Dementia Phenotype Research Articles

Relationship between hearing impairment and dementia and cognitive function: a Mendelian randomization study

BackgroundThere is a substantial body of observational research indicating an association between hearing impairment and dementia, yet the causal relationship and underlying mechanisms remain uncertain. This study aims to investigate the causal relationship between hearing impairment and its subtypes with dementia and cognitive function using two-sample Mendelian randomization (MR) analysis.MethodsWe performed two-sample MR analysis to examine the causal effects of hearing impairment and its subtypes, including conductive and sensorineural hearing loss (CSHL), conductive hearing loss (CHL), sensorineural hearing loss (SHL), and sudden sensorineural hearing loss (SIHL), on six dementia phenotypes (overall dementia, Alzheimer’s disease [AD], Lewy body dementia [DLB], frontotemporal dementia [FTD], Parkinson’s disease dementia, and vascular dementia) and four cognitive functions. Additionally, multivariable MR (MVMR) analysis was employed to investigate potential mediating mechanisms.ResultsGenetically determined CSHL was associated with an elevated risk of DLB (odds ratio [OR] 1.69; 95% CI 1.08 to 2.63; P = 0.021) and FTD (OR 1.66; 1.04 to 2.67; P = 0.035), but not AD (P = 0.958). Genetic predisposition to CHL was found to link with increased risks of AD (OR 1.07; 1.01 to 1.14; P = 0.031). Genetically determined SHL was causally associated with an elevated risk of semantic dementia (OR 3.81; 1.09 to 13.37; P = 0.037). Genetically predicted CHL and SIHL were both causally associated with lower general cognitive performance (β -0.015 and − 0.043; P = 0.007 and 0.013) and fluid intelligence score (β -0.045 and − 0.095; P = 0.037 and 0.040). In MVMR analysis, the causal relationship between hearing impairment and dementia was mediated by loneliness, depressed mood, and brain cortical volume, particularly the medial temporal lobe, but not by aging or ischemic stroke.ConclusionOverall, the study provides evidence supporting a causal relationship between hearing impairment and increased risks of different types of dementia (including AD, FTD, and DLB), as well as poorer general cognitive function. These findings underscore the importance of addressing hearing impairment as a modifiable risk factor for dementia.

Novel insights into presenilin 1 mutation associated with a distinctive dementia phenotype and cotton wool plaques.

The mutations in the presenilin 1 gene (PSEN1) are the main cause of familial Alzheimer's disease. PSEN1 mutations affect amyloid-beta peptide production, which accumulates in the brain as senile plaque and cotton wool plaques (CWPs) and relates to other neurodegenerative disorders. Here we report the second case of the PSEN1 G266S mutation, which showed distinctive neuropathological features, including abundant CWPs. Lewy body pathology, and altered amyloid-beta production. Using the proband's samples, we performed genetic analysis of the PSEN1, APP, MAPT, and APOE genes, histopathological and immunohistochemical analysis of the brain tissue, and biochemical analysis of Aβ production in COS cells transfected with wild-type or mutant PSEN1. The patient presented with memory loss, abnormal behavior, and visual hallucinations. Brain scans showed reduced blood flow, mild atrophy, and white matter lesions. Genetic analysis revealed a heterozygous mutation at codon 266 (G266S) of PSEN1 and polymorphism of MAPT (Q230R). The brain had many CWPs, severe cerebral amyloid angiopathy (CAA), senile plaque, Lewy bodies, and neurites. Electron microscopy displayed myelinated fiber degeneration, mitochondrial damage, and amyloid fibrils in the white matter. The production level of Aβ42 in PSEN1 G266S-transfected cells significantly increased. Our findings suggest that the PSEN1 G266S mutation may cause a heterogeneous clinical and pathological phenotype, influenced by other genetic or environmental factors.

Investigating the prevalence of MFN2 mutations in amyotrophic lateral sclerosis: insights from an Italian cohort.

The MFN2 gene encodes mitofusin 2, a key protein for mitochondrial fusion, transport, maintenance and cell communication. MFN2 mutations are primarily linked to Charcot-Marie-Tooth disease type 2A. However, a few cases of amyotrophic lateral sclerosis and amyotrophic lateral sclerosis/frontotemporal dementia phenotypes with concomitant MFN2 mutations have been previously reported. This study examines the clinical and genetic characteristics of an Italian cohort of amyotrophic lateral sclerosis patients with rare, non-synonymous MFN2 mutations. A group of patients (n = 385) diagnosed with amyotrophic lateral sclerosis at our Neurology Units between 2008 and 2023 underwent comprehensive molecular testing, including MFN2. After excluding pathogenic mutations in the main amyotrophic lateral sclerosis-related genes (i.e. C9orf72, SOD1, FUS and TARDBP), MFN2 variants were classified based on the American College of Medical Genetics and Genomics guidelines, and demographic and clinical data of MFN2-mutated patients were retrieved. We identified 12 rare, heterozygous, non-synonymous MFN2 variants in 19 individuals (4.9%). Eight of these variants, carried by nine patients (2.3%), were either pathogenic, likely pathogenic or variants of unknown significance according to the American College of Medical Genetics and Genomics guidelines. Among these patients, four exhibited a familial pattern of inheritance. The observed phenotypes included classic and bulbar amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/frontotemporal dementia, flail arm, flail leg and progressive muscular atrophy. Median survival after disease onset was extremely variable, ranging from less than 1 to 13 years. This study investigates the prevalence of rare, non-synonymous MFN2 variants within an Italian cohort of amyotrophic lateral sclerosis patients, who have been extensively investigated, enhancing our knowledge of the underlying phenotypic spectrum. Further research is needed to understand whether MFN2 mutations contribute to motor neuron disease and to what extent. Improving our knowledge regarding the genetic basis of amyotrophic lateral sclerosis is crucial both in a diagnostic and therapeutic perspective.

2351 Clinical phenotype and epidemiology of delirium-onset dementia with Lewy bodies – a scoping review

Abstract Introduction Dementia with Lewy bodies (DLB) is the second most common form of dementia, however it can be difficult to recognise and is often misdiagnosed. Many cognitive, motor and psychiatric symptoms occur in the prodromal phase of DLB, years before clinical diagnosis. Delirium-onset DLB is one of three purported prodromal pathways by which DLB develops (McKeith et al., 2020). As delirium itself is an under-recognised clinical syndrome, this scoping review aimed to determine the epidemiology and clinical phenotype of delirium-onset DLB. Methods Electronic databases MEDLINE (ALL), Embase, Web of Science and PsycINFO were searched in December 2023. Two reviewers then independently screened titles, abstracts and full-text reports. Conflicts were resolved by a third reviewer. Data were then extracted by the lead reviewer and quality assessments were conducted. Results Following the removal of duplicates, the search yielded 719 results. Of these, 154 studies underwent full-text review and 38 were eligible for inclusion. This review describes 64 cases of delirium-onset DLB in case studies/reports (n = 18), observational studies (n = 3), retrospective cohort studies (n = 12) and clinicopathological studies (n = 5). Conclusion Delirium-onset DLB is an under-researched area. There is a dearth of evidence regarding both the epidemiology and clinical phenotype of this prodromal phase. Clear and systematic methods for the diagnosis of both delirium and DLB are needed to elucidate this pathway. At present, it is not clear what role biomarkers play in the detection of delirium-onset DLB. Further investigation of these tools, combined with neuropathological studies, could shed light on the pathogenesis of this disease.

Impact of type 2 diabetes and its duration on incidence rates of dementia death and medication prescription in the Australian population during 2003–2016

AimsTo quantify rates of dementia treatment and death among Australians with type 2 diabetes relative to those without diabetes using linked national registries of Australia. MethodsThe study included 891,418 people with type 2 diabetes registered on the National Diabetes Services Scheme and a randomly sampled, population-based comparison group (n = 1,131,369). Outcomes included dementia death (all-cause dementia, Alzheimer’s disease (AD) or vascular dementia), and first prescription of cholinesterase inhibitors or memantine. ResultsExcess dementia risk was observed in the diabetes group for the composite outcome of all-cause dementia death or dementia medication prescription but varied with age at diabetes diagnosis and its duration. At age 70, the rate of dementia death/medication prescription was ∼1.3 (95% CI 1.2, 1.3) and 1.1 (95% CI 1.1, 1.2) times higher in people with ten and five years of diabetes duration, respectively. Individual outcomes showed that diabetes was associated with a higher incidence of vascular dementia death, whereas an increased risk of AD death was only observed beyond ∼10 years of diabetes duration. Further, the incidence of dementia medication prescription was lower among people with diabetes. ConclusionsA higher incidence of AD death in the setting of 10+ years of diabetes duration coupled with a lower incidence of AD treatment suggests an under-recognition of this dementia phenotype among people with type 2 diabetes.

The Importance of PET Imaging to Understanding Whole-Body Cortisol Metabolism in Alzheimer's Disease.

Excess cortisol is associated with more severe cognitive decline, Alzheimer's disease, and related dementia phenotypes. The intracellular enzyme 11β-HSD1 regenerates active cortisol from inactive cortisone. In this current issue, high regional brain occupancy of Xanamemtrademark, determined by [11C]TARACT PET imaging of 11β-HSD1, in cognitively normal individuals and mild cognitive impartment/Alzheimer's disease (AD) patients is presented. In the future, comprehensive kinetic modeling using arterial sampling for occupancy studies, and whole-body PET imaging of 11β-HSD1 enzyme levels, in combination with stable isotope studies of cortisol metabolism, can provide broad insight into enzyme levels and activity in AD and other relevant diseases.

Extending the phenotypic spectrum assessed by the CDR plus NACC FTLD in genetic frontotemporal dementia.

We aimed to expand the range of the frontotemporal dementia (FTD) phenotypes assessed by the Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains (CDR plus NACC FTLD). Neuropsychiatric and motor domains were added to the standard CDR plus NACC FTLD generating a new CDR plus NACC FTLD-NM scale. This was assessed in 522 mutation carriers and 310 mutation-negative controls from the Genetic Frontotemporal dementia Initiative (GENFI). The new scale led to higher global severity scores than the CDR plus NACC FTLD: 1.4% of participants were now considered prodromal rather than asymptomatic, while 1.3% were now considered symptomatic rather than asymptomatic or prodromal. No participants with a clinical diagnosis of an FTD spectrum disorder were classified as asymptomatic using the new scales. Adding new domains to the CDR plus NACC FTLD leads to a scale that encompasses the wider phenotypic spectrum of FTD with further work needed to validate its use more widely. The new Clinical Dementia Rating Dementia Staging Instrument plus National Alzheimer's Coordinating Center Behavior and Language Domains neuropsychiatric and motor (CDR plus NACC FTLD-NM) rating scale was significantly positively correlated with the original CDR plus NACC FTLD and negatively correlated with the FTD Rating Scale (FRS).No participants with a clinical diagnosis in the frontotemporal dementia spectrum were classified as asymptomatic with the new CDR plus NACC FTLD-NM rating scale.Individuals had higher global severity scores with the addition of the neuropsychiatric and motor domains.A receiver operating characteristic analysis of symptomatic diagnosis showed nominally higher areas under the curve for the new scales.

Primary Microgliopathy Presenting as Degenerative Dementias: A Case Series of Novel Gene Mutations from India

Introduction: Microglia exert a crucial role in homeostasis of white matter integrity, and several studies highlight the role of microglial dysfunctions in neurodegeneration. Primary microgliopathy is a disorder where the pathogenic abnormality of the microglia causes white matter disorder and leads to a neuropsychiatric disease. Triggering receptor expressed on myeloid cells (TREM2), TYRO protein tyrosine kinase binding protein (TYROBP) and colony-stimulating factor 1 receptor (CSF1R) are genes implicated in primary microgliopathy. The clinical manifestations of primary microgliopathy are myriad ranging from neuropsychiatric syndrome, motor disability, gait dysfunction, ataxia, pure dementia, frontotemporal dementia (FTD), Alzheimer’s dementia (AD), and so on. It becomes imperative to establish the diagnosis of microgliopathy masquerading as degenerative dementia, especially with promising therapies on horizon for the same. We aimed to describe a case series of subjects with dementia harbouring novel genes of primary microgliopathy, along with their clinical, neuropsychological, cognitive profile and radiological patterns. Methods: The prospective study was conducted in a university referral hospital in South India, as a part of an ongoing clinico-genetic research on dementia subjects, and was approved by the Institutional Ethics Committee. All patients underwent detailed assessment including sociodemographic profile, clinical and cognitive assessment, pedigree analysis and comprehensive neurological examination. Subjects consenting for blood sampling underwent genetic testing by whole-exome sequencing (WES). Results: A total of 100 patients with dementia underwent genetic analysis using WES and three pathogenic variants, one each of TREM2, TYROBP, and CSF1R and two variants of uncertain significance in CSF1R were identified as cause of primary microgliopathy. TREM2 and TYROBP presented as frontotemporal syndrome whereas CSF1R presented as frontotemporal syndrome and as AD. Conclusion: WES has widened the spectrum of underlying neuropathology of degenerative dementias, and diagnosing primary microglial dysfunction with emerging therapeutic options is of paramount importance. The cases of primary microgliopathy due to novel mutations in TREM2, TYROBP, and CSF1R with the phenotype of degenerative dementia are being first time reported from Indian cohort. Our study enriches the spectrum of genetic variants implicated in degenerative dementia and provides the basis for exploring complex molecular mechanisms like microglial dysfunction, as underlying cause for neurodegeneration.

In vivo PET classification of tau pathologies in patients with frontotemporal dementia.

Frontotemporal dementia refers to a group of neurodegenerative disorders with diverse clinical and neuropathological features. In vivo neuropathological assessments of frontotemporal dementia at an individual level have hitherto not been successful. In this study, we aim to classify patients with frontotemporal dementia based on topologies of tau protein aggregates captured by PET with 18F-florzolotau (aka 18F-APN-1607 and 18F-PM-PBB3), which allows high-contrast imaging of diverse tau fibrils in Alzheimer's disease as well as in non-Alzheimer's disease tauopathies. Twenty-six patients with frontotemporal dementia, 15 with behavioural variant frontotemporal dementia and 11 with other frontotemporal dementia phenotypes, and 20 age- and sex-matched healthy controls were included in this study. They underwent PET imaging of amyloid and tau depositions with 11C-PiB and 18F-florzolotau, respectively. By combining visual and quantitative analyses of PET images, the patients with behavioural variant frontotemporal dementia were classified into the following subgroups: (i) predominant tau accumulations in frontotemporal and frontolimbic cortices resembling three-repeat tauopathies (n = 3), (ii) predominant tau accumulations in posterior cortical and subcortical structures indicative of four-repeat tauopathies (n = 4); (iii) amyloid and tau accumulations consistent with Alzheimer's disease (n = 4); and (iv) no overt amyloid and tau pathologies (n = 4). Despite these distinctions, clinical symptoms and localizations of brain atrophy did not significantly differ among the identified behavioural variant frontotemporal dementia subgroups. The patients with other frontotemporal dementia phenotypes were also classified into similar subgroups. The results suggest that PET with 18F-florzolotau potentially allows the classification of each individual with frontotemporal dementia on a neuropathological basis, which might not be possible by symptomatic and volumetric assessments.

Identifying clinical phenotypes of frontotemporal dementia in post-9/11 era veterans using natural language processing.

Frontotemporal dementia (FTD) encompasses a clinically and pathologically diverse group of neurodegenerative disorders, yet little work has quantified the unique phenotypic clinical presentations of FTD among post-9/11 era veterans. To identify phenotypes of FTD using natural language processing (NLP) aided medical chart reviews of post-9/11 era U.S. military Veterans diagnosed with FTD in Veterans Health Administration care. A medical record chart review of clinician/provider notes was conducted using a Natural Language Processing (NLP) tool, which extracted features related to cognitive dysfunction. NLP features were further organized into seven Research Domain Criteria Initiative (RDoC) domains, which were clustered to identify distinct phenotypes. Veterans with FTD were more likely to have notes that reflected the RDoC domains, with cognitive and positive valence domains showing the greatest difference across groups. Clustering of domains identified three symptom phenotypes agnostic to time of an individual having FTD, categorized as Low (16.4%), Moderate (69.2%), and High (14.5%) distress. Comparison across distress groups showed significant differences in physical and psychological characteristics, particularly prior history of head injury, insomnia, cardiac issues, anxiety, and alcohol misuse. The clustering result within the FTD group demonstrated a phenotype variant that exhibited a combination of language and behavioral symptoms. This phenotype presented with manifestations indicative of both language-related impairments and behavioral changes, showcasing the coexistence of features from both domains within the same individual. This study suggests FTD also presents across a continuum of severity and symptom distress, both within and across variants. The intensity of distress evident in clinical notes tends to cluster with more co-occurring conditions. This examination of phenotypic heterogeneity in clinical notes indicates that sensitivity to FTD diagnosis may be correlated to overall symptom distress, and future work incorporating NLP and phenotyping may help promote strategies for early detection of FTD.

Sex differences for clinical correlates of substantia nigra neuron loss in people with Lewy body pathology

BackgroundLewy body dementia (LBD) phenotype is associated with the presence and degree of Lewy body, Alzheimer’s pathologies, and substantia nigra neuron loss. Nigral neuron loss is associated with parkinsonism in LBD, and females with LBD are less likely than males to have parkinsonism. As sex differences were reported for clinical correlates of Lewy body and Alzheimer’s pathologies, we aimed to investigate whether there are also sex differences for correlates of nigral neuron loss.MethodsData were obtained from the National Alzheimer’s Coordinating Center for females (n = 159) and males (n = 263) with brainstem, limbic, and neocortical Lewy body pathology. Sex differences for the nigral neuron loss’ association with Lewy body pathology staging and core clinical LBD features (cognitive fluctuations, visual hallucinations, rapid eye movement sleep behavior disorder, parkinsonism) during follow-up were analyzed with generalized linear models adjusting for age and Alzheimer’s pathology staging. Whether any of the core clinical features at the time of dementia onset can predict underlying nigral neuron loss for females and males were also analyzed with generalized linear models.ResultsCompared to males, females died older and had higher levels of Braak tau staging, but had similar levels of Lewy body pathology staging and nigral neuron loss. Females were less likely than males to have a clinical Lewy body disease diagnosis during follow-up. More advanced Lewy body pathology staging was associated with more nigral neuron loss, more so for males than females. More nigral neuron loss was associated with parkinsonism and clinical LBD diagnosis during follow-up, more so for males than females. Across the subgroup with dementia (40 females, 58 males), core LBD features at first visit with dementia were not associated with nigral neuron loss.ConclusionsNigral neuron loss’ association with Lewy body pathology staging and core LBD features can differ by sex. Compared to males, females with Lewy body pathology have a higher risk of underdiagnosis. There is a need to elucidate the mechanisms underlying sex differences for pathology and clinicopathological correlations to advance diagnostic and therapeutic efforts in LBD.

Proxy-analysis of the genetics of cognitive decline in Parkinson’s disease through polygenic scores

Cognitive decline is common in Parkinson’s disease (PD) and its genetic risk factors are not well known to date, besides variants in the GBA and APOE genes. However, variation in complex traits is caused by numerous variants and is usually studied with genome-wide association studies (GWAS), requiring a large sample size, which is difficult to achieve for outcome measures in PD. Taking an alternative approach, we computed 100 polygenic scores (PGS) related to cognitive, dementia, stroke, and brain anatomical phenotypes and investigated their association with cognitive decline in six longitudinal cohorts. The analysis was adjusted for age, sex, genetic ancestry, follow-up duration, GBA and APOE status. Then, we meta-analyzed five of these cohorts, comprising a total of 1702 PD participants with 6156 visits, using the Montreal Cognitive Assessment as a cognitive outcome measure. After correction for multiple comparisons, we found four PGS significantly associated with cognitive decline: intelligence (p = 5.26e–13), cognitive performance (p = 1.46e–12), educational attainment (p = 8.52e–10), and reasoning (p = 3.58e–5). Survival analyses highlighted an offset of several years between the first and last quartiles of PGS, with significant differences for the PGS of cognitive performance (5 years) and educational attainment (7 years). In conclusion, we found four PGS associated with cognitive decline in PD, all associated with general cognitive phenotypes. This study highlights the common genetic factors between cognitive decline in PD and the general population, and the importance of the participant’s cognitive reserve for cognitive outcome in PD.

Evaluating the Causal Effect of Type 2 Diabetes on Alzheimer's Disease Using Large-Scale Genetic Data.

Alzheimer's disease (AD) has a high comorbidity with type 2 diabetes (T2D). However, there is still some controversy over whether T2D has a causal impact on AD at present. We aimed to reveal whether T2D has a causal effect on AD using large-scale genetic data. Firstly, we performed a primary two-sample Mendelian randomization (MR) analysis to assess the potential causal effects of T2D on AD. For this analysis, we used the largest available genome-wide association studies (GWAS) T2D (T2D1, including 80,154 cases and 853,816 controls) and AD (AD1, including 111,326 cases and 677,663 controls) datasets. Additionally, we performed a validation MR analysis using two largely overlapping-sample datasets from FinnGen, including T2D (T2D2, including 57,698 cases and 308,252 controls) and AD (AD2, including 13,393 cases and 363,884 controls). In all MR analyses, the inverse variance-weighted method was used as the primary analysis method, supplemented by the weighted-median and MR-Egger techniques. In the primary analysis, we found that T2D was not associated with the risk of AD (OR: 0.98, CI: 0.95-1.01, P=0.241). Similarly, no significant association was detected in the validation MR analysis (OR: 0.97, CI: 0.64-1.47, P=0.884). Our findings provide robust evidence that T2D does not have a causal impact on AD. Future studies need to further explore the effect of T2D on the non-AD components of the dementia phenotype.

Parkinson Disease: Pathophysiology and Histopathological Overview

Parkinson's disease (PD) is distinguished by bradykinesia, stiffness, postural instability, and tremor. The syndrome can be caused by several pathological processes, but the characteristic pathological feature of Parkinson's disease is neurodegeneration accompanied by the presence of α-synuclein neuronal aggregates known as Lewy bodies. LBs and Lewy neurites are insoluble accumulations composed mainly of phosphorylated-synuclein, and they are distributed extensively in both the central and peripheral nervous systems. The distribution of Lewy bodies (LBs) may have a role in determining the phenotype of Lewy body dementia (LBD). Common misdiagnoses for ailments that are pathologically similar include Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, frontotemporal lobar degeneration, Creutzfeldt–Jakob disease, cerebrovascular illnesses, and essential tremor. This study examines the progression of pathology in cases of accidental and symptomatic Parkinson's disease, proposing a staging technique that is based on the easily identifiable spatial distribution of the lesions.

Biomarkers associated with the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive degenerative neurological illness with insidious onset. Due to the complexity of the pathogenesis of AD and different pathological changes, the clinical phenotypes of dementia are diverse, and these pathological changes also interact with each other. Therefore, it is of great significance to search for biomarkers that can diagnose these pathological changes to improve the ability to monitor the course of disease and treat the disease. The pathological mechanism hypothesis with high recognition of AD mainly includes the accumulation of β-amyloid (Aβ) around neurons and hyperphosphorylation of tau protein, which results in the development of neuronal fiber tangles (NFTs) and mitochondrial dysfunction. AD is an irreversible disease; currently, there is no clinical cure or delay in the disease process of drugs, and there is a lack of effective early clinical diagnosis methods. AD patients, often in the dementia stages and moderate cognitive impairment, will seek medical treatment. Biomarkers can help diagnose the presence or absence of specific diseases and their pathological processes, so early screening and diagnosis are crucial for the prevention and therapy of AD in clinical practice. β-amyloid deposition (A), tau pathology (T), and neurodegeneration/neuronal damage (N), also known as the AT (N) biomarkers system, are widely validated core humoral markers for the diagnosis of AD. In this paper, the pathogenesis of AD related to AT (N) and the current research status of cerebrospinal fluid (CSF) and blood related biomarkers were reviewed. At the same time, the limitations of humoral markers in the diagnosis of AD were also discussed, and the future development of humoral markers for AD was prospected. In addition, the contents related to mitochondrial dysfunction, prion virology and intestinal microbiome related to AD are also described, so as to understand the pathogenesis of AD in many aspects and dimensions, so as to evaluate the pathological changes related to AD more comprehensively and accurately.

Sporadic behavioral phenotype of Right Temporal Variant of Frontotemporal Dementia: a case report

AbstractBackgroundThere are two subtypes of the right Temporal Variant of Frontotemporal Dementia (rtv‐FTD). Semantic dementia (SMD) phenotype is defined by negative familiar history, word‐finding, anomia, comprehension difficulties, prosopagnosia, and topographagnosia. The behavioral frontotemporal dementia (bvFTD) phenotype is defined by personality changes, inappropriate behaviors, positive family history, and relatively poor performance on neurobehavioral testing with better performance on confrontational naming tests. (1) We present a rare interesting case.MethodWe describe the clinical and imaging features of a man who presented a sporadic behavioral phenotype of rtv‐FTD, showing negative genetic results.ResultA 62‐year‐old man with 8 years of progressive behavioral impairment. He showed personality changes, and compulsive‐like / ritualistic behaviors such as excessive unpurposed accumulation of items, washing hands repeatedly every five minutes, and walking and wandering repeatedly in circles. He also had hiperorality, cravings for sweet foods, social cognition impairment, associated with loss of empathy, and inappropriate social behavior (hypersexuality, verbal aggressivity to unrelated people, and talking bad words to neighbors with no reason). After years he followed with mild to moderate apathy. The neuropsychological evaluation showed impairment of executive functioning, episodic memory impairment, and MMSE 19/30. The neurological exam was unremarkable, and the familiar history was negative. Brain MRI revealed frontotemporal atrophy with a marked asymmetry in the right temporal lobe. The genetic testing was negative, illustrating and sporadic case.ConclusionTheoretically, rtv‐FTD is considered a right variant of semantic phenotype, and the general assumption is that is also a sporadic disorder. Although the behavioral phenotype of rtv‐FTD normally has a genetic basis, showing positive family history, It can be presented as a sporadic disorder with non‐familial variants of FTD, as in this case. (2)

Improving dementia phenotype prediction with functional mapping of genetic data in non‐European ancestries

AbstractBackgroundMany common genetic variants have been associated with dementia, but their ability to predict dementia prospectively is unknown, especially in non‐European ancestral populations. We sought to optimize dementia risk prediction models with machine learning in individuals of diverse genetic ancestries.MethodSamples were selected from the University of California Los Angeles Health System with their electronic health records (EHRs) and linked genetic data. Dementia phenotype was defined using diagnosis codes and mapped phecodes. Polygenic risk scores (PRSs) were built using summary statistics of different population‐based genome‐wide association studies (GWASs). Independent significant and functionally mapped single nucleotide polymorphisms (SNPs) were identified using the FUMA tool. Logistic regression models were built with 1) APOE status, 2) a single PRS, or 3) multiple PRSs. The model with age and sex only was built as the baseline model. We trained LASSO models to determine dementia risk SNPs from weighted SNP‐level genetic data. We compared the predictive performance of these models after five‐fold cross‐validation with area under precision‐recall curve (AUPRC) and area under receiver operating characteristic (AUC). Finally, identified risk SNPs were mapped to genes for biological interpretation.ResultThere were 975 individuals included in the final Hispanic Latinx American ancestry sample, of which 9.44% (N = 92) were dementia cases. The model with LASSO‐selected functional mapped SNPs from multiple neurodegenerative diseases GWASs outperformed all other genetic risk score models (AUPRC: 0.39, AUROC: 0.87), resulting in a 19.6% increase in AUPRC from the best PRS model, and a 26.9% increase from the baseline model. The best‐performing LASSO model included nine SNPs, mostly located in the 19q13, 4p15, and 17q21 regions. Results of mapped genes not only revealed well‐known risk genes of dementia but identified risk genes from other neurodegenerative diseases.ConclusionWe demonstrated that building genetic risk scores with trans‐ancestry GWAS and selecting potential causal SNPs can be beneficial for dementia prediction in non‐European ancestry populations. Further training using machine learning methods with functionally mapped SNP‐level genetic data showed significant improvement in predictive power compared to PRS models. Genetic risks of multiple neurodegenerative diseases may contribute to the predisposition to dementia.

The auditory phenotype of behavioural variant frontotemporal dementia

AbstractBackgroundPatients with behavioural variant frontotemporal dementia commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.MethodThe QSTAC was administered to 15 patients with behavioural variant frontotempoal dementia, 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also had pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.ResultAfter accounting for nonverbal executive and peripheral hearing performance, patients with behavioural variant frontotemporal dementia showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with behavioural variant frontotemporal dementia were further differentiated from primary progressive aphasia patients on their performance across QSTAC (sound recognition and localisation) subtests.ConclusionBehavioural variant frontotemporal dementia has a distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.

Disambiguating the macro‐scale anatomy of dysexecutive and behavioral degenerative diseases of the mind

AbstractBackgroundThere is a longstanding ambiguity regarding the clinical diagnosis of dementia syndromes predominantly targeting executive functions versus behavior/personality. This is due to a lack of knowledge about the macro‐scale anatomy underlying these symptomatologies, a partial overlap in clinical features, and the fact that a single underlying pathology can give rise to both phenotypes and vice‐versa.MethodWe included data from patients with genetic, biomarker, and/or autopsy evidence for fronto‐temporal lobar degeneration (FTLD) diagnosed with behavioral variant fronto‐temporal dementia (bvFTD, n = 30) and patients with biomarker and/or autopsy evidence for Alzheimer’s disease (AD) pathology diagnosed with either an initial and predominant dysexecutive (dAD, n = 52), behavioral (bvAD, n = 7), or amnestic (aAD, n = 28) syndrome. We assessed group‐wise differences in clinical/cognitive features and 18Fluorodeoxyglucose‐positron emission tomography (FDG‐PET) patterns. This was followed by a spectral covariance decomposition between FDG‐PET images to yield latent patterns of relative metabolism (“eigenbrains”). These eigenbrains were subsequently linked to clinical/cognitive data and meta‐analytic topics reflecting a wide range of mental abilities. We used a linear discriminant analysis (LDA) to perform eigenbrain‐based diagnostic predictions.ResultdAD and bvFTD patients were the youngest at symptom onset, followed by bvAD, then aAD. dAD patients had worse cognitive performance on nearly all cognitive domains compared to other groups. Hypometabolism was observed across associative cortices in dAD, temporo‐parietal areas in aAD, and fronto‐temporal areas in bvFTD and bvAD (Fig. 1). The spectral covariance decomposition yielded nine eigenbrains which explained 61% of the variance in patterns of FDG‐PET, and only the first three are presented (Fig. 2). These eigenbrains revealed that relative hypometabolism in association cortices, notably lateral parietal areas, associated with dysexecutive symptomatology and a lower likelihood of behavior/personality problems, whereas relative hypometabolism restricted to frontal and temporopolar areas showed opposite associations. The LDA yielded an accuracy of 82.1% in predicting diagnostic category (Fig. 3).ConclusionThis study suggests distinct macro‐scale underpinnings underlying predominant dysexecutive versus behavioral symptomatology in degenerative dementia phenotypes. This has implication for the implementation of clinical and research criteria for these dementia syndromes and highlights the importance of data‐driven techniques to inform the classification of degenerative diseases.

Challenges with phenotyping dementia in a low resource setting; Frontotemporal dementias (FTDs) as a case study in Nigeria

AbstractBackgroundPhenotyping dementia is a major problem in low resource settings like Nigeria and it has implication for research and management of people with dementia. Challenges associated with phenotyping dementia are embedded in poor health financing and lack of health personnel. This study aimed at scoping studies on dementia in Nigeria to identify those related to frontotemporal dementia (FTD) and describe the pattern of its presentation in a memory clinic as a means of highlighting challenges of phenotyping.MethodA literature search of studies on dementia that reported FTDs as a phenotype and or described profile or pattern of FTDs in Nigeria was conducted. In addition, a review of hospital records of all persons clinically diagnosed with dementia (PWD) using the ICD 10 criteria was conducted. Those with FTD phenotypes were identified. The cohort comes from a memory clinic in University College Hospital, Ibadan, Nigeria. Records of these individuals with FTDs were reviewed and data (including sociodemographic details, clinical profile and pattern of presentation) extracted for case series report.ResultsLiterature search yielded 2 studies; a retrospective study that reported dementia phenotypes including FTD and a case report. From a total of 216 PWD, we identified and included 14 persons with FTDs (6.5%) in this case series. Initially, 32 records of tentative diagnosis of FTD were identified, however, 18 persons with incomplete evaluation after the initial assessment were excluded. The mean age (±S.D) of those included (n = 14) is 67.7(±8.4). The main presenting complaints were behavioral with 57.1% presenting to the hospital at least a year after onset of symptoms. The most common behavioral problem identified was personality change accompanied with disinhibition in 9 persons (64.3%). Symptoms started before age 60 years in only one person. Two of the 14 persons had an initial diagnosis of schizophrenia until subsequent review with neuroimaging. Delay in carrying out neuroimaging due to financial constraint was a major challenge in making a diagnosis.ConclusionThere is paucity of data on FTDs in Nigeria. Out‐of‐pocket payment for assessment is a major setback in phenotyping dementia and it has implication on both clinical practice and research.