Detecting the Cognitive Prodrome of Dementia in Parkinson's Disease.

BACKGROUND: More than 75% of Parkinson's disease (PD) patients will develop dementia. Previous studies on the cognitive predictors of dementia in PD had some methodological limitations and the cognitive tests identified as good predictors vary greatly. OBJECTIVE: This prospective cohort study aims to identify the optimal cognitive predictors of dementia in PD using complementary statistical methods. METHODS: Eighty PD patients without dementia underwent polysomnographic recording, a neurological examination, and a complete neuropsychological assessment at baseline. They were then followed for a mean of 4.3 years. Baseline group comparisons and survival analyses were used to identify optimal cognitive predictors. Moreover, patients who developed dementia were pair-matched at baseline according to age, sex, and education to healthy controls (2 : 1), and receiver operating characteristic curves were calculated for cognitive tests. RESULTS: At follow-up, 23 patients (29%) developed dementia. PD patients who developed dementia had poorer baseline performance and a higher proportion of clinically impaired performance on several cognitive tests. Impaired baseline performance on the Block Design subtest was the best independent predictor of dementia (HR = 8). Moreover, the Trail Making Test part B (time) and Verbal Fluency (semantic) had the best psychometric properties (area under the curve >0.90) for identifying PD patients at risk of dementia. CONCLUSION: The present study identified three cognitive tests as the most accurate to detect individuals with PD at high risk of developing dementia.

Cortical and subcortical gray matter bases of cognitive deficits in REM sleep behavior disorder.

OBJECTIVE: To investigate cortical and subcortical gray matter abnormalities underlying cognitive impairment in patients with REM sleep behavior disorder (RBD) with or without mild cognitive impairment (MCI). METHODS: Fifty-two patients with RBD, including 17 patients with MCI, were recruited and compared to 41 controls. All participants underwent extensive clinical assessments, neuropsychological examination, and 3-tesla MRI acquisition of T1 anatomical images. Vertex-based cortical analyses of volume, thickness, and surface area were performed to investigate cortical abnormalities between groups, whereas vertex-based shape analysis was performed to investigate subcortical structure surfaces. Correlations were performed to investigate associations between cortical and subcortical metrics, cognitive domains, and other markers of neurodegeneration (color discrimination, olfaction, and autonomic measures). RESULTS: Patients with MCI had cortical thinning in the frontal, cingulate, temporal, and occipital cortices, and abnormal surface contraction in the lenticular nucleus and thalamus. Patients without MCI had cortical thinning restricted to the frontal cortex. Lower patient performance in cognitive domains was associated with cortical and subcortical abnormalities. Moreover, impaired performance on olfaction, color discrimination, and autonomic measures was associated with thinning in the occipital lobe. CONCLUSIONS: Cortical and subcortical gray matter abnormalities are associated with cognitive status in patients with RBD, with more extensive patterns in patients with MCI. Our results highlight the importance of distinguishing between subgroups of patients with RBD according to cognitive status in order to better understand the neurodegenerative process in this population.

How does dementia with Lewy bodies start? prodromal cognitive changes in REM sleep behavior disorder.

OBJECTIVE: We describe the progression of cognitive decline and identify the predictive values of cognitive tests in three groups of REM sleep behavior disorder (RBD) patients classified at their last follow-up as having Parkinson's disease (PD), dementia with Lewy bodies (DLB), or still-idiopathic. METHODS: Patients (n = 109) underwent polysomnographic, neurological, and neuropsychological assessments. We used linear mixed-model analyses to compare the progression of cognitive test performance between the three groups over a 3-year prodromal period, and performed linear regressions for a 6-year prodromal period. We compared the proportions of patients with clinically impaired performance (z scores < -1.5). DLB patients were pair-matched according to age, sex, and education to healthy controls (2:1 ratio), and receiver operating characteristic curves were performed to identify the psychometric properties of cognitive tests to predict dementia. RESULTS: At follow-up, 38 patients (35%) developed a neurodegenerative disorder: 20 had PD and 18 DLB. Cognitive performance changes over time were strongly associated with later development of dementia. Clear deficits in attention and executive functions were observed 6 years before diagnosis. Verbal episodic learning and memory deficits started later, deviating from normal approximately 5 to 6 years and becoming clinically impaired at 1 to 2 years before diagnosis. Visuospatial abilities progressed variably, with inconsistent prodromal latencies. The Trail Making Test (part B), Verbal Fluency (semantic), and Rey Auditory-Verbal Learning Test (total, immediate, and delayed recalls) were the best predictors for dementia (area under the curve = 0.90-0.97). INTERPRETATION: Prodromal DLB is detectible up to 6 years before onset. For clinical utility, the Trail Making Test (part B) best detects early prodromal dementia stages, whereas Verbal Fluency (semantic) and verbal episodic learning tests are best for monitoring changes over time. Ann Neurol 2018;83:1016-1026.

Detecting the Cognitive Prodrome of Dementia with Lewy Bodies: A Prospective Study of REM Sleep Behavior Disorder.

Study Objectives: Long-term studies in REM sleep behavior disorder (RBD) have shown a high rate of conversion into synucleinopathies. We aimed to prospectively follow-up a large cohort of RBD patients to identify cognitive markers for early detection of prodromal dementia. Methods: Seventy-six idiopathic RBD patients underwent polysomnography and a complete neuropsychological and neurological assessment and were then followed for a mean of 3.6 years. Cognitive characteristics at baseline were compared between patients who remained disease-free and those who developed a synucleinopathy, and between those who developed dementia first and those who developed parkinsonism first. Receiver operating characteristic curves were calculated to assess the diagnostic value of cognitive tests for detecting prodromal dementia. Results: At follow-up, 34 patients developed a neurodegenerative disease: 19 parkinsonism-first and 15 dementia-first. RBD patients who first developed dementia were impaired at baseline in all cognitive domains (attention/executive functions, learning/memory, and visuospatial) compared to patients who developed parkinsonism. Moreover, 93% of patients who first developed dementia had mild cognitive impairment at baseline compared to 42% of patients who developed parkinsonism. RBD patients who developed parkinsonism first were similar at baseline to disease-free RBD patients on cognition. In dementia-first patients, two cognitive tests assessing attention and executive functions (Stroop Color Word Test and Trail Making Test) reliably predicted dementia (area under the curve ≥0.85) compared to parkinsonism-first patients or controls. Conclusions: This study shows that cognitive tests assessing attention and executive functions strongly predict conversion to dementia in RBD patients, and may be useful endpoints to determine the effectiveness of interventions to prevent cognitive deterioration in RBD patients.

Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials.

OBJECTIVE: To precisely delineate clinical risk factors for conversion from idiopathic REM sleep behavior disorder (RBD) to Parkinson disease, dementia with Lewy bodies, and multiple system atrophy, in order to enable practical planning and stratification of neuroprotective trials against neurodegenerative synucleinopathy. METHODS: In a 10-year prospective cohort, we tested prodromal Parkinson disease markers in 89 patients with idiopathic RBD. With Kaplan-Meier analysis, we calculated risk of neurodegenerative synucleinopathy, and using Cox proportional hazards, tested the ability of prodromal markers to identify patients at higher disease risk. By combining predictive markers, we then designed stratification strategies to optimally select patients for definitive neuroprotective trials. RESULTS: The risk of defined neurodegenerative synucleinopathy was high: 30% developed disease at 3 years, rising to 66% at 7.5 years. Advanced age (hazard ratio [HR] = 1.07), olfactory loss (HR = 2.8), abnormal color vision (HR = 3.1), subtle motor dysfunction (HR = 3.9), and nonuse of antidepressants (HR = 3.5) identified higher risk of disease conversion. However, mild cognitive impairment (HR = 1.8), depression (HR = 0.63), Parkinson personality, treatment with clonazepam (HR = 1.3) or melatonin (HR = 0.55), autonomic markers, and sex (HR = 1.37) did not clearly predict clinical neurodegeneration. Stratification with prodromal markers increased risk of neurodegenerative disease conversion by 200%, and combining markers allowed sample size reduction in neuroprotective trials by >40%. With a moderately effective agent (HR = 0.5), trials with fewer than 80 subjects per group can demonstrate definitive reductions in neurodegenerative disease. CONCLUSIONS: Using stratification with simply assessed markers, it is now not only possible, but practical to include patients with RBD in neuroprotective trials against Parkinson disease, multiple system atrophy, and dementia with Lewy bodies.

Electroencephalogram slowing in rapid eye movement sleep behavior disorder is associated with mild cognitive impairment.

BACKGROUND: Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is a well-documented risk factor for synucleinopathies such as Parkinson disease (PD) and dementia with Lewy bodies (DLB). Moreover, approximately 50% of iRBD patients have mild cognitive impairment (MCI). The purpose of our study was to investigate waking electroencephalogram (EEG) abnormalities specific to iRBD patients with MCI. METHODS: Forty-two polysomnographically confirmed iRBD patients, including 23 iRBD [+]MCI patients 19 patients without MCI (iRBD [-]MCI), and 37 healthy subjects participated in the study. All participants underwent a complete neuropsychologic assessment for MCI diagnosis and a waking quantitative EEG recording. RESULTS: iRBD [+]MCI patients had a higher slow-to-fast frequency ratio than iRBD [-]MCI patients and controls in the parietal, temporal, and occipital regions. iRBD [+]MCI patients also had higher relative θ power in the parietal, temporal, and occipital regions and lower relative α power in the occipital region compared to iRBD [-]MCI patients and controls. Moreover, iRBD [+]MCI patients had higher relative θ power in the frontal and central areas and lower relative ß power in the central, parietal, and temporal regions compared to controls. The dominant occipital frequency also was slower in iRBD [+]MCI patients compared to controls. No between-group differences were observed between iRBD [-]MCI patients and controls. CONCLUSION: In iRBD patients, only those with concomitant MCI showed waking EEG slowing in the posterior cortical regions, providing a potential marker for an increased risk for developing DLB or PD.

Color discrimination deficits in Parkinson's disease are related to cognitive impairment and white-matter alterations.

Color discrimination deficit is a common nonmotor manifestation of Parkinson's disease (PD). However, the pathophysiology of this dysfunction remains poorly understood. Although retinal structure changes found in PD have been suggested to cause color discrimination deficits, the impact of cognitive impairment and cortical alterations remains to be determined. We investigated the contribution of cognitive impairment to color discrimination deficits in PD and correlated them with cortical anomalies. Sixty-six PD patients without dementia and 20 healthy controls performed the Farnsworth-Munsell 100 hue test and underwent a comprehensive neuropsychological assessment for mild cognitive impairment diagnosis. In a subgroup of 26 PD patients, we also used high-definition neuroanatomical magnetic resonance imaging for cortical thickness and diffusion tensor analysis. PD patients with mild cognitive impairment performed poorly on the Farnsworth-Munsell 100 hue test compared with PD patients without mild cognitive impairment and controls. In PD patients, performance on the Farnsworth-Munsell 100 hue test was correlated with measures of visuospatial abilities and executive functions. Neuroimaging analysis revealed higher mean and radial diffusivity values in right posterior white-matter structures that correlated with poor performance on the Farnsworth-Munsell 100 hue test. No cortical thickness correlation reached significance. This study showed that cognitive impairment makes a major contribution to the color discrimination deficits reported in PD. Thus, performance on the Farnsworth-Munsell 100 hue test may reflect cognitive impairment more than color discrimination deficits in PD. Poor performance on the Farnsworth-Munsell 100 hue test was also associated with white-matter alterations in right posterior brain regions.

Cognition in rapid eye movement sleep behavior disorder.

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by excessive muscle activity and undesirable motor events during REM sleep. RBD occurs in approximately 0.5% of the general population, with a higher prevalence in older men. RBD is a frequent feature of dementia with Lewy bodies (DLB), but is only rarely reported in Alzheimer's disease. RBD is also a risk factor for α-synuclein-related diseases, such as DLB, Parkinson's disease (PD), and multiple system atrophy. Therefore, RBD has major implications for the diagnosis and treatment of neurodegenerative disorders and for understanding specific neurodegeneration patterns. Several markers of neurodegeneration have been identified in RBD, including cognitive impairments such as deficits in attention, executive functions, learning capacities, and visuospatial abilities. Approximately 50% of RBD patients present mild cognitive impairment. Moreover, RBD is also associated with cognitive decline in PD.