Dementia Spectrum Research Articles

Med Check: Psilocybin for OCD, Nuplazid Vote, and More

Med Check: Psilocybin for OCD, Nuplazid Vote, and More

Gene Therapy in Amyotrophic Lateral Sclerosis.

Since the discovery of Cu/Zn superoxide dismutase (SOD1) gene mutation, in 1993, as the first genetic abnormality in amyotrophic lateral sclerosis (ALS), over 50 genes have been identified as either cause or modifier in ALS and ALS/frontotemporal dementia (FTD) spectrum disease. Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. During the last three decades, tremendous effort has been made worldwide to reveal biological pathways underlying the pathogenesis of these gene mutations in ALS/FTD. Accordingly, targeting etiologic genes (i.e., gene therapies) to suppress their toxic effects have been investigated widely. It includes four major strategies: (i) removal or inhibition of abnormal transcribed RNA using microRNA or antisense oligonucleotides (ASOs), (ii) degradation of abnormal mRNA using RNA interference (RNAi), (iii) decrease or inhibition of mutant proteins (e.g., using antibodies against misfolded proteins), and (iv) DNA genome editing with methods such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas). The promising results of these studies have led to the application of some of these strategies into ALS clinical trials, especially for C9orf72 and SOD1. In this paper, we will overview advances in gene therapy in ALS/FTD, focusing on C9orf72, SOD1, TARDBP, and FUS genes.

Neuroinflammation and protein aggregation co-localize across the spectrum of frontotemporal dementia

Frontotemporal dementia is clinically and neuropathologically heterogeneous, but each major phenotype has been associated with both aggregation of misfolded protein and neuroinflammation. We used positron emission tomography, with [11C]PK-11195 to measure activated microglia, and [18F]AV-1451 to quantify the burden of Tau or TDP-43, in 31 patients with frontotemporal dementia (10 behavioural variant, 11 semantic variant and 10 non-fluent variant) and 15 matched controls, to test the hypothesis that neuroinflamma- tion co-localises with pathological protein aggregation.Analyses included: (1) region-of-interest binding potentials; (2) pairwise correlation across regions between ligands; (3) principal component analysis of each ligand distribution and (4) multivariate classification of binding distributions.The analyses converged in showing (a) significant differences in [11C]PK-11195 binding between each patient group and controls in frontotemporal regions; (b) a strong positive correlation between [11C] PK-11195 and [18F]AV-1451 binding in all disease groups, across widespread cortical regions. Thesein vivoresults were confirmed bypost mortemimmunohistochemistry in 12 brains. In addition, we found (c) distinct distributional patterns of [11C]PK-11195 binding associated with different frontotemporal dementia syndromes, that supported more accurate classification of participants than [18F]AV-1451.Neuroinflammation may be important in shaping the clinical and neuropathological patterns of fronto- temporal dementia, and be a target for disease-modification.richard.bevanjones@doctors.org.uk

Clinical analysis of alcoholic pellagra: A single‐center retrospective study

Pellagra caused by niacin deficiency in alcoholics can be easily misdiagnosed because of similar symptoms to other alcohol-related diseases and the lack of the classical triad of signs. This study aimed to define the clinical presentation of alcoholic pellagra for early diagnosis and timely treatment. The clinical data of 16 alcohol-dependent patients who had pellagra and treated in our hospital from January 2002 to December 2019 were retrospectively analyzed. The local medical ethics committee approval (Medical Ethics Committee of Affiliated Hospital of XuZhou Medical University, XYFY2020-KL247-02) for this study has been obtained. The main complaints of the 16 patients were skin lesions (six cases), diarrhea (six cases), and mental disorders (four cases). Then, 13 cases had typical skin lesions, and 3 patients had a full spectrum of diarrhea, dementia, and dermatitis (3D). In terms of the main diagnosis, 2 patients had pellagra and Wernicke's encephalopathy, 3 patients had pellagra and alcohol-withdrawal syndrome, and the other patients had pellagra. After sufficient amounts of niacin and multivitamin B were given, clinical symptoms improved rapidly, and no sequelae were observed during follow-up. Pellagra is rarely manifested as a full 3D spectrum, with only one or two characteristics, which lack diagnostic specificity, especially in individuals with alcoholism. Physicians should maintain a high degree of suspicion of niacin deficiency in alcoholics. Alcohol-dependent patients with pellagra may be accompanied by complications of Wernicke's encephalopathy and alcohol-withdrawal syndrome. Prompt identification and timely treatment with a sufficient amount of niacin in combination with other vitamins and a certain amount of Zn can achieve a good prognosis of pellagra.

From clinical phenotype to proteinopathy: molecular neuroimaging in neurodegenerative dementias.

Neurodegenerative dementias are characterized by the abnormal accumulation of misfolded proteins. However, its diagnostic criteria are still based on the clinical phenotype. The development of biomarkers allowed in vivo detection of pathophysiological processes. This article aims to make a non-systematic review of the use of molecular neuroimaging as a biomarker. Molecular neuroimaging is based on the use of radiotracers for image acquisition. The radiotracer most used in PET is 18F-fluorodeoxyglucose (FDG), with which it is possible to study the regional brain glucose metabolism. The pattern of regional hypometabolism provides neuroanatomical information on the neurodegenerative process, which, in turn, has a good specificity for each type of proteinopathy. FDG is very useful in the differential diagnosis of neurodegenerative dementias through the regional pattern of involvement, including dementia with Lewy bodies and the spectrum of frontotemporal dementia. More recently, radiotracers with specific ligands to some of the pathological proteins have been developed. Pittsburgh compound B (PIB) labeled with 11C and the ligands that use 18F (florbetapir, florbetaben and flutemetamol) are the most used radiotracers for the detection of insoluble β-amyloid peptide in Alzheimer's disease (AD). A first generation of ligands for tau protein has been developed, but it has some affinity for other non-tau protein aggregates. A second generation has the advantage of having a higher affinity for hyperphosphorylated tau protein, including in primary tauopathies.

Schizotypal traits across the amyotrophic lateral sclerosis–frontotemporal dementia spectrum: pathomechanistic insights

BackgroundPsychiatric presentations similar to that observed in primary psychiatric disorders are well described across the amyotrophic lateral sclerosis–frontotemporal dementia (ALS–FTD) spectrum. Despite this, schizotypal personality traits associated with increased risks of clinical psychosis development and poor psychosocial outcomes have never been examined. The current study aimed to provide the first exploration of schizotypal traits and its neural underpinnings in the ALS–FTD spectrum to gain insights into a broader spectrum of psychiatric overlap with psychiatric disorders.MethodsSchizotypal traits were assessed using the targeted Schizotypal Personality Questionnaire in 99 participants (35 behavioural variant FTD, 10 ALS–FTD and 37 ALS patients, and 17 age-, sex- and education-matched healthy controls). Voxel-based morphometry analysis of whole-brain grey matter volume was conducted.ResultsRelative to controls, pervasive schizotypal personality traits across positive and negative schizotypy and disorganised thought disorders were identified in behavioural variant FTD, ALS (with the exception of negative schizotypy) and ALS–FTDALS–FTD patients (all p < .013), suggesting the presence of a wide spectrum of subclinical schizotypal symptoms beyond classic psychotic symptoms. Atrophy in frontal, anterior cingulate and insular cortices, and caudate and thalamus was involved in positive schizotypy, while integrity of the cerebellum was associated with disorganised thought disorder traits.ConclusionsThe frontal–striatal–limbic regions underpinning manifestation of schizotypy in the ALS–FTDALS–FTD spectrum are similar to that established in previous schizophrenia research. This finding expands the concept of a psychiatric overlap in ALS–FTD and schizophrenia, and suggests potentially common underlying mechanisms involving disruptions to frontal-striatal-limbic networks, warranting a transdiagnostic approach for future investigations.

The Role of VCP Mutations in the Spectrum of Amyotrophic Lateral Sclerosis-Frontotemporal Dementia.

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurological diseases which, respectively, and primarily affect motor neurons and frontotemporal lobes. Although they can lead to different signs and symptoms, it is now evident that these two pathologies form a continuum and that hallmarks of both diseases can be present within the same person in the so-called ALS-FTD spectrum. Many studies have focused on the genetic overlap of these pathologies and it is now clear that different genes, such as C9orf72, TARDBP, SQSTM1, FUS, and p97/VCP can be mutated in both the diseases. VCP was one of the first genes associated with both FTD and ALS representing an early example of gene overlapping. VCP belongs to the type II AAA (ATPases Associated with diverse cellular activities) family and is involved in ubiquitinated proteins degradation, autophagy, lysosomal clearance and mitochondrial quality control. Since its numerous roles, mutations in this gene lead to different pathological features, first and foremost TDP-43 mislocalization. This review aims to outline recent findings on VCP roles and on how its mutations are linked to the neuropathology of ALS and FTD.

Pain and the Alzheimer's Disease and Related Dementia Spectrum in Community-Dwelling Older Americans: A Nationally Representative Study

ContextPain is a significant concern among older adults with Alzheimer's disease and related dementias (ADRD). ObjectivesExamine the association between cognitive impairment across the ADRD spectrum and pain assessment and treatment in community-dwelling older Americans. MethodsThis cross-sectional, population-based study included 16,836 community-dwelling participants ≥ 50 years in the 2018 Health and Retirement Study. ADRD, assessed by validated cognitive measures, was categorized into “dementia,” “cognitive impairment, no dementia (CIND)” and “intact cognition.” Pain assessment included pain presence (often being troubled with pain), pain severity (degree of pain most of the time [mild/moderate/severe]), and pain interference (pain making it difficult to do usual activities). Pain treatment included recent use of over-the-counter pain medications and opioids (past 3 months), and regular intake of prescriptions for pain. ResultsDementia were associated with lower likelihood of reporting pain presence (Odds Ratio [OR]= 0.61, P = 0.01), pain interference (OR = 0.46, P < 0.001), reporting lower pain severity (e.g., moderate vs. no: Relative Risk Ratio = 0.38, P < 0.001), and lower likelihood of receiving pain treatment, that is, recent use of over-the-counter pain medications (OR = 0.60, P = 0.02) and opioids (OR = 0.33, P < 0.001), and regular intake of prescriptions for pain (OR = 0.461, P = 0.002). CIND was associated with reporting lower pain severity (e.g., moderate vs. no: Relative Risk Ratio = 0.75, P = 0.021), lower likelihood of reporting pain interference (OR = 0.79, P = 0.045) and recent over-the-counter pain medication use (OR = 0.74, P = 0.026). ConclusionCIND and dementia increased the risk of under-report and under-treatment of pain. Systematic efforts are needed to improve pain recognition and treatment among older adults with cognitive impairment, regardless of dementia diagnosis.

The Coaching for Cognition in Alzheimer's (COCOA) trial: Study design.

Comprehensive treatment of Alzheimer's disease (AD) requires not only pharmacologic treatment but also management of existing medical conditions and lifestyle modifications including diet, cognitive training, and exercise. We present the design and methodology for the Coaching for Cognition in Alzheimer's (COCOA) trial. AD and other dementias result from the interplay of multiple interacting dysfunctional biological systems. Monotherapies have had limited success. More interventional studies are needed to test the effectiveness of multimodal multi‐domain therapies for dementia prevention and treatment. Multimodal therapies use multiple interventions to address multiple systemic causes and potentiators of cognitive decline and functional loss; they can be personalized, as different sets of etiologies and systems responsive to therapy may be present in different individuals. COCOA is designed to test the hypothesis that coached multimodal interventions beneficially alter the trajectory of cognitive decline for individuals on the spectrum of AD and related dementias (ADRD). COCOA is a two‐arm prospective randomized controlled trial (RCT). COCOA collects psychometric, clinical, lifestyle, genomic, proteomic, metabolomic, and microbiome data at multiple timepoints across 2 years for each participant. These data enable systems biology analyses. One arm receives standard of care and generic healthy aging recommendations. The other arm receives standard of care and personalized data‐driven remote coaching. The primary outcome measure is the Memory Performance Index (MPI), a measure of cognition. The MPI is a summary statistic of the MCI Screen (MCIS). Secondary outcome measures include the Functional Assessment Staging Test (FAST), a measure of function. COCOA began enrollment in January 2018. We hypothesize that multimodal interventions will ameliorate cognitive decline and that data‐driven health coaching will increase compliance, assist in personalizing multimodal interventions, and improve outcomes for patients, particularly for those in the early stages of the AD spectrum.Highlights The Coaching for Cognition in Alzheimer's (COCOA) trial tests personalized multimodal lifestyle interventions for Alzheimer's disease and related dementias.Dense longitudinal molecular data will be useful for future studies.Increased use of Hill's criteria in analyses may advance knowledge generation.Remote coaching may be an effective intervention.Because lifestyle interventions are inexpensive, they may be particularly valuable in reducing global socioeconomic disparities in dementia care.

Do Personality Traits Influence the Association Between Depression and Dementia in Old Age?

Depression and personality traits are independent predictors of dementia or cognitive impairment. Despite the well-established relationship between these two psychosocial factors and dementia, no research has been documented on how personality traits can influence dementia in older adults exhibiting depressive symptoms. This study explores the influence of personality traits on the association between change in depression and dementia in old age. A population-based longitudinal cohort study involving two waves of data collected 5 years apart, containing 2210 American older adults, from the National Social Life, Health, and Aging Project to explore if personality traits influence how change in depression predicts the development of dementia. We assessed these relationships while adjusting for sociodemographic characteristics. Change in depression increased the likelihood of dementia at T2 by 4.2% (AOR = 1.04, p = 0.019) in the co-variate adjusted model. Personality traits, overall, did not influence how depression predicts the development of dementia. However, agreeableness individually nullified the effect of depression on the development of dementia, whereas extraversion was the only personality trait that significantly predicted dementia. Prosocial behaviors should be promoted in old age as these appear to be protective. In addition, early life education and a strong social support can keep the depression–dementia spectrum at bay in old age.

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia.

Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolyl cis-trans isomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of amyotrophic lateral sclerosis.Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of frontotemporal dementia, marked TDP-43 pathology and late-onset motor dysfunction.In the mouse brain, deficient PPIA induces mislocalization and aggregation of the GTP-binding nuclear protein Ran, a PPIA interactor and a master regulator of nucleocytoplasmic transport, also for TDP-43. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several patients with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia, and identified a PPIA loss-of-function mutation in a patient with sporadic amyotrophic lateral sclerosis . The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43.These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.

Racial considerations of age and white matter hyperintensities

AbstractBackgroundWhite matter hyperintensities (WMH) are regions that appear very bright on Fluid‐Attenuated Inversion Recovery (FLAIR) magnetic resonance images (MRI). They are generally attributed to cerebrovascular disease (CVD) and confer a greater risk for Alzheimer’s Disease (AD). Black individuals (BIs) typically have greater WMH burden than their white counterparts and have a two‐fold greater risk of developing AD in their lifetimes. For this project, we wanted to determine whether WMH were related to diagnostic category, and if this relationship differed according to race.MethodCohort 1 included middle‐aged cognitively normal black and white individuals (N=50). Cohort 2 included older black and white individuals on the dementia continuum (NC=47, MCI=10, AD=3). Data collection included a neuropsychological battery and magnetic resonance imaging (MRI). Fluid attenuated inversion recovery (FLAIR) MRI data were analyzed to obtain lobe specific WMH volumes (frontal, temporal, occipital, parietal, cerebellar). Because of age and diagnostic differences, we analyzed each cohort separately. We constructed multivariate linear models for each cohort with WMH volumes as the outcome variable, age, race, gender, and diagnostic category (Cohort 2 only) as independent variables. We included age X race, and race X diagnosis (Cohort 2 only) interaction terms.ResultThere were no racial or diagnostic differences in regional WMH volume. However, in Cohort 1, there was a significant race X age interaction in the parietal lobe such that in BIs, as age increased, WMH volume also increased (B=, t(3,46)=2.07, p =0.04). In Cohort 2, this relationship extended to the temporal (B=0.09, t(3,55)=2.95, p=0.04), and occipital lobes (B=0.09, t(3,55)=2.99, p=0.04). There was no such relationship observed in WIs.ConclusionAge conferred greater WMH volume in BIs than in WIs in cognitively normal individuals and individuals on the dementia spectrum. The relationship we observed between WMH and AD could be seen as additive rather than causative, as we observed only a relationship between age and WMH volume, not diagnostic category. The differential findings across race suggest that age has a greater effect on BIs on CVD and brain health. These findings, although not causal, should encourage AD researchers to collect more diverse samples, and consider underlying CVD in data analyses.

Microglial activation and atrophy in frontal cortex predict executive dysfunction in frontotemporal dementia

AbstractBackgroundFrontotemporal dementia is clinically and neuropathologically heterogeneous, but atrophy, neuroinflammation, and executive dysfunction occur in each of the principal variants. Across the clinical spectrum of frontotemporal dementia, we assessed the predictive value of in vivo neuroimaging measures of grey‐matter volume (from structural MRI) and microglial activation (from [11C]PK11195 PET) on the rate of future executive decline. We hypothesised a detrimental effect of inflammation and atrophy severity on executive dysfunction progression.MethodThirty patients with frontotemporal dementia underwent a baseline multi‐modal imaging assessment, including [11C]PK11195 PET to index microglial activation and structural MRI for atrophy, as part of the Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study. Cognitive impairments were assessed at baseline and serially for up to 5 years with the revised Addenbrooke's Cognitive Examination (ACE‐R). Regional grey‐matter volumes and [11C]PK11195 binding potentials were averaged in four regions of interest: left and right frontal and temporal lobes. Linear mixed models were applied to the longitudinal ACE‐R attention/executive sub‐score. Regional CSF‐corrected PET values and TIV‐corrected grey‐matter volumes were included in linear mixed models as predictors, with age and education as covariates. Specifically, negative associations of atrophy and inflammation with annual rate of executive decline were tested.ResultPatients showed a mean 3.3‐point loss per year on the ACE‐R attention/executive sub‐score (p&lt;0.001, Figure 1). Faster decline in ACE‐R was associated with reduced baseline grey‐matter volume of the left frontal lobe (beta=1.000, SE=0.285, p=0.000789, p‐FDR= 0.00316; Figure 2) and increased inflammation in frontal regions bilaterally (Left: beta=‐0.722, SE=0.251, p=0.00528, p‐FDR=0.0105, Figure 2; Right: Estimate=‐0.623, SE=0.256, p=0.0175, p‐FDR=0.0233). These associations remain significant when including both left frontal grey‐matter volume and [11C]PK11195 binding as predictors in the same model, and after controlling for baseline attention/executive scores. In these regions, grey‐matter volumes and inflammation levels were negatively correlated (left: r=‐0.414, p&lt;0.001; right: r=‐0.374, p&lt;0.001).ConclusionImaging markers for atrophy and microglial activation provide useful and independent information to evaluate and stratify patients with frontotemporal dementia. This may improve cohort selection in clinical trials and highlights the potential for immunomodulatory treatment strategies in frontotemporal dementia.

TMS for the characterization of different types of dementia disorders: A systematic review and meta‐analysis

AbstractBackgroundAt early stages, dementia disorders share similar clinical symptoms. For an appropriate classification, more practical and non‐invasive diagnostic methods are needed. Transcranial magnetic stimulation (TMS) assess non‐invasively the imbalance of cortical excitability and related neurotransmitters levels in the brain(1‐3). Characterizing the spectrum of dementia with TMS could enable a more accurate diagnosis and optimize interventions at earlier stages.MethodWe conducted a systematic review following PRISMA guidelines. Our search strategy included terms related to dementia of different etiologies and TMS. It was conducted in 4 databases (MEDLINE, EMBASE, Ovid and Scopus) from origin to April 2021. Two authors screened the studies in a 2‐stepwise approach. Original studies comparing dementia disorders using TMS were included. Risk of bias was assessed using QUADAS. Meta‐analyses comparing diverse TMS parameters between AD to FTD, DLB and VAD as well as FTD to DLB were made.ResultOur search yielded 2702 results, with 227 articles reviewed in full text. Finally, 14 articles were included in the review(4,5,14–17,6–13) and 11 in the meta‐analysis(4–14). A total of 983 patients were analyzed: Alzheimer disease (AD) 50.25%, frontotemporal dementia (FTD) 28.89%, dementia with Lewy bodies (DLB) 10.57%, vascular dementia (VaD) 5.59% and other dementias 4.7%. In the comparison between AD to FTD, the mean difference of resting motor threshold (RMT) short‐latency afferent inhibition (SAI), short‐acting cortical inhibition (SICI), intracortical facilitation (ICF) and central motor conduction time (CMCT) were statistically significant (Fig 1‐2). No significant difference when comparing the AD group to DLB nor VaD. Finally, RMT and SAI were the only parameters that differed between patients diagnosed with FTD and DLB (Fig 3). The main concerns of risk of bias were the retrospective study design and differences in diagnosis method and TMS protocols.ConclusionThe meta‐analysis of observational studies showed that TMS measurements as biomarkers seem to be useful for differentiating FTD from AD and DLB in patients with mild‐stage dementia. Accurate classification may allow more appropriate interventions and slow disease progression. However, study design and protocols may limit our results. Hence, more homogenous, and prospective studies with bigger sample size are needed.

Associations among clinical characteristics of sleep quality, cognitive performance, and brain architecture in Thai dementia spectrum disorders

AbstractBackgroundSleep disorders are increased with advancing age. Poor sleep quality is a risk factor for cognitive decline and dementia. We aimed 1) to explore the relationship between sleep quality, sleep architecture and cognition; 2) to investigate the association between brain volume and sleep parameters.MethodA total of 95 participants (70 female, mean age 67.18 ± 10 years) were included in this study. Thirty were those with major cognitive disorder patients, twenty‐five individuals had mild cognitive impairment (MCI), and forty were normal controls. Sleep parameters were measured using wrist actigraphy and subjective sleep questioners. The participants were evaluated with high‐resolution MRI. Three Dimensional sequences on Free‐Surfer morphometric procedure was used as the automated segmentation method to obtain brain volume. Demographic data, medical history, sleep characteristics, neuropsychological and mood evaluation were collected from participants.ResultMCI patients had significantly lower sleep efficiency than cognitive healthy persons, 81.30 + 7 .39 % vs. 85.12 + 5.09 %, p=0.04. 66 % of the participants had poor sleep quality. Prevalence of probable REM sleep behavior disorder (RBD) and restless leg syndrome was high in dementia group. Longer sleep latency was associated with worse performance on global cognition. Total sleep time was associated with entorhinal corex volume and hippocampal volume. Sleep latency was associated with hippocampal volumeConclusionSleep disorders were common in both cognitively healthy persons and dementia spectrum disorders. Lower sleep quality and disturbance of sleep maintenance were associated with the development of cognitive impairment. The causes and the consequences of poor sleep quality in patients with dementia spectrum disorders needed to be explored.

Diagnostic value of plasma P‐tau217 in frontotemporal dementia spectrum disorders

AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p &lt; 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

Repeatable battery for the assessment of neuropsychological status and its relationship to biomarkers of Alzheimer’s disease

Background: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) has been associated with commonly used biomarkers of Alzheimer’s disease (AD). However, prior studies have typically utilized small and poorly characterized samples, and they have not analyzed the subtests of the RBANS. The current study sought to expand on prior work by examining the relationship between the Indexes and subtest scores of the RBANS and three AD biomarkers: amyloid deposition via positron emission tomography, hippocampal volume via magnetic resonance imaging, and APOE ε4 status. Method: One-hundred twenty-one older adults across the AD continuum (intact, amnestic Mild Cognitive Impairment, mild AD), who were mostly Caucasian and well-educated, underwent assessment with the RBANS and collection of the three biomarkers. Results: Greater amyloid deposition was significantly related to lower scores on all five Indexes and the Total Scale score of the RBANS, as well as 11 of 12 subtests. For bilateral hippocampal volume, significant correlations were observed for 4 of the 5 Indexes, Total Scale score, and 9 of 12 subtests, with smaller hippocampi being related to lower RBANS scores. Participants with at least one APOE ε4 allele had significantly lower scores on 3 of the 5 Indexes, Total Scale score, and 8 of the 12 subtests. Conclusions: In this sample of participants across the dementia spectrum, most RBANS Indexes and subtests showed relationships with the amyloid deposition, hippocampal volumes, and APOE status, with poorer performance on the RBANS being associated with biomarker positivity. Although memory scores on the RBANS have traditionally been linked to biomarkers in AD, other Index and subtest scores also hold promise as indicators of AD. Replication in a more diverse sample is needed.

Inflammatory Bowel Disease and Patients With Mental Disorders: What Do We Know?

Inflammatory bowel disease (IBD) is a multisystemic disease with a wide range of extraintestinal manifestations in both ulcerative colitis and Crohn’s disease, while increasing evidence supports the interaction between gut and central nervous system, described as “gut-brain axis”. According to epidemiological studies, it seems that patients with IBD present more frequently with impaired mental status compared to the general population, leading to diagnostic and management problems in this group of patients. The association between IBD and mental disorders, such as dementia and autism spectrum disorders, has not been fully clarified; genetic factors and the gut-brain axis seem to be involved. The purpose of this review is to present and analyze the epidemiological data about this issue, describe the possible pathogenetic mechanisms and discuss some considerations about the management of patients with IBD and impaired mental status. J Clin Med Res. 2021;13(9):466-473 doi: https://doi.org/10.14740/jocmr4593

Inflammatory Bowel Disease and Patients With Mental Disorders: What Do We Know?

Inflammatory bowel disease (IBD) is a multisystemic disease with a wide range of extraintestinal manifestations in both ulcerative colitis and Crohn’s disease, while increasing evidence supports the interaction between gut and central nervous system, described as “gut-brain axis”. According to epidemiological studies, it seems that patients with IBD present more frequently with impaired mental status compared to the general population, leading to diagnostic and management problems in this group of patients. The association between IBD and mental disorders, such as dementia and autism spectrum disorders, has not been fully clarified; genetic factors and the gut-brain axis seem to be involved. The purpose of this review is to present and analyze the epidemiological data about this issue, describe the possible pathogenetic mechanisms and discuss some considerations about the management of patients with IBD and impaired mental status.

The role of genetics in neurodegenerative dementia: a large cohort study in South China

Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer’s disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p < 0.05). This study sheds insight into the genetic spectrum and clinical manifestations of neurodegenerative dementias in South China, further expands the existing repertoire of P/LP variants involved in known dementia-associated genes. It provides a new perspective for basic research on genetic pathogenesis and novel guiding for clinical practice of neurodegenerative dementia.