Summary Parkinson's disease is a progressive neurodegenerative disorder associated with Lewy body disease pathology in central and peripheral nervous system structures. Although the cause of ...Parkinson's disease is not fully understood, clinicopathological analyses have led to the development of a staging system for Lewy body disease-associated pathological changes. This system posits a predictable topography of progression of Lewy body disease in the CNS, beginning in olfactory structures and the medulla, then progressing rostrally from the medulla to the pons, then to midbrain and substantia nigra, limbic structures, and neocortical structures. If this topography and temporal evolution of Lewy body disease does occur, other manifestations of the disease as a result of degeneration of olfactory and pontomedullary structures could theoretically begin many years before the development of prominent nigral degeneration and the associated parkinsonian features of Parkinson's disease. One such manifestation of prodromal Parkinson's disease is rapid eye movement (REM) sleep behaviour disorder, which is a parasomnia manifested by vivid dreams associated with dream enactment behaviour during REM sleep. Findings from animal and human studies have suggested that lesions or dysfunction in REM sleep and motor control circuitry in the pontomedullary structures cause REM sleep behaviour disorder phenomenology, and degeneration of these structures might explain the presence of REM sleep behaviour disorder years or decades before the onset of parkinsonism in people who develop Parkinson's disease.
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia manifested by vivid, often frightening dreams associated with simple or complex motor behavior during REM sleep. The ...polysomnographic features of RBD include increased electromyographic tone +/- dream enactment behavior during REM sleep. Management with counseling and pharmacologic measures is usually straightforward and effective. In this review, the terminology, clinical and polysomnographic features, demographic and epidemiologic features, diagnostic criteria, differential diagnosis, and management strategies are discussed. Recent data on the suspected pathophysiologic mechanisms of RBD are also reviewed. The literature and our institutional experience on RBD are next discussed, with an emphasis on the RBD-neurodegenerative disease association and particularly the RBD-synucleinopathy association. Several issues relating to evolving concepts, controversies, and future directions are then reviewed, with an emphasis on idiopathic RBD representing an early feature of a neurodegenerative disease and particularly an evolving synucleinopathy. Planning for future therapies that impact patients with idiopathic RBD is reviewed in detail.
Summary The broad importance of dementia is undisputed, with Alzheimer's disease justifiably getting the most attention. However, dementia with Lewy bodies and Parkinson's disease dementia, now ...called Lewy body dementias, are the second most common type of degenerative dementia in patients older than 65 years. Despite this, Lewy body dementias receive little attention and patients are often misdiagnosed, leading to less than ideal management. Over the past 10 years, considerable effort has gone into improving diagnostic accuracy by refining diagnostic criteria and using imaging and other biomarkers. Dementia with Lewy bodies and Parkinson's disease dementia share the same pathophysiology, and effective treatments will depend not only on successful treatment of symptoms but also on targeting the pathological mechanisms of disease, ideally before symptoms and clinical signs develop. We summarise the most pertinent progress from the past 10 years, outlining some of the challenges for the future, which will require refinement of diagnosis and clarification of the pathogenesis, leading to disease-modifying treatments.
See Morris and Weil (doi:10.1093/brain/awz014) for a scientific commentary on this article.
In a prospective multicentre study involving 1280 patients with idiopathic RBD, Postuma et al. show that ...approximately 6% of patients each year (>73.5% over 12 years) convert to full neurodegenerative disease. They test the predictive power of 21 prodromal markers of neurodegeneration, providing a template for planning neuroprotective trials.
Abstract
Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing hazard ratio (HR) = 3.16, objective motor examination (HR = 3.03), olfactory deficit (HR = 2.62), mild cognitive impairment (HR = 1.91-2.37), erectile dysfunction (HR = 2.13), motor symptoms (HR = 2.11), an abnormal DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.
Task-free functional magnetic resonance imaging (TF-fMRI) has great potential for advancing the understanding and treatment of neurologic illness. However, as with all measures of neural activity, ...variability is a hallmark of intrinsic connectivity networks (ICNs) identified by TF-fMRI. This variability has hampered efforts to define a robust metric of connectivity suitable as a biomarker for neurologic illness. We hypothesized that some of this variability rather than representing noise in the measurement process, is related to a fundamental feature of connectivity within ICNs, which is their non-stationary nature. To test this hypothesis, we used a large (n = 892) population-based sample of older subjects to construct a well characterized atlas of 68 functional regions, which were categorized based on independent component analysis network of origin, anatomical locations, and a functional meta-analysis. These regions were then used to construct dynamic graphical representations of brain connectivity within a sliding time window for each subject. This allowed us to demonstrate the non-stationary nature of the brain's modular organization and assign each region to a "meta-modular" group. Using this grouping, we then compared dwell time in strong sub-network configurations of the default mode network (DMN) between 28 subjects with Alzheimer's dementia and 56 cognitively normal elderly subjects matched 1:2 on age, gender, and education. We found that differences in connectivity we and others have previously observed in Alzheimer's disease can be explained by differences in dwell time in DMN sub-network configurations, rather than steady state connectivity magnitude. DMN dwell time in specific modular configurations may also underlie the TF-fMRI findings that have been described in mild cognitive impairment and cognitively normal subjects who are at risk for Alzheimer's dementia.
Hereditary frontotemporal dementia associated with mutations in the microtubule‐associated protein tau gene (MAPT) is a protean disorder. Three neuropathologic subtypes can be recognized, based on ...the presence of inclusions made of tau isoforms with three and four repeats, predominantly three repeats and mostly four repeats. This is relevant for establishing a correlation between structural magnetic resonance imaging and positron emission tomography using tracers specific for aggregated tau. Longitudinal studies will be essential to determine the evolution of anatomical alterations from the asymptomatic stage to the various phases of disease following the onset of symptoms.
This article reviews the epidemiological evidence of features of α-synucleinopathies that precede clinical onset of disease, proposes a clinical timeline, and attempts to define the different ...premotor and clinical phenotypes associated with α-synucleinopathies.
The pathological hallmarks of the α-synucleinopathies (Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, and multisystem atrophy) begin years before a clinical diagnosis. Epidemiologic studies support the long gap between pathology and symptoms and suggest that certain nonmotor conditions (constipation, anxiety, and rapid eye movement sleep behavior disorder) precede the traditional motor Parkinson disease phenotype by long intervals.
Characterizing the temporal onset of these conditions will help to better recognize the premotor phase of the α-synucleinopathies and specific clinical phenotypes and will guide the search for predictive biomarkers and risk or protective factors for Parkinson disease and other synucleinopathies.
Complex biological systems are organized across various spatiotemporal scales with particular scientific disciplines dedicated to the study of each scale (e.g. genetics, molecular biology and ...cognitive neuroscience). When considering disease pathophysiology, one must contemplate the scale at which the disease process is being observed and how these processes impact other levels of organization. Historically Alzheimer's disease has been viewed as a disease of abnormally aggregated proteins by pathologists and molecular biologists and a disease of clinical symptoms by neurologists and psychologists. Bridging the divide between these scales has been elusive, but the study of brain networks appears to be a pivotal inroad to accomplish this task. In this study, we were guided by an emerging systems-based conceptualization of Alzheimer's disease and investigated changes in brain networks across the disease spectrum. The default mode network has distinct subsystems with unique functional-anatomic connectivity, cognitive associations, and responses to Alzheimer's pathophysiology. These distinctions provide a window into the systems-level pathophysiology of Alzheimer's disease. Using clinical phenotyping, metadata, and multimodal neuroimaging data from the Alzheimer's Disease Neuroimaging Initiative, we characterized the pattern of default mode network subsystem connectivity changes across the entire disease spectrum (n = 128). The two main findings of this paper are (i) the posterior default mode network fails before measurable amyloid plaques and appears to initiate a connectivity cascade that continues throughout the disease spectrum; and (ii) high connectivity between the posterior default mode network and hubs of high connectivity (many located in the frontal lobe) is associated with amyloid accumulation. These findings support a system model best characterized by a cascading network failure--analogous to cascading failures seen in power grids triggered by local overloads proliferating to downstream nodes eventually leading to widespread power outages, or systems failures. The failure begins in the posterior default mode network, which then shifts processing burden to other systems containing prominent connectivity hubs. This model predicts a connectivity 'overload' that precedes structural and functional declines and recasts the interpretation of high connectivity from that of a positive compensatory phenomenon to that of a load-shifting process transiently serving a compensatory role. It is unknown whether this systems-level pathophysiology is the inciting event driving downstream molecular events related to synaptic activity embedded in these systems. Possible interpretations include that the molecular-level events drive the network failure, a pathological interaction between the network-level and the molecular-level, or other upstream factors are driving both.
Summary Background Three subtypes of Alzheimer's disease (AD) have been pathologically defined on the basis of the distribution of neurofibrillary tangles: typical AD, hippocampal-sparing AD, and ...limbic-predominant AD. Compared with typical AD, hippocampal-sparing AD has more neurofibrillary tangles in the cortex and fewer in the hippocampus, whereas the opposite pattern is seen in limbic-predominant AD. We aimed to determine whether MRI patterns of atrophy differ between these subtypes and whether structural neuroimaging could be a useful predictor of pathological subtype at autopsy. Methods We identified patients who had been followed up in the Mayo Clinic Alzheimer's Disease Research Center (Rochester, MN, USA) or in the Alzheimer's Disease Patient Registry (Rochester, MN, USA) between 1992 and 2005. To be eligible for inclusion, participants had to have had dementia, AD pathology at autopsy (Braak stage ≥IV and intermediate to high probability of AD), and an ante-mortem MRI. Cases were assigned to one of three pathological subtypes—hippocampal-sparing, limbic-predominant, and typical AD—on the basis of neurofibrillary tangle counts in hippocampus and cortex and ratio of hippocampal to cortical burden, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss between groups and with age-matched control individuals. Neuroimaging was obtained at the time of first presentation. To summarise pair-wise group differences, we report the area under the receiver operator characteristic curve (AUROC). Findings Of 177 eligible patients, 125 (71%) were classified as having typical AD, 33 (19%) as having limbic-predominant AD, and 19 (11%) as having hippocampal-sparing AD. Most patients with typical (98 78%) and limbic-predominant AD (31 94%) initially presented with an amnestic syndrome, but fewer patients with hippocampal-sparing AD (eight 42%) did. The most severe medial temporal atrophy was recorded in patients with limbic-predominant AD, followed by those with typical disease, and then those with hippocampal-sparing AD. Conversely, the most severe cortical atrophy was noted in patients with hippocampal-sparing AD, followed by those with typical disease, and then limbic-predominant AD. The ratio of hippocampal to cortical volumes allowed the best discrimination between subtypes (p<0·0001; three-way AUROC 0·52 95% CI 0·47–0·52; ratio of AUROC to chance classification 3·1 2·8–3·1). Patients with typical AD and non-amnesic initial presentation had a significantly higher ratio of hippocampal to cortical volumes (median 0·045 IQR 0·035–0·056) than did those with an amnesic presentation (0·041 0·031–0·057; p=0·001). Interpretation Patterns of atrophy on MRI differ across the pathological subtypes of AD. MRI regional volumetric analysis can reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype of AD at autopsy. Funding US National Institutes of Health (National Institute on Aging).
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