Forsberg, Leah K.

AbstractBackgroundSeveral hypotheses exist regarding the neurologic substrate underlying visual hallucinations (VH) in Dementia with Lewy Bodies (DLB). Studies have suggested an association with regional cerebral hypometabolism in the primary visual or visual association cortices on FDG‐PET. We compared regional cerebral glucose metabolism and posterior cingulate island sign (CIS) ratios in DLB and in Mild Cognitive Impairment with Lewy Bodies (MCI‐LB) participants with (VH+) and without (VH‐) VH.MethodParticipants with clinically probable DLB or MCI‐LB and an FDG‐PET scan were identified from the Mayo ADRC database. Responses on the Visual Hallucinations and Delusions Questionnaire and Neuropsychiatric Inventory were used to assess presence or absence of VH. Standardized uptake value ratios (SUVr) were used to calculate regional cerebral glucose hypometabolism in the primary visual cortex (PVC), lateral occipital cortex (LOC), and whole occipital cortex (WOC). The CIS ratio was defined as posterior cingulate divided by the sum of the precuneus plus cuneus FDG‐PET uptake ratio.ResultTwo cohorts were identified (27 DLB and 18 MCI‐LB, 87% male). Eighteen DLB participants were VH+ and 9 were VH‐, whereas 5 MCI‐LB were VH+ and 13 were VH‐. There were no statistically significant differences in demographic (age, sex, education) and clinical features (MoCA, CDR, presence of other core DLB features, and UPDRS) between VH+ vs VH‐ in those with DLB, and between VH+ vs VH‐ in those with MCI‐LB. Similarly, there were no statistically significant differences in DLB between VH+ vs VH‐ in PVC (1.55±0.14 vs 1.58±0.15), LOC (1.22±0.16 vs 1.28±0.12), WOC (1.29±0.15 vs 1.34±0.11), or CIS ratio (1.16±0.08 vs 1.14±0.10), nor in MCI‐LB between VH+ vs VH‐ in PVC (1.68±0.19 vs 1.58±0.14), LOC (1.40±0.21 vs 1.32±0.14), WOC (1.45±0.20 vs 1.37±0.14), or CIS ratio (1.17±0.08 vs 1.19±0.10) (P>0.05 for all comparisons).ConclusionThese findings do not support a direct correlation between regional cerebral glucose metabolism and VH in DLB or MCI‐LB. Further work in DLB and MCI‐LB with larger numbers is warranted. Other neurologic substrates and mechanisms, such as REM sleep intrusions during wakefulness, neurotransmitter dysfunction, and disruption of functional connectivity across brain regions should be explored as contributors to VH in DLB.

AbstractBackgroundThe three most common genes responsible for the familial Frontotemporal Lobar Degeneration (f‐FTLD) are MAPT, GRN, and C9orf72, with the C9orf72 mutation being the most common cause of f‐FTLD. The ALLFTD Consortium targets to characterize f‐FTLD, including its preclinical stage, to prepare for clinical trials in FTLD. We sought to investigate the initial symptoms and clinical picture of f‐FTLD and compare them among the common pathogenic genes using longitudinal CDR® plus NACC FTLD.MethodWe longitudinally assessed the CDR® plus NACC FTLD among 292 asymptomatic participants of the ALLFTD Consortium who are family members of f‐FTLD caused by MAPT (n = 99), GRN (n = 67), or C9orf72 (n = 126) mutations, and described the detailed profiles of the CDR® plus NACC FTLD in the participants who developed Mild Behavioral and/or Cognitive Impairment (MBCI).ResultForty‐one participants (17 MAPT, 11 GRN, 13 C9orf72) developed MBCI during follow‐up visits . Age at the diagnosis of MBCI was 52.3±13.0 years (GRN 63.2±11.8, MAPT 43.5±8.6, C9orf72 54.7±10.7). Frequencies of abnormal rating on the eight CDR® plus NACC FTLD domains at the time of MBCI diagnosis were: “Memory” 44% (MAPT 47%, GRN 55%, C9orf72 31%); “Orientation” 7% (MAPT 6%, GRN 9%, C9orf72 8%); “Judgment and Problem Solving” 39% (MAPT 41%, GRN 55%, C9orf72 23%); “Community Affairs” 22% (MAPT 24%, GRN 18%, C9orf72 23%); “Home and Hobbies” 22% (MAPT 35%, GRN 0%, C9orf72 23%); “Personal Care” 0%; “Behavior/Comportment/Personality” 51% (MAPT 59%, GRN 55%, C9orf72 38%); “Language” 29% (MAPT 18%, GRN 55%, C9orf72 23%).ConclusionInitial symptoms and clinical picture of f‐FTLD in MBCI stage differ among responsible FTLD genes, which could be useful in detecting very early features of f‐FTLD in pathogenic mutation carriers.

AbstractBackgroundThe ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Study, is the unification of prior FTD research studies, ARTFL and LEFFTDS. ALLFTD aims to evaluate sporadic (s‐) and familial (f‐) frontotemporal lobar degeneration (FTLD) patients and asymptomatic family members of f‐FTLD patients, characterizing the cohorts longitudinally and informing clinical trial design.MethodALLFTD participants completed the ALLFTD‐specific, Internet and Social Media (ISM) Usage Survey. This survey was created to learn more about participants’ ISM habits. The survey asks participants to report on the frequency with which they use ISM for personal reasons and contains additional questions about reasons for use and general gaming and social media habits.ResultIn conjunction with their scheduled ALLFTD visit, 194 participants completed the ALLFTD ISM Usage Survey. Fifty one percent of participants identified as female. The mean age was 56.6 (SD 14.61), and the mean education level was 15.9 (SD 3.53). Most participants reported using ISM 1‐5 hours per day (56.7%). Participants also reported using ISM at less common frequencies: more than 5 hours per day (12.9%), less than 1 hour per day (13.9%), weekly (3.1%), 2‐3 times a week (2.1%), 2‐3 times a month (2.1%), and never (9.3%). “Moderate and Severely impaired” participants (CDR© + NACC FTLD > = 2) reported using ISM less frequently than “mildly symptomatic” participants (CDR© + NACC FTLD = 1, p<0.0001), and those who are “normal and questionably impaired” CDR© + NACC FTLD < = 0.5, p<0.0001). Those who are mildly symptomatic reported using ISM at a similar frequency to those who are normal or questionably impaired (p<0.01). When reporting on personal use, most participants stated that they used the internet for email (45.5%), news (37.5%), social media (32.4%), and entertainment (33.5%). Additionally, most participants reported playing games (56.2%) and using social media (59.8%). Participants predominantly indicated that they use social media to connect with family and friends (90.5%). Comparison of ISM usage frequency to reported anxiety, agitation, or depression on the NPI‐Q found evidence of a difference in ISM usage frequency; directional comparison studies are forthcoming.ConclusionFrequency of ISM usage is consistent between ALLFTD participants. Additional analyses of ISM usage are forthcoming.

AbstractBackgroundTo gather user input iteratively to develop a matching algorithm for peer‐to‐peer support and to assess the feasibility and usability of a web‐based program to conduct matching.Method32 caregivers of persons with dementia (PwD) participated in semi‐structured focus groups and completed surveys to provide input regarding characteristics deemed valuable in someone they would choose to be connected with for emotional support. Through an iterative process as new information emerged, a web‐based prototype and matching algorithm were developed. Caregivers interacted with the prototype and provided feedback indicating ease of accessibility and use, initial impression, and comfort/satisfaction with profile content.ResultAll 32 caregivers (age 40‐90, education 12/GED‐20, sex 88% female, 31% Black/African‐American) completed online profiles. Of those who interacted with the prototype, 23 completed the feedback survey, on which 87% had no or only mild difficulty accessing the site, 91% had no difficulty with technology once there, 86% had a very or quite positive initial impression, 91% found it very or quite easy to navigate, 87% rated a very or quite high level of comfort with completing the personal profile questions, and 82% felt very or quite confident the questions asked would lead to a good match.ConclusionA large majority of caregivers of PwD demonstrated the web‐based platform was easy to access and navigate, provided a positive experience, and gathered information that would lead to a good supportive relationship with another caregiver. Phase II will optimize the design and algorithm and evaluate the matching process in 350 caregivers.

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.

AbstractBackgroundClinical trials for tauopathies require novel biomarkers for disease detection and monitoring. One previous study found functional connectivity (FC) alterations in presymptomatic (preSx) MAPT mutation carriers (Whitwell et al., 2011), yet studies have not examined FC networks along the MAPT disease continuum. We hypothesized that both symptomatic (Sx) and preSx MAPT mutation carriers would show FC alterations compared to healthy controls (HC).MethodLeveraging task‐free fMRI data from the UCSF Memory and Aging Center and the ARTFL/LEFFTDS Consortia (Boeve et al., 2019), we compared 14 Sx and 33 preSx to 80 HC to characterize their FC profiles. Using a seed‐based approach, we studied FC within networks associated with different MAPT clinical syndromes (i.e., salience network [SN] for behavioral variant frontotemporal dementia, default mode network [DMN] for Alzheimer’s‐like amnestic syndrome, corticobasal syndrome [CBS] and progressive supranuclear palsy [PSP] networks). Complementing the seed‐based approach, we next calculated whole‐brain intra‐/inter‐network FC matrices for 14 networks (Brown et al., 2019), and applied K‐means clustering to assess whether preSx displayed heterogeneous connectivity profiles. ComBat was applied to harmonize multi‐site imaging data (Fortin et al., 2017, 2018). Thresholding was set at a joint height and extent threshold of p<0.05 (uncorrected) with age, sex, education and handedness as nuisance covariates.ResultCompared to HC, Sx featured disrupted FC within key hubs of all four networks, and regions of cerebellar and pontine hyperconnectivity within CBS and PSP networks. As seen in Sx vs. HC, preSx had similar anatomical patterns of SN/CBS network hypoconnectivity and CBS/PSP network hyperconnectivity vs. HC. In contrast to Sx, who had DMN disruption, preSx showed DMN hyperconnectivity vs. HC.Whole‐brain analyses revealed that Sx had disrupted intra‐/inter‐network FC in networks involving the insula/anterior temporal lobe. Clustering analysis identified two preSx subgroups. Compared to HC, preSx1 principally had disrupted FC across networks including those disrupted in Sx, whereas preSx2 mainly demonstrated hyperconnectivity.ConclusionSx and preSx both demonstrated robust FC alterations. Future studies will investigate whether the preSx subgroup whose whole‐brain FC was similar to Sx in that it showed principally FC disruption may be at greater risk for imminent symptom conversion and/or neurodegeneration.

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.