Changes in insomnia subtypes in early Parkinson disease.

OBJECTIVE: To examine the development of factors associated with insomnia in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis. METHODS: One hundred eighty-two drug-naive patients with PD derived from a population-based incident cohort and 202 control participants were assessed for insomnia before treatment initiation and were repeatedly examined after 1, 3, and 5 years. Insomnia was diagnosed according to the Stavanger Sleepiness Questionnaire. The Parkinson's Disease Sleep Scale was used to differentiate sleep initiation problems from problems of sleep maintenance. Generalized estimating equation models were applied for statistical measures. RESULTS: The prevalence of insomnia in general was not higher in patients with PD compared to controls at the 5-year follow-up. There were changes in the prevalence of the different insomnia subtypes over the 5-year follow-up. The prevalence of solitary problems in sleep maintenance increased from 31% (n = 18) in the drug-naive patients at baseline to 49% (n = 29) after 1 year and were associated with the use of dopamine agonists and higher Montgomery-Åsberg Depression Rating Scale scores. The prevalence of solitary sleep initiation problems decreased continuously from 21% (n = 12) at baseline to 7.4% (n = 4) after 5 years; these were associated with less daytime sleepiness. CONCLUSIONS: The prevalence rates of the different insomnia subtypes changed notably in patients with early PD. The frequency of sleep maintenance problems increased, and these problems were associated with dopamine agonist use and depressive symptoms, while the total number of patients with insomnia remained stable. Our findings reflect the need for early individual assessments of insomnia subtypes and raise the possibility of intervention to reduce these symptoms in patients with early PD.

Development of excessive daytime sleepiness in early Parkinson disease.

OBJECTIVE: To examine the frequency, development, and risk factors of excessive daytime sleepiness (EDS) in a cohort of originally drug-naive patients with incident Parkinson disease (PD) during the first 5 years after diagnosis. METHODS: One hundred fifty-three drug-naive patients with early PD derived from a population-based incident cohort and 169 control participants were assessed for EDS and reevaluated after 1, 3, and 5 years on medication. EDS was diagnosed according to the Epworth Sleepiness Scale. Cutoff score above 10 was applied. Generalized estimating equation models for correlated data were used to examine associated and risk factors for EDS. RESULTS: Patients reported EDS more often than control participants at the time of diagnosis and during follow-up. The frequency of EDS in PD increased from 11.8% at baseline to 23.4% after 5 years. Associated factors were male sex, the use of dopamine agonists, and higher Montgomery-Åsberg Depression Rating Scale and Unified Parkinson's Disease Rating Scale-activities of daily living scores. Main risk factor for developing EDS was an increased Epworth Sleepiness Scale score at baseline. CONCLUSION: EDS is more frequent in PD even before treatment initiation compared with control participants and increases in occurrence with disease progression. The main risk factor for developing EDS with time is an early predisposition for sleepiness. In addition, the use of dopamine agonists was associated with the development of EDS. These findings necessitate caution in patients with PD and early increased sleep propensity and when using dopamine agonists.

The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease.

A rare variant in TREM2 (p.R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aß42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aß42 suggesting that TREM2's role in AD may involve tau dysfunction.

CSF Aß42 predicts early-onset dementia in Parkinson disease.

OBJECTIVE: To test in vivo the proposal from clinicopathologic studies that ß-amyloid (Aß) pathology shortens the time to dementia in Parkinson disease (PD), and to explore the utility of CSF Aß and related measures as early prognostic biomarkers of dementia in an incident PD cohort. METHODS: We assessed a population-based incident cohort of 104 patients with PD who underwent lumbar puncture at diagnosis. We analyzed CSF concentrations of Aß42, Aß40, and Aß38 using a multiplexed immunoassay with electrochemiluminescence (ECL) detection and levels of Aß42, total tau, and phosphorylated tau using ELISA. Patients were followed prospectively for 5 years. Dementia was diagnosed according to published criteria. RESULTS: CSF levels of Aß42 were significantly decreased in patients who developed dementia (n = 20, 19.2%) compared to those who did not (n = 84, 80.8%), as measured by ECL (-33%, p = 0.006) as well as ELISA (-36%, p < 0.001). No differences were observed for other markers. Low Aß42 values predicted a substantially increased risk for subsequent dementia at high sensitivity (≥ 85%), with hazard ratios of 9.9 (95% confidence interval 2.3-43.5, p = 0.002) for Aß42ECL <376 pg/mL and 7.6 (2.2-26.4, p = 0.001) for Aß42ELISA <443 pg/mL, after adjustment for baseline age and PD-mild cognitive impairment (MCI) status. Aß42 reductions tended to precede the onset of PD-MCI that progressed to dementia. CONCLUSIONS: These in vivo data support the role of Aß pathology in the etiology and highlight the potential utility of CSF Aß42 as an early prognostic biomarker of dementia associated with PD.

Mapping cortical atrophy in Parkinson's disease patients with dementia.

BACKGROUND: Cognitive impairment is very common in patients with Parkinson's disease (PD). Brain changes accompanying cognitive decline in PD are still not fully established. METHODS: We applied cortical pattern matching and cortical thickness analyses to the three-dimensional T1-weighted brain MRI scans of 14 age-matched cognitively normal elderly (NC), 12 cognitively normal PD (PDC), and 11 PD dementia (PDD) subjects. We used linear regression models to investigate the effect of diagnosis on cortical thickness. All maps were adjusted for multiple comparisons using permutation testing with a threshold p < 0.01. RESULTS: PDD showed significantly thinner bilateral sensorimotor, perisylvian, lateral parietal, as well as right posterior cingulate, parieto-occipital, inferior temporal and lateral frontal cortices relative to NC (left p(corrected) = 0.06, right p(corrected) = 0.009). PDD showed significantly thinner bilateral sensorimotor, right frontal and right parietal-occipital cortices relative to PDC (right p(corrected) = 0.05). The absolute difference in cortical thickness between PDD and the other diagnostic groups ranged from 3% to 19%. CONCLUSION: Our data shows that cognitive decline in PD is associated with cortical atrophy. PDD subjects have the most widespread gray matter atrophy suggesting more cortical involvement as PD patients progress to dementia.

Cerebrospinal fluid Aß levels correlate with structural brain changes in Parkinson's disease.

ParkWest is a large Norwegian multicenter study of newly diagnosed drug-naïve subjects with Parkinson's disease (PD). Cognitively normal PD subjects (PDCN) and PD subjects with mild cognitive impairment (PDMCI) from this cohort have significant hippocampal atrophy and ventricular enlargement, compared to normal controls. Here, we aimed to investigate whether the same structural changes are associated with cerebrospinal fluid (CSF) levels of amyloid beta (Aß)38 , Aß40 , Aß42 , total tau (t-tau), and phosphorylated tau (p-tau). We performed three-dimensional radial distance analyses of the hippocampi and lateral ventricles using the MRI data from ParkWest subjects who provided CSF at baseline. Our sample consisted of 73 PDCN and 18 PDMCI subjects. We found significant associations between levels of all three CSF Aß analytes and t-tau and lateral ventricular enlargement in the pooled sample. In the PDCN sample, all three amyloid analytes showed significant associations with the radial distance of the occipital and frontal horns of the lateral ventricles. CSF Aß38 and Aß42 showed negative associations, with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and a negative association with the occipital horns in PDMCI. CSF Aß levels in early PD correlate with ventricular enlargement, previously associated with PD dementia. Therefore, CSF and MRI markers may help identify PD patients at high risk for developing cognitive decline and dementia in the course of their illness. Contrary to Alzheimer's disease, we found no associations between CSF t-tau and p-tau and hippocampal atrophy.

The economic impact of cognitive impairment in Parkinson's disease.

BACKGROUND: We investigated to what extent cognitive impairment and dementia were related to the direct medical and nonmedical costs in Parkinson's disease. METHODS: Sixty-one patients with Parkinson's disease from a population-based cohort were assessed for motor and cognitive symptoms in 1993, 1997, and 2001. Data on use of health care and social services were collected. RESULTS: The costs of patients with dementia were 3.3 times higher (€34,980) than those of nondemented patients (€10,626) per year of survival. Institutional care was the largest cost factor, representing 67% of the costs. Cognitive functioning predicted direct costs by 29.4%. Cognitive decline was associated with increased costs, even in nondemented subjects. CONCLUSIONS: Our findings suggest that dementia has a substantial impact on direct costs in Parkinson's disease, mainly due to high costs for institutional care. In addition, there were indications that even patients with mild cognitive impairment have higher nonmedical costs.

Ventricular enlargement and mild cognitive impairment in early Parkinson's disease.

Mild cognitive impairment (MCI) may predict future development of dementia in Parkinson's disease (PD). We aimed to examine the extent of subcortical brain atrophy in patients with early PD with and without MCI compared to normal controls (NC). Participating in a population-based study were 43 early, drug-naïve PD patients and 41 NC. Eleven patients were classified with MCI (MCI PD) and 32 patients without (non-MCI PD). Volumetric segmentation of 3D-T1 weighted brain MRI was performed using FreeSurfer. Groups were compared applying MANCOVA corrected for total intracranial volume, age, and sex. Results showed that left inferior lateral ventricle and third ventricle volumes were significantly larger in MCI PD than in non-MCI PD and NC. Fourth ventricular size in MCI PD was significantly different from NC and highly correlated with memory performance in MCI PD patients. This suggests that cognitive dysfunction in early PD may be associated with ventricular enlargement.

Hippocampal, caudate, and ventricular changes in Parkinson's disease with and without dementia.

Parkinson's disease (PD) has been associated with mild cognitive impairment (PDMCI) and with dementia (PDD). Using radial distance mapping, we studied the 3D structural and volumetric differences between the hippocampi, caudates, and lateral ventricles in 20 cognitively normal elderly (NC), 12 cognitively normal PD (PDND), 8 PDMCI, and 15 PDD subjects and examined the associations between these structures and Unified Parkinson's Disease Rating Scale (UPDRS) Part III:motor subscale and Mini-Mental State Examination (MMSE) performance. There were no hippocampal differences between the groups. 3D caudate statistical maps demonstrated significant left medial and lateral and right medial atrophy in the PDD vs. NC, and right medial and lateral caudate atrophy in PDD vs. PDND. PDMCI showed trend-level significant left lateral caudate atrophy vs. NC. Both left and right ventricles were significantly larger in PDD relative to the NC and PDND with posterior (body/occipital horn) predominance. The magnitude of regionally significant between-group differences in radial distance ranged between 20-30% for caudate and 5-20% for ventricles. UPDRS Part III:motor subscale score correlated with ventricular enlargement. MMSE showed significant correlation with expansion of the posterior lateral ventricles and trend-level significant correlation with caudate head atrophy. Cognitive decline in PD is associated with anterior caudate atrophy and ventricular enlargement.

Gray matter correlations of cognition in incident Parkinson's disease.

We aimed to investigate whether mild cognitive impairment (MCI) in Parkinson's disease (PD) is characterized by region-specific gray matter (GM) atrophy and to explore correlations between GM and cognition in PD. Magnetic resonance images of 42 newly diagnosed PD patients (of which 11 had MCI) and 37 normal controls were analyzed using voxel-based morphometry. Analyses comparing groups showed no regional atrophy, and in patients there were no significant correlations between cognitive domain test performance and GM loss. In conclusion, GM atrophy does not seem to be a major feature of cognitive dysfunction in incident PD.

Brain atrophy and white matter hyperintensities in early Parkinson's disease(a).

The purpose of this research was to examine the extent of global brain atrophy and white matter hyperintensities (WMH) in early Parkinson's disease (PD) compared to normal controls (NC), to explore the relationship between the MRI variables and cognition in PD. In this multicenter study we included 155 PD patients (age 65.6 +/- 9.1 years, disease duration 26.7 +/- 19.9 months) and 101 age-matched NC. On 3D-T1-WI, we calculated normalized brain volumes using SIENAX software. WMH volumes were assessed semiautomatically. In PD patients, correlation and regression analyses investigated the association between atrophy and WMH outcomes and global, attention-executive, visuospatial, and memory cognitive functions. Regression analysis was controlled for age, education, depression score, motor severity, cerebrovascular risk, and sex. No significant MRI variable volume group differences were found. The models did not retain any of the imaging variables as significant predictors of cognitive impairment. There was no evidence of brain atrophy or higher WMH volume in PD compared to NC, and MRI volumetric measurements were not significant predictors of cognitive functions in PD patients. We conclude that global structural brain changes are not a major feature in patients with incident PD.

White matter hyperintensities do not impact cognitive function in patients with newly diagnosed Parkinson's disease.

The objective of this study was to investigate total volume and spatial distribution of white matter hyperintensities (WMH) in a large sample of newly diagnosed Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI) compared to normal controls (NC). Furthermore, we aimed to examine the impact of the WMH on attention-executive performance in PD. MCI is regarded as a pre-dementia stage. Studies on MCI have found WMH associated with reduced cognitive function, especially in the attention and executive domains. The present study included 163 incident, drug-naïve PD patients (66.2+/-9.1 years and disease duration 27.1+/-19.8 months) and 102 age-matched NC (65.7+/-9.4 years). Thirty (30) subjects in the PD sample presented MCI, whereas 133 did not. MCI was classified based on tests for memory, attention-executive and visuospatial function compared to the NC group, taking age, sex and education into consideration. WMH were outlined on FLAIR scans using a semi-automated technique. Total WMH volumes were compared between the 3 study groups, and spatial distribution of normalized WMH masks in each group were compared using voxel-wise probability maps. Regression analysis examined the possible impact of WMH on attention-executive scores in the PD group. Analysis showed that there were no significant differences between the 3 groups in total volume or spatial distribution of WMH. In addition there was no significant relationship between total volume or spatial distribution of WMH and attention-executive functions in PD. We conclude that in this PD cohort, cognitive impairment seems to be independent of WMH damage.

Cortical serotonin 1A receptor levels are associated with depression in patients with dementia with Lewy bodies and Parkinson's disease dementia.

BACKGROUND: Serotonin 1A receptors (5-HT(1A)) have not been studied in dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD) patients with depression. AIM: To examine 5-HT(1A) in DLB and PDD postmortem in relation to depression. METHODS: [(3)H]8-hydroxy-2-dipropylaminotetralin binding to 5-HT(1A) was determined in temporal cortex (Brodmann areas, BA20 and BA36) from 10 DLB patients, 17 PDD patients and 9 controls. RESULTS: 5-HT(1A) density was significantly higher in BA36 in combined DLB/PDD patients with depression, but was unaltered in BA20. CONCLUSION: Higher BA36 5-HT(1A) density in PDD and DLB patients than in control is dependent on whether the patient had experienced depression during life, not DLB/PDD diagnosis. A 5-HT(1A) antagonist adjuvant may improve treatment of depression in dementia.

Gray matter atrophy in Parkinson disease with dementia and dementia with Lewy bodies.

BACKGROUND: The nosologic relationship between dementia with Lewy bodies (DLB) and Parkinson disease with dementia (PDD) is continuously being debated. We conducted a study using voxel-based morphometry (VBM) to explore the pattern of cortical atrophy in DLB and PDD. METHODS: Seventy-four patients and healthy elderly were imaged (healthy elderly n = 20, PDD n = 15, DLB n = 18, and Alzheimer dementia [AD] n = 21).Three dimensional T1-weighted MRI were acquired, and images analyzed using VBM. The following diagnostic criteria were used: criteria proposed by the third report of the DLB Consortium for DLB, the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Diseases Association criteria for AD, and Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria for dementia in PDD. RESULTS: Overall dementia severity was similar in the dementia groups. We found more pronounced cortical atrophy in DLB than in PDD in the temporal, parietal, and occipital lobes. Patients with AD had reduced gray matter concentrations in the temporal lobes bilaterally, including the amygdala, compared to PDD. Compared to DLB, the AD group had temporal and frontal lobe atrophy. CONCLUSION: We found that despite a similar severity of dementia, patients with dementia with Lewy bodies (DLB) had more cortical atrophy than patients with Parkinson disease with dementia (PDD), indicating different brain substrates underlying dementia in the two syndromes. Together with previous studies reporting subtle clinical and neurobiologic differences between DLB and PDD, our findings support the hypothesis that PDD and DLB are not identical entities, but rather represent two subtypes of a spectrum of Lewy body disease.

A magnetic resonance imaging study of patients with Parkinson's disease with mild cognitive impairment and dementia using voxel-based morphometry.

BACKGROUND: Dementia is common in Parkinson's disease, but the underlying brain pathology is not yet fully understood. AIM: To examine the changes in the brain of patients with Parkinson's disease with mild cognitive impairment (MCI) and dementia, using structural magnetic resonance imaging. METHODS: Using voxel-based morphometry, the grey matter atrophy on brain images of patients with Parkinson's disease and dementia (PDD; n = 16) and Parkinson's disease without dementia (PDND; n = 20), and healthy elderly subjects (n = 20) was studied. In the PDND group, 12 subjects had normal cognitive status and 8 had MCI. Standardised rating scales for motor, cognitive and psychiatric symptoms were used. RESULTS: Widespread areas of cortical atrophy were found in patients with PDD compared with normal controls (in both temporal and frontal lobes and in the left parietal lobe). Grey matter reductions were found in frontal, parietal, limbic and temporal lobes in patients with PDD compared with those with PDND. In patients with PDND with MCI, areas of reduced grey matter in the left frontal and both temporal lobes were found. CONCLUSION: These findings show that dementia in Parkinson's disease is associated with structural neocortical changes in the brain, and that cognitive impairment in patients with PDND may be associated with structural changes in the brain. Further studies with larger groups of patients are needed to confirm these findings.

Visual rating of white matter hyperintensities in Parkinson's disease.

Dementia is a common complication of Parkinson's disease (PD), but the cause is incompletely understood. In previous studies, dementia has been associated with an increase in hyperintense lesions in the cerebral white matter. The aim of this study was to explore whether white matter hyperintensities (WMH) on cerebral magnetic resonance imaging (MRI) are associated with dementia in PD. For this study, 35 patients with PD, 16 with dementia (PDD) and 19 without (PDND), and 20 control subjects were recruited. MRI scans of patients and controls were rated for WMH, blind to diagnosis, using the Scheltens visual rating scale. Both bivariate and multivariate statistical analyses were carried out. Cerebrovascular risk factors, education, gender, or age were similar across groups. Compared with the PDND group, the PDD group had significantly higher level of WMH in the deep white matter and in the periventricular areas. WMH in the deep white matter was the only variable that was associated significantly with Mini-Mental State Examination score and explained 38% of the variance in the multivariate linear regression analysis. Our findings suggest that WMH in the deep white matter may contribute to dementia in PD.

Exclusion of PINK1 as candidate gene for the late-onset form of Parkinson's disease in two European populations.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recently, mutations in the PINK1 (PARK6) gene were shown to rarely cause autosomal-recessively transmitted, early-onset parkinsonism. In order to evaluate whether PINK1 contributes to the risk of common late-onset PD we analysed PINK1 sequence variations. A German (85 patients) and a Norwegian cohort (90 patients) suffering from late-onset PD were screened for mutations and single nucleotide polymorphisms (SNPs) in the PINK1 gene. Both cohorts consist of well-characterized patients presenting a positive family history of PD in approximately 17%. Investigations were performed by single strand conformation polymorphism (SSCP), denaturating high performance liquid chromatography (DHPLC) and sequencing analyses. SNP frequencies were compared by the chi2 test. RESULTS: Several common SNPs were identified in our cohorts, including a recently identified coding variant (Q115L) in exon 1. Genotyping of the Q115L variation did not reveal significant frequency differences between patients and controls. Pathogenic mutations in the PINK1 gene were not identified, neither in the German nor in the Norwegian cohort. CONCLUSION: Sequence variation in the PINK1 gene appears to play a marginal quantitative role in the pathogenesis of the late-onset form of PD, in German and Norwegian cohorts, if at all.

Disorders of motivation, sexual conduct, and sleep in Parkinson's disease.

Apathy and fatigue, sexual disturbances, mania, sleep disturbances, personality changes, pathologic gambling, and addiction to antiparkinson agents occur in patients with PD and may pose considerable stress on the patients themselves and their caregivers. With the exception of apathy and fatigue, little is known regarding the prevalence of these symptoms in patients with PD. The pathophysiologic mechanisms are unknown, although disturbances of the mesolimbic and mesocortical dopaminergic pathways are probably involved. Antiparkinsonian drugs or surgery seem to be the main etiologic factors for sexual disturbance, hypomania, addiction, and pathologic gambling, whereas hypodopaminergic states may contribute to symptoms such as apathy, fatigue, RBD, and possibly personality changes. Although some placebo-controlled trials have been published recently, no established treatments are currently available for these symptoms (85) (see Table 5-2), and thus future clinical trials are needed.

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

Twenty-two patients with Parkinson's disease drawn from a community-based study were followed prospectively until their deaths. Even though 18 patients had dementia, none fulfilled Braak and Braak or The National Institute on Aging and Ronald and Nancy Reagan Institute of the Alzheimer's Association, whereas all patients had limbic or neocortical Lewy body disease. The Lewy body score and Braak and Braak stage were significantly associated with the rate of cognitive decline, but only the Lewy body score was associated with the rate of cognitive decline in the univariate analyses. This study strongly suggests that Lewy body disease is the main substrate driving the progression of cognitive impairment in Parkinson's disease.

Neuroleptic sensitivity in Parkinson's disease and parkinsonian dementias.

BACKGROUND: Severe sensitivity to neuroleptic agents is a major clinical problem in dementia with Lewy bodies (DLB), but has not been determined in Parkinson's disease (PD) and PD with dementia (PDD). METHOD: Severe neuroleptic sensitivity reactions (NSRs) were evaluated according to an operationalized definition blind to clinical and neuropathologic diagnoses in prospectively studied patients exposed to neuroleptics from 2 centers. The study was conducted from June 1995 to May 2003. RESULTS: Ninety-four patients were included (15 with DLB, 36 with PDD, 26 with PD, 17 with Alzheimer's disease, all diagnosed with various operational criteria). Severe NSR only occurred in patients with Lewy body disease: DLB (8 [53%]), PDD (14 [39%]), and PD (7 [27%]), but did not occur in Alzheimer's disease (p = .006). Severe NSR was not associated with other clinical or demographic features. In DLB, severe NSR was not associated with neuropathologic indices (Consortium to Establish a Registry for Alzheimer's Disease staging, Braak staging, or cortical distribution of Lewy bodies). CONCLUSIONS: An operationalized evaluation of severe NSR blind to diagnosis confirmed the high prevalence in DLB and identified high frequencies in Parkinson's disease and PDD with important implications for clinical practice.