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Pelizaeus-Merzbacher disease is a rare X-linked leukodystrophy accompanied by central nervous system hypomyelination with a spectrum of clinical phenotypes. This is the first survey of caregivers of individuals with Pelizaeus-Merzbacher disease to investigate the presenting symptoms, path to diagnosis, identity and impact of most bothersome symptoms, and needs that future treatment should address. One hundred participants completed the survey. Results from this survey demonstrate that the majority of Pelizaeus-Merzbacher disease symptoms manifest before 2 years of age and commonly include deficits in gross and fine motor skills, speech, and communication. Caregivers rated difficulty crawling, standing, or walking as the most bothersome symptoms due to Pelizaeus-Merzbacher disease, with constipation and difficulty with sleep, manual dexterity, and speech and communication rated nearly as high. The most important treatment goals for caregivers were improved mobility and communication. The survey findings present a caregiver perspective of the impact of symptoms in Pelizaeus-Merzbacher disease and provide helpful guidance to affected families, physicians, and drug developers on the often-long path to diagnosis and the unmet medical needs of this patient population. [ABSTRACT FROM AUTHOR]

Background: Development of endpoints for clinical trials in frontotemporal dementia (FTD) is increasingly urgent. In other neurodegenerative diseases composite scores are often used as outcome measures but are, as of yet, lacking in FTD. The aim of this study was to create gene‐specific cognitive composite scores for MAPT, GRN and C9orf72 mutation carriers and provide recommendations on recruitment and trial duration. Method: 69 C9orf72, 41 GRN, 28 MAPT mutation carriers with a CDR® plus NACC‐FTLD global score ≥0.5 and 275 controls completed a neuropsychological battery covering five cognitive domains. Logistic regression was used to identify the combination of tests that discriminated best between mutation carrier groups and controls. Weighted averages of the test scores in the models were calculated based on the regression coefficients (GENFI‐cog). Sample size estimates were calculated for individual tests and composite. The treatment effect was estimated as the mean difference between CDR® plus NACC‐FTLD 0.5 and 1 groups. Time‐to‐event analysis was used to determine the fraction of patients within GENFI that converted from CDR® plus NACC‐FTLD 0.5 to ≥1. Result: The most sensitive model in C9orf72 mutation carriers included a combination of executive, social cognitive and visuoconstructive tests (Table 1). A combination of executive, social cognitive, semantic and memory tests was most sensitive in GRN mutation carriers, and a combination of social cognitive, attention, semantic and memory tests in MAPT mutation carriers, resulted in the most sensitive model. The estimated sample size to detect a treatment effect was lower for the composite than for most individual tests (Table 2). A Kaplan‐Meier curve (Figure 1) showed that after three years 50% of individuals convert from CDR® plus NACC‐FTLD global score 0.5 to 1 or more. Conclusion: We created gene‐specific cognitive composite scores for C9orf72, GRN and MAPT mutation carriers (GENFI‐cog) which resulted in substantially lower estimated sample sizes to detect a treatment effect than most individual cognitive tests. Only 50% of patients with a CDR® plus NACC‐FTLD of 0.5 convert to ≥1 in a three‐year period. GENFI‐cog has potential as a cognitive endpoint for upcoming trials and the results from this study provide important information concerning trial duration and sample sizes. [ABSTRACT FROM AUTHOR]

Background: Previous investigations suggest carrier status for Karlow‐variant single‐nucleotide polymorphism (SNP) of butyrylcholinesterase (BCHE‐K) is associated with an earlier age‐at‐onset of AD in APOE4 carriers. Method: In 45 mild AD patients, 50‐74 years, recruited into a clinical trial (NCT03186989), baseline characteristics were evaluated by BCHE‐K and APOE4 allelic status. Hypothesis tested that age‐at‐diagnosis of AD in APOE4 carriers was lowered in BCHE‐K carriers. Exploratory investigations conducted of associations of neuroimaging (ventricular and hippocampal volumes) and CSF biomarkers of amyloid (Aβ42), tau (p‐tau181), and neurodegenerative (NfL, Ng, PSD‐95) pathologies and glial activation (YKL‐40, GFAP, MCP‐1) across gender and genotype subgroups. Result: In APOE4 carriers (N = 33), mean age‐at‐diagnosis of AD in BCHE‐K carriers (N = 11) was 6.4 years earlier than in BCHE‐K non‐carriers (N = 22, p < 0.001). In APOE4 non‐carriers (N = 12) there was no similar influence of BCHE‐K, but men (N = 8) had an age‐at‐diagnosis about 11 years earlier than women (N = 4). In APOE4 carriers, accumulation of amyloid and tau pathologies was slightly greater and ∼6 years earlier in BCHE‐K carriers versus non‐carriers. APOE4 allele frequency‐dependent increase in amyloid pathology observed with highest amyloid burden in APOE4 homozygotes that contrasted with lowest tau burden. Multiple regression analyses demonstrated that factors associated with amyloid accumulation included APOE4 carrier status (p < 0.05), larger total brain ventricle volume (p < 0.05), less synaptic injury (PSD‐95, p = 0.01; Ng, p < 0.001), and less tau (t‐tau and p‐tau181, p < 0.01). Factors associated with tau pathology included higher neuroaxonal damage (NfL, p = 0.002), higher synaptic injury (Ng, p <0.001; PSD‐95, p < 0.001), and higher glial activation (YKL‐40, p = 0.01). Phenotypic spectrum observed from predominant amyloid and limbic‐amnestic, exemplified by APOE4 homozygotes with BCHE‐K, to predominant tau, limbic‐sparing and multi‐domain cognitive impairment, exemplified in older women non‐carriers of APOE4 and BCHE‐K. Conclusion: In mild AD APOE4 carriers aged < 75 years, the mean age‐at‐diagnosis of AD was reduced by about 6 years in BCHE‐K carriers relative to non‐carriers. Relationships between biomarkers of amyloid and tau pathologies, neurodegeneration and glial activation, and putative cortical cholinergic denervation, suggested an age‐, gender‐ and genotype‐dependent phenotypic spectrum. [ABSTRACT FROM AUTHOR]

Background: Mutations in the MAPT gene are known to cause frontotemporal dementia (FTD), but there is heterogeneity in FTD phenotype across individuals. Here we used an unsupervised learning algorithm – Subtype and Stage Inference (SuStaIn) – to relate phenotypic heterogeneity to specific mutations in the MAPT gene. Method: SuStaIn evaluates the optimal grouping of individuals into disease subtypes, where each subtype consists of a sequence (set of stages) in which biomarkers transition between different z‐scores. We applied SuStaIn to cross‐sectional regional brain volumes extracted from T1‐weighted MRI data from MAPT carriers in the GENFI study to find the best stratification of the data into subtypes, and the temporal progression of each subtype. We used data from 82 MAPT carriers (57 presymptomatic and 25 symptomatic) to identify subtypes and data from a control group of 300 non‐carriers to derive z‐scores. We subtyped and staged individuals at up to five annual follow‐up visits to assess the consistency of the subtypes longitudinally. We compared the specific mutations and clinical and neuropsychological test scores of individuals assigned to each subtype. Result: SuStaIn identified two groups of MAPT carriers with distinct atrophy patterns (Figure 1), which we termed a 'temporal' subtype and a 'frontotemporal' subtype. The subtype assignments were consistent at follow‐up visits (Table 1): there were no individuals that changed from the temporal to the frontotemporal subtype or vice‐versa. Subtype assignment was strongly associated with IVS10+16, R406W and P301L mutations (Table 2): there was a one‐to‐one mapping between IVS10+16 and R406W mutations and the temporal subtype, and a near one‐to‐one mapping between P301L mutations and the frontotemporal subtype. The temporal subtype was associated with memory problems, whereas the frontotemporal subtype was associated with worse performance on tests of attention and visuospatial skills (Table 3). Conclusion: Our results demonstrate the utility of SuStaIn for identifying disease subgroups and associating imaging patterns with genetics and cognition. We show that different MAPT mutations give rise to distinct atrophy patterns and clinical syndromes, providing insights into the underlying disease biology, and potential utility for patient stratification. [ABSTRACT FROM AUTHOR]

Objective: Frontotemporal dementia (FTD) is typically associated with changes in behaviour, language and movement. However, recent studies have shown that patients can also develop an abnormal response to pain, either heightened or diminished. We aimed to investigate this symptom in mutation carriers within the Genetic FTD Initiative (GENFI).Methods: Abnormal responsiveness to pain was measured in 462 GENFI participants: 281 mutation carriers and 181 mutation-negative controls. Changes in responsiveness to pain were scored as absent (0), questionable or very mild (0.5), mild (1), moderate (2) or severe (3). Mutation carriers were classified into C9orf72 (104), GRN (128) and MAPT (49) groups, and into presymptomatic and symptomatic stages. An ordinal logistic regression model was used to compare groups, adjusting for age and sex. Voxel-based morphometry was performed to identify neuroanatomical correlates of abnormal pain perception.Results: Altered responsiveness to pain was present to a significantly greater extent in symptomatic C9orf72 expansion carriers than in controls: mean score 0.40 (SD 0.71) vs 0.00 (0.04), reported in 29% vs 1%. No significant differences were seen between the other symptomatic groups and controls, or any of the presymptomatic mutation carriers and controls. Neural correlates of altered pain perception in C9orf72 expansion carriers were the bilateral thalamus and striatum as well as a predominantly right-sided network of regions involving the orbitofrontal cortex, inferomedial temporal lobe and cerebellum.Conclusion: Changes in pain perception are a feature of C9orf72 expansion carriers, likely representing a disruption in somatosensory, homeostatic and semantic processing, underpinned by atrophy in a thalamo-cortico-striatal network. [ABSTRACT FROM AUTHOR]

Our awareness of time, specifically of longer intervals spanning hours, days, months, and years, is critical for ensuring our sense of self-continuity. Disrupted time awareness over such intervals is a clinical feature in a number of frontotemporal dementia syndromes and Alzheimer's disease, but has not been studied and compared systematically in these diseases. We used a semi-structured caregiver survey to capture time-related behavioral alterations in 71 patients representing all major sporadic and genetic syndromes of frontotemporal dementia, in comparison to 28 patients with typical Alzheimer's disease and nine with logopenic aphasia, and 32 healthy older individuals. Survey items pertained to apparent difficulties ordering past personal events or estimating time intervals between events, temporal rigidity and clockwatching, and propensity to relive past events. We used a logistic regression model including diagnosis, age, gender, and disease severity as regressors to compare the proportions of individuals exhibiting each temporal awareness symptom between diagnostic groups. Gray matter associations of altered time awareness were assessed using voxel-based morphometry. All patient groups were significantly more prone to exhibit temporal awareness symptoms than healthy older individuals. Clinical syndromic signatures were identified. While patients with typical and logopenic Alzheimer's disease most frequently exhibited disturbed event ordering or interval estimation, patients with semantic dementia were most prone to temporal rigidity and clockwatching and those with behavioral variant frontotemporal dementia commonly exhibited all these temporal symptoms as well as a propensity to relive past events. On voxel-based morphometry, the tendency to relive past events was associated with relative preservation of a distributed left-sided temporo-parietal gray matter network including hippocampus. These findings reveal a rich and complex picture of disturbed temporal awareness in major dementia syndromes, with stratification of frontotemporal dementia syndromes from Alzheimer's disease. This is the first study to assess symptoms of altered temporal awareness across frontotemporal dementia syndromes and provides a motivation for future work directed to the development of validated clinical questionnaires, analysis of underlying neurobiological mechanisms and design of interventions. [ABSTRACT FROM AUTHOR]

Background: Chronic glial dysfunction may contribute to the pathogenesis of frontotemporal dementia (FTD). Cerebrospinal fluid (CSF) levels of glia-derived proteins YKL-40 and chitotriosidase are increased in Alzheimer's disease (AD) but have not been explored in detail across the spectrum of FTD. Methods: We investigated whether CSF YKL-40 and chitotriosidase levels differed between FTD patients and controls, across different clinical and genetic subtypes of FTD, and between individuals with a clinical FTD syndrome due to AD versus non-AD (frontotemporal lobar degeneration, FTLD) pathology (based on CSF neurodegenerative biomarkers). Eighteen healthy controls and 64 people with FTD (behavioural variant FTD, n = 20; primary progressive aphasia [PPA], n = 44: nfvPPA, n = 16, svPPA, n = 11, lvPPA, n = 14, PPA-NOS, n = 3) were included. 10/64 had familial FTD, with mutations in GRN(n = 3), MAPT(n = 4), or C9orf72 (n = 3). 15/64 had neurodegenerative biomarkers consistent with AD pathology. Levels were measured by immunoassay and compared using multiple linear regressions. We also examined relationships of YKL-40 and chitotriosidase with CSF total tau (T-tau), phosphorylated tau 181 (P-tau) and β-amyloid 1–42 (Aβ42), with each other, and with age and disease du-ration. Results: CSF YKL-40 and chitotriosidase levels were higher in FTD, particularly lvPPA (both) and nfvPPA (YKL-40), compared with controls. GRN mutation carriers had higher levels of both proteins than controls and C9orf72 expansion carriers, and YKL-40 was higher in MAPT mutation carriers than controls. Individuals with underlying AD pathology had higher YKL-40 and chitotriosidase levels than both controls and those with likely FTLD pathology. CSF YKL-40 and chitotriosidase levels were variably associated with levels of T-tau, P-tau and Aβ42, and with each other, depending on clinical syndrome and underlying pathology. CSF YKL-40 but not chitotriosidase was associated with age, but not disease duration. Conclusion: CSF YKL-40 and chitotriosidase levels are increased in individuals with clinical FTD syndromes, particularly due to AD pathology. In a preliminary analysis of genetic groups, levels of both proteins are found to be highly elevated in FTD due to GRN mutations, while YKL-40 is increased in individuals with MAPT mutations. As glia-derived protein levels generally correlate with T-tau and P-tau levels, they may reflect the glial response to neurodegeneration in FTLD. [ABSTRACT FROM AUTHOR]

Impaired processing of emotional signals is a core feature of frontotemporal dementia syndromes, but the underlying neural mechanisms have proved challenging to characterize and measure. Progress in this field may depend on detecting functional changes in the working brain, and disentangling components of emotion processing that include sensory decoding, emotion categorization and emotional contagion. We addressed this using functional MRI of naturalistic, dynamic facial emotion processing with concurrent indices of autonomic arousal, in a cohort of patients representing all major frontotemporal dementia syndromes relative to healthy age-matched individuals. Seventeen patients with behavioural variant frontotemporal dementia [four female; mean (standard deviation) age 64.8 (6.8) years], 12 with semantic variant primary progressive aphasia [four female; 66.9 (7.0) years], nine with non-fluent variant primary progressive aphasia [five female; 67.4 (8.1) years] and 22 healthy controls [12 female; 68.6 (6.8) years] passively viewed videos of universal facial expressions during functional MRI acquisition, with simultaneous heart rate and pupillometric recordings; emotion identification accuracy was assessed in a post-scan behavioural task. Relative to healthy controls, patient groups showed significant impairments (analysis of variance models, all P < 0.05) of facial emotion identification (all syndromes) and cardiac (all syndromes) and pupillary (non-fluent variant only) reactivity. Group-level functional neuroanatomical changes were assessed using statistical parametric mapping, thresholded at P < 0.05 after correction for multiple comparisons over the whole brain or within pre-specified regions of interest. In response to viewing facial expressions, all participant groups showed comparable activation of primary visual cortex while patient groups showed differential hypo-activation of fusiform and posterior temporo-occipital junctional cortices. Bi-hemispheric, syndrome-specific activations predicting facial emotion identification performance were identified (behavioural variant, anterior insula and caudate; semantic variant, anterior temporal cortex; non-fluent variant, frontal operculum). The semantic and non-fluent variant groups additionally showed complex profiles of central parasympathetic and sympathetic autonomic involvement that overlapped signatures of emotional visual and categorization processing and extended (in the non-fluent group) to brainstem effector pathways. These findings open a window on the functional cerebral mechanisms underpinning complex socio-emotional phenotypes of frontotemporal dementia, with implications for novel physiological biomarker development. [ABSTRACT FROM AUTHOR]

Background: ISIS 814907 (BIIB080) is an antisense oligonucleotide (ASO) that hybridizes to a complementary nucleotide sequence of mRNA of the human microtubule‐associated protein tau (MAPT) gene, preventing production of tau protein. Accumulation of hyperphosphorylated tau is associated with cognitive decline and brain atrophy in Alzheimer's Disease (AD). The placebo controlled period of the Phase 1b multiple ascending dose (MAD) study of ISIS 814907 in patients with mild AD is complete and the open‐label long term extension (LTE) is ongoing in the UK, Canada, Germany, Sweden, Netherlands and Finland (EudraCT: 2016‐002713‐22; NCT03186989). Methods: The study is divided into 2 parts. Part 1 is the MAD study, comprising a 3‐month Treatment Evaluation (TE) Period and a 6‐month Post‐Treatment (PT) Period. Part 2 is the open‐label LTE, comprising a 12‐month TE Period and a 4‐ or 6‐month PT Period. Four ascending dose cohorts were enrolled sequentially and randomized 3:1 to intrathecal (IT) bolus administrations of ISIS 814907 or placebo. Male or female patients aged 50‐74 years with mild AD and confirmed amyloid positivity (via CSF) at Screening were considered eligible. The primary objective was to assess safety and tolerability of multiple IT bolus administrations of ISIS 814907. The secondary objective was to evaluate CSF pharmacokinetics (PK). Exploratory objectives include assessment of plasma PK, target engagement and disease biomarkers, genotype and clinical endpoints relevant to AD. Results: All subjects (N=46) completed the MAD TE Period and 43 subjects completed the PT Period. All AEs were mild/moderate in severity. No serious AEs occurred in subjects receiving ISIS 814907. Dose‐dependent mean reduction from baseline in CSF total tau and phospho‐tau was observed in the TE period and continued in the PT period. CSF total tau and phospho‐tau reductions were comparable. Conclusions: IT bolus administration of multiple ascending doses of ISIS 814907 over 3 months was well‐tolerated in patients with mild AD. The robust lowering of CSF total tau and phospho‐tau warrants further investigation for the treatment of AD. [ABSTRACT FROM AUTHOR]

Background: Episodic memory is increasingly reported in frontotemporal dementia (FTD) and it has been suggested to differ between genetic forms of FTD. However, systematic investigations of episodic memory in familial FTD, and specifically the presymptomatic stage, are scarce. This cross‐sectional study investigates performance on the Free Cued and Selective Reminding Test (FCSRT) in the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort. Method: 685 participants were tested with the FCSRT (52 presymptomatic and 21 symptomatic MAPT, 135 presymptomatic and 42 symptomatic GRN, 109 presymptomatic and 63 symptomatic C9orf72 mutation carriers and 263 non‐carriers). The presymptomatic mutation carriers were split into an early and late presymptomatic period (more than or within ten years of expected symptom onset). Groups were compared using linear regression models, adjusted for age and education, with bootstrapping. Result: Performance on all FCSRT test scores had a negative correlation with age (0.18 > r < 0.38) and immediate free recall (r = 0.21), immediate total recall (r = 0.14) and delayed free recall (r = 0.24) had a positive correlation with education. All symptomatic mutation carrier groups scored significantly lower than controls on immediate free recall (MAPT: −2.54 ± 1.52; GRN: −3.15 ± 2.13; C9orf72: −2.67 ± 1.32), immediate total recall (MAPT: −4.83 ± 4.42; GRN: −6.65 ± 5.69; C9orf72: −3.63 ± 3.99), delayed free recall (MAPT: −2.66 ± 1.98; GRN: −3.08 ± 2.17; C9orf72: −2.64 ± 1.41) and delayed total recall (MAPT: −4.32 ± 4.49; GRN: −6.48 ± 6.63; C9orf72: −4.32 ± 4.49). In the presymptomatic group, C9orf72 participants performed significantly lower on immediate (late: −0.75 ± 0.93) and delayed free recall (early: −0.11 ± 1.12; late: −0.57 ± 1.14) measures. Conclusion: Episodic memory is impaired in genetic FTD, with decline already starting in the presymptomatic period in C9orf72 mutation carriers. The differences between mutation carriers groups in free versus cued recall formats corroborates the notion that the clinical presentation of episodic memory deficits (i.e. as a result of executive impairment versus "true" consolidation problems) in FTD depend on the underlying mutation, and thus atrophy pattern. Our next step is to replicate results in a larger dataset and correlate performance on the FCSRT to grey matter density in each genetic group using voxel‐based morphometry. [ABSTRACT FROM AUTHOR]