Frontotemporal Dementia Spectrum Research Articles

Clinical heterogeneity within the ALS-FTD spectrum in a family with a homozygous optineurin mutation.

Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA-binding protein 43 kDa (TDP-43) pathology, in addition to accumulations of tau and alpha-synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole-exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS-FTLD pattern associated with prominent neuronal and oligodendroglial TDP-43 pathology, and an atypical limbic 4-repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). OPTN mutations can be associated with extensive TDP-43 pathology and limbic-predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS-FTD spectrum within the same family.

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.

Clinical spectrum of frontotemporal dementia: schizophrenia-like symptoms and amyotrophic lateral sclerosis (family case study)

Frontotemporal dementia is a heterogeneous pathology with various clinical, histological, and genetic variants. The behavioral variant of frontotemporal dementia (bvFTD) in some cases presents differential diagnostic difficulties when distinguishing from primary mental disorders. The article provides an observation of patient K., who was observed at the initial stage of the disease with a diagnosis of schizophrenia. The comparison of psychopathological and behavioral symptoms with the presence of a family history of amyotrophic lateral sclerosis (ALS) served as a turning point to a different interpretation of the pathology and recognition and confirmation of the “definite diagnosis” — bvFTD.

Neurofilaments Light Chain in Neurodegenerative Dementias: A Review of Imaging Correlates.

Neurofilaments light chain (NfLs) are currently recognized as a marker of axonal injury and degeneration. Their measurement in biological fluids has a promising role in the diagnosis, prognosis, and monitoring of the therapeutic response in neurological diseases, including neurodegenerative dementias. In recent years, their relationship with clinical phenotypes and measures of disease severity has been extensively studied. Here, we reviewed studies investigating the association between NfLs and imaging measures of grey matter (GM) and white matter (WM) damage in neurodegenerative dementias. We identified a large number of studies investigating this association in Alzheimer's disease (AD) and disorders of the frontotemporal dementia (FTD) spectrum. Results were heterogeneous, possibly due to different methodological approaches-both in NfL measurements and imaging analyses-and inclusion criteria. However, a positive association between NfL levels and GM atrophy, WM microstructural disruption, glucose hypometabolism, and protein accumulation emerged invariably, confirming the role of NfLs as a reliable biomarker for neurodegenerative dementias, albeit not specific.

Amyotrophic lateral sclerosis; clinical features, differential diagnosis and pathology.

Amyotrophic lateral sclerosis (ALS) is a late-onset syndrome characterized by the progressive degeneration of both upper motor neurons (UMN) and lower motor neurons (LMN). ALS forms a clinical continuum with frontotemporal dementia (FTD), in which there are progressive language deficits or behavioral changes. The genetics and pathology underlying both ALS and FTD overlap as well, with cytoplasmatic misvocalization of TDP-43 as the hallmark. ALS is diagnosed by exclusion. Over the years several diagnostic criteria have been proposed, which in essence all require a history of slowly progressive motor symptoms, withUMN and LMN signs on neurological examination, clear spread of symptoms through the body, the exclusion of other disorder that cause similar symptoms and an EMG that it is compatible with LMN loss. ALS is heterogeneous disorder that may present in multitude ways, which makes the diagnosis challenging. Therefore, a systematic approach in the diagnostic process is required in line with the most common presentations. Subsequently, assessing whether there are cognitive and/or behavioral changes within the spectrum of FTD and lastly determining the cause is genetic. This chapter, an outline on how to navigate this 3 step process.

Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aβ)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aβ42/40 . GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

DTI changes of thalamic subregions in genetic frontotemporal dementia: findings from the GENFI cohort

AbstractBackgroundAtrophy of thalamic subregions has been observed across the spectrum of frontotemporal dementia (FTD). To gain better insight into underlying tissue changes, we investigated how thalamic subregional fractional anisotropy (FA) and mean diffusivity (MD) derived from diffusion tensor imaging (DTI) are altered in genetic FTD.MethodWe used our newly developed thalamus segmentation tool, which jointly combines structural and diffusion input MRI data, to segment thalami and extract thalamic subregional FA and MD values for 163 genetic mutation carriers and 126 non‐carriers with suitable 3T MRI data from the GENetic FTD Initiative (GENFI). Mutation carriers were divided according to their genetic diagnosis and CDR®+NACC FTLD global scores into presymptomatic/prodromal (≤0.5: 41 C9orf72, 59 GRN, 34 MAPT) and symptomatic (≥1: 8 C9orf72, 11 GRN, 10 MAPT) groups. Mean FA and MD values for thalamic subregions were obtained using diffusion tensors interpolated in the log domain and weighted by segmentation posterior probabilities. Thalamic subregional FA and MD values for presymptomatic and symptomatic mutation carriers within each genetic group were compared with non‐carriers using analysis of covariance with bootstrapping, where age, scanner type, and sex were covariates. We corrected for multiple comparisons and calculated percentage changes in adjusted FA and MD mean values for mutation carriers relative to non‐carriers.ResultThe only significant change at the presymptomatic stage was found for C9orf72 expansion carriers, who showed FA reduction in the intralaminar subregion (5%) (Figure 1, Table 1). In symptomatic C9orf72 expansion carriers, FA was reduced in the laterodorsal (21%), lateral posterior (13%), anteroventral (13%) and intralaminar (11%) subregions. Symptomatic MAPT mutation carriers also showed FA reduction in the laterodorsal (15%) and anteroventral (11%) subregions. No significant FA reductions were found for GRN mutation carriers and no significant MD changes were observed for any group after correction for multiple comparisons.ConclusionWe detected FA reductions of thalamic subregions only for C9orf72 expansion carriers at the presymptomatic stage, and for C9orf72 and MAPT mutation carriers at the symptomatic stage. Combined with the lack of robust MD changes, our findings may warrant further assessment of thalamic microstructure with more advanced diffusion models.

Sleep disturbance associated with temporal lobe degeneration in frontotemporal dementia

AbstractBackgroundSleep abnormalities are increasingly recognized as markers and potential drivers of neurodegenerative proteinopathies. However, the sleep phenotype of less common dementias remains poorly characterised. In particular, clinical experience suggests that patients with focal temporal lobe degeneration in the frontotemporal dementia spectrum can experience sometimes striking sleep disruption. We recently had the opportunity to corroborate this clinical impression in a small series of representative patients participating in a larger cohort study.MethodsTo date, we have studied seven patients and three healthy age‐matched controls. The patients’ diagnoses comprise behavioural variant frontotemporal dementia associated with focal right temporal lobe atrophy (n = 3), semantic dementia associated with focal left temporal lobe atrophy (n = 2), young onset Alzheimer’s disease and logopenic aphasia (each n = 1). No participant had a past history of a clinical sleep disorder. Detailed data on sleep patterns, adapted standard sleep questionnaires (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale), overnight oximetry and neuropsychological test scores (covering domains of executive function, emotion processing, memory, and auditory perceptual learning) pre‐/post‐overnight sleep were collected with the assistance of patients’ caregivers.ResultsTwo patients with right temporal lobe atrophy and one with left temporal lobe atrophy had marked sleep fragmentation, in one right temporal case accompanied by frequent sleep attacks, with increased overall time in bed and/or attempting to sleep. Epworth and Pittsburgh indices in these patients indicated significant daytime sleepiness and reduced sleep quality; none had evidence of significant sleep apnoea on overnight oximetry. Comparatively mild clinical sleep disturbances were reported in patients with other dementia diagnoses. However, there was evidence for reduced auditory perceptual learning benefit from overnight sleep relative to healthy older controls, particularly in the patients with underlying Alzheimer pathology.ConclusionsThese preliminary findings suggest that focal temporal lobe degeneration may be associated with clinically relevant sleep disruption, as part of the more pervasive derangement of homeostasis in these syndromes. Further work is indicated to define the hypnic phenotype in detail, with sleep electrophysiology and correlative behavioural, neuroimaging and laboratory data in larger patient cohorts.

Functional neuroanatomy of music perception in frontotemporal dementia

AbstractBackgroundDespite considerable interest in music as an index of brain function and a therapeutic modality in dementia, the neural correlates of music processing in different dementias remain poorly defined. In the frontotemporal dementia spectrum, behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) are often associated with striking changes in musical function and/or retained musical skills, suggesting frontotemporal dementia may be an instructive disease model in which to assess brain mechanisms of music processing in neurodegenerative pathologies. Here we addressed this issue using activation fMRI in patients with frontotemporal dementia.MethodNineteen patients (10 svPPA, nine bvFTD) and 26 healthy age‐matched controls underwent 3‐Tesla ‘sparse’ fMRI in which they listened passively to musical melodies. In a 2×2 factorial design, stimulus conditions were manipulated to probe two key dimensions of music processing: semantic memory (familiarity: familiar vs. novel melodies) and perceptual features (temporal structure: isochronous vs. anisochronous melodies). Post‐scan behavioral testing assessed participants’ ability to discriminate melodies under each of the two manipulated stimulus dimensions. Information about participant demographics and musical background was also collected.ResultThe healthy older control group showed separable profiles of activation in posterior superior temporal cortex for processing musical temporal structure, and in anterior temporal and inferior frontal cortices for processing musical familiarity. Compared with healthy older listeners, syndromic groups showed differential patterns of engagement of these distributed neural networks. In post‐scan behavioral testing, patients with bvFTD also exhibited significantly impaired musical familiarity judgments relative to healthy controls.ConclusionFrontotemporal dementia syndromes show distinct functional neuroanatomical signatures of music perception. Future work should explore fMRI of music processing as a probe of neural function in particular molecular pathologies and a candidate marker of therapeutic potential in dementia.

Microtubule‐binding region tau fragment tau368 as a biomarker of Alzheimer’s disease

AbstractBackgroundRecent studies suggest that microtubule‐binding region (MTBR) tau fragments may be markers of tau tangles in Alzheimer’s disease (AD) when used in ratio with total tau (MTBR‐tau/T‐tau) to normalize for T‐tau secretion. One such candidate marker is MTBR‐tau containing residue 368 (MTBR‐tau368). In this study, it was cross‐sectionally evaluated in participants from a memory clinic cohort and an autopsy series.MethodsWe included Aβ‐negative cognitively unimpaired (CU) individuals, individuals in the AD continuum (Aβ‐positive CU, mild cognitive impairment (MCI) and AD dementia), and with non‐AD dementia from the BioFINDER‐1 study, who all underwent [18F]‐flortaucipir‐PET. Further, we included CU and CI participants from UCSD Alzheimer’s disease research center (UCSD‐ADRC) who underwent lumbar puncture (LP) antemortem and then donated their brain for autopsy, examining AD neuropathologic change (ADNC) and non‐AD pathologies. All participants had immunoassay‐based CSF measures of T‐tau and MTBR‐tau368 by commercial immunoassays (Euroimmun [BioFINDER‐1] and Lumipulse [UCSD‐ADRC] T‐tau) and an in‐house Single molecule array (Simoa) assay, respectively. Statistical analyses were performed using linear models (covarying for age and sex) and Pearson correlations.ResultsSixty‐seven individuals from UCSD‐ADRC (mean [SD] age at LP 74.3 [8.4] years, 4.3 [2.1] years before death) and 181 from BioFINDER‐1 (72.5 [7.4] years) were included for this study. There were no group‐level differences in MTBR‐tau368 levels alone in any of the cohorts. In the UCSD‐ADRC cohort, MTBR‐tau368/T‐tau was decreased in participants with high (estimated marginal mean [EM = 0.06) vs. low (EM = 0.09, P = 0.01) or no (EM = 0.1, P = 0.001) ADNC and with higher Braak stage (V‐VI; EM = 0.06 vs. III‐IV; EM = 0.08, P<0.05, and I‐II; EM = 0.09, P<0.001). In BioFINDER‐1, Aβ‐positive MCI and AD dementia had lower MTBR‐tau368/T‐tau (EM∼0.04) compared with all other groups (EM = 0.06‐0.07, P<0.05‐<0.001). Further, MTBR‐tau368/T‐tau inversely correlated with tau‐PET in Braak‐like regions III‐IV and V‐VI (r = ‐0.35 and ‐0.42, P<0.001). MTBR‐tau368/T‐tau was unchanged in individuals in the frontotemporal dementia (FTD) spectrum (behavioral variant FTD/semantic dementia, and corticobasal syndrome/progressive supranuclear palsy).ConclusionConcordant with recent data, MTBR‐tau fragments alone do not change in AD or other neurodegenerative disorders. However, when normalizing MTBR fragments to T‐tau secretion, their capability of reflecting the extent of tau pathology provides opportunities of staging AD using CSF biomarkers.

Association of plasma biomarkers with cognitive domains across three neurodegenerative diseases and cerebrovascular disease

AbstractBackgroundIt is critical to better understand the value of plasma biomarkers in predicting cognitive deficits before widespread use as diagnostic and prognostic tools in specialized clinics and as markers of neurodegenerative disease progression in trials. Herein, we investigate their association with five cognitive domains across three common neurodegenerative diseases and cerebrovascular disease.MethodPatients from the curated multi‐site Ontario Neurodegenerative Disease Research Initiative (ONDRI) were included in this study, classified by diagnostic group: Alzheimer’s disease/Mild cognitive impairment (AD/MCI, n = 126, age = 71.0±8.2, 55%M), frontotemporal dementia spectrum disorders (FTD, n = 53, age = 67.8±7.1, 64%M), Parkinson’s disease (PD, n = 140, age = 67.9±6.3, 78%M) and cerebrovascular disease (CVD, n = 161, age = 69.2±7.4, 68%M). Plasma concentrations of Aβ40 and Aβ42 (Aβ42/40 ratio), glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and phosphorylated‐tau181 (p‐tau181) were measured using high‐sensitivity Simoa assays. Scores from a 26‐test comprehensive neuropsychological assessment were used to compute composite z‐scores for five cognitive domains: attention & working memory, executive function, language, memory, and visuospatial function. Linear regression models controlling for age, sex, education and APOE E4 allele were used to test the association between plasma biomarkers and cognitive domains in each group separately.ResultIn AD/MCI, higher levels of GFAP, NfL and p‐tau181 were all associated with worse attention & working memory, executive function, and memory. In PD, higher levels of NfL were associated with worse attention & working memory, executive function, and visuospatial function; higher levels of GFAP were also associated with worse executive function. In CVD, higher levels of GFAP were associated with worse executive function, memory and visuospatial function; higher levels of p‐tau181 were also associated with worse memory. In FTD, no associations were found.ConclusionPlasma biomarkers indicative of neuronal and glial pathology are useful to predict the severity of widespread cognitive deficits in AD/MCI, PD, and CVD. Interestingly, p‐tau181 predicted memory deficits in both AD/MCI and CVD, suggesting potential mixed disease or pathological overlap. Plasma Aβ42/40 does not appear to predict any cognitive deficits in any of the neurodegenerative diseases studied. As FTD is highly heterogeneous and had the least number of patients, we are possibly lacking power to detect effects in this group.

Frequency of repetitive head impacts and influence on clinical variability among male patients with Alzheimer’s disease and frontotemporal dementia

AbstractBackgroundRepetitive head impacts (RHI) occur routinely in sports like American football (AmFootball) and are the most well‐established risk factor for chronic traumatic encephalopathy, a neurodegenerative tauopathy. However, RHI is not routinely evaluated in older adults with other suspected neurodegenerative diseases. The prevalence of RHI among older adults with neurodegenerative diseases and the influence on clinical symptoms is unknown.MethodsRHI was defined by AmFootball participation and analyzed based on frequency of any and “substantial” exposure (> 4 years). The Boston University Head Impact Exposure Assessment was administered to 195 older adult males at the UCSF Memory and Aging Center. Of these 106 (54%) were clinically normal (CN) participants in the Brain Aging Network for Cognitive Health (BRANCH) study and 89 (46%) were cognitively impaired participants from the Alzheimer’s Disease Research Center. Diagnostic groups included AD‐related phenotypes (“clinAD”; amnestic‐predominant MCI/dementia, logopenic PPA; N = 26) and frontotemporal dementia spectrum conditions (“FTD”; behavioral variant FTD, semantic PPA, nonfluent PPA; N = 46). Our aims were: 1) investigate frequency of prior RHI between diagnostic groups (chi square), 2) compare age of symptom onset between participants with and without prior RHI (ANOVA), and 3) evaluate associations between RHI and cognition within the largest single diagnostic group (bvFTD N = 20; ANCOVA adjusted for age and education). Cohen’s d effect sizes are reported.ResultsMales with clinAD (27%; χ2 = 8.3, p = .009; d = 0.53) and FTD (21%; χ2 = 5.6, p = .02, d = 0.40) were more likely than CN (7%) to have had substantial prior RHI. Prior RHI was associated with younger age of symptom onset (62.1±7.6 vs. 56.7±7.7 years old; p = .001, d = 0.69). This effect was stronger within clinAD (63.1±7.2 vs. 53.3±7.5; d = 1.3) than FTD (60.1±7.0 vs. 55.9±6.0; d = 0.54). In participants with bvFTD, those with prior RHI scored significantly worse on memory testing (w‐scores ‐2.6±1.1 vs. ‐1.1±1.2, p = .02, d = 1.4).ConclusionsRHI through AmFootball is more common in AD and FTD than healthy controls. Prior RHI may contribute to variability in age of symptom onset in both AD and FTD. Exposure to RHI may also partly explain why some participants with bvFTD, a classically nonamnestic syndrome, develop memory decline. Prior RHI should be routinely evaluated in neurodegenerative disease workups.

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.

57 Traumatic Brain Injury and Concussion in Patients with Frontotemporal Dementia Spectrum Diagnoses

Objective:Traumatic brain injury (TBI) and concussion are associated with increased dementia risk. Accurate TBI/concussion exposure estimates are relatively unknown for less common neurodegenerative conditions like frontotemporal dementia (FTD). We evaluated lifetime TBI and concussion frequency in patients diagnosed with a range of FTD spectrum conditions and related prior head trauma to cavum septum pellucidum (CSP) characteristics observable on MRI.Participants and Methods:We administered the Ohio State University TBI Identification and Boston University Head Impact Exposure Assessment to 108 patients (age 69.5 ± 8.0, 35% female, 93% white or unknown race) diagnosed at the UCSF Memory and Aging Center with one of the following FTD or related conditions: behavioral variant frontotemporal dementia (N=39), semantic variant primary progressive aphasia (N=16), nonfluent variant PPA (N=23), corticobasal syndrome (N=14), or progressive supranuclear palsy (N=16). Data were also obtained from 217 controls (“HC”; age 76.8 ± 8.0, 53% female, 91% white or unknown race). CSP characteristics were defined based on width or “grade” (0-1 vs. 2+) and length of anterior-posterior separation (millimeters). We first describe frequency of any and multiple (2+) prior TBI based on different but commonly used definitions: TBI with loss of consciousness (LOC), TBI with LOC or posttraumatic amnesia (LOC/PTA), TBI with LOC/PTA or other symptoms like dizziness, nausea, “seeing stars,” etc. (“concussion”). TBI/concussion frequency was then compared between FTD and HC using chi-square. Associations between TBI/concussion and CSP characteristics were analyzed with chi-square (CSP grade) and Mann-Whitney U tests (CSP length). We explored sex differences due to typically higher rates of TBI among males.Results:History of any TBI with LOC (FTD=20.0%, HC=19.2%), TBI with LOC/PTA (FTD:32.2%, HC=31.5%), and concussion (FTD: 50.0%, HC=44.3%) was common but not different between study groups (p’s>.4). In both FTD and HC, prior TBI/concussion was nominally more frequent in males but not significantly greater than females. Frequency of repeat TBI/concussion (2+) also did not differ significantly between FTD and HC (repeat TBI with LOC: 6.7% vs. 3.3%, TBI with LOC/PTA: 12.2% vs. 10.3%, concussion: 30.2% vs. 28.7%; p’s>.2). Prior TBI/concussion was not significantly related to CSP grade or length in the total sample or within the FTD or HC groups.Conclusions:TBI/concussion rates depend heavily on the symptom definition used for classifying prior injury. Lifetime symptomatic TBI/concussion is common but has an unclear impact on risk for FTD-related diagnoses. Larger samples are needed to appropriately evaluate sex differences, to evaluate whether TBI/concussion rates differ between specific FTD phenotypes, and to understand the rates and effects of more extensive repetitive head trauma (symptomatic and asymptomatic) in patients with FTD.

Navigating the ALS Genetic Labyrinth: The Role of MAPT Haplotypes.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by wide clinical and biological heterogeneity, with a large proportion of ALS patients also exhibiting frontotemporal dementia (FTD) spectrum symptoms. This project aimed to characterize risk subtypes of the H1 haplotype within the MAPT (microtubule-associated protein tau) gene, according to their possible effect as a risk factor and as a modifying factor in relation to the age of disease onset. One hundred patients from Bulgaria with sporadic ALS were genotyped for the variants rs1467967, rs242557, rs1800547, rs3785883, rs2471738, and rs7521. Haploview 4.2 and SHEsisPlus were used to reconstruct haplotype frequencies using genotyping data from the 1000 Genomes project as controls. Genotype-phenotype correlation was investigated in the context of age of disease onset and risk of disease development. While the individual variants of the subtypes do not influence the age of onset of the disease, a correlation was found between the specific haplotype GGAGCA (H1b) and the risk of developing sALS, with results showing that individuals harboring this haplotype have a nearly two-fold increased risk of developing sALS compared to other H1 subtypes. The results from this study suggest that fine transcriptional regulation at the MAPT locus can influence the risk of ALS.

Psychopharmacological Medication Use in Frontotemporal Dementia at the Time of Diagnosis: Comparison with Alzheimer's Disease.

Due to the significant presence of neuropsychiatric symptoms in patients with frontotemporal dementia (FTD) spectrum disorders, psychiatric misdiagnoses, diagnostic delay, and use of psychiatric treatments are common prior to the FTD diagnosis. Furthermore, treatment of diagnosed FTD patients mainly relies on off-label psychopharmacological approaches. Currently, limited real-world data are available regarding the actual use of psychopharmacological medications in FTD. To evaluate psychopharmacological medication use at the time of FTD diagnosis. Psychopharmacological medication use was evaluated in a Finnish FTD cohort containing 222 FTD patients, including the major clinical disease phenotypes (behavioral, language, and motor variants) and genetic patients carrying the C9orf72 repeat expansion. A cohort of 214 Alzheimer's disease (AD) patients was used as a neurodegenerative disease reference group. Active use of psychopharmacological medications at the time of diagnosis was significantly more common in FTD compared to AD, especially in the case of antidepressants (26.1% versus 15.0%, OR = 2.01, p = 0.008), antipsychotics (23.9% versus 9.3%, OR = 3.15, p < 0.001), and mood-stabilizers (6.3% versus 1.9%, OR = 2.93, p = 0.085; not statistically significant), whereas the use of cholinesterase inhibitors or memantine was nearly nonexistent in FTD patients. Female gender and behavioral variant of FTD phenotype alongside with depressive and psychotic symptoms were the most prominent factors associating with the use of these medications among the FTD spectrum patients. Use of off-label psychopharmacological medication and polypharmacy is substantially common at the time of FTD diagnosis. This likely reflects the challenges in using symptom-driven treatment approaches, especially prior to the eventual diagnosis.

Genetic and Neuroimaging Analysis of SIGMAR1 for Frontotemporal Dementia.

Recently, Sigma nonopioid intracellular receptor 1 (SIGMAR1) variants have been shown harboring C9orf72 pathogenic repeat expansions in some frontotemporal dementia (FTD) cases. However, no SIGMAR1 genotype analysis has been reported in a cohort absent of C9orf72 pathogenic repeat expansions to date. The present study investigated the contribution of SIGMAR1 independent of C9orf72 gene status to FTD spectrum syndromes. We directly sequencing the entire coding region and a minimum of 50 bp from each of the flanking introns of SIGMAR1 gene in 82 sporadic FTD patients (female: male = 42 : 40) and 417 controls. For the patient carrying SIGMAR1 variant, a follow-up 3T MR imaging was performed in the study. Gene sequencing of SIGMAR1 revealed a rare 3'UTR nucleotide variation rs192856872 in a male patient with semantic dementia independent of C9orf72 gene status. The MR imaging showed asymmetrical atrophy in the anterior temporal lobes and the degeneration extends caudally into the posterior temporal lobes as the disease progresses. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores, which is predicted to affect normal splicing. We found a novel SIGMAR1 variant independent of C9orf72 gene status associated with semantic dementia phenotype.

The E3 Ubiquitin Ligase SCF Cyclin F Promotes Sequestosome-1/p62 Insolubility and Foci Formation and is Dysregulated in ALS and FTD Pathogenesis

Amyotrophic lateral sclerosis (ALS)- and frontotemporal dementia (FTD)-linked mutations in CCNF have been shown to cause dysregulation to protein homeostasis. CCNF encodes for cyclin F, which is part of the cyclin F-E3 ligase complex SCFcyclinF known to ubiquitylate substrates for proteasomal degradation. In this study, we identified a function of cyclin F to regulate substrate solubility and show how cyclin F mechanistically underlies ALS and FTD disease pathogenesis. We demonstrated that ALS and FTD-associated protein sequestosome-1/p62 (p62) was a canonical substrate of cyclin F which was ubiquitylated by the SCFcyclinF complex. We found that SCFcyclin F ubiquitylated p62 at lysine(K)281, and that K281 regulated the propensity of p62 to aggregate. Further, cyclin F expression promoted the aggregation of p62 into the insoluble fraction, which corresponded to an increased number of p62 foci. Notably, ALS and FTD-linked mutant cyclin F p.S621G aberrantly ubiquitylated p62, dysregulated p62 solubility in neuronal-like cells, patient-derived fibroblasts and induced pluripotent stem cells and dysregulated p62 foci formation. Consistently, motor neurons from patient spinal cord tissue exhibited increased p62 ubiquitylation. We suggest that the p.S621G mutation impairs the functions of cyclin F to promote p62 foci formation and shift p62 into the insoluble fraction, which may be associated to aberrant mutant cyclin F-mediated ubiquitylation of p62. Given that p62 dysregulation is common across the ALS and FTD spectrum, our study provides insights into p62 regulation and demonstrates that ALS and FTD-linked cyclin F mutant p.S621G can drive p62 pathogenesis associated with ALS and FTD.

Phenotypical differences of C9ORF72 gene-positive and negative amyotrophic lateral sclerosis: a comparative case series

BackgroundHexanucleotide repeat expansions of C9ORF72 account for a significant proportion of autosomal dominant neurodegenerative diseases in the amyotrophic lateral sclerosis (ALS)–frontotemporal dementia spectrum. In the absence of a family history,...

New Approaches to the Treatment of Frontotemporal Dementia.

Frontotemporal dementia (FTD) comprises a diverse group of clinical neurodegenerative syndromes characterized by progressive changes in behavior, personality, executive function, language, and motor function. Approximately 20% of FTD cases have a known genetic cause. The three most common genetic mutations causing FTD are discussed. Frontotemporal lobar degeneration refers to the heterogeneous group of neuropathology underlying FTD clinical syndromes. While there are no current disease-modifying treatments for FTD, management includes off-label pharmacotherapy and non-pharmacological approaches to target symptoms. The utility of several different drug classes is discussed. Medications used in the treatment of Alzheimer's disease have no benefit in FTD and can worsen neuropsychiatric symptoms. Non-pharmacological approaches to management include lifestyle modifications, speech-, occupational-, and physical therapy, peer and caregiver support, and safety considerations. Recent developments in the understanding of the genetics, pathophysiology, neuropathology, and neuroimmunology underlying FTD clinical syndromes have expanded possibilities for disease-modifying and symptom-targeted treatments. Different pathogenetic mechanisms are targeted in several active clinical trials, opening up exciting possibilities for breakthrough advances in treatment and management of FTD spectrum disorders.