The Neural Signature of Impaired Dual-Tasking in Idiopathic Rapid Eye Movement Sleep Behavior Disorder Patients.

Dual-task gait can be a useful biomarker for cognitive decline and a sensitive predictor of future neurodegeneration in certain clinical populations, such as patients with idiopathic rapid eye movement sleep behavior disorder. OBJECTIVES: The objective of this cross-sectional study was to determine the neural signature of dual-tasking deficits in idiopathic rapid eye movement sleep behavior disorder using a validated gait paradigm. METHODS: Fifty-eight participants (28 controls; 30 idiopathic rapid eye movement sleep behavior disorder patients) were recruited; 52 participants had functional MRI scans as they performed a validated dual-task virtual reality gait paradigm using foot pedals. Forty-one participants completed single- and dual-task "overground walking" on a pressure sensor carpet. RESULTS: Idiopathic rapid eye movement sleep behavior disorder patients showed deficits in dual-tasking (i.e., greater mean step time) compared to controls during "overground walking." Functional MRI revealed that idiopathic rapid eye movement sleep behavior disorder patients had reduced blood-oxygen-level-dependent signal change in the dorsal caudate nucleus, and significantly different corticostriatal functional connectivity patterns from controls, when dual-tasking in high versus low cognitive load. While controls showed greater connectivity between frontoparietal and motor networks, idiopathic rapid eye movement sleep behavior disorder patients exhibited less change in this connectivity as a function of cognitive load. CONCLUSIONS: These findings demonstrate evidence of dual-task gait deficits in idiopathic rapid eye movement sleep behavior disorder patients, underpinned by disrupted corticostriatal connectivity. Minimal differences in the level of functional connectivity between dual-tasking conditions of high and low cognitive load suggest that idiopathic rapid eye movement sleep behavior disorder patients recruit cognitive networks to control gait even when the cognitive demands are low. This may indicate a compensatory strategy for early cognitive decline in idiopathic rapid eye movement sleep behavior disorder. © 2020 International Parkinson and Movement Disorder Society.

Evaluating the Sustained Attention Response Task to Quantify Cognitive Fluctuations in Dementia With Lewy Bodies.

Cognitive fluctuations (CFs) are a core diagnostic feature of dementia with Lewy bodies (DLB). Detection of CF is still mostly based on subjective reports from the patient or informant; more quantitative measures are likely to improve the accuracy for the diagnosis of DLB. The purpose of the current study is to test whether performance on the Sustained Attention Response Task (SART) could distinguish those patients with DLB with and without CF. Twenty-four patients with DLB were tested on the SART and performance was related to scores on the Clinical Assessment of Fluctuations (CAFs) and One Day Fluctuation Assessment Scale (ODFAS). The number of "misses" made was a significant predictor of their fluctuation severity, attentional performance, disorganized thinking, and language production ratings on the ODFAS. However, measures on the SART did not correlate with measures on the CAF scale. In conclusion, these findings suggest that SART is a feasible measure of sustained attention in this population and has clinical and diagnostic relevance to the measurement of CF, particularly those aspects measured by the ODFAS.

Impaired Color Discrimination-A Specific Marker of Hallucinations in Lewy Body Disorders.

There is emerging evidence indicating that color discrimination impairments can predict the development of Lewy body dementia in patients with rapid eye movement sleep behavior disorder, Parkinson disease, and in patients with mild cognitive impairment. Despite this clear relationship, color vision deficits are not seen uniformly in patients with dementia with Lewy bodies (DLB), suggesting a more nuanced association with the underlying neuropathology. Visual hallucinations represent a discriminating feature of DLB, and recent evidence implicates visual pathway dysfunction as a significant contributor to this phenomenon. In this study, we examined the relationship between color vision impairment and visual hallucinations, along with other clinical and neuropsychological features in 24 well-characterized patients with DLB alongside 25 healthy controls. Color discrimination impairment was seen in 16 (67%) of 24 DLB participants with a higher error score relative to controls (P = .001). We demonstrate for the first time a strong association between color discrimination errors on the Farnsworth-Munsell 100 hue test and both the presence and severity of hallucinatory symptoms in DLB based on clinician-derived (P = .008) and questionnaire-derived (P = .03) measures. Correlation with clinical and neuropsychological variables revealed that color discrimination is significantly related to visuospatial difficulties measured by the clock-drawing task (P = .02) but not to global measures of cognition, motor severity, age, or disease duration in our cohort. Factor analysis confirmed a unique relationship between color discrimination, visual hallucinations, and visuospatial function. Our results suggest that color discrimination does not simply relate to dementia but rather indexes higher order perceptual deficits that may predict visual hallucinations in Lewy body disorders and share a common pathophysiological substrate.

Dysfunction in attentional processing in patients with Parkinson's disease and visual hallucinations.

Mechanistic insights into visual hallucinations (VH) in Parkinson's disease (PD) have suggested a role for impaired attentional processes. The current study tested 25 PD patients with and 28 PD patients without VH on the attentional network test. Hallucinators had significantly lower accuracy rates compared to non-hallucinators, but no differences were found in reaction times. This suggests that hallucinators show deficits in attentional processes and conflict monitoring. Our findings provide novel behavioural insights that dovetail with current neurobiological frameworks of VH.

Exploring the Sensitivity of Prodromal Dementia with Lewy Bodies Research Criteria.

Dementia with Lewy bodies (DLB) is an insidious neurodegenerative disease characterised by a precipitous decline in cognition, sleep disturbances, motor impairment and psychiatric features. Recently, criteria for prodromal DLB (pDLB) including clinical features and biomarkers have been put forward to aid the classification and research of this ambiguous cohort of patients. Researchers can use these criteria to classify patients with mild cognitive impairment (MCI) with Lewy bodies (MCI-LB) as either possible (either one core clinical feature or one biomarker are present) or probable pDLB (at least two core clinical features, or one core clinical feature and at least one biomarker present). However, as isolated REM sleep behaviour disorder (iRBD) confirmed with polysomnography (PSG) can be included as both a clinical and a biomarker feature, potentially reducing the specificity of these diagnostic criteria. To address this issue, the current study classified a cohort of 47 PSG-confirmed iRBD patients as probable prodromal DLB only in the presence of an additional core feature or if there was an additional non-PSG biomarker. Thirteen iRBD patients demonstrated MCI (iRBD-MCI). In the iRBD-MCI group, one presented with parkinsonism and was thus classified as probable pDLB, whilst the remaining 12 were classified as only possible pDLB. All patients performed three tasks designed to measure attentional deficits, visual hallucinations and visuospatial impairment. Patients also attended clinical follow-ups to monitor for transition to DLB or another synucleinopathy. Findings indicated that the only patient categorised by virtue of having two core clinical features as probable pDLB transitioned over 28 months to a diagnosis of DLB. The performance of this probable pDLB patient was also ranked second-highest for their hallucinatory behaviours and had comparatively lower visuospatial accuracy. These findings highlight the need for more stringent diagnostic research criteria for pDLB, given that only one of the 13 patients who would have satisfied the current guidelines for probable pDLB transitioned to DLB after two years and was indeed the patient with two orthogonal core clinical features.

An Adaptive Measure of Visuospatial Impairment in Dementia with Lewy Bodies.

Background: Dementia with Lewy bodies (DLB) is a common cause of dementia with poor prognosis and high hospitalization rates. DLB is frequently misdiagnosed, with clinical features that overlap significantly with other diseases including Parkinson's disease (PD). Clinical instruments that discriminate and track the progression of cognitive impairment in DLB are needed. Objectives: The current study was designed to assess the utility of a mental rotation (MR) task for assessing visuospatial impairments in early DLB. Methods: Accuracy of 22 DLB patients, 22 PD patients and 22 age-matched healthy controls in the MR task were compared at comparing shapes with 0°, 45° and 90° rotations. Results: Healthy controls and PD patients performed at similar levels while the DLB group were significantly impaired. Further, impairment in the visuospatial and executive function measures correlated with MR poor outcomes. Conclusion: These findings support the MR task as an objective measure of visuospatial impairment with the ability to adjust difficulty to suit impairments in a DLB population. This would be a useful tool within clinical trials.

Narrow doorways alter brain connectivity and step patterns in isolated REM sleep behaviour disorder.

BACKGROUND: Motor impairments in those with isolated REM sleep behaviour disorder (iRBD) significantly increases the likelihood of developing Lewy body disease (e.g. Parkinson's disease and Dementia with Lewy Bodies). OBJECTIVE: This study sought to explore the prodromal process of neurodegeneration by examining the neural signature underlying motor deficits in iRBD patients. METHODS: A virtual reality (VR) gait paradigm (which has previously been shown to elicit adaptive changes in gait performance whilst navigating doorways in Parkinson's Disease - PD) was paired with fMRI to investigate whether iRBD patients demonstrated worsened motor performance and altered connectivity across frontoparietal, motor and basal ganglia networks compared to healthy controls. Forty participants (23 iRBD and 17 healthy controls) completed the virtual reality gait task whilst in the MRI scanner, and an additional cohort of 19 Early PD patients completed the behavioural virtual reality gait task. RESULTS: As predicted, iRBD patients demonstrated slower and more variable stepping compared to healthy control participants and demonstrated an exaggerated response when navigating narrow compared to wide doorways, a phenomenon characteristically seen in PD. The iRBD patients also demonstrated less BOLD signal change in the left posterior putamen and right mesencephalic locomotor region, as well as reduced functional connectivity between the frontoparietal network and the motor network, when navigating narrow versus wide doorways compared to healthy control participants. CONCLUSIONS: Taken together, this study demonstrates that iRBD patients have altered task-related brain connectivity, which may represent the neural underpinnings of early motor impairments that are evident in iRBD.

Dynamic network impairments underlie cognitive fluctuations in Lewy body dementia.

Cognitive fluctuations are a characteristic and distressing disturbance of attention and consciousness seen in patients with Dementia with Lewy bodies and Parkinson's disease dementia. It has been proposed that fluctuations result from disruption of key neuromodulatory systems supporting states of attention and wakefulness which are normally characterised by temporally variable and highly integrated functional network architectures. In this study, patients with DLB (n = 25) and age-matched controls (n = 49) were assessed using dynamic resting state fMRI. A dynamic network signature of reduced temporal variability and integration was identified in DLB patients compared to controls. Reduced temporal variability correlated significantly with fluctuation-related measures using a sustained attention task. A less integrated (more segregated) functional network architecture was seen in DLB patients compared to the control group, with regions of reduced integration observed across dorsal and ventral attention, sensorimotor, visual, cingulo-opercular and cingulo-parietal networks. Reduced network integration correlated positively with subjective and objective measures of fluctuations. Regions of reduced integration and unstable regional assignments significantly matched areas of expression of specific classes of noradrenergic and cholinergic receptors across the cerebral cortex. Correlating topological measures with maps of neurotransmitter/neuromodulator receptor gene expression, we found that regions of reduced integration and unstable modular assignments correlated significantly with the pattern of expression of subclasses of noradrenergic and cholinergic receptors across the cerebral cortex. Altogether, these findings demonstrate that cognitive fluctuations are associated with an imaging signature of dynamic network impairment linked to specific neurotransmitters/neuromodulators within the ascending arousal system, highlighting novel potential diagnostic and therapeutic approaches for this troubling symptom.

Evaluating a novel behavioral paradigm for visual hallucinations in Dementia with Lewy bodies.

The aim of this study was to evaluate the utility of the Bistable Percept Paradigm (BPP), a computerised behavioural task that has previously been utilised for the assessment of visual hallucinations in Parkinson's Disease, in a Dementia with Lewy bodies (DLB) cohort. Dementia with Lewy bodies patients demonstrated poorer performance than healthy controls (HC) on the BPP with significantly more misperceptions and a greater failure to detect bistable percepts correctly compared to HC. Further, the number of misperceptions was also correlated with the severity of hallucinations. The findings from this study demonstrate that the BPP is a viable tool to measure misperceptions in DLB patients.

Changes in structural network topology correlate with severity of hallucinatory behavior in Parkinson's disease.

Inefficient integration between bottom-up visual input and higher order visual processing regions is implicated in visual hallucinations in Parkinson's disease (PD). Here, we investigated white matter contributions to this perceptual imbalance hypothesis. Twenty-nine PD patients were assessed for hallucinatory behavior. Hallucination severity was correlated to connectivity strength of the network using the network-based statistic approach. The results showed that hallucination severity was associated with reduced connectivity within a subnetwork that included the majority of the diverse club. This network showed overall greater between-module scores compared with nodes not associated with hallucination severity. Reduced between-module connectivity in the lateral occipital cortex, insula, and pars orbitalis and decreased within-module connectivity in the prefrontal, somatosensory, and primary visual cortices were associated with hallucination severity. Conversely, hallucination severity was associated with increased between- and within-module connectivity in the orbitofrontal and temporal cortex, as well as regions comprising the dorsal attentional and default mode network. These results suggest that hallucination severity is associated with marked alterations in structural network topology with changes in participation along the perceptual hierarchy. This may result in the inefficient transfer of information that gives rise to hallucinations in PD.

Postural instability and falls in Parkinson's disease.

Postural instability (PI) is one of the most debilitating motor symptoms of Parkinson's disease (PD), as it is associated with an increased risk of falls and subsequent medical complications (e.g. fractures), fear of falling, decreased mobility, self-restricted physical activity, social isolation, and decreased quality of life. The pathophysiological mechanisms underlying PI in PD remain elusive. This short review provides a critical summary of the literature on PI in PD, covering the clinical features, the neural and cognitive substrates, and the effects of dopaminergic medications and deep brain stimulation. The delayed effect of dopaminergic medication combined with the success of extrastriatal deep brain stimulation suggests that PI involves neurotransmitter systems other than dopamine and brain regions extending beyond the basal ganglia, further challenging the traditional view of PD as a predominantly single-system neurodegenerative disease.

Motor symptoms in Parkinson's disease: A unified framework.

Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (akinesia and bradykinesia, tremor and rigidity), PD patients show additional motor deficits, including: gait disturbance, impaired handwriting, grip force and speech deficits, among others. Some of these motor symptoms (e.g., deficits of gait, speech, and handwriting) have similar clinical profiles, neural substrates, and respond similarly to dopaminergic medication and deep brain stimulation (DBS). Here, we provide an extensive review of the clinical characteristics and neural substrates of each of these motor symptoms, to highlight precisely how PD and its medical and surgical treatments impact motor symptoms. In conclusion, we offer a unified framework for understanding the range of motor symptoms in PD. We argue that various motor symptoms in PD reflect dysfunction of neural structures responsible for action selection, motor sequencing, and coordination and execution of movement.

Neural substrates and potential treatments for levodopa-induced dyskinesias in Parkinson's disease.

Parkinson's disease (PD) is primarily a motor disorder that involves the gradual loss of motor function. Symptoms are observed initially in the extremities, such as hands and arms, while advanced stages of the disease can effect blinking, swallowing, speaking, and breathing. PD is a neurodegenerative disease, with dopaminergic neuronal loss occurring in the substantia nigra pars compacta, thus disrupting basal ganglia functions. This leads to downstream effects on other neurotransmitter systems such as glutamate, γ-aminobutyric acid, and serotonin. To date, one of the main treatments for PD is levodopa. While it is generally very effective, prolonged treatments lead to levodopa-induced dyskinesia (LID). LID encompasses a family of symptoms ranging from uncontrolled repetitive movements to sustained muscle contractions. In many cases, the symptoms of LID can cause more grief than PD itself. The purpose of this review is to discuss the possible clinical features, cognitive correlates, neural substrates, as well as potential psychopharmacological and surgical (including nondopaminergic and deep brain stimulation) treatments of LID.

Interrelations between cognitive dysfunction and motor symptoms of Parkinson's disease: behavioral and neural studies.

Parkinson's disease (PD) is characterized by a range of motor symptoms. Besides the cardinal symptoms (tremor, bradykinesia/akinesia, and rigidity), PD patients also show other motor deficits, including gait disturbance, speech deficits, and impaired handwriting. However, along with these key motor symptoms, PD patients also experience cognitive deficits in attention, executive function, working memory, and learning. Recent evidence suggests that these motor and cognitive deficits of PD are not completely dissociable, as aspects of cognitive dysfunction can impact motor performance in PD. In this article, we provide a review of behavioral and neural studies on the associations between motor symptoms and cognitive deficits in PD, specifically akinesia/bradykinesia, tremor, gait, handwriting, precision grip, and speech production. This review paves the way for providing a framework for understanding how treatment of cognitive dysfunction, for example cognitive rehabilitation programs, may in turn influence the motor symptoms of PD.

The cerebellum and psychiatric disorders.

The cerebellum has been considered for a long time to play a role solely in motor coordination. However, studies over the past two decades have shown that the cerebellum also plays a key role in many motor, cognitive, and emotional processes. In addition, studies have also shown that the cerebellum is implicated in many psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorders, schizophrenia, bipolar disorder, major depressive disorder, and anxiety disorders. In this review, we discuss existing studies reporting cerebellar dysfunction in various psychiatric disorders. We will also discuss future directions for studies linking the cerebellum to psychiatric disorders.

Impairments of working memory in schizophrenia and bipolar disorder: the effect of history of psychotic symptoms and different aspects of cognitive task demands.

Comparisons of cognitive impairments between schizophrenia (SZ) and bipolar disorder (BPD) have produced mixed results. We applied different working memory (WM) measures (Digit Span Forward and Backward, Short-delay and Long-delay CPT-AX, N-back) to patients with SZ (n = 23), psychotic BPD (n = 19) and non-psychotic BPD (n = 24), as well as to healthy controls (HC) (n = 18) in order to compare the level of WM impairments across the groups. With respect to the less demanding WM measures (Digit Span Forward and Backward, Short-delay CPT-AX), there were no between group differences in cognitive performance; however, with respect to the more demanding WM measures (Long-delay CPT-AX, N-back), we observed that the groups with psychosis (SZ, psychotic BPD) did not differ from one another, but performed poorer than the group without a history of psychosis (non-psychotic BPD). A history of psychotic symptoms may influence cognitive performance with respect to WM delay and load effects as measured by Long-delay CPT-AX and N-back tests, respectively. We observed a positive correlation of WM performance with antipsychotic treatment and a negative correlation with depressive symptoms in BPD and with negative symptoms in SZ subgroup. Our study suggests that WM dysfunctions are more closely related to a history of psychosis than to the diagnostic categories of SZ and BPD described by psychiatric classification systems.