Rojas, Julio C.

AbstractBackgroundThere is a critical need for tau PET radiotracers that accurately detect non‐Alzheimer’s disease (AD) tau pathology. We aim to evaluate [18F]PI‐2620 PET tracer retention in patients with non‐AD, 4R tau‐related clinical syndromes, including progressive supranuclear palsy (PSP) with Richardson’s syndrome (PSP‐RS) and with predominant parkinsonism (PSP‐P), corticobasal syndrome (CBS), and nonfluent/agrammatic variant of primary progressive aphasia (nfvPPA).Method38 participants underwent amyloid and [18F]PI‐2620 PET (Table 1). 5 mCi ± 10% of [18F]PI‐2620 was administered. [18F]PI‐2620 PET SUVR images were generated using an inferior cerebellar gray matter reference from PET data acquired 30‐60 minutes post‐injection. Mean SUVR values were extracted from each participant in neuroanatomical structures that have elevated tau burden in PSP and CBS due to corticobasal degeneration (regions of interest in Table 2). Comparison between each diagnostic group and healthy controls (HCs) was performed using a one‐tailed, independent‐samples t‐test. Spearman correlation was used to evaluate the relationship between tracer binding (SUVR) and disease severity (PSP rating scale) in patients with PSP‐RS.ResultPatients with PSP‐RS had increased tracer retention in the left globus pallidus internus and externus, left subthalamic nucleus, and left dorsolateral prefrontal cortex compared to HCs (all p < 0.05). CBS and nfvPPA patients did not have increased tracer retention at any ROIs compared to HCs, but there were low numbers of patients in these groups (Table 2, Figures 1‐3). PSP rating scale values did not correlate with tracer binding in PSP‐RS (no correlations in any regions, rs < 0.44, p > 0.05 uncorrected).Conclusion[18F]PI‐2620 PET 30‐60 minute SUVR images may have limited ability to distinguish PSP from HCs, especially on visual read, and tracer uptake did not correlate with PSP disease severity. Other post‐injection PET acquisition windows (e.g., 30‐40 minute SUVR, 0‐60 minute DVR) will be evaluated to determine if they can maximize differences between PSP and HCs. A limitation of this preliminary study is the modest number of patients and controls, with most controls provided from a different study. Additional participants are being scanned in the multicenter 4RTNI study to understand the utility of this tracer as a neuroimaging biomarker for 4R tauopathies.

AbstractBackgroundTAR 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.MethodsVeri‐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.ResultsThe 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.ConclusionThe 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.

AbstractBackgroundRemote 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.MethodA 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).ResultSmartphone 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).ConclusionALLFTD 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.

ImportancePhysical activity is associated with cognitive health, even in autosomal dominant forms of dementia. Higher physical activity is associated with slowed cognitive and functional declines over time in adults carrying autosomal dominant variants for frontotemporal lobar degeneration (FTLD), but whether axonal degeneration is a potential neuroprotective target of physical activity in individuals with FTLD is unknown.ObjectiveTo examine the association between physical activity and longitudinal neurofilament light chain (NfL) trajectories in individuals with autosomal dominant forms of FTLD.Design, Setting, and ParticipantsThis cohort study included individuals from the ALLFTD Consortium, which recruited patients from sites in the US and Canada. Symptomatic and asymptomatic adults with pathogenic variants in one of 3 common genes associated with FTLD (GRN, C9orf72, or MAPT) who reported baseline physical activity levels and completed annual blood draws were assessed annually for up to 4 years. Genotype, clinical measures, and blood draws were collected between December 2014 and June 2019; data were analyzed from August 2021 to January 2022. Associations between reported baseline physical activity and longitudinal plasma NfL changes were assessed using generalized linear mixed-effects models adjusting for baseline age, sex, education, functional severity, and motor symptoms.ExposuresBaseline physical activity levels reported via the Physical Activity Scale for the Elderly. To estimate effect sizes, marginal means were calculated at 3 levels of physical activity: 1 SD above the mean represented high physical activity, 0 SD represented average physical activity, and 1 SD below the mean represented low physical activity.Main Outcomes and MeasuresAnnual plasma NfL concentrations were measured with single-molecule array technology.ResultsOf 160 included FTLD variant carriers, 84 (52.5%) were female, and the mean (SD) age was 50.7 (14.7) years. A total of 51 (31.8%) were symptomatic, and 77 carried the C9orf72 variant; 39, GRN variant; and 44, MAPT variant. Higher baseline physical activity was associated with slower NfL trajectories over time. On average, NfL increased 45.8% (95% CI, 22.5 to 73.7) over 4 years in variant carriers. Variant carriers with high physical activity demonstrated 14.0% (95% CI, −22.7 to −4.3) slower NfL increases compared with those with average physical activity and 30% (95% CI, −52.2 to −8.8) slower NfL increases compared with those with low physical activity. Within genotype, C9orf72 and MAPT carriers with high physical activity evidenced 18% to 21% (95% CI, −43.4 to −7.2) attenuation in NfL, while the association between physical activity and NfL trajectory was not statistically significant in GRN carriers. Activities associated with higher cardiorespiratory and cognitive demands (sports, housework, and yardwork) were most strongly correlated with slower NfL trajectories (vs walking and strength training).Conclusions and RelevanceIn this study, higher reported physical activity was associated with slower progression of an axonal degeneration marker in individuals with autosomal dominant FTLD. Physical activity may serve as a primary prevention target in FTLD.

AbstractBackgroundFrontotemporal dementia spectrum disorders (FTD) display complex neuropathological substrates and poor clinicopathological correlations, which hinders therapy development. Plasma P‐tau217 is an emerging tool to screen for Alzheimer’s disease (AD) pathology and may have diagnostic value in FTD.MethodPlasma P‐tau217 was measured cross‐sectionally by electrochemiluminescence in FTD patients referred to ALLFTD from ARTFL (n = 628, 45.7% female, median age 66 ± 12 years). P‐tau217 differences by baseline phenotype, disease severity and genotype were determined with non‐parametric tests and general linear models. Associations between P‐tau217 and measures of disease severity and neuropsychological performance were determined with linear regressions corrected for age, sex, phenotype and APOE.ResultThe sample included 33% behavioral variant FTD, 23.6% primary progressive aphasia (PPA), 28.5% atypical parkinsonism, 1.6% amnestic dementia (AmDem), 2.8% FTD/motoneuron disease, 3% mild cognitive/behavioral impairment and 7.5% healthy controls. Only 1.6% carried FTD‐causing mutations. P‐tau217 was not related to age (r = 0.034, 95%CI ‐0.03 – 0.12, p = 0.4). Compared to controls (0.18 ± 0.07 pg/mL), P‐tau217 was elevated only in AmDem (0.58 ± 0.9 pg/mL, p = 0.001) and logopenic PPA (lvPPA, 0.71 ± 0.62 pg/mL p < 0.001). P‐tau217 ≥ 0.42 pg/mL effectively discriminated AmDem and lvPPA from all other phenotypes (AUC 0.87, 95%CI 0.77 – 0.96, p = 0.001, 77% sensitivity, 92% specificity). AmDem (60%) and lvPPA (91.7%) had the highest prevalence of high (≥ 0.42 pg/mL) P‐tau217, and the highest prevalence of APOE4 (AmDem 40%, lvPPA 63.6%). APOE4 carriers (0.23 ± 0.22 pg/mL) had higher P‐tau217, than non‐carriers (0.19 ± 0.09 pg/mL), regardless of phenotype (APOE effect p = .002, APOE x phenotype, p = 0.44). P‐tau217 was associated with worse clinical severity, mood, memory and executive function, but not with worse motor symptoms or social cognition.ConclusionWhen FTD is suspected, high plasma P‐tau217 is strongly associated with amnestic dementia and logopenic PPA phenotypes. Pending completion of ongoing neuropathological, CSF and molecular neuroimaging analyses, the data support the use of plasma P‐tau217 to identify atypical AD as a cause or AD as a co‐pathology contributing to FTD clinical presentation.

AbstractBackgroundProgranulin (GRN) mutations cause autosomal dominant frontotemporal lobar degeneration. Clinical trials for GRN‐targeted therapies are underway, yet reliable biomarkers to predict onset and track disease progression remain elusive. Task‐free functional MRI (tf‐fMRI) connectivity may be more sensitive than structural measures for detecting presymptomatic changes (Dopper, 2014; Premi, 2016). Presymptomatic GRN feature tf‐fMRI hyperconnectivity that is more pronounced in older carriers presumably closer to symptom onset, suggesting hyperconnectivity may be a harbinger of disease (Lee, 2019). To aid the interpretation of hyperconnectivity, we explored relationships of structural and tf‐fMRI measures with candidate fluid biomarkers for GRN: CSF complement proteins C3b and C1q, which drive neurodegeneration in GRN ‐/‐ mice (Lui, 2016) and plasma neurofilament light chain (NfL), a marker of axonal injury.MethodWe studied 20 symptomatic GRN (Sx), 39 presymptomatic GRN (preSx), and 67 healthy‐controls (HC). Cross‐sectional CSF C3b, C1q, and plasma NfL concentrations were compared between groups. Correlations controlling for age assessed relationships between fluid biomarkers and symptom severity (CDR®+NACC‐FTLD box score). Voxelwise multiple regression models examined interactions between fluid biomarkers and gene status on grey matter probability maps (GM) and voxelwise tf‐fMRI whole‐brain weighted degree (WBD) maps.ResultComplement concentrations were similar between Sx, preSx, and HC. Across all GRN, C3b concentrations increased with symptom severity (r=0.34, p=0.04). In Sx, but not preSx, higher C3b was associated with increased WBD in medial‐frontal regions, left insula, and thalamus compared to HC. Sx had higher NfL concentrations compared to preSx and HC. Across all GRN and in Sx, higher NfL was associated with greater symptom severity (r=0.60, p<0.001; r=0.72, p<0.001). In Sx, higher NfL was associated with lower GM in precuneus and bilateral frontoinsular cortices, but not WBD, compared to HC. In preSx, higher NfL was associated with increased WBD in thalamus and right temporal regions, but not GM, compared to HC.ConclusionC3b and NfL concentrations correlated with symptom severity. C3b concentrations were associated with tf‐fMRI connectivity alterations in Sx while NfL concentrations were associated with connectivity alterations in preSx. Longitudinal studies are needed to determine temporal relationships between altered connectivity, atrophy, complement, NfL rise, and symptom onset.

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p < 0.001), p‐NfH (β = 0.68, p < 0.001) and tau (β = 0.46, p < 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p < 0.001), low p‐tau (β = ‐0.33, p < 0.001) and high NfL (β = 0.42, p < 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.

AbstractBackgroundUp to 30% of frontotemporal dementia (FTD) cases are due to known pathogenic mutations (f‐FTD). Little is known about the factors that predict who will choose to learn their results. Upcoming clinical trials in f‐FTD may require disclosure prior to enrollment, even before symptom onset, and thus characterizing this sample is important. Furthermore, understanding the mood impacts of genetic disclosure may guide genetic counseling practice.MethodF‐FTD participants (n=568) from families with a known pathogenic mutation (MAPT, C9orf72, GRN) were enrolled through the ARTFL/LEFFTDS Longitudinal FTD Study (ALLFTD) and provided the opportunity for disclosure. Independent‐sample t‐tests compared demographic and psychosocial factors between participants who did and did not receive their results. In participants who were asymptomatic at baseline and follow up (n=199,177 with follow‐up), linear mixed effects modeling was used to investigate pre‐ to post‐disclosure changes in the 15‐item Geriatric Depression Scale (GDS).ResultOf participants from families with a known pathogenic genetic mutation, 47% received genetic disclosure. Of the asymptomatic subset (n=386), 36% know their mutation status. Of these asymptomatic learners, 46% received disclosure through the study, and the remainder learned their genetic status prior to study enrollment. None of the analyzed demographic or psychosocial factors (i.e., sex, age, education, having children) differed between learners and non‐learners (p’s > 0.05). In the longitudinal analysis of asymptomatic participants, learners showed a pre‐ to post‐increase of 0.31 GDS points/year (95%CI: ‐0.08, 0.69, p = 0.12), whereas non‐learners showed a slight decline (‐0.15 points/year, 95%CI: ‐0.36, 0.06, p = 0.16). This difference between slopes was statistically significant (0.46, 95%CI: 0.02, 0.89, p=0.04) but represents a small clinical effect. In asymptomatic learners, slopes did not differ based on mutation status (0.28, 95%CI: ‐0.66, 1.20, p=0.55). Conclusions were based on the estimates and full range of confidence intervals.ConclusionThe majority of asymptomatic research participants do not know their genetic status, which will be a consideration for clinical trials that require disclosure. No considered demographic factors were strongly associated with the decision to receive disclosure. The findings suggest that disclosure in asymptomatic participants has minimal impact on depressive symptoms regardless of genetic results.

AbstractBackgroundFrontotemporal 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.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing 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.Results29% 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%).ConclusionsFavorable 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.