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Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson’s 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.

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.

This pilot randomized trial tested an intervention aimed at enhancing resourcefulness in family caregivers of persons with dementia, postulating that caregivers’ emotional outcomes (anxiety and depression) and role outcomes (reward, strain, mutuality, and preparedness) would be improved, and problem behaviors in the care recipients (persons with dementia) would be reduced as a result of the intervention. Subjects were stratified by race (white or African American) and by baseline resourcefulness (high or low). Family caregivers were randomly assigned to an intervention group in which subjects attended six resourcefulness training sessions, meeting for 2 hours weekly over 6 weeks, or to a control group that received no treatment. Small to medium effects were shown for the intervention program on resourcefulness, anxiety, and preparedness of the caregivers and on frequency of behavior problems in the care recipients. Caregivers in the intervention group reported significantly more resourcefulness skills, with a medium effect at week 6 and a small effect 12 weeks later, compared with the control group. Persons with dementia had fewer behavior problems in the intervention group compared with control, although the difference was not significant. Caregivers’ anxiety was reduced in the intervention group at 12 weeks.

INTRODUCTION We aimed to determine whether 123I‐ioflupane single‐photon emission computed tomography (SPECT) striatal binding ratio (SBR) correlated with parkinsonian motor symptoms in dementia with Lewy bodies (DLB) and if SBR predicts worsening of parkinsonism over time. METHODS A retrospective cohort study of the U.S. Dementia with Lewy Bodies Consortium dataset including individuals with DLB with baseline 123I‐ioflupane SPECT analyzed with DaTQUANT and baseline and 24‐month Movement Disorder Society Unified Parkinson's Disease Rating Scale–Part III (MDS‐UPDRS‐III). A subset had cerebrospinal fluid α‐synuclein seed amplification assay (SAA) evaluation. RESULTS Baseline mean SBRs were significant predictors of baseline and 24‐month MDS‐UPDRS‐III scores, although they did not predict meaningful worsening over time. SAA positivity was associated with lower SBRs; Z score cut‐off values are provided. DISCUSSION In suspected DLB, 123I‐ioflupane SPECT, at diagnosis, could be used to confirm underlying dopamine deficiency; it does not predict meaningful worsening of motor parkinsonism. More severe dopamine deficiency increases confidence in presence of synucleinopathy. Highlights 123I‐ioflupane single‐photon emission computed tomography (SPECT) can confirm underlying dopamine deficiency. Striatal binding ratio (SBR) Z scores predicted 24‐month Unified Parkinson's Disease Rating Scale–Part III (UPDRS‐III) scores. SBR Z scores are not predictive of subsequent meaningful worsening of parkinsonism. More severe dopamine dysfunction on SPECT is associated with presence of seed amplification assay (SAA). SBR Z score cut‐offs that indicate cerebrospinal fluid SAA positivity are provided.

We aimed to determine whether I-ioflupane single-photon emission computed tomography (SPECT) striatal binding ratio (SBR) correlated with parkinsonian motor symptoms in dementia with Lewy bodies (DLB) and if SBR predicts worsening of parkinsonism over time. A retrospective cohort study of the U.S. Dementia with Lewy Bodies Consortium dataset including individuals with DLB with baseline I-ioflupane SPECT analyzed with DaTQUANT and baseline and 24-month Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). A subset had cerebrospinal fluid α-synuclein seed amplification assay (SAA) evaluation. Baseline mean SBRs were significant predictors of baseline and 24-month MDS-UPDRS-III scores, although they did not predict meaningful worsening over time. SAA positivity was associated with lower SBRs; Z score cut-off values are provided. In suspected DLB, I-ioflupane SPECT, at diagnosis, could be used to confirm underlying dopamine deficiency; it does not predict meaningful worsening of motor parkinsonism. More severe dopamine deficiency increases confidence in presence of synucleinopathy. I-ioflupane single-photon emission computed tomography (SPECT) can confirm underlying dopamine deficiency. Striatal binding ratio (SBR) Z scores predicted 24-month Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III) scores. SBR Z scores are not predictive of subsequent meaningful worsening of parkinsonism. More severe dopamine dysfunction on SPECT is associated with presence of seed amplification assay (SAA). SBR Z score cut-offs that indicate cerebrospinal fluid SAA positivity are provided.

INTRODUCTION The National Institute on Aging – Alzheimer's Association (NIA‐AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre‐mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis. METHODS The cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated. RESULTS We observed a significant difference in Aβ42/40 after 12 months in the A+T− group. Post mortem neuropathologic analyses indicated that most of the p‐Tau 181 positive (T+) cases also had a high Braak stage. DISCUSSION This suggests that DLB patients who are A+ but T− may need to be monitored to determine whether they remain A+ or ever progress to T positivity. Highlights Some A+T‐ DLB subjects transition from A+ to negative after 12‐months. Clinically diagnosed DLB with LBP‐AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP‐AD (A+T+) maintain their positivity. Monitoring of the A+T‐ sub‐type of DLB may be necessary.

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 < .001) and poor MMSE performance (B = −2.13; 95% CI, −3.13 to −1.13;P < .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.

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurodegenerative disease commonly characterized by a triad of dementia, gait, and urinary disturbance. Advancements in diagnosis and treatment have aided in properly identifying and improving symptoms in patients. However, a large proportion of iNPH patients remain either undiagnosed or misdiagnosed. Using PubMed search engine of keywords “normal pressure hydrocephalus,” “diagnosis,” “shunt treatment,” “biomarkers,” “gait disturbances,” “cognitive function,” “neuropsychology,” “imaging,” and “pathogenesis,” articles were obtained for this review. The majority of the articles were retrieved from the past 10 years. The purpose of this review article is to aid general practitioners in further understanding current findings on the pathogenesis, diagnosis, and treatment of iNPH.

LR11 is an ApoE receptor that is enriched in the brain. We have shown that LR11 is markedly downregulated in patients with sporadic Alzheimer disease (AD). This finding led us to explore whether reduced LR11 expression reflects a primary mechanism of disease or merely a secondary consequence of other AD-associated changes. Therefore, LR11 expression was assessed in a transgenic mouse model of AD and familial AD (FAD) brains. Immunohistochemistry and immunoblotting of LR11 in PS1/APP transgenic and wild-type mice indicated that LR11 levels are not affected by genotype or accumulation of amyloid pathology. LR11 expression was also evaluated based on immunoblotting and LR11 immunostaining intensity in human frontal cortex in controls, sporadic AD, and FAD, including cases with presenilin-1 (PS1) and presenilin-2 (PS2) mutations. Although LR11 was reduced in sporadic AD, there was no difference in protein level or staining intensity between control and FAD cases. The finding that LR11 expression is unaffected in both a mouse model of AD and autosomal-dominant forms of AD suggests that LR11 is not regulated by amyloid accumulation or other AD neuropathologic changes. We hypothesize that LR11 loss may be specific to sporadic AD and influence amyloid pathology through mechanisms independent of substrate-enzyme interactions regulated by FAD mutations.

[...] a series of conditions were provided which, when present, make it impossible to diagnose PDD accurately, and these include: acute confusional states which may be secondary to systemic illness, major depression, and features highly compatible with the diagnosis of a vascular dementia. Primary and secondary stroke interventions may be similar regardless of whether patients present with motor or primarily cognitive features. [...] it could be argued that DLB and PDD are one entity when therapies are developed that influence pathological alpha-synuclein protein aggregation and other common biological alterations.