Association of CSF α-Synuclein Seeding Amplification Assay Results With Clinical Features of Possible and Probable Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: The clinical diagnosis of dementia with Lewy bodies (DLB) depends on identifying significant cognitive decline accompanied by core features of parkinsonism, visual hallucinations, cognitive fluctuations, and REM sleep behavior disorder (RBD). Hyposmia is one of the several supportive features. α-Synuclein seeding amplification assays (αSyn-SAAs) may enhance diagnostic accuracy by detecting pathologic αSyn seeds in CSF. In this study, we examine how different clinical features associate with CSF αSyn-SAA positivity in a large group of clinically diagnosed participants with DLB. METHODS: Cross-sectional and longitudinal CSF samples from the multicentered observational cohort study of the DLB Consortium and similar studies within the Parkinson's Disease Biomarker Program, contributed by academic medical centers in the United States, underwent αSyn-SAA testing. Participants included those clinically diagnosed with DLB and 2 control cohorts. Associations between core DLB features and olfaction with αSyn-SAA positivity were evaluated using logistic regression. RESULTS: CSF samples from 191 participants diagnosed with DLB (mean age 69.9 ± 6.8, 15% female), 50 age-matched and sex-matched clinical control participants, and 49 younger analytical control participants were analyzed. Seventy-two percent (137/191) of participants with DLB had positive αSyn-SAAs vs 4% of the control groups. Among participants with DLB, those who were αSyn-SAA-positive had lower Montreal Cognitive Assessment scores (18.8 ± 5.7 vs 21.2 ± 5.2, p = 0.01), had worse parkinsonism on the Movement Disorders Society Unified Parkinson's Disease Rating Scale part III (33.8 ± 15.1 vs 25.6 ± 16.4, p = 0.001), were more likely to report RBD (114/133 [86%] vs 33/53 [62%], p < 0.0001), and had worse hyposmia on the University of Pennsylvania Smell Identification Test (UPSIT) (94/105 [90%] below 15th percentile vs 14/44 [32%], p < 0.0001). UPSIT percentile had the highest area under the curve (0.87, 95% CI 0.81-0.94) in predicting αSyn-SAA positivity and participants scoring at or below the 15th percentile of age and sex normative values had 18.3 times higher odds (95% CI 7.52-44.6) of having a positive αSyn-SAA test. Among 82 participants with longitudinal CSF samples, 81 (99%) had the same αSyn-SAA result for initial and follow-up specimens. DISCUSSION: A substantial proportion of clinically diagnosed participants with DLB had negative αSyn-SAA results. Hyposmia was the strongest clinical predictor of αSyn-SAA positivity. Hyposmia and αSyn-SAA may have utility in improving the diagnostic assessment of individuals with potential DLB. CLASSIFICATION OF EVIDENCE: This study provided Class III evidence that CSF αSyn-SAA distinguishes patients with clinically diagnosed DLB from normal controls.

Metabolic and Environmental Biomarkers in Mild Cognitive Impairment and Dementia: An Exploratory Study.

Objective: To determine the frequency with which suspected pathogenic factors, including metals and metabolites that might contribute to Alzheimer's disease (AD), may be found in patients with cognitive impairment through commonly available blood tests. Methods: A variety of serum studies, including metals, ammonia, homocysteine, vitamin B12, folate, thyroid tests, metabolic products, and inflammatory markers, were measured in two cohorts: one meeting mild cognitive impairment (MCI) criteria and the other meeting mild-to-moderate dementia (DE) criteria. Medications these patients received were reviewed. Results: Metal abnormalities were detected in over half the subjects, including evidence of mercury, lead, and arsenic elevation as well as instances of excessive essential metals, iron (Fe), and copper. Some metal aberration was detected in 64% of the DE group and 66% of the MCI group. Females were more likely to have elevated copper, consistent with hormonal effects on copper excretion. Homocysteinemia was the most common abnormality, detected in 71% with DE and 67% with MCI, while methylmalonic acid was not elevated. Slight hyperammonemia was moderately common (38%) suggesting a hepatic factor in this subset. Findings of moderate insulin resistance were present in nearly half (44% DE, 52% MCI). Sixty of 65 (92%) had at least one abnormal biomarker and 60% had two or more. The most common drug taken by the total cohort was proton pump inhibitors at 22% DE and 38% MCI. Conclusions: This study suggests that both toxic metals and excessive vital metals such as copper and iron, as well as common metabolic and hepatic factors are detectable at both stages of MCI and DE. There appears to be a multiplicity of provocative factors leading to DE. Individualized interventions based on these parameters may be a means to reduce cognitive decline leading to DE. A more comprehensive prospective study of these environmental and metabolic factors with corrective early interventions appears warranted.

ATN cerebrospinal fluid biomarkers in dementia with Lewy bodies: Initial results from the United States Dementia with Lewy Bodies Consortium.

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 Aß42/40 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.

Tolerability of memantine monotherapy versus adding memantine as combination therapy.

INTRODUCTION: Prior studies have focused on the clinical efficacy of combination therapy, donepezil and memantine, for patient's diagnosed with Alzheimer's disease. As a result, it has become increasingly routine for providers to prescribe both medications for all-cause neurodegenerative disorders in variable stages of disease. However, the potential adverse drug reactions while described as mild can have serious sequelae in older adults who are already managing the side effects of polypharmacy. This study looks to explore the tolerability of switching cholinesterase inhibitors to memantine monotherapy versus adding memantine as combination therapy for all-cause neurodegenerative disorders. MATERIALS & METHODS: The study is an IRB approved retrospective chart review that includes 175 patients diagnosed with neurocognitive disorders (ICD 10 F00-F03.91 and ICD10 G30-G31.84). Only side effects reported to and recorded by a neurocognitive subspecialist at Jefferson's Memory Disorder Center from 2016 to 2019 were included. RESULTS & DISCUSSION: The odds of a patient reporting side effects on combination therapy in comparison with those patients on memantine monotherapy reporting side effects were significantly greater (OR = 4.33, CI 95% (1.62, 11.52), p = 0.003). In our patient sample, more than 80% of the patients reporting side effects qualified as polypharmacy or excessive polypharmacy (Table 2). As a result, variable polypharmacy (p = 0.047) was statistically significant in the in a binary logistic regression model for predicting outcomes for patients on combination therapy (Table 3). Therefore, as a patient progresses to moderate-severe stages of disease, we recommend switching CI monotherapy to memantine monotherapy as opposed to adding memantine as combination therapy for those patients on more than 10 other medications to increase tolerability. Given the limitations of a smaller sample size, variables such as severity of disease, renal and liver impairment as well as medication dosing were not significant predictors (Table 3) for those reporting side effects on combination therapy.

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

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.

Amyloid Beta Oligomers Target to Extracellular and Intracellular Neuronal Synaptic Proteins in Alzheimer's Disease.

Introduction: ß-Amyloid protein (Aß) putatively plays a seminal role in synaptic loss in Alzheimer's disease (AD). While there is no consensus regarding the synaptic-relevant species of Aß, it is known that Aß oligomers (AßOs) are noticeably increased in the early stages of AD, localizing at or within the synapse. In cell and animal models, AßOs have been shown to attach to synapses and instigate synapse dysfunction and deterioration. To establish the pathological mechanism of synaptic loss in AD, it will be important to identify the synaptic targets to which AßOs attach. Methods: An unbiased approach using far western ligand blots has identified three synaptic proteins to which AßOs specifically attach. These proteins (p100, p140, and p260) were subsequently enriched by detergent extraction, ultracentrifugation, and CHT-HPLC column separation, and sequenced by LC-MS/MS. P100, p140, and p260 were identified. These levels of AßOs targets in human AD and aging frontal cortexes were analyzed by quantitative proteomics and western-blot. The polyclonal antibody to AßOs was developed and used to block the toxicity of AßOs. The data were analyzed with one-way analysis of variance. Results: AßOs binding proteins p100, p140, and p260 were identified as Na/K-ATPase, synGap, and Shank3, respectively. α3-Na/K-ATPase, synGap, and Shank3 proteins showed loss in the postsynaptic density (PSD) of human AD frontal cortex. In short term experiments, oligomers of Aß inhibited Na/K-ATPase at the synapse. Na/K-ATPase activity was restored by an antibody specific for soluble forms of Aß. α3-Na/K-ATPase protein and synaptic ß-amyloid peptides were pulled down from human AD synapses by co-immunoprecipitation. Results suggest synaptic dysfunction in early stages of AD may stem from inhibition of Na/K-ATPase activity by Aß oligomers, while later stages could hypothetically result from disrupted synapse structure involving the PSD proteins synGap and Shank3. Conclusion: We identified three AßO binding proteins as α3-Na/K-ATPase, synGap, and Shank3. Soluble Aß oligomers appear capable of attacking neurons via specific extracellular as well as intracellular synaptic proteins. Impact on these proteins hypothetically could lead to synaptic dysfunction and loss, and could serve as novel therapeutic targets for AD treatment by antibodies or other agents.

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

Importance: Evidence shows that sleep dysfunction and ß-amyloid (Aß) deposition work synergistically to impair brain function in individuals with normal cognition, increasing the risk of developing dementia later in life. However, whether Aß 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 Aß 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, Aß 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 Aß 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 Aß 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 Aß 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 Aß and cognitive impairment, suggesting that there is an underlying sleep-dependent mechanism that links Aß burden in the brain to cognitive decline. Further elucidation of this mechanism may improve understanding of disease processes associated with Aß accumulation.

Lewy Body Dementia Association's Research Centers of Excellence Program: Inaugural Meeting Proceedings.

The first Lewy Body Dementia Association (LBDA) Research Centers of Excellence (RCOE) Investigator's meeting was held on December 14, 2017, in New Orleans. The program was established to increase patient access to clinical experts on Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), and to create a clinical trials-ready network. Four working groups (WG) were created to pursue the LBDA RCOE aims: (1) increase access to high-quality clinical care, (2) increase access to support for people living with LBD and their caregivers, (3) increase knowledge of LBD among medical and allied (or other) professionals, and (4) create infrastructure for a clinical trials-ready network as well as resources to advance the study of new therapeutics.

Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study.

BACKGROUND: Loss-of-function mutations in GRN cause frontotemporal lobar degeneration (FTLD). Patients with GRN mutations present with a uniform subtype of TAR DNA-binding protein 43 (TDP-43) pathology at autopsy (FTLD-TDP type A); however, age at onset and clinical presentation are variable, even within families. We aimed to identify potential genetic modifiers of disease onset and disease risk in GRN mutation carriers. METHODS: The study was done in three stages: a discovery stage, a replication stage, and a meta-analysis of the discovery and replication data. In the discovery stage, genome-wide logistic and linear regression analyses were done to test the association of genetic variants with disease risk (case or control status) and age at onset in patients with a GRN mutation and controls free of neurodegenerative disorders. Suggestive loci (p<1 × 10-5) were genotyped in a replication cohort of patients and controls, followed by a meta-analysis. The effect of genome-wide significant variants at the GFRA2 locus on expression of GFRA2 was assessed using mRNA expression studies in cerebellar tissue samples from the Mayo Clinic brain bank. The effect of the GFRA2 locus on progranulin concentrations was studied using previously generated ELISA-based expression data. Co-immunoprecipitation experiments in HEK293T cells were done to test for a direct interaction between GFRA2 and progranulin. FINDINGS: Individuals were enrolled in the current study between Sept 16, 2014, and Oct 5, 2017. After quality control measures, statistical analyses in the discovery stage included 382 unrelated symptomatic GRN mutation carriers and 1146 controls free of neurodegenerative disorders collected from 34 research centres located in the USA, Canada, Australia, and Europe. In the replication stage, 210 patients (67 symptomatic GRN mutation carriers and 143 patients with FTLD without GRN mutations pathologically confirmed as FTLD-TDP type A) and 1798 controls free of neurodegenerative diseases were recruited from 26 sites, 20 of which overlapped with the discovery stage. No genome-wide significant association with age at onset was identified in the discovery or replication stages, or in the meta-analysis. However, in the case-control analysis, we replicated the previously reported TMEM106B association (rs1990622 meta-analysis odds ratio [OR] 0·54, 95% CI 0·46-0·63; p=3·54 × 10-16), and identified a novel genome-wide significant locus at GFRA2 on chromosome 8p21.3 associated with disease risk (rs36196656 meta-analysis OR 1·49, 95% CI 1·30-1·71; p=1·58 × 10-8). Expression analyses showed that the risk-associated allele at rs36196656 decreased GFRA2 mRNA concentrations in cerebellar tissue (p=0·04). No effect of rs36196656 on plasma and CSF progranulin concentrations was detected by ELISA; however, co-immunoprecipitation experiments in HEK293T cells did suggest a direct binding of progranulin and GFRA2. INTERPRETATION: TMEM106B-related and GFRA2-related pathways might be future targets for treatments for FTLD, but the biological interaction between progranulin and these potential disease modifiers requires further study. TMEM106B and GFRA2 might also provide opportunities to select and stratify patients for future clinical trials and, when more is known about their potential effects, to inform genetic counselling, especially for asymptomatic individuals. FUNDING: National Institute on Aging, National Institute of Neurological Disorders and Stroke, Canadian Institutes of Health Research, Italian Ministry of Health, UK National Institute for Health Research, National Health and Medical Research Council of Australia, and the French National Research Agency.

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 10-6). Postmortem neuropathology of five TIA1 mutations carriers showed a consistent pathological signature with numerous round, hyaline, TAR DNA-binding protein 43 (TDP-43)-positive inclusions. TIA1 mutations significantly increased the propensity of TIA1 protein to undergo phase transition. In live cells, TIA1 mutations delayed stress granule (SG) disassembly and promoted the accumulation of non-dynamic SGs that harbored TDP-43. Moreover, TDP-43 in SGs became less mobile and insoluble. The identification of TIA1 mutations in ALS/FTD reinforces the importance of RNA metabolism and SG dynamics in ALS/FTD pathogenesis.

Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.

The Dementia with Lewy Bodies (DLB) Consortium has refined its recommendations about the clinical and pathologic diagnosis of DLB, updating the previous report, which has been in widespread use for the last decade. The revised DLB consensus criteria now distinguish clearly between clinical features and diagnostic biomarkers, and give guidance about optimal methods to establish and interpret these. Substantial new information has been incorporated about previously reported aspects of DLB, with increased diagnostic weighting given to REM sleep behavior disorder and 123iodine-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. The diagnostic role of other neuroimaging, electrophysiologic, and laboratory investigations is also described. Minor modifications to pathologic methods and criteria are recommended to take account of Alzheimer disease neuropathologic change, to add previously omitted Lewy-related pathology categories, and to include assessments for substantia nigra neuronal loss. Recommendations about clinical management are largely based upon expert opinion since randomized controlled trials in DLB are few. Substantial progress has been made since the previous report in the detection and recognition of DLB as a common and important clinical disorder. During that period it has been incorporated into DSM-5, as major neurocognitive disorder with Lewy bodies. There remains a pressing need to understand the underlying neurobiology and pathophysiology of DLB, to develop and deliver clinical trials with both symptomatic and disease-modifying agents, and to help patients and carers worldwide to inform themselves about the disease, its prognosis, best available treatments, ongoing research, and how to get adequate support.

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 ß-amyloid (Aß) 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 Aß 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.

Arguing against the proposed definition changes of PD.

As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article titled "Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease." In particular, we suggest that the 1-year rule distinguishing Parkinson's disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice and clinical and basic science research and when helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, "PD (dementia with Lewy bodies subtype)," will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Idiopathic Normal Pressure Hydrocephalus: A Review for General Practitioners.

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.

Dementia With Lew Body: Impacts of Surgery.

Patients who have dementia with Lewy bodies (DLB) and undergo surgery may develop aggravated postoperative cognitive dysfunction or postoperative delirium. Many patients with DLB respond poorly to surgery and anesthesia, and their conditions may worsen if they have other medical complications along with dementia. They may also face high risk of prolonged hospital stay, increased medical problems and/or mortality, causing significant physical, psychosocial, and financial burdens on individuals, family members, and society. Anesthesia, pain medications, old age, and surgery-related stresses are usually held responsible for the complications; however, the exact causes are still not fully understood. Literature on surgery-related complications for patients with DLB appears to be inadequate, and hence the topic merits detailed and systematic research. This article reviews postoperative complications and various surgery-related risk factors for DLB in light of other dementias such as Alzheimer's disease, as their neuropathologic features overlap with those of DLB.

Clinical Subtypes of Frontotemporal Dementia.

Frontotemporal dementia (FTD) was one of the lesser known dementias until the recent advancements revealing its genetic and pathological foundation. This common neurodegenerative disorder has three clinical subtypes- behavioral, semantic and progressive non fluent aphasia. The behavioral variant mostly exhibits personality changes, while the other two encompass various language deficits. This review discusses the basic pathology, genetics, clinical and histological presentation and the diagnosis of the 3 subtypes. It also deliberates the different therapeutic modalities currently available for frontotemporal dementia and the challenges faced by the caregivers. Lastly it explores the scope of further research into the diagnosis and management of FTD.

Enhancing resourcefulness to improve outcomes in family caregivers and persons with Alzheimer's disease: a pilot randomized trial.

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.

Genetic modifiers in carriers of repeat expansions in the C9ORF72 gene.

BACKGROUND: Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are causative for frontotemporal dementia (FTD) and motor neuron disease (MND). Substantial phenotypic heterogeneity has been described in patients with these expansions. We set out to identify genetic modifiers of disease risk, age at onset, and survival after onset that may contribute to this clinical variability. RESULTS: We examined a cohort of 330 C9ORF72 expansion carriers and 374 controls. In these individuals, we assessed variants previously implicated in FTD and/or MND; 36 variants were included in our analysis. After adjustment for multiple testing, our analysis revealed three variants significantly associated with age at onset (rs7018487 [UBAP1; p-value = 0.003], rs6052771 [PRNP; p-value = 0.003], and rs7403881 [MT-Ie; p-value = 0.003]), and six variants significantly associated with survival after onset (rs5848 [GRN; p-value = 0.001], rs7403881 [MT-Ie; p-value = 0.001], rs13268953 [ELP3; p-value = 0.003], the epsilon 4 allele [APOE; p-value = 0.004], rs12608932 [UNC13A; p-value = 0.003], and rs1800435 [ALAD; p-value = 0.003]). CONCLUSIONS: Variants identified through this study were previously reported to be involved in FTD and/or MND, but we are the first to describe their effects as potential disease modifiers in the presence of a clear pathogenic mutation (i.e. C9ORF72 repeat expansion). Although validation of our findings is necessary, these variants highlight the importance of protein degradation, antioxidant defense and RNA-processing pathways, and additionally, they are promising targets for the development of therapeutic strategies and prognostic tests.