Highlights FDG-PET can detect cerebral glucose hypometabolism in presymptomatic C9orf72 carriers. Metabolic changes are seen in cingulate gyrus, frontal and temporal cortices and thalami. Glucose metabolic changes are detectable up to 10 years prior to symptom onset. Glucose metabolic changes are detectable prior to changes in gray matter volume.

Background: A large proportion of Alzheimer’s disease (AD) patients have coexisting subcortical vascular dementia (SVaD), a condition referred to as mixed dementia (MixD). Brain imaging features of MixD presumably include those of cerebrovascular disease and AD pathology, but are difficult to characterize due to their heterogeneity. Objective: To perform an exploratory analysis of conventional and non-conventional structural magnetic resonance imaging (MRI) abnormalities in MixD and to compare them to those observed in AD and SVaD. Methods: We conducted a cross-sectional, region-of-interest-based analysis of 1) hyperintense white-matter signal abnormalities (WMSA) on T2-FLAIR and hypointense WMSA on T1-weighted MRI; 2) diffusion tensor imaging; 3) quantitative susceptibility mapping; and 4) effective transverse relaxation rate (R2*) in N = 17 participants (AD:5, SVaD:5, MixD:7). General linear model was used to explore group differences in these brain imaging measures. Results: Model findings suggested imaging characteristics specific to our MixD group, including 1) higher burden of WMSAs on T1-weighted MRI (versus both AD and SVaD); 2) frontal lobar preponderance of WMSAs on both T2-FLAIR and T1-weighted MRI; 3) higher fractional anisotropy values within normal-appear white-matter tissues (versus SVaD, but not AD); and 4) lower R2* values within the T2-FLAIR WMSA areas (versus both AD and SVaD). Conclusion: These findings suggest a preliminary picture of the location and type of brain imaging characteristics associated with MixD. Future imaging studies may employ region-specific hypotheses to distinguish MixD more rigorously from AD or SVaD.

A large proportion of familial frontotemporal dementia is caused by TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) proteinopathies. Accordingly, carriers of autosomal dominant mutations in the genes associated with TAR DNA binding protein 43 aggregation, such as chromosome 9 open reading frame 72 (C9orf72) or progranulin (GRN), are at risk of later developing frontotemporal dementia. Brain imaging abnormalities that develop before dementia onset in mutation carriers may serve as proxies for the presymptomatic stages of familial frontotemporal dementia due to genetic cause. Our study objective was to investigate brain MRI-based white matter changes in predementia participants carrying mutations in C9orf72 or GRN genes. We analyzed mutation carriers and their family member controls (Noncarriers) from the University of British Columbia Familial frontotemporal dementia study. First, a total of 42 participants (8 GRN carriers; 11 C9orf72 carriers; 23 Noncarriers) had longitudinal T1-weighted MRI over approximately two years. White matter signal hypointensities were segmented and volumes were calculated for each participant. General linear models were applied to compare the baseline burden and the annualized rate of accumulation of signal abnormalities among mutation carriers and Noncarriers. Second, a total of 60 participants (9 GRN carriers; 17 C9orf72 carriers; 34 Noncarriers) had cross-sectional diffusion tensor MRI available. For each participant, we calculated the average fractional anisotropy and mean, radial, and axial diffusivity parameter values within the normal-appearing white matter tissues. General linear models were applied to compare whether mutation carriers and Noncarriers had different trends of diffusion tensor imaging parameter values as they neared the expected age of onset. Baseline volumes of white matter signal abnormalities were not significantly different among mutation carriers and Noncarriers. Longitudinally, GRN carriers had significantly higher annualized rates of accumulation (estimated mean: 15.87%/y) compared to C9orf72 carriers (3.69%/y) or Noncarriers (2.64%/y). A significant relationship between diffusion tensor imaging parameter values and increasing expected age of onset was found in periventricular normal-appearing white matter region. Specifically, GRN carriers had a tendency of faster increase of mean and radial diffusivity values and C9orf72 carriers had a tendency of faster decline of fractional anisotropy values as they reached closer to the expected age of dementia onset. These findings suggest that white matter changes may represent early markers of familial frontotemporal dementia due to genetic cause. However, GRN and C9orf72 mutation carriers may have different mechanisms leading to tissue abnormalities.

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 followup, 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+

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).