Association of β-Amyloid Burden With Sleep Dysfunction and Cognitive Impairment in Elderly Individuals With Cognitive Disorders.

Importance: Evidence shows that sleep dysfunction and β-amyloid (Aβ) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aβ continues to play an integral role in sleep dysfunction after the onset of cognitive decline in individuals with dementia is unclear. Objective: To determine whether Aβ deposition in the brain is associated with subjective measures of sleep quality and cognition in elderly individuals with cognitive disorders. Design, Setting, and Participants: A nested survey study was conducted at the Cognitive Disorders and Comprehensive Alzheimer Disease Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. Participants included patients aged 65 years and older with cognitive disorders verified by neuropsychological testing. Eligible participants were identified from a referral center-based sample of patients who underwent fluorine 18-labeled florbetaben positron emission tomography imaging at Thomas Jefferson University Hospital as part of the multicenter Imaging Dementia-Evidence for Amyloid Scanning study. Data collection and analysis occurred between November 2018 and March 2019. Main Outcomes and Measures: Sleep quality was measured via responses to sleep questionnaires, Aβ deposition was measured via fluorine 18-labeled florbetaben positron emission tomography, and cognition was measured via Mini-Mental State Examination (MMSE) performance. Results: Of the 67 eligible participants, 52 (77.6%) gave informed consent to participate in the study. Of the 52 enrolled participants (mean [SD] age, 76.6 [7.4] years), 27 (51.9%) were women. Daytime sleepiness was associated with Aβ deposition in the brainstem (B = 0.0063; 95% CI, 0.001 to 0.012; P = .02), but not MMSE performance (B = -0.01; 95% CI, -0.39 to 0.37; P = .96). The number of nocturnal awakenings was associated with Aβ deposition in the precuneus (B = 0.11; 95% CI, 0.06 to 0.17; P \u3c .001) and poor MMSE performance (B = -2.13; 95% CI, -3.13 to -1.13; P \u3c .001). Mediation analysis demonstrated an indirect association between Aβ deposition and poor MMSE performance that relied on nocturnal awakenings as an intermediary (B = -3.99; 95% CI, -7.88 to -0.83; P = .01). Conclusions and Relevance: Nighttime sleep disruption may mediate the association between Aβ and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aβ burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aβ accumulation

Lewy Body Dementia: Caregiver Burden and Unmet Needs

Lewy body dementia (LBD) is a common cause of dementia but to date, little is known about caregiver burden. The Lewy Body Dementia Association (www.LBDA.org) conducted a web-based survey of 962 caregivers (mean age 56y; 88% women). The most common initial symptoms were cognitive (48%), motor (39%), or both (13%). Caregivers expressed concerns about fear of future (77%), feeling stressed (54%), loss of social life (52%) and uncertainty about what to do next (50%). Caregivers reported moderate to severe burden; 80% felt the people around them did not understand their burden and 54% reported feelings of isolation with spousal caregivers reporting more burden than non-spousal caregivers. Only 29% hired in-home assistance while less than 40% used respite or adult day care, geriatric case managers or attended a support group meeting. Lack of service utilization occurred despite two-thirds of caregivers reporting medical crises requiring emergency services, psychiatric care or law enforcement. Caregivers reported preferences for web-based information, directories of LBD expert providers, information on LBD research and location of local support groups. These findings highlight significant unmet needs for LBD caregivers and provide targets for intervention to reduce caregiver burden. Community resources such as the Lewy Body Dementia Association may serve this end, while also providing practical information and support for caregivers

Lewy body dementia: The caregiver experience of clinical care

Lewy body dementia (LBD) is the second most common cause of dementia, however, little is known about how the clinical diagnosis of LBD is obtained in the community or the caregiver experience while seeking the diagnosis

Pathological Role of Peptidyl-Prolyl Isomerase Pin1 in the Disruption of Synaptic Plasticity in Alzheimer’s Disease

Synaptic loss is the structural basis for memory impairment in Alzheimer’s disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-amyloid (Aβ) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse. We localized Pin1 to dendritic rafts and postsynaptic density (PSD) and found the pathological loss of Pin1 within the synapses of AD brain cortical tissues. The loss of Pin1 activity may alter the ubiquitin-regulated modification of PSD proteins and decrease levels of Shank protein, resulting in aberrant synaptic structure. The loss of Pin1 activity, induced by oxidative stress, may also render neurons more susceptible to the toxicity of oligomers of Aβ and to excitation, thereby inhibiting NMDA receptor-mediated synaptic plasticity and exacerbating NMDA receptor-mediated synaptic degeneration. These results suggest that loss of Pin1 activity could lead to the loss of synaptic plasticity in the development of AD

Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials.

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson\u27s disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson\u27s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p \u3c 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p \u3e 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Verbal Learning and Memory Deficits across Neurological and Neuropsychiatric Disorders: Insights from an ENIGMA Mega Analysis.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15-90. The effects of dementia, mild cognitive impairment, Parkinson's disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders

Mechanisms Underlying CNS Degenerative Diseases

The CNS degenerative diseases are so diverse that no single mechanism of action can be proposed. Alterations that may result in neuronal death include increased or decreased quantity of the expressed protein, altered protein conformation, or changes in the biochemical or biophysical properties of proteins leading to a gain or loss of its function