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Objective: We compared the accuracy of amyloid and [18F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD). Methods: Participants with FTP‐PET, amyloid‐PET, and diagnosis of dementia‐AD (n = 102), MCI‐AD (n = 41), non‐AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid‐PET was classified as positive/negative using tracer‐specific criteria. FTP‐PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau‐MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD‐like pattern (tau‐CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia‐AD). Results: Sensitivity of amyloid‐PET for MCI/dementia‐AD was 95.8% (95% confidence interval 91.1–98.4%), which was comparable to tau‐CTX+ 92.3% (86.7–96.1%, p = 0.67) and tau‐MTL+ 97.2% (93.0–99.2%, p = 0.27). Specificity of amyloid‐PET for biomarker‐negative healthy and disease controls was 84.4% (75.5–91.0%), which was like tau‐CTX+ 88.5% (80.4–94.1%, p = 0.34), and trended toward being higher than tau‐MTL+ 75.0% (65.1–83.3%, p = 0.08). Tau‐CTX+ had higher specificity than tau‐MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI‐AD (80.5% [65.1–91.2] vs. 95.1% [83.5–99.4], p = 0.03). Interpretation: Amyloid‐ and tau‐PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau‐PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI‐AD. ANN NEUROL 2024;96:476–487 [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated. METHODS: We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD. RESULTS: We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini‐Mental Status Examination (MMSE) decline over time (p = 0.033). DISCUSSION: Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort. Highlights: Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation?Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09).Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008).Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022).Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033). [ABSTRACT FROM AUTHOR]

INTRODUCTION: Lewy body disease (LBD) is a common primary or co‐pathology in neurodegenerative syndromes. An alpha‐synuclein seed amplification assay (αSyn‐SAA) is clinically available, but clinical performance, especially lower sensitivity in amygdala‐predominant cases, is not well understood. METHODS: Antemortem CSF from neuropathology‐confirmed LBD cases was tested with αSyn‐SAA (N = 56). Diagnostic performance and clinicopathological correlations were examined. RESULTS: Similar to prior reports, sensitivity was 100% for diffuse and transitional LBD (9/9), and overall specificity was 96.3% (26/27). Sensitivity was lower in amygdala‐predominant (6/14, 42.8%) and brainstem‐predominant LBD (1/6, 16.7%), but early spread outside these regions (without meeting criteria for higher stage) was more common in αSyn‐SAA‐positive cases (6/7, 85.7%) than negative (2/13, 15.4%). DISCUSSION: In this behavioral neurology cohort, αSyn‐SAA had excellent diagnostic performance for cortical LBD. In amygdala‐ and brainstem‐predominant cases, sensitivity was lower, but positivity was associated with anatomical spread, suggesting αSyn‐SAA detects early LBD progression in these cohorts. Highlights: A cerebrospinal fluid alpha‐synuclein assay detects cortical LBD with high sensitivity/specificity.Positivity in prodromal stages of LBD was associated with early cortical spread.The assay provides precision diagnosis of LBD that could support clinical trials.The assay can also identify LBD co‐pathology, which may impact treatment responses. [ABSTRACT FROM AUTHOR]

INTRODUCTION: With emergence of disease‐modifying therapies, efficient diagnostic pathways are critically needed to identify treatment candidates, evaluate disease severity, and support prognosis. A combination of plasma biomarkers and brief digital cognitive assessments could provide a scalable alternative to current diagnostic work‐up. METHODS: We examined the accuracy of plasma biomarkers and a 10‐minute supervised tablet‐based cognitive assessment (Tablet‐based Cognitive Assessment Tool Brain Health Assessment [TabCAT‐BHA]) in predicting amyloid β positive (Aβ+) status on positron emission tomography (PET), concurrent disease severity, and functional decline in 309 older adults with subjective cognitive impairment (n = 49), mild cognitive impairment (n = 159), and dementia (n = 101). RESULTS: Combination of plasma pTau181, Aβ42/40, neurofilament light (NfL), and TabCAT‐BHA was optimal for predicting Aβ‐PET positivity (AUC = 0.962). Whereas NfL and TabCAT‐BHA optimally predicted concurrent disease severity, combining these with pTau181 and glial fibrillary acidic protein was most accurate in predicting functional decline. DISCUSSION: Combinations of plasma and digital cognitive markers show promise for scalable diagnosis and prognosis of ADRD. Highlights: The need for cost‐efficient diagnostic and prognostic markers of AD is urgent.Plasma and digital cognitive markers provide complementary diagnostic contributions.Combination of these markers holds promise for scalable diagnosis and prognosis.Future validation in community cohorts is needed to inform clinical implementation. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau‐related clinical progression in females. However, sex differences in plasma phosphorylated tau (p‐tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p‐tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain‐specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p‐tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p‐tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p‐tau217. Plasma GFAP and NfL exhibited similar female‐specific prediction of medial temporal lobe atrophy in CU. Plasma p‐tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p‐tau217 may capture earlier Alzheimer's disease (AD)‐related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology. [ABSTRACT FROM AUTHOR]

Background: It is unclear whether primary progressive apraxia of speech (PPAOS) and progressive agrammatic aphasia (PAA) represent the two ends of a clinical continuum or exist as distinct syndromic entities with specific pathologic/prognostic correlates. We aimed to characterize the main clinical features along the spectrum of progressive non‐fluent speech‐language disorders (nf‐SLD) and explore the existence of data‐driven symptom clusters with etiological/prognostic value. Method: We included 98 participants presenting with progressive motor speech impairment and/or agrammatism, of which 43 had an autopsy‐confirmed neuropathological diagnosis. Speech pathologists rated motor speech features indicative of dysarthria and AOS. Quantitative measures of expressive/receptive agrammatism were obtained and compared with healthy controls. Baseline and longitudinal disease severity was assessed with the Clinical Dementia Rating sum‐of‐boxes (CDR‐SB). We explored the clustering tendency of the data to form robust symptom clusters and used principal component analysis to extract data‐driven clinical components. The longitudinal CDR‐SB change was estimated with linear mixed‐effects models. Result: Ninety‐one participants fitted previously reported clinical profiles (69 AOS+agrammatism, 18 PPAOS and 4 PAA), while 7 remained unclassifiable and were characterized by nonfluent speech and dysarthria in the absence of apraxia of speech or agrammatism. None of the baseline clinical features discriminated between FTLD subgroups. The Hopkins statistic ruled out the existence of syndromic clusters in the whole sample. Three data‐driven components explained 71% of the variance ([i]severity‐agrammatism, [ii]AOS, and [iii]dysarthria). The component characterized by prominent dysarthria was more specific to patients with Progressive Supranuclear Palsy while the component characterized by severity‐agrammatism predicted a faster CDR‐SB increase. Conclusion: Our results suggest that nf‐SLD represents a clinical continuum. Splitting this continuum into different clinical phenotypes based on its major clinical features does not improve clinical‐pathological correlations, stressing the need for new clinical and biological markers. The term nf‐SLD could be used to group together these speech‐language phenotypes strongly associated with FTLD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer disease (AD) is defined by the presence of cerebral amyloid‐β plaques and tau neurofibrillary tangles (NFT). Neurophysiological manifestations which depict the functional changes of neurons and circuits, demonstrate that amyloid‐β and tau have distinct effects—high cerebral amyloid‐β burden is associated with increased neural oscillatory activity while high tau burden with decreased activity. With the recent proliferation of fluid biomarkers, plasma p‐tau181 is known to reflect accumulation of amyloid‐β as well as tau, detected from molecular imaging and neuropathological analyses. It remains unknown whether the neurophysiological consequences of soluble p‐tau reflects the effects of amyloid‐β or those of NFT. Method: We used multimodal imaging combining magnetoencephalography (MEG) to cross‐sectionally study the spectral signatures and positron emission tomography with Aβ binding tracers to define the global amyloid burden in early‐stage neuropathological spectrum including Aβ+ cognitively‐unimpaired (CU, n = 9), Aβ+ mild‐cognitive‐impairment (MCI, n = 20), and Aβ‐negative CU controls (n = 45). Plasma p‐tau181 and neurofilament light (NFL) were measured with Simoa. Using statistical mixed models we examined the associations of neural oscillatory signatures with plasma p‐tau181 and NFL. Result: The characteristic oscillatory signature of increased delta‐theta and reduced alpha spectrum were detectable even in the earliest stages of global amyloid accumulation (Aβ+CU vs. Aβ‐CU; Fig.1). Increased p‐tau181 was associated with increased spectral signatures across the frequency spectrum in Aβ+ individuals (Fig.2). These positive correlations were more robust within delta‐theta (2‐7Hz) than alpha (8‐12 Hz) spectrum. Plasma NFL in Aβ+ individuals, in contrast, was associated with reduced spectral signatures. We also found APOE‐ɛ4 carriers have greater degree of neurodegeneration which modulated the associations between p‐tau181 and neural oscillations (Fig.3). Conclusion: Previous neurophysiological studies have demonstrated that Aβ accumulation is associated with increased oscillatory activity while tau accumulation is associated with reduced oscillatory activity. Positive correlations of p‐tau181 across the spectrum is therefore consistent with the effects of Aβ accumulation and not with tau accumulation. Plasm NFL may represent early effects of neurodegeneration. Collectively our findings indicate that p‐tau181 reflects earliest functional effects of Aβ rather than tau and have implications for the interpretation of plasma p‐tau along the AT(N) stages. [ABSTRACT FROM AUTHOR]

Background: Mutations in microtubule‐associated protein tau (MAPT), granulin (GRN), and hexanucleotide expansion repeat in the open reading frame of chromosome 9 (C9orf72) are found in 60% of familial frontotemporal dementia (FTD) cases. The current study aims to delineate brain regions with reduced glucose metabolism in patients with genetic FTD in comparison with cognitively normal controls. Methods: (18)F‐ fluorodeoxyglucose (FDG)‐positron emission tomography (PET) images were retrospectively obtained from 17 genetic FTD patients. All patients were symptomatic at the time of imaging, and the autopsy was available for 13. Pittsburgh compound B (PiB) amyloid PET scans were done for 13 patients (Table 1). FDG‐PET was collected at Lawrence Berkeley National Laboratory on a PET or PET‐CT scanner as six 5‐min frames acquired 30 min post tracer injection. Standard Uptake Value Ratio (SUVR) images were created for each patient using pons as a reference region. W‐score (age‐adjusted Z‐score) maps were created for each patient's FDG SUVR using a group of neurologically unimpaired controls (N=74, Mean age 65+16, 41 female) as reference. Result: On review of single‐subject w‐maps, all patients with MAPT mutation showed hypometabolism in the anteromedial temporal lobes with 66% showing anterolateral temporal hypometabolism and 33% in the frontal and dorsolateral parietal lobes. Hypometabolism in temporal lobes was seen in all GRN patients and 75% had frontal and parietal hypometabolism in an asymmetric pattern. 80% of theC9orf72 patients had hypometabolism in anteromedial temporal and orbitofrontal regions. 60% showed hypometabolism in dorsolateral prefrontal, medial frontal, and anterolateral temporal lobes. Posterior temporal, posterior cingulate, parietal lobe, cerebellum, insula, thalamus, and caudate were hypometabolic in less than 40% of the C9orf72 patients (Figure 1). On group‐level analysis, compared to controls, patients with C9orf72 showed hypometabolism in the frontotemporal regions, cerebellum and thalamus. Hypometabolism in the frontotemporal and parietal regions was seen with GRN mutation. MAPT mutation carriers showed frontal and anteromedial temporal hypometabolism (Figure 2). Conclusion: Hypometabolism in the posterior regions and cerebellum is more suggestive of C9orf72 repeat expansion. An asymmetric pattern of hypometabolism was seen in all GRN mutation carriers. MAPT mutation resulted in a greater degree of hypometabolism in the anterior medial temporal lobes. [ABSTRACT FROM AUTHOR]

Background: Plasma measurements of phosphorylated tau (ptau) have emerged as promising biomarkers for Alzheimer's disease (AD). Studies have shown strong associations between ptau and tau‐PET that are mainly driven by the difference between amyloid‐positive and amyloid‐negative patients. However, the relationship between ptau and tau‐PET is not well characterized within patients with AD. We conducted a head‐to‐head comparison between plasma ptau‐217 and tau‐PET in patients at the clinical stage of AD and assessed biomarker relationships with demographic and clinical variables. Methods: Eighty‐seven amyloid‐positive patients (age=66±10, 48% women) with mild cognitive impairment (n=53) or dementia (n=34) underwent structural MRI, amyloid‐PET (11C‐PIB), tau‐PET (18F‐flortaucipir, FTP), Mini‐Mental State Examination (MMSE, with 28 patients having longitudinal measures 1.5±0.7 years after baseline) and blood draw within a year. Mean cortical PET‐Standardized Uptake Value Ratio (SUVR) were extracted using FreeSurfer5.3. Plasma ptau‐217 concentrations were measured using an electrochemiluminescence‐based assay on the Meso Scale Discovery platform. Results: Ptau‐217 and cortical FTP‐SUVR were strongly correlated (r=0.61, p<.001, Figure 1). Younger age and female sex, but not APOE4, were associated with higher ptau‐217 and FTP‐SUVR (Figure 2). Amyloid‐PET levels were mildly associated with FTP‐SUVR (r=0.26, p=0.02), not ptau‐217 (r=0.10, p=0.36, Figure 2). The relationship between ptau‐217 and cortical FTP‐SUVR was not modified by age, sex, APOE4, or PIB‐PET (interactions: p's>0.25). In the whole group, ptau‐217 was associated with FTP‐SUVR in temporo‐parietal and dorsal prefrontal cortices (Figure 3A). However, ptau‐217‐FTP association patterns varied with amyloid burden: in patients with moderate amyloid (<97.7 Centiloids), ptau‐217 was more strongly associated with temporal FTP‐SUVR whereas associations were stronger in primary cortices in patient with higher amyloid levels (Figure 3B). Cross‐sectionally, higher ptau‐217 and FTP‐SUVR were independently associated with lower MMSE (Table 1; Figure 4A). In separate mixed effect models, higher baseline ptau‐217 and FTP‐SUVR were associated with more severe longitudinal decline in MMSE (Figure 4B); when both biomarkers were entered in the same model, only FTP‐SUVR remained significant (Table 2). Conclusions: In amyloid‐PET‐positive patients with cognitive deficits, ptau‐217 and tau‐PET had comparable patterns of association with demographic and clinical variables. However, cross‐modal and clinical associations tended to be stronger for tau‐PET than ptau‐217. [ABSTRACT FROM AUTHOR]

Blood‐based markers (BBMs) have recently shown promise to revolutionize the diagnostic and prognostic work‐up of Alzheimer's disease (AD), as well as to improve the design of interventional trials. Here we discuss in detail further research needed to be performed before widespread use of BBMs. We already now recommend use of BBMs as (pre‐)screeners to identify individuals likely to have AD pathological changes for inclusion in trials evaluating disease‐modifying therapies, provided the AD status is confirmed with positron emission tomography (PET) or cerebrospinal fluid (CSF) testing. We also encourage studying longitudinal BBM changes in ongoing as well as future interventional trials. However, BBMs should not yet be used as primary endpoints in pivotal trials. Further, we recommend to cautiously start using BBMs in specialized memory clinics as part of the diagnostic work‐up of patients with cognitive symptoms and the results should be confirmed whenever possible with CSF or PET. Additional data are needed before use of BBMs as stand‐alone diagnostic AD markers, or before considering use in primary care. [ABSTRACT FROM AUTHOR]

Background: The reliability of the Progressive Supranuclear Palsy Rating Scale (PSPRS) using teleneurology has not been assessed. Objectives: To test whether removing items inadequately assessed by video would impact measurement of PSP severity and progression. Methods: We performed secondary analyses of two data sets: the phase 2/3 trial of Davunetide in PSP and a large single‐center cohort. We examined two modifications of the PSPRS: (1) removing neck rigidity, limb rigidity, and postural stability (25 items; mPSPRS‐25) and (2) also removing three ocular motor items and limb dystonia (21 items; mPSPRS‐21). Proportional agreement relative to the possible total scores was measured using the intraclass correlation coefficient, compared to the original PSPRS baseline values and change over 6 and 12 months. We examined the ability of both scales to predict survival in the single‐center cohort using proportional hazards models. Results: The mPSPRS‐25 showed excellent agreement (0.99; P < 0.001) with the original PSPRS at baseline, 0.98 (P < 0.001) agreement in measuring change over 6 months, and 0.98 (P < 0.001) over 12 months. The mPSPRS‐21 showed agreement of 0.94 (P < 0.001) with the original PSPRS at baseline, 0.92 (P < 0.001) at 6 months, and 0.95 (P < 0.001) at 12 months. Baseline and 6‐month change in both modified scales were highly predictive of survival in the single‐center cohort. Conclusions: Modified versions of the PSPRS which can be administered remotely show excellent agreement with the original scale and predict survival in PSP. The mPSPRS‐21 should facilitate clinical care and research in PSP via teleneurology. © 2022 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau‐related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first‐ever Tau2020 Global Conference in Washington, DC, co‐organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research‐advancing tools and insights that are now rapidly accelerating the pace of tau research. [ABSTRACT FROM AUTHOR]

Background: Aducanumab, a monoclonal antibody that clears amyloid aggregates, received FDA approval for early‐stage Alzheimer's Disease (AD). Clinicopathologic studies from patients treated with aducanumab are as yet unavailable, and may inform clinical use. Therefore, we report the clinical course, PET, and autopsy results from two patients treated with aducanumab. Methods: Patients were seen at UCSF and enrolled in ENGAGE (NCT02477800). Florbetapir (FBP) PET was obtained, including the initial six‐month treatment interval. Additional data, including flortaucipir (FTP) PET, was available through UCSF ADRC. PET was analyzed locally, and neuropathological analyses were performed by the UCSF Neurodegenerative Disease Brain Bank. Results: Patient 1: 77‐year‐old male (ApoE3/3) with vascular risk factors; onset age 63 with slowed processing, memory loss, and executive dysfunction. Fourteen doses aducanumab (6mg/kg) were administered in ENGAGE and 3 doses (1mg/kg) in EMBARK (NCT04241068). FBP demonstrated 8% reduction in amyloid centiloids (67.8→62.7). FTP encompassing four‐year interval from diagnosis to ENGAGE closure showed increase in metatemporal SUVR (1.175→1.273), with progression of cortical atrophy on MRI. He died of myocardial infarction (FBP‐to‐autopsy interval: 577d). Autopsy revealed intermediate ADNC (Thal 3, Braak 5, CERAD frequent), and substantial vascular pathology including chronic multifocal microinfarcts. Patient 2: 64‐year‐old female (ApoE4/4); onset age 55 with rapid forgetting, executive dysfunction, prominent anxiety, and dream enactment. Fourteen doses aducanumab (10mg/kg) were administered prior to early‐termination due to disease progression. FBP showed 38% reduction in amyloid centiloids (42.1→26.2). After discontinuation, she developed dysautonomia, parkinsonism, and paranoia, later dying in status epilepticus (FBP‐to‐autopsy interval: 1120d). Autopsy revealed high ADNC (Thal 5, Braak 6, CERAD frequent), extensive cortical Lewy bodies disease (LBD, Braak 6), moderate cerebral amyloid angiopathy, and amygdalar TDP‐43 (LATE‐NC Stage 1). Conclusion: Vascular disease and LBD, both common co‐pathologies in AD, likely contributed to the clinical phenomenology and course of these patients. In the first case, low‐dose aducanumab did not substantially reduce amyloid, and the patient later died from unrelated heart disease. In the second case, despite substantial amyloid clearance on high‐dose, co‐morbid LBD led to clinical progression and discontinuation. Additional autopsy studies are needed to clarify the neuropathological effects of aducanumab, and the role of AD co‐pathology. [ABSTRACT FROM AUTHOR]

Introduction: The impact of hepatorenal function on plasma biomarkers of neuropathology is unknown. Herein, we measured several plasma biomarkers in patients with cirrhosis. Methods: Plasma phosphorylated tau (p‐tau181), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t‐tau), and ubiquitin carboxyl‐terminal hydrolase L1 (UCHL1) were measured in 135 adults with cirrhosis and 22 healthy controls using Simoa. Within cirrhosis, associations between biomarkers and hepatorenal function were explored using linear regression. Results: p‐tau181, NfL, t‐tau, and UCHL1 were increased 2‐ to 4‐fold in cirrhosis, whereas GFAP was not increased. Within cirrhosis, creatinine moderately correlated with p‐tau181 (β = 0.75, P <.01), NfL (β = 0.32, P <.01), and t‐tau (β = 0.31, P <.01), but not GFAP (β = –0.01, P =.88) or UCHL1 (β = –0.05, P =.60), whereas albumin showed weak, inverse correlations: p‐tau181 (β = –0.18, P <.01), NfL (β = –0.22, P <.01), GFAP (β = –0.17, P <.05), t‐tau (β = –0.20, P =.02), and UCHL1 (β = –0.15, P =.09). Conclusions: Elevated p‐tau181, NfL, and t‐tau in cirrhosis were associated with renal impairment and hypoalbuminemia, suggesting that hepatorenal function may be important when interpreting plasma biomarkers of neuropathology. [ABSTRACT FROM AUTHOR]

Introduction: Ethnoracial differences in cerebrospinal fluid (CSF; amyloid beta 42 [Aβ42], total tau [t‐tau], phosphorylated tau 181 [p‐tau181], and plasma (p‐tau181, neurofilament light [NfL]) biomarkers of Alzheimer's disease (AD) are incompletely understood. Methods: We performed cross‐sectional analyses with and without adjustment for covariates comparing baseline CSF (Aβ42, t‐tau, p‐tau181) and plasma (p‐tau181, NfL) values in 47 African Americans (AAs) matched to 141 non‐Hispanic Whites (NHWs) and 43 Latinos (LAs) matched to 129 NHWs from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Unadjusted comparisons revealed no significant differences in plasma or CSF biomarkers between AAs and NHWs. A trend toward a lower CSF t‐tau and p‐tau181 in LAs compared to NHWs was observed, without significant differences in plasma biomarkers. After adjusting for covariates, there were no significant differences in CSF or plasma biomarkers between AAs and NHWs or between LAs and NHWs. Discussion: Plasma and CSF AD biomarkers may perform similarly across diverse populations but future studies in large, diverse cohorts are needed. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular health plays an important role in brain aging; yet its role in development of autosomal dominant forms of dementia and frontotemporal dementia (FTD) has not been fully elucidated. Life's Simple 7 (LS7) is a metric of cardiovascular health associated with reduced dementia risk and may represent a transdiagnostic heuristic to promote brain health. We examined the extent to which baseline LS7 associated with cognitive and brain aging trajectories in individuals with genetic FTD. Method: 243 adults carrying autosomal dominant genetic mutations for FTD and 189 non‐carriers completed neuroimaging, neuropsychological testing, and medical interviews. LS7 at baseline was computed following established procedures based on physical activity, diet, body mass index, smoking, hypertension, diabetes, and hypercholesterolemia; higher scores indicate more optimal cardiovascular health. We examined interactions between baseline LS7 and mutation carrier status on cognitive and brain structural outcomes at baseline (via linear regression) and longitudinally (via linear mixed‐effects models). All models adjusted for baseline age, sex, and education, and CDR®+NACC FTLD. Result: Mutation carriers and non‐carriers did not significantly differ on baseline LS7 (t = ‐1.42, p = 0.156). At baseline, there were significant interactions between LS7 and carrier status on frontotemporal (FTL) volume and executive functioning (all p‐values<0.046), such that positive associations between LS7 and neurobehavioral outcomes were stronger among mutation carriers versus noncarriers. Longitudinally, there was also a significant interaction between carrier status and baseline LS7 on memory over time (b = 0.04,p = 0.035) and the interaction approached significance for language trajectories (b = 0.03,p = 0.079); again, the association between higher LS7 and slower cognitive decline was stronger among mutation carriers versus noncarriers, even when excluding symptomatic carriers (b = 0.04,p = 0.047). Among mutation carriers only, higher baseline LS7 related to slower memory (b = 0.04,p = 0.006) and language declines over time (b = 0.044,p = 0.004), but did not significantly relate to FTL volume (b = ‐0.01,p = 0.307) or executive functioning trajectories (b = 0.004,p = 0.913) Conclusion: Better cardiovascular health relates to larger baseline frontotemporal volume and slower cognitive decline in individuals with autosomal dominant FTD. Interaction models suggested the degree to which cardiovascular health associates with better neurobehavioral outcomes is stronger in mutation carriers. Optimizing cardiovascular health may be a particularly important, modifiable approach to mitigate the symptoms associated with pathogenic variants of FTD. [ABSTRACT FROM AUTHOR]

Background: Smartphone‐based cognitive and motor tests enable frequent remote assessments in observational research studies and clinical trials, limiting travel burden and increasing access to research for underrepresented groups. One such smartphone tool is the ALLFTD Mobile App, which was designed to capture the clinical features of neurodegenerative diseases via a battery of cognitive, speech, and motor tasks. In this study, we focus on recruiting a demographically diverse normative sample. We have partnered with the UCSF Brain Health Registry (BHR) to recruit 1,000 cognitively healthy participants across the lifespan. Here we describe the study design and initial feasibility results. Methods: We designed an automated workflow in which participants never interact with the study team except for troubleshooting. BHR participants without reported cognitive impairment were contacted by email to participate in this study (n = 668). Interested participants downloaded the app onto their smartphone and completed in‐app electronic consent. They were asked to complete three ∼30‐minute sessions of cognitive, motor and speech measures over two weeks. Adherence was determined by evaluating the completion rate of app tasks. In a subset who completed a user experience questionnaire (n = 116), responses were quantified using descriptive statistics. Results: The current enrollment rate is 23.20% (155/668) of contacted participants. Average age is 62 (SD = 8.2, range = 25‐84). Average adherence is 76%. Participants reported a range of perceived task difficulty: 38% indicated tasks were "very easy" or "somewhat easy", 26% indicated they were "neutral," 36% found the tasks "somewhat difficult," and none reported them to be "very difficult." The time commitment was reported to be acceptable by 97% of participants, and 20% were willing to complete additional tasks. Over half (59%) of participants indicated that they preferred using a smartphone to complete cognitive assessments over traditional pen‐and‐paper measures. Conclusions: Our preliminary results demonstrate the feasibility and acceptability of recruiting participants, including older adults, through a registry and conducting remote smartphone testing via a fully automated workflow that is highly scalable. Future analysis will study the effects of demographic factors on feasibility and investigate the reliability and validity of the app measures in this sample. [ABSTRACT FROM AUTHOR]

Background: There has been a rise in remote cognitive testing for neurodegenerative diseases. The ALLFTD Mobile App is designed to capture clinical features of frontotemporal dementia (FTD) through repeated remote assessment on smartphones. This is a departure from traditional neuropsychological practice in which a single examiner‐led assessment occurs in a controlled setting. When participants complete tasks on their own, those with greater disease severity may be more variable in their performance for a variety of reasons (e.g. greater distractibility, less engagement). Here we study whether intraindividual cognitive variability (IIV) is associated with older age and increasing disease severity. Method: Participants were 279 (mean age = 54.9) healthy controls and participants with sporadic FTD or from familial FTD kindreds with a range of disease severities based on FTLD Clinical Dementia Rating scale (CDR®+NACC‐FTLD Global) scores: 0 (n = 132), 0.5 (n = 54), and ≥1 (n = 47). Participants completed three cognitive tasks at least two times across twelve days. Measures included an adaptive memory task and gamified versions of Flanker and Go/no‐go tasks. IIV was operationalized as the standard deviation in performance on each task. Regression analyses investigated the relationship of IIV with CDR®+NACC‐FTLD group, and with age in those without symptoms. Education and gender were included as covariates in all analyses. Result: Greater disease severity (CDR®+NACC‐FTLD) was associated with greater variability on Flanker (p<.001) and Go/No‐go (p =.02) tasks; a positive but non‐significant association was seen with memory testing (p =.16). Post‐hoc comparisons found that those with CDR®+NACC‐FTLD of 0.5 had significantly more IIV on the Flanker task (훃 =.39, p =.004) than those with CDR®+NACC‐FTLD's of 0. Moreover, those with a CDR®+NACC‐FTLD ≥1 had significantly greater IIV on the Flanker (훃 =.85, p<.001) and Go/No‐go tasks (훃 =.51, p =.007) than those with a CDR®+NACC‐FTLD of 0. In those without symptoms (CDR®+NACC‐FTLD = 0), age was associated with increased IIV on the Flanker (훃 =.27, p<.001) and Go/no‐go (훃 =.23, p<.001) tasks. Conclusion: Increased IIV, particularly on processing speed/executive functioning tasks, was associated with greater age and greater functional impairment, even in the mildest stages. Future investigations exploring predictors of IIV and the prognostic value of IIV are warranted. [ABSTRACT FROM AUTHOR]

Background: The ALLFTD (ARTFL‐LEFFTDS Longitudinal Frontemporal Lobar Degeneration) study is an NIH‐funded effort to prepare for clinical trials in sporadic (s‐FTLD) and familial (f‐FTLD) FTLD syndromes by characterizing cohorts, developing new clinical trial outcome measures, and evaluating disease progression. ALLFTD represents the merger and continuation of two prior studies: Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS). Methods: ALLFTD recruits participants with FTLD spectrum disorders (bvFTD, svPPA, nfvPPA, FTD‐ALS, CBS or PSP), with strong family histories of FTLD, or known FTLD‐associated genetic variants within the family. 26 sites in North America enroll participants for clinical and neuropsychological evaluations, MR Imaging, blood draws, and CSF collection in willing participants; participants are requested to return annually for follow‐up evaluation. All participants are genotyped for dementia‐associated mutations. Participants also enroll in the FTD Disorders Registry for follow‐up surveys. A subset of participants undergo remote assessment via the ALLFTD app. Visits conducted under ARTFL and LEFFTDS are included in the ALLFTD dataset. Results: ALLFTD has been successful in developing methods to conduct remote or hybrid visits and in actively evaluating participants. Since ALLFTD began in January 2020, 1034 participants (736 new; 298 previously enrolled in ARTFL or LEFFTDS) have been evaluated in the longitudinal arm; an additional 119 participants have been participated in a shortened, biofluid‐focused visit. 349 have returned for follow‐up visits. Including prior participants, the ALLFTD dataset contains 3871 visits from 2343 individuals. 1277 people have sporadic syndromes; 1045 were enrolled as familial. Among s‐FTLD, bvFTD is the most common phenotype (32.8%) followed by PSP (15.9%). 61.4% of f‐FTLD participants were clinically normal at first visit; bvFTD is the most common syndrome in symptomatic f‐FTLD (40%). 477 are confirmed carriers of FTLD‐associated genetic mutations. MRIs were obtained for 2594 visits; 3492 visits have associated blood biospecimens banked; 978 visits have associated CSF samples. Conclusions: The ALLFTD consortium is actively evaluating participants across North America to better characterize FTLD syndromes and support the planning and development of FTLD clinical trials. Longitudinal datasets including clinical, genetic, and imaging data are available by request. [ABSTRACT FROM AUTHOR]

Background: Memory impairment is generally considered minimal to absent in those with behavioral variant frontotemporal dementia (bvFTD). We sought to assess the frequencies of subjective and objective memory impairment in individuals with mild bvFTD according to consensus criteria. Method: Assessments were performed in mildly symptomatic bvFTD [defined by global FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD) = 1] mutation carriers (Familial) and non‐mutation carriers (Sporadic) who are participants in the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD, www.allftd.org) study. Mutation carriers had a pathogenic mutation in the MAPT, GRN or C9orf72 gene. The presence of subjective memory impairment was defined by a rating >0 on the memory domain of the CDR®+NACC FTLD. Evidence of objective memory impairment was based on performance across 7 memory measures, which include the National Alzheimer's Coordinating Center Uniform Data Set Version 3 – Craft Story Immediate Recall (CSImm) and Delayed Recall (CSDel), Benson Figure Delayed Recall (BenDel), and the California Verbal Learning Test – Learning (CVLearn), Immediate Recall (CVImm), Delayed Recall (CVDel), and Recognition (CVRecog). Performance was considered abnormal for z‐scores ≤ ‐1.5. Result: Data from 38 Familial (mean age 60±8 years, 61% male), and 109 Sporadic (mean age 63±7 years, 70% male) participants were analyzed. Memory ratings >0 on the CDR®+NACC FTLD were common for both Familial (84%) and Sporadic (88%). The frequencies of abnormal performance in the Familial vs Sporadic groups, respectively, per memory measure were: CSImm 43.8% vs 45.9%, p = 0.83; CSDel 46.9% vs 52.6%, p = 0.58; BenDel 29.4% vs 46.4%, p = 0.08; CVLearn 54.8% vs 39.8, p = 0.14; CVImm 64.5% vs 50%, p = 0.16, CVDel 80.6% vs 55.1%, p = 0.01, and CVRecog 51.6 vs 49%, p = 0.80. The frequencies of abnormal performance did not differ (all p>0.05) between Familial and Sporadic for ≥2 tests (79.3% vs 67.7%), ≥4 tests (55.2% vs 44.1%) and ≥6 tests (34.5% vs 31.2%). Conclusion: These data suggest that among those with a mild global severity of bvFTD features: 1) subjective and objective memory impairment are relatively frequent, and 2) the frequency of impairment across memory measures is largely similar between familial and sporadic bvFTD. The presence of memory impairment should not preclude a diagnosis of bvFTD. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a leading cause of dementia in individuals under age 65. Due to limitations in access to in‐person evaluations, there is an urgent need to examine remote, accessible, and low‐burden assessment techniques for FTD. Unobtrusive monitoring of at‐home computer use in older adults has shown that those with mild cognitive impairment (MCI) have significant declines in computer use over time. To extend these findings, we characterized daily trajectories in smartphone battery percentage, a proxy of smartphone use, and examined relationships with clinical indicators of disease severity in FTD. Method: Participants included 250 adults enrolled in the ALLFTD Mobile App study (mean age = 53.9 [SD = 14.9]; 59% women; 94% White). To assess clinical disease severity, all participants completed the FTLD Clinical Dementia Rating scale (CDR®+NACC FTLD), a brief neuropsychological battery, the Neuropsychiatric Inventory Questionnaire (NPI‐Q), and brain MRI. The ALLFTD Mobile App was installed onto participants' smartphones for remote, passive, continuous monitoring of smartphone use (average days of monitoring = 82 [range = 7‐541]). Battery percentage was collected every 15 minutes. Linear mixed effects models examined linear, quadratic, and cubic effects of time of day (i.e., hour; modeled as person‐specific random effects) and their interactions with each measure of disease severity on battery percentage. Models covaried for age. Result: 57% of participants were clinically normal, 21% had MCI, and 22% had dementia. CDR®+NACC FTLD Global score interacted with hour such that participants with MCI and dementia had flatter battery curves (i.e., less change in battery percentage throughout the day – a proxy of less smartphone use) than clinically normal participants (ps<0.001). Additional models showed that worse memory (hour3 x memory score: 훃 = 0.59, p<0.001) and executive functioning (hour3 x executive score: 훃 = 0.64, p<0.001), more neuropsychiatric symptoms (hour3 x NPI‐Q: 훃 = ‐0.22, p = 0.004), and smaller gray matter volumes (controlling for intracranial volume; hour3 x volume: 훃 = 0.49, p<0.001) were also statistically significantly related to less battery usage throughout the day. Conclusion: These findings are proof‐of‐concept that passively acquired smartphone data, specifically battery usage, can provide insights about disease progression in FTD. Results support future research focusing on the development of passively collected digital metrics sensitive to clinical declines in neurodegenerative disease. [ABSTRACT FROM AUTHOR]

Background: Pathogenic mutations in the MAPT (tau) gene cause familial frontotemporal lobar degeneration (f‐FTLD). No disease‐modifying treatments exist. Tau therapeutics being tested in other tauopathies may be suitable candidates, but the small number of identified mutation carriers prohibits traditional clinical trial designs from achieving adequate power. Platform trial designs permit multiple therapies to be tested in parallel and improve power by sharing placebo groups across treatment arms. We evaluate whether a platform design could improve the likelihood of identifying an effective treatment for MAPT mutation carriers. Method: ALLFTD and GENFI observational data were used to simulate MAPT prevention and early symptomatic clinical trials (CDR®+NACC‐FTLD≤1). Only presymptomatic participants (CDR®+NACC‐FTLD = 0) within 2.5 years of expected symptom onset based on disease progression models (DPM) were included. First, we evaluated the time and sample size required to test five treatments using a platform design compared to sequential randomized control trials. Platform designs assumed a max of three treatment arms at any time, with new arms enrolling upon completion of prior arms. Each arm randomized 60 mutations carriers 3:1 treatment to placebo, with a placebo group shared across arms. Minimum follow up was 1.5 years with common close. Sequential trials assumed 90 participants allocated 1:1 treatment to placebo, with three‐month intervals between trials. Using a platform design, we compared a novel method for testing therapeutic effects using DPMs to account for differential rates of expected progression compared to traditional mixed models for repeated measures (MMRM) tests controlling for baseline CDR®+NACC‐FTLD. Result: Five treatments could be tested in a platform design using 300 participants (75% treated) over five years, compared to 450 participants (50% treated) over 13 years using traditional, sequential trials. Platform trial simulations indicated that with 80% power, DPM‐based analytic approach could detect a 25% treatment effect, whereas traditional MMRM could only detect a 40% effect. Conclusion: Platform designs combined with DPM‐based analyses provide a path to testing more treatments with fewer participants. Adequately powered MAPT platform trials are feasible but require a global clinical trial infrastructure. [ABSTRACT FROM AUTHOR]

Background: Given the rarity of genetic frontotemporal dementia (FTD), researchers across the world have come together to form the FTD Prevention Initiative (FPI) in an effort to improve prevention trials design. As this initiative begins to bring together large‐scale data from worldwide cohort series, including ALLFTD in North America and GENFI in Europe and Canada, it is critical for FPI to quantify the level of relatedness between all participants. Here we provide the most recent update to these ongoing analyses. Methods: Genome‐wide SNP genotyping data from 1,684 ALLFTD and 568 GENFI participants was used to perform lineage analyses using PLINK. Briefly, QC was performed similarly in all datasets to remove individuals with low call rate and filter autosomal SNPs for missingness, frequency, and deviation from Hardy‐Weinberg equilibrium. Genetic ancestry was inferred by projecting genotyped samples into the principal components of the 1000 Genomes reference panel, using R package bigsnpr. Overlapping ALLFTD and GENFI genotyping data was then used, in a two‐stage approach, to calculate pairwise identity‐by‐descent (IBD) estimates and KING coefficients, followed by family‐network identification and pedigree reconstruction using PRIMUS. Results: First, we calculated IBD estimates among all participants by restricting pairs to those with estimates>0.1875 (up to second‐degree relatives). Overall, we identified a total of 292 second‐degree family networks, including 168 ALLFTD and 120 GENFI families, mostly associated with pathogenic variants in the 3 major FTD‐causing genes. We also identified 4 family networks with participants enrolled in both the ALLFTD and GENFI series, as well as several multi‐site families within the ALLFTD consortium. This first, overall approach allowed us to predict close relationships even between individuals with different ancestral backgrounds, including at least 4 confirmed admixed families. More distant relationships were also detected within ALLFTD and GENFI by performing ancestry‐based analysis among participants with estimated European ancestry, using the KING‐robust algorithm. Conclusions: These lineage analyses allowed us to identify, otherwise unknown, close (and distant) relatives from different study sites, as well as within the ALLFTD and GENFI series. This dataset will be a crucial resource to increase statistical accuracy and power in upcoming collaborative FPI studies. [ABSTRACT FROM AUTHOR]

Background: The ALLFTD Consortium aims to characterize preclinical and prodromal stage of familial Frontotemporal Lobar Degeneration (f‐FTLD) to prepare for clinical trials in FTLD. Method: We prospectively followed 320 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD with a mutation in MAPT (n = 106), GRN (n = 74), or C9orf72 (n = 140), and describe the ratings on the eight domains of CDR® plus NACC FTLD (FTLD‐CDR) in those who phenoconverted to Mild Behavioral and/or Cognitive Impairment (MBCI). MBCI was diagnosed by the proposed research criteria for MBCI‐FTD (Barker MS, et al. Brain 2022). Participants who were diagnosed as MBCI but returned to asymptomatic at the following visit were excluded from the FTLD‐CDR assessment. ANOVA was used to compare continuous variables, and chi‐square test was used to compare categorical variables across the groups. Result: Thirty‐six participants (15 MAPT, 9 GRN, 12 C9orf72) developed MBCI during follow‐up visits, 13 participants (5 MAPT, 3 GRN, 5 C9orf72) were diagnosed as MBCI but were characterized as asymptomatic at the following visit, and 271 participants stayed asymptomatic. Percentage of male in MBCI participants was 50% (MAPT 60%, GRN 33%, C9orf72 50%, p = 0.45). Age at phenoconversion to MBCI was 53.6±13.0 years old, the youngest in MAPT and the oldest in GRN participants (MAPT 44.3±8.3, GRN 63.1±11.3, C9orf72 56.4±10.8, p<0.001). Abnormal rating on each of the eight CDR® plus NACC FTLD domains at the initial visit of MBCI phenoconversion were observed in: "Memory" 36% (MAPT 33%, GRN 33%, C9orf72 44%, p = 0.95); "Orientation" 8% (MAPT 7%, GRN 8%, C9orf72 11%, p = 0.93); "Judgment/Problem Solving" 44% (MAPT 47%, GRN 50%, C9orf72 33%, p = 0.73); "Community Affairs" 22% (MAPT 27%, GRN 17%, C9orf72 22%, p = 0.82); "Home/Hobbies" 25% (MAPT 40%, GRN 8%, C9orf72 22%, p = 0.16); "Personal Care" 0%; "Behavior/Comportment/Personality" 44% (MAPT 60%, GRN 42%, C9orf72 22%, p = 0.19); "Language" 31% (MAPT 13%, GRN 50%, C9orf72 33%, p = 0.12). Conclusion: The three most common FTLD‐CDR domains initially disturbed in the prodromal stage of fFTLD were "Behavior/Comportment/Personality", "Judgment/Problem Solving", and "Memory", while "Orientation" was intact in the majority of the individuals. Memory impairment without disorientation was seen in one‐third of the prodromal fFTLD participants. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal Dementia (FTD) patients are geographically dispersed and often have behavioral and/or motor deficits that limit access to in‐person clinical trials and research. To address these participation barriers, we investigated the feasibility of installing in‐home sensor technologies to remotely assess everyday functioning in FTD. Method: We aimed to recruit 20 FTD participants with a variety of clinical syndromes, including behavioral variant FTD (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS), and progressive supranuclear palsy (PSP). We also aimed to enroll a study partner for each participant that lived in the same home to serve as a control. The Collaborative Aging Research Using Technology (CART) platform was installed in participants' homes to collect continuous data for up to two years, using motion sensors, physiological monitoring devices (e.g., scales, sleep sensors), electronic pillboxes, and wearable actigraphs. Computer use and driving patterns were also tracked. Technology was installed either via a study coordinator visit or remotely through video and written instructions, based on schedule and logistics. Participants were asked to complete a weekly Qualtrics survey about time away from home, visitors, and health changes. Result: Of the 159 UCSF participants available for recruitment through ALLFTD and other FTD projects, 28% (N = 45) met inclusion criteria. Of those 45, ten were ineligible due to advanced disease severity or relocation to an assisted living facility. A third (36%, N = 17) declined due to overwhelmed study partners (N = 3), declined any subproject participation (N = 7), sensitivity to participant's diagnosis (N = 2), or lack of response (N = 5). Two additional participants were recruited through UCLA's ALLFTD cohort. The platform has been installed in 19 homes (bvFTD: n = 10; PPA: n = 5; CBS/PSP: n = 4). Two homes discontinued due to death or relocation to assisted living facility. Mean data collection is 360 days (max = 527). Of 103 reported technological issues, 92% were resolved without additional home visits, either by phone or email. Participants completed 65% of weekly health questionnaires. Conclusions: Although there were some recruitment and retention challenges, these findings generally provide preliminary support for the feasibility and sustainability of conducting comprehensive in‐home passive data research in FTD. [ABSTRACT FROM AUTHOR]

Background: Corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) display phenotypic heterogeneity. CBS pathology can include 4‐repeat (4‐R) tau and Alzheimer's disease (AD) pathology/co‐pathology; while PSP involves predominantly 4‐R tau with AD co‐pathology. We evaluated whether in vivo biomarkers of AD pathology in CBS and PSP are associated with specific brain atrophy and default mode network (DMN) alterations and relates to specific clinical manifestations. Method: We analyzed MRIs of 110 patients with a clinical diagnosis of CBS and PSP from 4RTNI‐1, 4RTNI‐2 and the Toronto Western Hospital and 30 healthy controls. Patients were separated according to AD biomarker positivity (CBS/PSP‐AD, n = 23) and negativity (CBS/PSP‐noAD, n = 87) based on blood and cerebrospinal fluid AD biomarkers. Patients' cortical and subcortical volumes were obtained using Freesufer segmentation and compared against controls. The DMN connectivity was compared across groups using two‐sample t‐tests. In a subgroup of patients, we analyzed Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating (CDR), PSP Rating Scale (PSPRS) and delayed memory on the California Verbal Learning Test (CVLT). Spearman partial correlations were performed to relate the PSPRS and CVLT scores with whole‐brain grey matter volumes. Neuroimaging analyses were controlled for age, site and total intracranial volume. Result: CBS/PSP‐AD displayed atrophy in temporal and parietal regions and hippocampus; while CBS/PSP‐noAD, in frontal and temporal regions, basal ganglia and thalamus (p<0.05, Bonferroni corrected). Reduced connectivity within the DMN was found in frontal‐temporal regions for CBS/PSP‐AD, and in frontal‐parietal regions for CBS/PSP‐noAD versus controls; and in temporal regions for CBS/PSP‐AD versus CBS/PSP‐noAD (p<0.001, uncorrected). No differences were obtained for MoCA, CDR and CVLT. The CBS/PSP‐AD group showed lower scores in the PSPRS in comparison to the CBS/PSP‐noAD [t(81) = 2.39, p = 0.02)]. Left thalamus grey matter volume negatively correlated with PSPRS scores [r:‐0.44, p = 0.02, Bonferroni corrected] in CBS/PSP‐noAD but no associations were found in CBS/PSP‐AD. Conclusion: Distinct patterns of atrophy and connectivity were observed in CBS/PSP‐AD compared to CBS/PSP‐noAD, suggesting selective vulnerability to AD pathology. As well, severity of disease was related to thalamic atrophy only in CBS/PSP‐noAD. Selective vulnerability to diverse proteinopathies, leading to different atrophy and connectivity patterns, may help explain phenotypic heterogeneity in CBS and PSP. [ABSTRACT FROM AUTHOR]

Background: Alpha‐synuclein (αSyn) is the underlying neuropathology in both Parkinson's Disease (PD) and non‐PD neurodegenerative syndromes, e.g. dementia with Lewy bodies (DLB). Importantly, αSyn is also a common co‐pathology, especially in Alzheimer's disease (AD), where autopsy studies reveal comorbid αSyn in >50% of cases. A seeded aggregation amplification (SAA) assay (SynTap) has been shown to be highly sensitive and specific for pathogenic αSyn seeds in patients with PD and DLB, with lower performance in amygdalar‐predominant Lewy Body disease (LBD). Here we evaluated the antemortem CSF performance of SynTap in patients with non‐PD syndromes, with specific attention to performance in brainstem‐predominant αSyn and patients with atypical PD, e.g. progressive supranuclear palsy Richardson's syndrome (PSP‐RS, N = 6) and corticobasal syndrome (CBS, N = 11). Method: Patients were evaluated through observational studies at the UCSF Alzheimer's Disease Research Center and neuropathologic evaluation was performed by the Neurodegenerative Disease Brain Bank. Antemortem CSF samples were tested with SynTap. Operators were blinded to diagnosis, and all samples were run as a single batch. Sensitivity and specificity were compared, and clinical correlations were examined across pathological groups and clinical diagnoses, using antemortem clinical records. Result: Overall, in 56 patients, SynTap was 59% sensitive and 96% specific for autopsy‐confirmed αSyn pathology of any type. SynTap had perfect performance for diffuse (4/4) and transitional (5/5) LBD, and correctly identified 3/3 cases where LBD was primary. Consistent with prior reports, sensitivity was low in amygdalar‐predominant LBD (6/14, 43%), and lower in brainstem‐predominant LBD (1/6, 17%). A false positive result was present in 1/27 cases (4%). In the PSP‐RS cohort, SynTap positively identified 1 case caused by diffuse LBD and AD, and was true negative in 5/5. Within CBS, SynTap positively identified 1/1 case with diffuse LBD co‐pathology, 1/2 cases with brainstem‐predominant LBD, but missed 1 case with amygdalar‐predominant LBD. Conclusion: SynTap best identifies αSyn pathology in patients with diffuse and transitional LBD, though specificity is high in the entire cohort. The etiology of low sensitivity in amygdalar‐ and brainstem‐predominant LBD co‐pathology requires further elucidation. The test may aid diagnostically in atypical PD syndromes, but results should be carefully considered, given the possibility of co‐pathology. [ABSTRACT FROM AUTHOR]

Background: The pathophysiological mechanisms driving frontotemporal lobar degeneration (FTLD) disease progression and corresponding biomarkers that capture these changes are not fully understood. We leveraged high‐throughput proteomics to identify networks of co‐expressed CSF proteins and candidate biomarkers for prediction of disease progression in adults with autosomal dominant FTLD mutations. Method: 113 adults carrying autosomal dominant FTLD mutations (C9orf72/GRN/MAPT) and 38 noncarrier controls from the ALLFTD consortium completed baseline lumbar puncture and longitudinal neuropsychological testing. CSF was assayed for SOMAmer proteomics on SOMAscan® v3.0 (4,140 proteins). Network analysis identified weighted protein co‐expression modules, which were annotated via gene ontology and cell‐type enrichment analysis. Disease age estimates that capture proximity to symptom onset were derived from a Bayesian disease progression model incorporating genotype‐specific clinical (cognition, CDR®+NACC FTLD) and biomarker (brain volume, plasma NfL) information. At baseline, local‐weighted regression examined module z‐scores (based on mean/SD of module levels [first principal component] in noncarriers) in relation to disease age. Longitudinal linear mixed‐effects models examined global cognitive trajectories in relation to baseline module z‐scores, as well as individual proteins within prognostic modules. Result: Network analysis identified 32 CSF protein co‐expression modules (37 to 223 proteins/module). 16 modules showed mutation‐related deviations from noncarriers. Deviations in ion transport, neurodevelopmental, metabolic, and transcriptional modules occurred several decades before estimated symptom onset (disease age: ‐30 to ‐20 years) and persisted across disease age. Deviations in neuroinflammatory and ubiquitination/autophagy modules occurred ∼10 years before estimated symptom onset. Sharp deviations in RNA binding, protein phosphorylation, neurogenesis, synaptic function, and lysosomal modules occurred near symptom onset (disease age: ‐1 to 4 years). Baseline synaptic and neurogenesis modules were the strongest prognosticators of cognitive decline (module x time: bs>.10, ps<.05). Within these modules, individual proteins with stronger intramodular connectivity exhibited stronger associations with cognitive decline (e.g., synaptic/transmembrane module: r =.40, p = 2.85e‐6; e.g., EPHA5, LRRTM2). Conclusion: Large‐scale analysis of the CSF proteome reveals a biologically‐diverse landscape of protein networks associated with presymptomatic and symptomatic stages of autosomal dominant FTLD. Synaptic and neuron‐enriched protein networks exhibited prodromal deviations that forecasted incipient cognitive decline. 'Hub' proteins derived from these affected networks warrant further validation as candidate biomarkers for early FTLD disease progression. [ABSTRACT FROM AUTHOR]

Introduction: Cognitive composite scores offer a means of precisely measuring executive functioning (EF). Methods: We developed the Uniform Data Set v3.0 EF composite score (UDS3‐EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item‐response theory and applied nonlinear and linear demographic adjustments. The UDS3‐EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models. Results: Final model fit was good‐to‐excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3‐EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease‐dementia ≈ behavioral variant frontotemporal dementia; P < 0.001). The UDS3‐EF correlated most strongly with other EF tests (βs = 0.50 to 0.85, Ps < 0.001) and more with frontal, parietal, and temporal lobe gray matter volumes (βs = 0.18 to 0.33, Ps ≤ 0.004) than occipital gray matter (β = 0.12, P = 0.04). The total sample needed to detect a 40% reduction in UDS3‐EF change (n = 286) was ≈40% of the next best measure (F‐words; n = 714). Conclusions: The UDS3‐EF is well suited to quantify EF in research and clinical trials and offers psychometric and practical advantages over its component tests. [ABSTRACT FROM AUTHOR]

Objective: MAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach. Methods: We studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel‐based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype. Results: Symptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers. Interpretation: A subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration. [ABSTRACT FROM AUTHOR]

Introduction: The Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility.We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring. Methods: Linear regressions compared baseline performances in 1655 National Alzheimer’s Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 185), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n=109), and controls (n=581)). Sample sizes to detect treatment effects were estimated using longitudinal data. Results: Among PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change. Discussion: The FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates. Objective: The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. Methods: Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation. Results: 29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%). Conclusions: Favorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation. [ABSTRACT FROM AUTHOR]

Background: Differences in CSF and plasma Alzheimer's disease biomarkers between African Americans (AA), Latinos (LA), and non‐Hispanic Whites (NHW) have been reported. The Alzheimer's Disease Neuroimaging Initiative (ADNI) may offer insights into ethnoracial biomarker differences important for understanding disease trajectory variations among diverse populations. Method: We queried the ADNI database for all participants with available plasma pTau181 and NfL (Simoa) and linked CSF biomarkers within 1 year of blood draw (Aβ42, pTau181, T‐tau, Elecsys). Baseline data for 47 AA and 43 LA with plasma biomarkers were matched to separate groups of NHW (1:3 nearest neighbor matching on propensity score), considering age, sex, education, CDR, APOE ε4 alleles and family history of dementia (Table 1). Cross‐sectional analyses compared biomarker levels between matched cohorts without (non‐parametric Mann‐Whitney U‐test) and with adjustment for demographics, clinical, biomarker, and medical characteristics (multi‐linear regression). Statistical threshold was set at two‐tailed p<0.05. Result: Unadjusted comparisons between AA and NHW revealed no significant differences in plasma NfL [29.3 (IQR: 21.6‐42.5) vs 35.5 (27.0‐49.6), p=.12], plasma pTau181 [14.5 (9.4‐22.9) vs 15.5 (10.1‐22.8), p=.83], CSF Aβ42 [933.1 (649.5‐1590.8) vs 926.7 (677.7‐1697.8), p=.83], CSF T‐tau [214.6 (152.4‐290.7) vs 251.9 (194.5‐351.4), p=.17] or CSF pTau181 [19.6 (14.4‐27.3) vs 22.7 (17.0‐33.3), p=.32] (Fig. 1a‐b). No significant differences were identified in any of the biomarkers after adjustment for relevant covariates. Unadjusted comparisons between LA and NHW revealed no significant differences in plasma NfL [36.7 (24.4‐50.4) vs 35.6 (25.6‐47.1), p=1], plasma pTau181 [18.0 (11.3‐25.0) vs 15.7 (10.9‐23.4), p=.81], or CSF Aβ42 [852.7 (787.1‐1213.0) vs 951.6 (651.1‐1530.5), p=1]. A trend towards lower CSF T‐Tau [216.5 (147.1‐270.5) vs 257.2 (197.2‐360.9), p=.076] and CSF pTau181 [19.4 (13.6‐27.9) vs 24.7 (17.5‐33.4), p=.076] in LA was observed (Fig. 2a‐b). After adjustment for covariates, LA were found to have significantly lower levels of CSF T‐tau (β=0.154, p<.05) and CSF pTau181 (β=0.164, p<.05), while differences in plasma markers were not significant. Conclusion: No significant biomarker differences between AA and NHW were observed. Lower CSF pTau181 and CSF T‐Tau in LA compared to NHW after covariate adjustment may represent subtle differences driven by biological factors or unmeasured sociocultural determinants (income, occupation, neighborhood environment); larger studies are needed. [ABSTRACT FROM AUTHOR]

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off‐label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence‐based knowledge to guide future treatment decisions. Objectives: To describe an open‐label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP‐Richardson's syndrome (PSP‐RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. Methods: For 6 months, 10 PSP‐RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP‐RS patients from the davunetide clinical trial and the 4‐Repeat Tauopathy Neuroimaging Initiative. Results: Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (–0.07 ± 0.03), young plasma (–0.06 ± 0.03), and historical controls (–0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. Conclusions: Neither salsalate nor young plasma had a detectable effect on disease progression in PSP‐RS. Focused open‐label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP‐directed therapies. [ABSTRACT FROM AUTHOR]

Introduction: Differential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic‐predominant", (3) "hippocampal‐sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy‐defined subtypes. Methods: The four subtypes were replicated using a clustering method on MRI data in 260 amyloid‐β‐positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline. Results: Voxel‐wise and region‐of‐interest analyses revealed the greatest neocortical tau load in hippocampal‐sparing (frontoparietal‐predominant) and typical (temporal‐predominant) patients, while limbic‐predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal‐sparing patients showed the most rapid global cognitive decline. Discussion: Our data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD. [ABSTRACT FROM AUTHOR]

Introduction: Frontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed. Methods: In March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD. Results: Challenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges. Discussion: New personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors. [ABSTRACT FROM AUTHOR]

Introduction: Familial frontotemporal lobar degeneration (f‐FTLD) due to autosomal dominant mutations is an important entity for developing treatments for FTLD. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) longitudinal studies were designed to describe the natural history of f‐FTLD. Methods: We summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f‐FTLD. Results: Published and emerging studies are producing data on all phases of f‐FTLD, including the asymptomatic and symptomatic phases of disease, as well as the transitional phase when symptoms are just beginning to develop. These data indicate that rates of change increase along with disease severity, which is consistent with commonly cited models of neurodegeneration, and that measurement of biomarkers may predict onset of symptoms. Discussion: Data from large multisite studies are producing important data on the natural history of f‐FTLD that will be critical for planning intervention trials. [ABSTRACT FROM AUTHOR]

Background: The rural‐urban commuting area (RUCA) codes classify communities using measures of population density, urbanization, and daily commuting from U.S. Census Bureau information. The ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study generated RUCA codes for enrolled participants to better understand our cohort demographics. The rural‐urban distribution of participants may provide important insights for clinical trial planning. Methods: The current RUCA codes are generated from the 2010 decennial census and the 2006‐10 American Community Survey data. The codes are numbers (1‐10) that describe metropolitan, micropolitan, small town, and rural commuting areas based on the size and direction of the primary (largest) commuting flows. Results: RUCA codes were generated on 784 ALLFTD participants. At their most recent visit, participant median age was 60, 51.1% female, and a median education of 16 years. Participants were classified as clinically normal (39.1%), behavioral variant FTD (25%), nonfluent PPA (6.7%), semantic variant PPA (6.6%), PSP (4.7%), MBCI (4.8%), corticobasal syndrome (5.9%), and the remaining 7% of participants had other dementia‐related diagnoses. For participants with sporadic disease, 87.4% live in a metropolitan area, 6.7% a micropolitan area, 3.2% a small‐town area, and 3.2% live in a rural area. In familial FTLD, a larger percentage of participants live in micropolitan or small town/rural community (18.8% combined; p = 0.029), driven largely by MAPT family participants (n = 101). 10% of those with a familial MAPT mutation live in a rural area; with an additional 18% in micropolitan (12.9%) or small‐town areas (5%). Among those with a familial C9orf72 expansion, 83.3% live in a metropolitan area, 8.9% micropolitan area, 5.6% in a small‐town area, and 2.2% in a rural area. Participants with a familial GRN mutation show a similar distribution: 84.7% live in a metropolitan area, 5.6% micropolitan, 6.9% small‐town, 2.8% rural. Conclusions: Additional analyses to better understand if FTD families are disproportionately living in rural communities are underway. These analyses will better characterize sporadic and familial FTD demographics to assist with clinical trial design. [ABSTRACT FROM AUTHOR]

Background: The DEMQOL (Dementia Quality of Life) scale is a patient reported questionnaire and proxy form that captures subjective life quality. Participants in ALLFTD and their Study Partners (SP) complete these questionnaires at each study visit. Method: We analyzed the DEMQOL in participants and their SPs when the SP was reported to be a spouse or equivalent. Analyses focused on the final overall quality of life (QoL) rating for the participant (poor, fair, good, or very good). Result: DEMQOL responses from 907 dyads (participant: mean age 58.3±13.4 years, 44% female, and mean education 15.9±2.5 years) were analyzed. Participants rated their overall QoL as very good (45.8%), good (36.5%), fair (14%), and poor (3.5%). SPs rated their participant's overall QoL as very good (33.6%), good (41%), fair (19.4%), and poor (6%). There was a discordance in ratings between participants and SPs (p<0.0001); in almost 50% of cases, participants rated their QoL better (33.2%) or worse (15.2%) than their SP rated their QoL. When considering disease severity (CDR®+NACC‐FTLD global score), participants rated their QoL better than their SP rated their QoL (CDR®+NACC‐FTLD = 0: 19.4%, CDR®+NACC‐FTLD = 0.5: 42%, and CDR®+NACC‐FTLD = 1+: 33.2%), worse than (CDR®+NACC‐FTLD = 0: 15.1%, CDR®+NACC‐FTLD = 0.5: 13.3%, and CDR®+NACC‐FTLD = 1+: 15.2%), or the same (CDR®+NACC‐FTLD = 0: 65.6%, CDR®+NACC‐FTLD = 0.5: 44.8%, and CDR®+NACC‐FTLD = 1+: 51.6%). Conclusion: Among participants and SPs, similarities and differences in QoL ratings are fairly consistent regardless of global CDR®+NACC‐FTLD rating. Generally, participants are equally or more optimistic about QoL than their SPs. Longitudinal analyses are forthcoming. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) often occur during the prodromal stage of frontotemporal dementia (FTD), as evidenced by the presence of early psychiatric diagnosis in approximately 50% of bvFTD patients prior to their dementia diagnosis. We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased baseline burden and rates of progression of NPS compared to non‐carrier individuals prior to onset of dementia symptoms based on the Clinical Dementia Rating (CDR) scale. Method: Participants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. NPS were assessed with Neuropsychiatric Inventory‐Questionnaire (NPI‐Q), Geriatric Depression Scale (GDS), Interpersonal Reactivity Index (IRI), Social Behaviour Checklist (SBOCL), and Behavioral Inhibition Scale (BIS) annually for up to five years. We selected participants with CDR scores of 0 and 0.5. If a participant's CDR changed to above 0.5 during the follow‐up, we only analyzed observations collected before the conversion. We used mixed effects models to compare the baseline burden and the longitudinal progression of NPS measures between carriers and controls, adjusted for baseline age, sex, education, and baseline Montreal Cognitive Assessment (MoCA) scores. Result: We analyzed data from 607 participants (111 C9orf72+, 47 GRN+, 67 MAPT+ and 382 non‐carrier controls). There were no significant group differences in baseline demographic features, except that MAPT+ was significantly younger than other groups (average age: C9orf72+ = 45, GRN+ = 53, MAPT+ = 41, controls = 54). Baseline NPS scores were not significantly different between carriers and controls, except that C9orf72+ had significantly lower GDS compared to controls (p = 0.002). Longitudinally, GRN+ (p = 0.02) and MAPT+ (p = 0.009) had significantly higher rates of NPI‐Q increases compared to controls, while the progression of NPI‐Q in C9orf72+ was comparable to controls. The rates of GDS, IRI, SBOCL and BIS progression were not significantly different between carriers and controls. Conclusion: Prior to the onset of dementia, GRN+ and MAPT+ have a faster progression of NPS, as measured by NPI‐Q, compared to controls. Future work will investigate whether different mutation carriers are affected by specific type/cluster of symptoms. [ABSTRACT FROM AUTHOR]

Background: The ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) research consortium is actively enrolling participants across 23 North American centers to characterize sporadic and familial frontotemporal dementia (FTD) and prepare for disease‐modifying clinical trials. The ability to identify, otherwise unknown, relatives among these participants is critical to rigorously build family structures for downstream clinical and genetic research studies. Methods: Genome‐wide SNP genotyping data from ALLFTD participants was used to perform lineage analyses using PLINK. Briefly, QC was performed to remove individuals with low call rate and filter autosomal SNPs for missingness, allele frequency, and deviation from Hardy‐Weinberg equilibrium, before pruning SNPs for linkage disequilibrium. Identity‐by‐descent (IBD) estimates were then calculated for determining relatedness, followed by family‐network identification and pedigree reconstruction using PRIMUS. Results: About 46% of ALLFTD participants that were genotyped and passed QC (n = 1,453) had reported a family history, while 50% (n = 721) did not and were considered sporadic. We identified a total of 460 participants that had at least one relative who was second degree or closer (PI_HAT>0.1875) based on IBD sharing, resulting in 150 family networks. This included 9 participants who self‐identified as sporadic, demonstrating the utility of direct genetic characterization to determine familiality in FTD. Most of the predicted families were associated with disease causing variants in the 3 major FTD‐causing genes: 66 families with known C9orf72 repeat expansion carriers, 35 with MAPT (including 11 families with the variant historically known as p.P301L) and 30 with GRN pathogenic variant carriers, as well as 2 families with carriers of both a C9orf72 expansion and a GRN pathogenic variant. We also identified 5 families with carriers of pathogenic variants in other familial dementia genes (2 TARDBP, 2 VCP and 1 PSEN1), as well as 12 families with yet unknown genetic etiology. Conclusions: This dataset sets up a crucial resource to increase statistical accuracy and power in downstream association studies using the clinical, neuropsychological, neuroimaging and biomarker data currently being generated by the ALLFTD consortium. It will also facilitate genetic studies aimed at novel gene discovery, and identification of haplotypes and genetic modifiers associated with the 3 major FTD causal genes. [ABSTRACT FROM AUTHOR]

Background: White matter signal abnormalities (WMSA) are frequently observed on magnetic resonance imaging (MRI) scans of people with frontotemporal dementia (FTD). We hypothesized that carriers of mutations in progranulin (GRN+), chromosome 9 open reading frame 72 (C9orf72+) and microtubule associated protein tau (MAPT+) have increased rates of progression of WMSA compared to non‐carrier individuals prior to onset of dementia, and that different mutations may have different rates of WMSA accumulation. Method: Participants were recruited through the ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study. We selected participants with Clinical Dementia Rating scale (CDR) scores of 0 and 0.5. If a participant developed FTD during the follow‐up, we only analyzed observations collected before the conversion. WMSA were defined as hyperintensities on FLAIR MRI. Total WMSA volumes were normalized to the respective intracranial volumes. We used a linear mixed effects model, with random intercepts and slopes, to compare the baseline burden and the longitudinal progression of total WMSA volumes between mutation carriers and controls. The model was adjusted for baseline age, sex, education, baseline Montreal Cognitive Assessment (MoCA) scores, and MRI acquisition sites. Result: We analyzed MRI data from 199 participants who had at least two MRI visits (46 C9orf72+, 17 GRN+, 35 MAPT+, 101 non‐carrier controls; up to five years of follow‐up). We did not find significant group differences in baseline demographic features, except that MAPT+ was younger than non‐carrier controls (average age: C9orf72+ = 47, GRN+ = 56, MAPT+ = 40, controls = 47). Baseline WMSA volumes were not significantly different between mutation carriers and controls. Longitudinally, the rates of WMSA volume increase in C9orf72+ and MAPT+ were comparable to controls; whereas, GRN+ had higher rates of WMSA volume increases compared to controls (p = 0.01). Conclusion: WMSA may accumulate at higher rates in GRN+ prior to the onset of FTD, which is consistent with the frequent presence of white matter diseases observed in symptomatic FTD patients with GRN mutations. Future work is warranted to investigate the association between white matter structural changes and cognitive/psychiatric changes in FTD mutation carriers. [ABSTRACT FROM AUTHOR]

Introduction: We sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [11C]PIB–positron emission tomography ([11C]PIB‐PET) analyzed with the Centiloid (CL) method, a standardized scale for Aβ‐PET quantification. Methods: Four centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. Results: CL values increased with each CERAD neuritic plaque score increment (median −3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aβ phases (increases were detected starting at phase 2) with overlap between scores/phases. PET‐pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate‐to‐frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate‐to‐high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). Discussion: Our study demonstrated the robustness of a multisite Centiloid [11C]PIB‐PET study and established a range of pathology‐based CL thresholds. [ABSTRACT FROM AUTHOR]

Background: It is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials. Method: As part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020. Result: As of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT, 192 in GRN, 370 in C9orf72, 4 with mutations in both GRN and C9orf72, and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection. Conclusion: The data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886. [ABSTRACT FROM AUTHOR]

Background: Few studies have evaluated the relationship between in vivo [18F]Flortaucipir (FTP) PET and post‐mortem pathology. Method: We sought to compare antemortem FTP‐PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative diseases. 80‐100 min FTP‐PET standardized uptake value ratio (SUVR) images were created using an inferior cerebellar gray matter reference. W‐score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. Mean SUVRs were calculated for Braak stage regions of interest (ROIs), and these values were compared to SUVRs derived from young, non‐autopsy, cognitively normal controls used as a standard for tau negativity. Result: Nineteen patients were included (mean age at PET 61 [range 34‐76]; 8 female; mean PET‐to‐autopsy time of 30 months [range 4‐59 months]; Table 1). Eight patients had primary Alzheimer's disease (AD) pathology, 9 had non‐AD tauopathies (progressive supranuclear palsy [PSP], corticobasal degeneration [CBD], argyrophilic grain disease [AGD], and frontotemporal lobar degeneration [FTLD] with tau inclusions), 2 patients had non‐tau related FTLD. There was excellent correspondence between areas of FTP retention and neurofibrillary tangle (NFT) distribution in patients with primary AD neuropathology. Patients with non‐AD tauopathies showed a range of tracer retention that was less than AD and more than age‐matched, cognitively normal controls, with CBD and FTLD due to MAPT mutations showing the most extensive and distinct binding patterns (Figure 1). Patients with non‐tau related FTLD also showed small areas of tracer retention (Figure 1). Overall, binding across both tau‐positive and tau‐negative non‐AD disorders did not reliably correspond with post‐mortem tau pathology. Quantification of FTP‐PET SUVR images at Braak stage ROIs reliably detected high Alzheimer's Disease Neuropathologic Change (Braak VI) pathology. However, patients with earlier Braak stages did not show elevated tracer uptake in these regions compared to young, tau‐negative controls (Figure 2). Conclusion: In summary, PET‐to‐autopsy correlations confirm that FTP‐PET is a reliable biomarker of advanced tau pathology in AD. The tracer cannot reliably differentiate non‐AD tauopathies and may not detect early Braak stages of NFT pathology. [ABSTRACT FROM AUTHOR]

Background: TAR DNA‐binding protein 43 (TDP‐43) mislocalization is present in over 50% of patients with frontotemporal dementia and about 20% of patients with Alzheimer's disease, but there is still an unmet need for clinical trials targeting sporadic TDP‐43 pathology in patients with dementia. The semantic variant of primary progressive aphasia (svPPA) is highly predictive of frontotemporal lobar degeneration with TDP‐43 mislocalization (FTLD‐TDP) and presents an ideal cohort in which to explore therapeutics with potential benefit across the spectrum of TDP‐43 pathology. Oxidative stress promotes mislocalization of TDP‐43 in neurons and may be a viable therapeutic target in svPPA and other FTLD‐TDP disorders. Verdiperstat is a potent, oral, CNS penetrant, myeloperoxidase inhibitor that reduces production of oxidative species from microglia. The Veri‐T trial (NCT05184569) explores the therapeutic potential of verdiperstat and is the first clinical trial to focus on patients suffering from svPPA. Methods: Veri‐T is a multisite, phase 1, randomized, double‐blind, placebo‐controlled trial. N = 64 participants with svPPA will be randomized 3:1 to oral verdiperstat (titrated to a dose of 600mg BID) or placebo for 6 months of double‐blind therapy. Neuropsychological assessments, plasma, CSF, and volumetric brain imaging are collected prior to and upon conclusion of treatment. Recruitment is ongoing at 5 ARTFL LEFFTDS Longitudinal FTLD (ALLFTD) research network clinical centers. Results: The primary objective is to determine the safety and tolerability of verdiperstat in svPPA. The secondary objective is to determine the pharmacokinetic profile of verdiperstat in this cohort. Exploratory endpoints are focused on identifying potential pharmacodynamic effects and identifying endpoints for future efficacy trials including plasma myeloperoxidase activity, CSF biomarkers of glial activity (chitinase‐family proteins), neurodegeneration (neurofilament light chain), and unbiased CSF proteomics (Somalogics), as well volumetric MRI changes unique to svPPA, and cognitive and language impairments measured using the ALLFTD Mobile App. Conclusion: The Veri‐T trial examines the safety, tolerability and pharmacokinetic properties of verdiperstat in svPPA, and explores novel pharmacodynamic biomarkers and outcome measures that could be employed in future efficacy studies. Veri‐T is the first multicenter clinical trial of a potentially disease modifying agent for svPPA, and the first to leverage resources of the ALLFTD network. [ABSTRACT FROM AUTHOR]

Background: Motor disturbances are common in patients with a variety of neurodegenerative and neurological syndromes, such as Parkinson's disease and Frontotemporal Dementia (FTD). Accurately quantifying motoric changes could enable earlier detection and monitoring of these syndromes, and remote quantification may allow for more frequent assessments and may improve access to research for underrepresented and geographically dispersed participants. With these benefits in mind, investigators from the ALLFTD consortium developed smartphone tests of balance and finger tapping speed. Here we present preliminary test‐retest reliability and associations with gold standard tests. Method: The tasks were analyzed in two independent samples. The first was an in‐person cohort of healthy older adults (n = 7), mild cognitive impairment (MCI, n = 1) and FTD (n = 3) who completed the smartphone standing/balance and finger tapping tests (FTT) twice in person. The second sample included 31 ALLFTD participants with a range of clinical presentations (healthy older adults [n = 11], FTD [n = 5], MCI [n = 2], unknown [n = 13]) who were asked to complete the balance test three times over two weeks at home. The primary outcomes were total taps for the FTT and root mean squared acceleration for the balance test. Test‐retest reliability was calculated using an intraclass correlation coefficient (ICC); given the small sample size, outliers (n = 6) were removed from the balance test. We tested the association of smartphone FTT with the gold standard mechanical FTT and the balance task with the CDR®+NACC‐FTLD‐SB (disease severity) using Spearman's correlations. A Wilcoxon‐sign rank test compared participants with motor features on the Progressive Supranuclear Palsy Rating Scale (PSPRS>0) to those without (PSPRS = 0). Result: The smartphone FTT showed good test‐retest reliability (ICC = 0.78) and a strong correlation (r = 0.8,p<0.05) with mechanical FTT. The test‐retest reliability for the balance task was excellent for the remote sample (ICC = 0.97) and in‐person (ICC = 0.89) samples. In the remote sample, greater acceleration was correlated with higher CDR®+NACC‐FTLD‐SB (r = 0.7,p = 0.003), and participants with motor features on the PSPRS had higher acceleration than those without (W = 11,p = 0.04). Conclusion: These findings provide preliminary support for the reliability and validity of the ALLFTD Mobile App tests of motor function. Replication in a larger sample is required. [ABSTRACT FROM AUTHOR]

Background: Frontotemporal dementia (FTD) is a collection of neurodegenerative diseases affecting behavior, cognition, and motor functions. FTD treatment trials will benefit from sensitive assessments capable of detecting and longitudinally tracking cognitive changes. Remote smartphone cognitive tests may improve the sensitivity to detect and monitor cognitive decline via novel methods of data capture and more frequent assessments within ecologically valid environments, while simultaneously reducing patient burden. The first step in determining the utility of these measures is establishing their reliability. We previously reported baseline reliability estimates for the ALLFTD Mobile App cognitive tests in a small pilot sample. Here we extend these results using a larger sample and evaluate six‐month stability. Method: We enrolled a diagnostically mixed sample of 128 participants (CDR®+NACC‐FTLD = 0 [n = 84]; CDR®+NACC‐FTLD = 0.5 [n = 21]; CDR®+NACC‐FTLD≥1 [n = 23]) from ongoing studies of healthy aging (Hillblom Network) and frontotemporal dementia (ALLFTD). Participants self‐administered five cognitive tests from the ALLFTD Mobile App on their own smartphone; they were asked to complete each test three times within two weeks. Tests included gamified versions of N‐back, Stroop, Flanker, and Go/No‐Go paradigms, and an adaptive short‐term memory test. We evaluated the internal consistency of each test's first occurrence using Spearman‐Brown split‐half reliability (100 simulations). Test‐retest reliability over the first three baseline replicates (as available) was evaluated by calculating intraclass correlations (ICC). In a preliminary analysis, we tested the six‐month stability of test performance in nine functionally intact participants who completed baseline and follow‐up Flanker, N‐Back, and adaptive memory assessments by calculating Spearman's rho. Result: Split‐half reliability estimates were in the good to excellent range (r's: 0.81–0.97). Test‐retest reliability estimates were in the adequate to excellent range (ICCs: 0.72–0.96). ICC estimates were comparable for participants with and without clinical impairment (CDR®+NACC‐FTLD = 0 (0.74–0.95) and CDR®+NACC‐FTLD >0 (0.67–0.95). Among functionally intact individuals, baseline and 6‐months scores were highly correlated (r's: 0.76–0.93, p's<.05). Conclusion: Our findings of adequate to excellent internal consistency, test‐retest reliability, and 6‐month stability support the feasibility of remote, smartphone‐based cognitive testing among a diagnostically mixed sample typical of healthy aging and frontotemporal dementia research studies. [ABSTRACT FROM AUTHOR]

Background: Remote digital cognitive assessments validated for use in frontotemporal dementia (FTD) and other neurodegenerative diseases would benefit clinical trials and clinical care. The ALLFTD Mobile App includes several smartphone‐based measures of cognition, and prior studies have provided preliminary support for their reliability. Here we evaluate their validity by testing associations with gold standard clinical outcomes and expected neural correlates. Method: A diagnostically mixed sample of 92 participants (CDR®+NACC‐FTLD = 0 [n = 33]; CDR®+NACC‐FTLD = 0.5 [n = 15]; CDR®+NACC‐FTLD≥1 [n = 16]; unknown [n = 28]) were recruited from a UCSF healthy aging study (Hillblom Network) and a North American FTD study (ALLFTD). Participants were asked to remotely complete four ALLFTD Mobile App tests of executive functioning (EF) and a memory test on their smartphones. Gold standard clinical measures were also collected; outcomes were the UDSv3 EF composite, CVLT‐SF Total Immediate Recall (memory), and CDR®+NACC‐FTLD Box Score (disease severity). Volumetric brain MRI measurements were available for a subset (n = 37). Expected neural correlates were frontoparietal gray matter volume for EF tests and hippocampal volume for the memory test. Linear models were fitted to evaluate the association of app tests with the gold standard outcomes, controlling for education, sex, and total intracranial volume (imaging only). Result: Smartphone EF measures were strongly and positively associated with the UDS3‐EF composite (ß's = 0.6–0.8, all p<.001). The memory test was strongly correlated with the CVLT‐SF (ß = 0.7, p<.001). Tests were less strongly associated with divergent cognitive domains (e.g., associations with a visuospatial test were ß's = 0.1–0.3). Worse performance on all tests was significantly associated with greater disease severity (ß's = 0.5–0.7, all p<.001). Worse app‐based EF scores were associated with lower frontoparietal volume (ß's = 0.4–0.6, all p<.015) and worse memory scores with lower hippocampal volume (ß = 0.5, p<.001). Conclusion: ALLFTD Mobile App scores were strongly associated with gold standard neuropsychological tests of the same cognitive domain (i.e., convergent validity) and less associated with measures of a different domain (i.e., divergent validity). Worse performance on the smartphone tests was associated with increasing disease severity and volume loss in expected brain regions. These results provide preliminary support for the construct validity of the ALLFTD Mobile App cognitive tests. [ABSTRACT FROM AUTHOR]