Early-onset Dementia Research Articles

57 Clinical Utility of Neuropsychological Evaluation in the Differential Diagnosis Between Late-Onset Primary Progressive Aphasia Semantic Variant (PPA-SV) Versus Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE): A Case Report

Objective:Primary progressive aphasia semantic variant (PPA-SV) is an atypical dementia subtype on the frontotemporal dementia (FTD) spectrum. PPA-SV is clinically defined by naming and semantic deficits, with progressive language decline that generalizes to other domains over time. Typically, it presents as an early-onset dementia with TDP-43 pathology, but 33-46% of PPA-SV cases display initial onset after age 65 with potentially different clinical features. Limbic Predominant Age-Related TDP-43 Encephalopathy (LATE), a more recently discovered neurodegenerative entity, is defined by an older age of onset, hippocampal sclerosis/atrophy, and TDP-43 pathology with a gradually progressive amnestic profile that expands to other cognitive deficits over time. The authors present a case report with overlapping features and suspected TDP-43 neuropathology ante-mortem for two reasons: first, to highlight the need for clinical criteria to formally diagnose LATE, and second, to address a gap in the literature on the possible clinical differences of late-onset PPA-SV.Participants and Methods:The authors present a case of a 78-year-old Indian bilingual man (English dominant) with 18 years of education, noncontributory medical history, and gradually progressive cognitive complaints reported over the past few years who was seen for outpatient neuropsychological evaluation. Prior workup was notable for negative amyloid PET scan, negative p-tau 217 blood test, and abnormal brain MRI revealing marked bilateral hippocampal atrophy with ex vacuo ventriculomegaly and minimal cerebrovascular disease. He scored 23/30 on prior MMSE, was diagnosed with amnestic MCI, prescribed Namenda and Exelon, and complained of minor memory and word-finding difficulties with reportedly intact IADLs and no signs of NPH.Results:Neuropsychological testing revealed a profound dysnomia (RBANS Naming raw score = 1/10), and he provided 0 words on two semantic fluency tasks but 15 words on letter fluency. Receptive vocabulary score was also impaired (PPVT-4, <1st %). Memory performance also demonstrated rapid forgetting of information (RBANS List Recall raw = 0/10, Story Recall raw = 0/12) with no benefit to recognition cues (RBANS List Recognition raw = 12/20), but slightly better visual memory recall, albeit still impaired (RBANS Figure Recall raw = 4/20). Grooved pegboard scores were significantly worse with right-hand than left-hand. Irregular word reading (NAART = 16th %ile) was significantly below expectations and thought to reflect more of a surface dyslexia rather than a cultural confounder given that he has lived in the US for over 50 years and his occupational and educational history was completed in English.Conclusions:Results support the clinical utility of neuropsychological evaluation in the differential diagnosis to support a predominant clinical syndrome of PPA-SV despite overlapping features with LATE and suspected TDP-43 pathology. This case report highlights the diagnostic issue with the lack of literature describing the typical clinical progression or suggested diagnostic criteria of LATE. These findings also indicate that late-onset PPA-SV may include greater memory deficits earlier in the course, but this may also be a clinical masquerade that is more reflective of the extent of language deficits. Further research on late-onset manifestations of PPA-SV and LATE consensus clinical guidelines is advised.

Digestive System Diseases, Genetic Risk, and Incident Dementia: A Prospective Cohort Study

Introduction: Although digestive system disease affects gut microbiota and their metabolites associated with dementia risk, the association between digestive system diseases and incident dementia has not yet been established. Methods: This cohort analysis included 458,181 participants free of baseline dementia in the UK Biobank (2006-2021). The associations of fourteen digestive system diseases with dementia incidence were examined in 2022 using Cox proportional hazards regression models. Analyses were performed to differentiate the associations for early- (< 65 years) and late-onset (≥ 65 years) dementia. Interaction and stratification analyses were performed for polygenic risk score (RPS), and apolipoprotein E (APOE). Results: During a median follow-up of 12.4 years, 6415 incident dementia cases were diagnosed. Eleven digestive system diseases showed significant associations with an increased risk of dementia after controlling for covariates and multiple testing. Compared to individuals without digestive system diseases, the hazard ratios of dementia increased from 1.15 (95% confidence interval 1.09-1.23) for patients with intestinal diverticular disease to 2.31 (95% confidence interval 1.98-2.70) for patients with cirrhosis. The associations were different between certain digestive system diseases and dementia by onset age. The associations appeared to be stronger for cirrhosis (Q = 0.001), irritable bowel syndrome (Q < 0.001), gastritis and duodenitis (Q =0.002), gastroesophageal reflux disease (Q < 0.001), ulcerative colitis (Q=0.047), gallbladder disease (Q=0.012) and peptic ulcer (Q = 0.030) with early-onset dementia. There were no interactions for PRS or APOE (P >0.05). Conclusions: These findings suggest an increased need for dementia prevention among patients with digestive system diseases.

Depressive/Anxiety Disorders in People with Early Onset Dementia in South Korea

Abstract Background Early-onset dementia (EOD) relatively occurs at a young age. We know that the burden of family care and difficulties in economic activities greatly affect not only EOD but also the family. However, the healthcare policy for EOD is still less than that for late-onset dementia (LOD). In addition, there are few studies on mental disorders of EOD using national data in South Korea. We aimed to analyze the current status of depressive/anxiety disorders in EOD using national data and provide basic data for establishing EOD mental healthcare services and policies. Methods A total of 3,882,915 EOD and LOD with depressive/anxiety disorders were compared for gender, residential area, health insurance premium, and type of insurance using NHIS DB (National Health Insurance Service Database) from 2016 to 2021. Results There were differences according to socio-economic demographic factors for both depressive/anxiety disorders. During the observation period, the diagnosis rate of depressive/anxiety disorders in EOD was higher than LOD. After adjusting for gender, residential area, health insurance premium, and type of insurance, the risk of depressive disorder was 1.87 times higher (i.e., EOD higher, adjusted odds ratio [aOR]: 1.87, 95% confidence interval [CI]: 1.78-1.95) among EOD compared to LOD. The risk of anxiety disorder was 1.24 times higher (aOR: 1.24, 95% CI: 1.16-1.32) among EOD compared to LOD. Conclusions During the observation period, the diagnosis rate and risk of depressive/anxiety disorders in EOD were much higher than LOD. Therefore, this study suggests that mental healthcare services for EOD should be provided, treatment burden and economic difficulties should be reduced, and additional research on preventing and treating mental disorders should be conducted. Key messages • The diagnosis rate and risk of depressive/anxiety disorders in EOD were much higher than LOD. • The healthcare policy for EOD is still less than that for LOD.

B - 103 Early Onset Frontotemporal Dementia: a Neuropsychological Case Study.

A neuropsychological case review of Early-Onset Frontotemporal Dementia (FTD) utilizing the Meyers Neuropsychological Battery (MNB). FTD is a degeneration of brain nerve cells resulting in behavioral deterioration and other effects upon personality and brain functions. Due to early onset of FTD, diagnostic ambiguity is often the case. The current case was a patient referred by neurology to rule-out adult ADHD/LD. The patient is a 51-year-old, Caucasian, right-handed male. Initially, his symptoms were sleep changes, anxiety, reduced attention concentration, and memory. The medical community indicated the possibility of an undiagnosed ADHD condition. MRI and EEG of the brain revealed an arachnoid cyst and focal slowing in the left temporal region. In addition, asymmetric enlargement of the left Sylvian fissure and brain parenchyma were noted. MNB neurocognitive findings were diffuse and revealed lateralized motor impairments in primary and psychomotor abilities. MNB Premorbid Estimate (T-48), OTBM (T-31), and DTBM (T-27) were comparatively significant. Psychological findings were consistent with an anxiety disorder. Contrary to the medical community diagnostic initial impression, ADHD was ruled out. MNB revealed a pattern of findings consistent with a neurodegenerative condition (FTD, Cor. = 0.74, Conf. = 0.80). This study highlights the importance of administering a full thorough neuropsychological examination rather than assessing the patient's complaints of "reduced attention concentration." FTD is statistically increasing, hence the importance to fully evaluate across the lifespan, especially in consideration to early onset FTD.

A - 21 Sex Differences in Cortical Thickness and Cognition in Individuals with Autosomal Dominant Alzheimer's Disease.

Cortical thinning is a marker of neurodegeneration. Individuals with autosomal dominant Alzheimer's disease (ADAD) develop early-onset dementia with virtually 100% certainty. Cortical thickness fluctuates across the ADAD lifespan, from early-life increased thickness to atrophy proximal to clinical onset. Females have higher cortical thickness and better cognition than males as they age. We examined sex differences in cortical thickness and cognitive performance in adults with ADAD. We assessed 85 Presenilin-1 E280A mutation carriers (74 cognitively-unimpaired, 11 mildly-impaired) from the Colombia-Boston Biomarker Study of ADAD. Mean age was 35.7 (SD = 10), education 10.2 (SD = 9), and 55 were female. Global cognition was measured using Mini-Mental State Examination (MMSE), and memory using CERAD Word List Delayed Recall. Participants underwent structural brain MRI. T-tests assessed between-group differences. Pearson correlations examined associations between cortical thickness and cognition. There were no sex differences in cortical thickness or cognitive performance (all ps > =0.05). For carriers, greater cortical thickness was associated with higher MMSE (r = 0.40, p < 0.001) and memory recall scores (r = 0.43, p < 0.01). Female carriers drove this effect, where greater cortical thickness was associated with higher MMSE (r = 0.46, p < 0.001) and memory recall scores (r = 0.47, p < 0.001); these associations were non-significant in male carriers alone. In cognitively-unimpaired female carriers, increased cortical thickness was associated with worse MMSE (r = -0.44, p < 0.001). We found sex differences in the relation between cortical thickness and cognition in ADAD carriers, which may be relevant to the differential vulnerability and progression of ad in females and males. Future work should investigate potential underlying mechanisms contributing to this sex difference.

H - 06 Associations between Non-verbal Reasoning Abilities and Brain Pathology in a Colombian Cohort with Autosomal Dominant Alzheimer's Disease.

Declines in non-verbal reasoning abilities have been linked to Alzheimer's disease (ad) progression. Individuals with autosomal dominant ad (ADAD) are genetically determined to develop early-onset dementia. We examined the relation between non-verbal reasoning abilities and brain pathology in a Colombian cohort with ADAD due to the Presenilin-1 (PSEN1) E280A mutation. A total of 25 carriers of the PSEN1 E280A mutation (16 cognitively-unimpaired carriers [x- age = 35.25 +/- 4.04]; 9 with mildly impaired (age = 45.56 +/- 2.60), and 27 non-carriers (age = 36.11 +/- 5.59) were included. A summary non-verbal reasoning score was calculated from performance on the Judgment of Line Orientation and the Spanish WAIS-IV Matrix Reasoning and Visual Puzzles subtests. Participants also completed the Mini-mental State Examination (MMSE) and underwent amyloid and tau PET imaging. Mann-Whitney U test and education-adjusted Spearman partial correlations were used to examine group differences and associations between pathology levels and non-verbal reasoning. Compared to carriers, non-carriers had higher MMSE and non-verbal reasoning scores (p = 0.006). In carriers only, lower non-verbal reasoning was associated with greater mean cortical amyloid (r = -0.427, p = 0.037) and greater precuneus tau (r = -0.516, p = 0.010). No significant associations were observed after excluding the impaired carriers from the analyses. Our findings suggest that changes in non-verbal reasoning abilities are evident in early symptomatic ADAD stages and are related to ad brain pathology. Future longitudinal work is needed to characterize the progression of non-verbal reasoning deficits in ADAD. Future research should also examine performance between older adults and people at risk for sporadic ad.

Utility of the INECO Frontal Screening and the Frontal Assessment Battery in detecting executive dysfunction in early-onset cognitive impairment and dementia.

The INECO Frontal Screening (IFS) and the Frontal Assessment Battery (FAB) are executive dysfunction (ED) screening tools that can distinguish patients with neurodegenerative disorders from healthy controls and, to some extent, between dementia subtypes. This paper aims to examine the suitability of these tests in assessing early-onset cognitive impairment and dementia patients. In a memory clinic patient cohort (age mean = 57.4 years) with symptom onset at ≤65 years, we analyzed the IFS and the FAB results of four groups: early-onset dementia (EOD, n = 49), mild cognitive impairment due to neurological causes (MCI-n, n = 34), MCI due to other causes such as depression (MCI-o, n = 99) and subjective cognitive decline (SCD, n = 14). Data were gathered at baseline and at 6 and 12 months. We also studied the tests' accuracy in distinguishing EOD from SCD patients and ED patients from those with intact executive functioning. Correlations with neuropsychological measures were also studied. The EOD group had significantly (p < .05) lower IFS and FAB total scores than the MCI-o and SCD groups. Compared with the FAB, the IFS showed more statistically significant (p < .05) differences between diagnostic groups, greater accuracy (IFS AUC = .80, FAB AUC = .75, p = .036) in detecting ED and marginally stronger correlations with neuropsychological measures. We found no statistically significant differences in the EOD group scores from baseline up to 6- or 12-months follow-up. While both tests can detect EOD among memory clinic patients, the IFS may be more reliable in detecting ED than the FAB.

Radiotherapy-induced vascular cognitive impairment 20 years after childhood brain tumor.

Studies have established that radiotherapy for childhood brain tumors (BTs) increases the risk of cerebrovascular disease (CVD); however, it is unclear how this will affect cognitive function. This study aimed to investigate the associations between radiotherapy-induced CVD, white matter hyperintensities (WMHs), and neurocognitive outcomes in adult survivors of childhood BTs. In a cross-sectional setting, we conducted a national cohort that included 68 radiotherapy-treated survivors of childhood BTs after a median follow-up of 20 years. Markers of CVD and WMHs were evaluated using brain MRI, and the sum of CVD-related findings was calculated. Additionally, the associations among CVD findings, WMHs, and neuropsychological test results were analyzed. Of the 68 childhood BT survivors, 54 (79%) were diagnosed with CVD and/or WMHs at a median age of 27 years. CVD and/or WMHs were associated with lower scores for verbal intelligence quotient, performance intelligence quotient (PIQ), executive function, memory, and visuospatial ability (P < .05). Additionally, survivors with microbleeds had greater impairments in the PIQ, processing speed, executive function, and visuospatial ability (P < .05). WMHs and CVD burden were associated with greater difficulties in memory function and visuospatial ability (P < .05). Small-vessel disease burden was associated with PIQ scores, processing speed, working memory, and visuospatial ability. The study results suggest that markers of radiotherapy-induced CVD, the additive effect of CVD markers, and risk factors of dementia are associated with cognitive impairment, which may suggest that the survivors are at a high risk of developing early-onset dementia.

Leisure-Time Television Viewing and Computer Use, Family History, and Incidence of Dementia

Introduction: Time spent on screen-based sedentary activities is significantly associated with dementia risk, however, whether the associations vary by family history (FHx) of dementia is currently unknown. We aimed to examine independent associations of two prevalent types of screen-based sedentary activities (television [TV] viewing and computer use) with dementia and assess the modifying effect of FHx. Methods: We included 415,048 individuals free of dementia from the UK Biobank. Associations of TV viewing, computer use, and FHx with dementia risk were determined using Cox regression models. We estimated both multiplicative- and additive-scale interactions between TV viewing and computer use and FHx. Results: During a median follow-up of 12.6 years, 5,549 participants developed dementia. After adjusting for potential confounding factors, we observed that moderate (2–3 h/day; hazard ratio [HR] 1.13, 95% confidence interval 0.03–1.23) and high (>3 h/day; 1.33, 1.21–1.46) TV viewing was associated with a higher dementia risk, compared with low (0–1 h/day) TV viewing. Using restricted cubic spline models, the relationship of TV viewing with dementia was nonlinear (relative to 0 h/day; p for nonlinear = 0.005). We found that >3 h/day of TV viewing was associated with a 42% (1.42, 1.18–1.71) higher dementia risk in participants with FHx while a 30% (1.30, 1.17–1.45) in those without FHx. For computer use, both low (0 h/day; 1.41, 1.33–1.50) and high (>2 h/day; 1.17, 1.05–1.29) computer use were associated with elevated dementia risk, compared with moderate (1–2 h/day) computer use. We observed a J-shaped relationship with dementia (relative to 2 h/day; p for nonlinear <0.001). Compared with 1–2 h/day of computer use, the HRs of dementia were 1.46 (1.29–1.65) and 1.10 (0.90–1.36) for 0 h/day and >2 h/day of computer use in participants with FHx, respectively, while the corresponding HRs were 1.40 (1.30–1.50) and 1.19 (1.06–1.33) in those without FHx. We observed a positive additive interaction (RERI 0.29, 0.06–0.53) between computer use and FHx, while little evidence of interaction between TV viewing and FHx. Conclusions: The time spent on TV viewing and computer use were independent risk factors for dementia, and the adverse effects of computer use and FHx were additive. Our findings point to new behavioral targets for intervention on preventing an early onset of dementia, especially for those with FHx.

Brain Sagging Dementia.

Brain sagging dementia (BSD) is a rare but devastating form of early-onset dementia characterized by intracranial hypotension and behavioral changes resembling behavioral variant frontotemporal dementia. This review aims to provide a comprehensive overview of BSD, highlighting its pathomechanism, diagnostic tools, and available treatment options. BSD exhibits a complex clinical manifestation with insidious onset and gradual progression of behavioral disinhibition, apathy, inertia, and speech alterations. Additionally, patients may exhibit brainstem and cerebellar signs such as hypersomnolence and gait disturbance. Although headaches are common, they may not always demonstrate typical orthostatic features. Recent radiological advances have improved the detection of CSF leaks, enabling targeted treatment and favorable outcomes. Understanding the pathomechanism and available diagnostic tools for BSD is crucial for a systematic approach to timely diagnosis and treatment of this reversible form of early-onset dementia, as patients often endure a complex and lengthy clinical course.

External Causes of Death From Death Certificates in Patients With Dementia.

We aim to analyze the risk of death from specific external causes, including falls, complications of medical and surgical care, unintentional injuries, and suicide, in dementia patients. Swedish nationwide cohort study integrating 6 registers from May 1, 2007, through December 31, 2018, including the Swedish Registry for Cognitive/Dementia Disorders (SveDem). Population-based study. Patients diagnosed with dementia from 2007 to 2018 and up to 4 controls matched on year of birth (±3years), sex, and region of residence. The exposures of this study were diagnosis of dementia and dementia subtypes. Number of deaths and causes of mortality were obtained from death certificates compiled into the Cause of Death Register. Hazard ratios (HRs) and 95% CIs were estimated using Cox and flexible models, adjusted for sociodemographics and medical and psychiatric disorders. The study population included 235,085 patients with dementia [96,760 men (41.2%); mean age 81.5 (SD 8.5) years] and 771,019 control participants [341,994 men (44.4%); mean age 79.9 (SD 8.6) years], over 3,721,687 person-years. Compared with control participants, patients with dementia presented increased risk for unintentional injuries (HR 3.30, 95% CI 3.19-3.40) and falls (HR 2.67, 95% CI 2.54-2.80) during old age (≥75y), and suicide (HR 1.56, 95% CI 1.02-2.39) in middle age (<65y). Suicide risk was 5.04 times higher (HR 6.04, 95% CI 4.22-8.66) in patients with both dementia and 2 or more psychiatric disorders relative to controls (incidence rate per person-years, 1.6 vs 0.3). For dementia subtypes, frontotemporal dementia had the highest risks of unintentional injuries (HR 4.28, 95% CI 2.80-6.52) and falls (HR 3.83, 95% CI 1.98-7.41), whereas subjects with mixed dementia were less likely to die from suicide (HR 0.11, 95% CI 0.03-0.46) and complications of medical and surgical care (HR 0.53, 95% CI 0.40-0.70) compared to controls. Suicide risk screening and psychiatric disorders management in early-onset dementia and early interventions for unintentional injuries and falls prevention in older dementia patients should be provided.

Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia.

Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant frontotemporal dementia. This retrospective analysis drew its population from two clinical samples recruited from memory clinics at university hospitals in the USA and The Netherlands. Individuals with sporadic behavioural variant frontotemporal dementia were enrolled between 2000 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. The study population consisted of 186 individuals with sporadic behavioural variant frontotemporal dementia (113 males and 73 females), mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus [60.2 years (8.54)] versus individuals who did not [57.76 (8.05)], 95% confidence interval > 0.41, P = 0.02. Education was not associated with age at onset (β = -0.05, P = 0.75). The presence of a right paracingulate sulcus was associated with an 83% increased risk of death per year after age at onset (hazard ratio 1.83, confidence interval [1.09-3.07], P < 0.02), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus (P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant frontotemporal dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant frontotemporal dementia that may be important in the design of trials for future therapeutic approaches.

Developing a Gene Therapy for the Treatment of Autosomal Dominant Alzheimer's Disease.

Autosomal dominant Alzheimer's disease (ADAD) is a rare early-onset form of Alzheimer's disease, caused by dominant mutations in one of three genes: presenilin 1, presenilin 2, and amyloid β precursor protein (APP). Mutations in the presenilin 1 gene (PSEN1) account for the majority of cases, and individuals who inherit a single-mutant PSEN1 allele go on to develop early-onset dementia, ultimately leading to death. The presenilin 1 protein (PS1) is the catalytic subunit of the γ-secretase protease, a tetrameric protease responsible for cleavage of numerous transmembrane proteins, including Notch and the APP. Inclusion of a mutant PS1 subunit in the γ-secretase complex leads to a loss of enzyme function and a preferential reduction of shorter forms of Aβ peptides over longer forms, an established biomarker of ADAD progression in human patients. In this study, we describe the development of a gene therapy vector expressing a wild-type (WT) copy of human PSEN1 to ameliorate the loss of function associated with PSEN1 mutations. We have carried out studies in mouse models using a recombinant AAV9 vector to deliver the PSEN1 gene directly into the central nervous system (CNS) and shown that we can normalize γ-secretase function and slow neurodegeneration in both PSEN1 conditional knockout and PSEN1 mutant knockin models. We have also carried out biodistribution studies in nonhuman primates (NHPs) and demonstrated the ability to achieve broad PS1 protein expression throughout the cortex and the hippocampus, two regions known to be critically involved in ADAD progression. These studies demonstrate preclinical proof of concept that expression of a WT human PSEN1 gene in cells harboring a dominant PSEN1 mutation can correct the γ-secretase dysfunction. In addition, direct administration of the recombinant AAV9 into the NHP brain can achieve broad expression at levels predicted to provide efficacy in the clinic.

Frontotemporal lobar degeneration.

Frontotemporal lobardegeneration (FTLD)is one of the most common causes of early-onset dementia and presents with early social-emotional-behavioural and/or language changes that can be accompanied by a pyramidal or extrapyramidal motor disorder. About 20-25% of individuals with FTLD are estimated to carry a mutation associated with a specific FTLD pathology. The discovery of these mutations has led to important advances in potentially disease-modifying treatments that aim to slow progression or delay disease onset and has improved understanding of brain functioning. In both mutation carriers and those with sporadic disease, the most common underlying diagnoses are linked to neuronal and glial inclusions containing tau(FTLD-tau) or TDP-43 (FTLD-TDP), although 5-10% of patients may have inclusions containing proteins from the FUS-Ewing sarcoma-TAF15 family (FTLD-FET). Biomarkers definitively identifying specific pathological entities in sporadic disease have been elusive, which has impeded development of disease-modifying treatments. Nevertheless, disease-monitoring biofluid and imaging biomarkers are becoming increasingly sophisticated and are likely to serve as useful measures of treatment response during trials of disease-modifying treatments. Symptomatic trials using novel approaches such as transcranial direct current stimulation are also beginning to show promise.

Alteration of microglial metabolism and inflammatory profile contributes to neurotoxicity in a hiPSC-derived microglia model of frontotemporal dementia 3

Frontotemporal dementia (FTD) is a common cause of early-onset dementia, with no current treatment options. FTD linked to chromosome 3 (FTD3) is a rare sub-form of the disease, caused by a point mutation in the Charged Multivesicular Body Protein 2B (CHMP2B). This mutation causes neuronal phenotypes, such as mitochondrial deficiencies, accompanied by metabolic changes and interrupted endosomal-lysosomal fusion. However, the contribution of glial cells to FTD3 pathogenesis has, until recently, been largely unexplored. Glial cells play an important role in most neurodegenerative disorders as drivers and facilitators of neuroinflammation. Microglia are at the center of current investigations as potential pro-inflammatory drivers. While gliosis has been observed in FTD3 patient brains, it has not yet been systematically analyzed. In the light of this, we investigated the role of microglia in FTD3 by implementing human induced pluripotent stem cells (hiPSC) with either a heterozygous or homozygous CHMP2B mutation, introduced into a healthy control hiPSC line via CRISPR-Cas9 precision gene editing. These hiPSC were differentiated into microglia to evaluate the pro-inflammatory profile and metabolic state. Moreover, hiPSC-derived neurons were cultured with conditioned microglia media to investigate disease specific interactions between the two cell populations. Interestingly, we identified two divergent inflammatory microglial phenotypes resulting from the underlying mutations: a severe pro-inflammatory profile in CHMP2B homozygous FTD3 microglia, and an “unresponsive” CHMP2B heterozygous FTD3 microglial state. These findings correlate with our observations of increased phagocytic activity in CHMP2B homozygous, and impaired protein degradation in CHMP2B heterozygous FTD3 microglia. Metabolic mapping confirmed these differences, revealing a metabolic reprogramming of the CHMP2B FTD3 microglia, displayed as a compensatory up-regulation of glutamine metabolism in the CHMP2B homozygous FTD3 microglia. Intriguingly, conditioned CHMP2B homozygous FTD3 microglia media caused neurotoxic effects, which was not evident for the heterozygous microglia. Strikingly, IFN-γ treatment initiated an immune boost of the CHMP2B heterozygous FTD3 microglia, and conditioned microglia media exposure promoted neural outgrowth. Our findings indicate that the microglial profile, activity, and behavior is highly dependent on the status of the CHMP2B mutation. Our results suggest that the heterozygous state of the mutation in FTD3 patients could potentially be exploited in form of immune-boosting intervention strategies to counteract neurodegeneration.

Role Identity Transition: A Conceptual Framework for Being the Spouse of a Person With Early Onset Dementia.

Informal caregivers of persons with early onset dementia (PWEOD) are usually the spouses of affected individuals. These caregivers face unique challenges related to the unexpected nature of disease onset at this early life stage along with the accompanying symptoms, which can be different from those in late onset dementia. The current study explores the meanings these caregivers make of their situations and actions in response to their experiences. Findings provide a basis for development of a conceptual framework illustrating the basic, psychosocial processes underlying their shared situation. Grounded theory methodology was used. Qualitative data were collected through semi-structured interviews with 15 participants. Data were analyzed using constant comparative techniques and situational analysis. A distinction was made across participants between identifying as spouse versus caregiver for their PWEOD. Each participant had made or was making an identity transition from viewing their role as becoming more caregiver-like toward an eventual, complete shift to that of caregiver in a stepwise fashion. Incremental shifts in identity reflected challenges to the notion held of what it means to be a spouse. Results support prior research highlighting the unique experiences of caregivers of PWEOD while providing a framework for understanding the unique situations of these care-givers. Findings also inform nursing interventions tailored for spouses of PWEOD. [Journal of Gerontological Nursing, 49(8), 27-34.].

Early onset dementia with parkinsonism in a patient with pathogenic mutations in CSF1R and ABCD1 gene

Early onset dementia with parkinsonism in a patient with pathogenic mutations in CSF1R and ABCD1 gene

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Dementia incidence and population-attributable fraction for dementia risk factors in Republic of Korea: a 12-year longitudinal follow-up study of a national cohort.

We aimed to investigate the incidence of dementia by age and year as well as the population-attributable fractions (PAFs) for known dementia risk factors in Republic of Korea. A 12-year, nationwide, population-based, retrospective cohort study was conducted. We used customized health information from the National Health Insurance Service (NHIS) data from 2002 to 2017. We analyzed age- and sex-adjusted incidence rates and PAF of dementia for each risk factor such as depression, diabetes, hemorrhagic stroke, ischemic stroke, hypertension, osteoporosis and physical inactivity using Levin's formula. Of the 794,448 subjects in the dementia-free cohort, 49,524 (6.2%) developed dementia. Dementia incidence showed annual growth from 1.56 per 1,000 person-years in 2006 to 6.94 per 1,000 person-years in 2017. Of all dementia cases, 34,544 subjects (69.8%) were female and 2,479 subjects (5.0%) were early onset dementia. AD dementia accounted for 66.5% of the total dementia incidence. Considering relative risk and prevalence, physical inactivity attributed the greatest to dementia (PAF, 8.1%), followed by diabetes (PAF, 4.2%), and hypertension (PAF, 2.9%). Altogether, the significant risk factors increased the risk of dementia by 18.0% (overall PAF). We provided the incidence of dementia and PAFs for dementia risk factors in Republic of Korea using a 12-year, nationwide cohort. Encouraging lifestyle modifications and more aggressive control of risk factors may effectively prevent dementia.

MicroRNA-based predictor for diagnosis of frontotemporal dementia.

This study aimed to explore the non-linear relationships between cell-free microRNAs (miRNAs) and their contribution to prediction of Frontotemporal dementia (FTD), an early onset dementia that is clinically heterogeneous, and too often suffers from delayed diagnosis. We initially studied a training cohort of 219 subjects (135 FTD and 84 non-neurodegenerative controls) and then validated the results in a cohort of 74 subjects (33 FTD and 41 controls). On the basis of cell-free plasma miRNA profiling by next generation sequencing and machine learning approaches, we develop a non-linear prediction model that accurately distinguishes FTD from non-neurodegenerative controls in ~90% of cases. The fascinating potential of diagnostic miRNA biomarkers might enable early-stage detection and a cost-effective screening approach for clinical trials that can facilitate drug development.