 +/- 6.0 years; 263 patients (44%) amantadine treated). The endpoint of dementia was reached by 116 patients (20%). PD duration until dementia was significantly longer for AM patients (9.1 +/- 5.7 years) than for NoAM patients (5.9 +/- 4.6 years, P = 0.006). The duration of amantadine exposure positively correlated with PD duration until dementia (P = 0.0001). Survival analysis, taking dementia onset as endpoint, showed slower mental decline in AM patients (Log rank P = 0.0049, Wilcoxon P = 0.0024). Mini-Mental State Examination scores were significantly higher for AM patients than for the NoAM group (P = 0.01). Age of PD onset also significantly influenced the duration of PD until dementia. Amantadine use may delay the onset of dementia in PD patients and may attenuate its severity.     

Brain atrophy rates in Parkinson's disease with and without dementia using serial magnetic resonance imaging.

Increased rates of brain atrophy are seen in Alzheimer's disease, but whether rates are similarly increased in other dementias such as Parkinson's disease dementia (PDD) has not been well examined. We determined the rates of brain atrophy using serial magnetic resonance imaging (MRI) in PDD and compared this finding to rates seen in cognitively intact Parkinson's disease (PD) patients and age-matched control subjects. Thirty-one patients (PD = 18, PDD = 13) and 24 age-matched controls underwent serial volumetric 1.5 T MRI scans, approximately 1 year apart. Baseline and repeat scans were registered and quantification of the brain boundary shift integral was used to determine whole-brain atrophy rates. Rates of brain atrophy were significantly increased in PDD (1.12 +/- 0.98%/year) compared to PD (0.31 +/- 0.69%/year; P = 0.018) and control subjects (0.34 +/- 0.76%/year; P = 0.015). There were no differences in atrophy rates between controls and PD (P = 0.79). No correlations between increased atrophy rates and age or dementia severity (Mini-Mental State Examination score) were observed. Serial MRI may be a useful tool for monitoring disease progression in PDD and further studies should investigate its utility for early diagnosis.     

Prevalence and relation of dementia to various factors in Parkinson's disease

Aims: Parkinson's disease is a chronic neurodegenerative disorder characterized by bradykinesia, rigidity, and resting tremor. Dementia, among its non‐motor symptoms, is a debilitating complication affecting intellectual functioning. The aim of the present study was to determine the prevalence of dementia in Parkinson's disease and its relation to age, gender and stage of the disease. Methods: A retrospective chart analysis was performed on Parkinson's disease patients seen in a community‐based Parkinson's disease and movement disorder clinic between 2005 and 2010. Results: A total of 310 patients were included in this survey, among whom 61 patients (19.7%) with Parkinson's disease met the criteria for dementia. Age was found to be a significant factor in developing dementia, with 90% of patients with dementia aged ≥70. Gender, however, was not correlated with dementia in Parkinson's disease. On analysis of stage at which dementia developed, progression of the disease was positively correlated with prevalence of dementia. Conclusions: As age increases, the chances of developing dementia increase. Dementia, contrarily, is not selective between genders. The likelihood of developing dementia increases as the stage of disease advances. Further research is required in order to understand underlying mechanisms of dementia in Parkinson's disease.     

Cognitive profiles of individual patients with Parkinson's disease and dementia: comparison with dementia with lewy bodies and Alzheimer's disease.

We describe the pattern of cognitive profiles within a community-based sample of patients with Parkinson's disease (PD) and dementia (PDD) using cluster analyses, and compare the results with data from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Fifty patients with PDD and 39 with AD from Stavanger, Norway, and 62 patients with DLB from San Diego, CA, USA were diagnosed by either standardized clinical procedures or criteria (all PDD and all AD cases) or necropsy (all DLB cases). Four subgroups were identified: two subgroups with a subcortical cognitive profile (one with mild and one with moderate dementia severity), one subgroup with global impairment and severe dementia, and one subgroup with a cortical cognitive profile and moderate dementia. Of the patients with PDD and with DLB, 56% and 55%, respectively, had a subcortical cognitive profile, compared with only 33% of the AD patients. Conversely, 30% of the patients with PDD and 26% of those with DLB had a cortical cognitive profile, compared with 67% of the patients with AD. These findings suggest that in some patients with PDD, frontosubcortical changes are the main contributing factor to dementia, whereas in other patients, cortical and hippocampal changes are more important.     

SCOPA‐cognition cutoff value for detection of Parkinson's disease dementia

The SCOPA‐Cognition is a reliable and valid test to evaluate cognitive functioning in Parkinson's disease and is widely used in clinical and research settings. Recently, the Movement Disorder Society introduced criteria for Parkinson's disease dementia. The objective of the present study was to use these criteria to determine SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. A total of 282 patients with Parkinson's disease were assessed with the SCOPA‐Cognition and the Movement Disorder Society's Parkinson's disease dementia criteria. From the 275 patients with a complete assessment of the dementia criteria, 12% (n = 32) fulfilled the criteria. Data from 268 patients with complete assessments of both the dementia criteria and the SCOPA‐Cognition were used to determine cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The area under the curve was 0.91 (95% confidence interval, 0.85–0.97), showing a strong association between the dementia criteria and the SCOPA‐Cognition. The cutoff for maximum accuracy was 22/23, based on the highest sum of sensitivity (0.80) and specificity (0.87), with positive and negative predictive values of 0.43 and 0.97, respectively. The optimal screening cutoff was 24/25, and the optimal diagnostic cutoff was 17/18. Using the recently published Parkinson's disease dementia criteria as a reference, the current study presents SCOPA‐Cognition cutoffs for maximum accuracy, screening, and diagnosing of Parkinson's disease dementia. The availability of SCOPA‐Cognition cutoffs for Parkinson's disease dementia may contribute to the scale's usefulness and promote its further use in both clinical and research settings. © 2011 Movement Disorder Society     

Extrapyramidal features in Parkinson's disease with and without dementia and dementia with Lewy bodies: A cross-sectional comparative study.

Risk factors predicting an increased risk of dementia in Parkinson's disease (PD) are not fully established. The dementia associated with PD (PDD) closely resembles dementia with Lewy bodies (DLB). Based upon a high frequency of non-dopaminergic mediated clinical features in DLB, we predicted that a motor subtype comprising postural instability and balance problems would be more common in PDD. We examined extrapyramidal, cognitive, and affective features in 38 PD, 43 PDD, and 26 DLB patients in a cross-sectional study design. Motor subtype was subdivided into postural-instability gait difficulty (PIGD) or tremor (TD) dominant. The PIGD-subtype was more common in PDD (88% of cases) and DLB (69% of cases) groups compared with the PD group (38% of cases), in which TD and PIGD sub-types were more equally represented (P < 0.001). Although the mean depression scores overall were modest, PDD patients scored significantly higher than PD, but not DLB patients (Cornell; P = 0.006, and Geriatric Depression scale, GDS-15; P = 0.001), while within the PD group, those patients with a PIGD subtype had greater depression scores than the TD subtype (GDS-15; P < 0.05). We conclude that non-dopaminergic motor features are frequent in PDD. Neurodegeneration within the cholinergic system is likely to mediate many of these motor problems, as well as playing a significant role in determining the neuropsychiatric symptomatology of both PDD and DLB.     

Osteoporosis in Parkinson's disease.

There are few studies of osteoporosis in Parkinson's disease (PD). We assessed the prevalence of osteoporosis in a PD clinic cohort. All subjects with a confirmed diagnosis of PD attending a clinic were invited to participate. All consenting subjects had bone density measured by dual energy X-ray absorptiometry scanning. Further data, including demography, disease duration, and disease severity, were collected. One hundred five subjects participated; median age was 75 (54-92) years. Fifty-one (49%) patients were men. Of the men: median T score, -1.3 (range, -4.7 to 3.8); median Z score, 0.0 (-3.2 to 4.7); diagnostic categories: osteoporosis, 20%; osteopenia, 41%; normal, 39%. Of the women: median T score -2.7 (-4.7 to 1.4); median Z score, -0.25 (-2.6 to 4.2); diagnostic categories: osteoporosis, 63%; osteopenia, 28%; and normal, 9%. Whole sample: osteoporosis, 42%; osteopenia, 34%; and normal, 24%. There were associations between age, depression, disease duration, and osteoporosis but not with disease severity. Female gender was an independent predictor of osteoporosis. The prevalence of osteoporosis/osteopenia is considerable in PD patients but does not exceed that of other people of similar age. Osteoporosis/osteopenia was present in almost all women of this age group with PD.     

Finding hope in the midst of despair: My decade with Parkinson's disease and Lewy body dementia

Living for 10 years with Parkinson's disease (PD) and Lewy body dementia (LBD) author Thomas B. Graboys, MD recounts the various losses — physical, emotional, social and intellectual — that ultimately add up to a loss of self inflicted by these progressive neurological diseases. No longer able to practice medicine, engage in athletics, or engage fully with his extended family, soon to include 11 grandchildren, Graboys nevertheless writes that there is one aspect of self PD and LBD cannot steal: the soul. © 2012 Movement Disorder Society     

The Sydney multicenter study of Parkinson's disease: The inevitability of dementia at 20 years

After 20 years follow‐up of newly diagnosed patients with Parkinson's disease (PD), 100 of 136 (74%) have died. The mortality rate fell in the first 3 years of treatment, then rose compared to the general population, the standardized mortality ratio from 15 to 20 years reaching 3.1. Drug induced dyskinesia and end of dose failure were experienced by most patients, but the main current problems relate to the non‐levodopa responsive features of the disease. Dementia is present in 83% of 20‐year survivors. Dementia correlates with increasing age and probably reflects an interplay of multiple pathologies. Seventeen people with dementia had postmortems. Eight had diffuse Lewy bodies as the only cause of dementia, while others had mixed neuropathology. Only one person lives independently and 48% are in nursing homes. Excessive daytime sleepiness is noted in 70%, falls have occurred in 87%, freezing in 81%, fractures in 35%, symptomatic postural hypotension in 48%, urinary incontinence in 71%, moderate dysarthria in 81%, choking in 48%, and hallucinations in 74%. The challenge is to understand the cellular mechanisms underlying the diverse features of advanced PD that go far beyond a lack of dopamine. © 2008 Movement Disorder Society