Jones, David T.

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.

AbstractBackgroundIsolated REM Sleep Behavior Disorder (iRBD) patients are known to be at high risk for developing an overt synucleinopathy – particularly Dementia with Lewy Bodies (DLB) and Parkinson’s Disease (PD). Reduced nigrostriatal uptake on 123I‐FP‐CIT SPECT reflects dopamine deficiency, which is common in the overt synucleinopathies. We sought to assess how 123I‐FP‐CIT SPECT imaging in iRBD changes longitudinally and whether an abnormal 123I‐FP‐CIT SPECT scan precedes and predicts future transition to an overt synucleinopathy.MethodParticipants with polysomnography‐confirmed iRBD from the Mayo Clinic Alzheimer’s Disease Research Center database +/‐ North American Prodromal Synucleinopathy (NAPS) Consortium who had two or more longitudinal 123I‐FP‐CIT SPECT scans and been followed prospectively for at least 24 months were included in this analysis. Striatonigral dopamine transporter uptake was evaluated semi‐quantitatively with 123I‐FP‐CIT SPECT using DaTQUANT software (GE Healthcare) to calculate z‐scores of putamen uptake.ResultThirty‐five iRBD participants (86% male) were evaluated prospectively (mean 62.5 ± 19.4 months) and underwent two or more 123I‐FP‐CIT SPECT scans at a minimum of 12 months intervals. Thirteen participants (37%) developed an overt synucleinopathy (11 DLB and 2 PD; phenoconverters) and 22 participants (63%) remained as iRBD (stable iRBD). Phenoconverters were older (mean 70.8 ± 7.0 vs 63.4 ± 6.0 years old) and had more negative DaTQUANT putamen z‐scores (mean ‐1.68 ± 1.42 vs ‐0.33 ± 1.52) than stable iRBD participants at baseline. Among phenoconverters, nine participants (69%) had one or more 123I‐FP‐CIT SPECT scans with DaTQUANT putamen z‐score of <‐2.0 prior to phenoconversion, and mean time from initial DaTQUANT putamen z‐score of <‐2.0 to phenoconversion was 36.8 ± 28.7 months. In stable RBD participants, eight participants (36%) showed a decline in DaTQUANT putamen z‐score of >1 between the most recent and the baseline scan, and four participants (18%) presented DaTQUANT putamen z‐score of <‐2.0 at the most recent scan.ConclusionThese findings suggest that a decline in putamen uptake on 123I‐FP‐CIT SPECT in iRBD serves as a predictor and a surrogate biomarker for progression of iRBD to an overt synucleinopathy.

AbstractBackgroundProgressive dysexecutive syndrome (dAD) is an atypical presentation of early onset Alzheimer’s disease (AD) with increased frontal and parietal region hypometabolism on FDG‐PET imaging compared to classic amnestic AD. We compared electroencephalogram (EEG) and FDG‐PET in dAD patients to determine if there was a correlation between EEG spectral activity and standard uptake value ratios (SUVR) in those regions.MethodFDG‐PET and resting state scalp EEG were obtained on AD‐biomarker confirmed, behavioral neurologist diagnosed cases of dAD (n = 11). We isolated awake‐eyes‐closed segments (mean duration: 113s, median:118s, range: 58‐138s) of each EEG and calculated the relative power of delta, theta, alpha, beta, and gamma bands within a wideband of 0.5‐40 Hz. In bilateral frontal and parietal regions, we averaged select channels across 6 to 14 10‐second windows per subject (fig.1). We evaluated the correlation between relative band powers and SUVRs of the regions by linear regression analysis.ResultThere is a strong negative correlation (R2 = 0.54, p < 0.01) between alpha band relative power and SUVR in bilateral frontal regions (fig 2). Delta band relative power showed a strong positive correlation (R2 = 0.54, p < 0.05) with SUVR in the left frontal region. A positive trend was noted in the delta band in the right frontal region but did not reach statistical significance. Beta band relative power was negatively correlated with frontal region SUVR bilaterally, but only the left side reached statistical significance. These findings remained significant after multiple comparisons correction. No statistically significant correlations were noted in the parietal regions. Exploratory analysis revealed negative correlations between alpha bands and temporal region SUVRs bilaterally.ConclusionIn this small sample of selected individuals with dysexecutive AD, we report a strong correlation between EEG relative spectral power and PET regional SUVR in multiple EEG frequency bands and brain regions. In the bilateral frontal regions, slower delta frequencies and faster alpha and beta frequencies were associated with lower FDG‐PET signal. Future studies are needed to determine if this spectral power pattern and other EEG properties of dAD differ from other clinical dementia phenotypes and its clinical significance.

AbstractBackgroundThe overarching goal of the Longitudinal Early‐onset Alzheimer Disease study (LEADS) is to optimally characterize early‐onset AD (EOAD) and establish an EOAD clinical trials network. Here we report the baseline demographic and imaging biomarker comparisons of the LEADS cohort to late‐onset AD (LOAD) subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI3).Method123 amyloid‐positive EOAD, 47 amyloid‐negative EOnonAD, 60 cognitively normal young controls were compared to 130 amyloid‐positive LOAD, 110 amyloid‐negative LOnonAD and 286 amyloid‐negative cognitively normal older controls. To account for the effect of cognitive aging between EO and LO populations, each cognitive measure was Z‐transformed. Cortical and hippocampal atrophy were quantified using W‐scores adjusted for age, sex and total intracranial volume. Z‐scores and W‐scores were compared using t‐test or Wilcoxson rank test as appropriate. All p‐values were corrected for multiple comparisons using the false discovery rate correction.ResultEOAD showed greater pathology burden and greater cortical atrophy (AD signature) relative to LOAD. EOAD also showed greater cognitive impairment across all cognitive tests. EOAD showed greater functional impairment, more depression but less neuropsychiatric behaviors overall compared to LOAD (Table 1 and Figure 1, all ps<0.05). Repeating the analyses stratified by cognitive stage (MCI/dementia) or CDR global rating (0.5/1) did not result in any major differences.EOnonAD differed from LOnonAD by also showing greater impairment on all cognitive and functional measures There were no significant differences in amyloid and tau burden, or atrophy W‐scores between these groups. EOnonAD were more depressed and showed more functional impairment compared to LOnonAD (Table 2 and Figure 2, all ps<0.05). Repeating the analyses split by cognitive stage (MCI/dementia) or CDR global rating (0.5/1) did not result in any major differences.ConclusionConsistent with our preexisting hypotheses, EOAD and EOnonAD perform much worse relative to their LO counterparts. EOAD also show greater pathological burden as expected. The reported analyses were done in chronological rather than disease time (time since disease onset). Benchmarking individuals along the disease spectrum might prove to be a better strategy especially when conducting analyses on rate of disease progression.

AbstractBackgroundThe Neurodegenerative Research Group (NRG) at Mayo clinic has followed patients with degenerative speech and/or language disorders for over a decade. In this presentation I will present data from this cohort to inform a broader discussion about the importance of apraxia of speech (AOS) and its subtypes, heterogeneity within the agrammatic PPA variant, and perils of mixed phenotypes.MethodWe reviewed the NRG database to identify patients who initially presented with isolated (PPAOS), AOS in conjunction with agrammatic aphasia (AOS‐PAA), isolated agrammatic aphasia (PAA), and patients who had PAA or AOS overlapping with another degenerative diagnosis. Data from the following clinical instruments were abstracted: WAB AQ (aphasia severity), UPDRS III (parkinsonism), WAB Praxis (ideomotor apraxia), and the MoCA (cognitive ability). We assessed the effect of baseline diagnosis and AOS subtype on these outcomes over time using Bayesian linear mixed effects models. We qualitatively reviewed longitudinal diagnostic trajectories. Preliminary analyses were done on available autopsy data.ResultPAA was associated with greater aphasia at baseline and more rapid decline; PPAOS was associated with normal language at baseline and slow decline; and PAA‐AOS with intermediate baseline aphasia and decline. However, for those with AOS longitudinal decline differed based on AOS subtype: prosodic PPAOS was associated with the slowest decline and phonetic PAA‐AOS with the fastest. Some patients met criteria for non‐PPA disorders during follow up. However, compared to patients who met criteria for these disorders at enrollment, the speech/language‐first patients remained qualitatively distinct, and neither resembled the cases that were mixed at onset. Preliminary autopsy data suggests that AOS is predictive of tau and that the specific tauopathy may be related to the initial syndrome and AOS subtype.ConclusionThe differences between PAA, PAA‐AOS and PPAOS suggest that these disorders should not be lumped. In fact, the longitudinal trajectories are sufficiently different that doing so would add noise to observational and interventional studies. Instead, more detailed phenotyping, including AOS subtype, can aid prognostication and may improve prediction of the underlying pathology. Finally, caution should be exercised when considering PPAOS and PPA patients for other FTLD diagnostic categories.

AbstractBackgroundImpaired olfaction has been associated with neurodegenerative diseases and may be a useful tool to aid in diagnosis or track disease progression. We sought to compare olfaction in participants with the clinical diagnoses of idiopathic REM sleep behavior disorder (RBD), dementia with Lewy bodies (DLB), or Alzheimer’s disease dementia (AD).MethodParticipants from the Mayo Clinic Alzheimer’s Disease Research Center database who had a diagnosis of RBD (n=27, 56% male), DLB (n=51, 84% male), or AD (n=83, 47% male), and were given the Brief Smell Identification Test (B‐SIT) were included in this analysis. The B‐SIT score was calculated as the sum of correct responses (12 possible). Scores were categorized as reflecting anosmia (<6), hyposmia (6‐10), and normal olfactory function (>10). All participants underwent clinical and neuropsychological evaluations.ResultGlobal cognition was lower in AD and DLB than RBD (MMSE 21.5 ±4.9 in AD, 23.3 ±4.3 in DLB, 28.8 ± 1.2 in RBD; p <0.001). The mean B‐SIT total score was significantly lower for DLB (4.5 ± 3.1) compared to RBD (7.5 ± 3.0) or AD (7.0 ± 2.7) (p<0.001) using an ANOVA F‐test. Anosmia was present in 76% of DLB, which compared to 32% in RBD, and 32% in AD (p=0.9). Hyposmia was present in 18% of DLB, 47% of RBD, and 52% of AD (p=ns). Of 22 patients with normal olfaction, X% were DLB, X% RBD, and X% AD (p=X). An item analysis illustrated that participants with DLB were less likely to identify Menthol, Clove, Strawberry, Smoke, and Soap than those with RBD and AD. On serial examination, 12 RBD (60%) patients’ B‐SIT score decreased by at least one point at their most recent visit compared to their baseline visit.ConclusionThese findings suggest that impaired olfactory function is frequent in RBD, DLB and AD, with olfaction being worst in DLB in this cohort. Olfaction was declining in most of those with RBD who underwent serial evaluations. Further analyses are needed to determine if any scents are more sensitive to phenotype, progression, and degree of cognitive impairment. Supported by: NIH grants AG016574, NS100620, AG056639, AG015866

AbstractBackgroundEarly changes in white matter (WM) measured using diffusion tensor imaging (DTI) are sensitive markers of WM degeneration and predict future cognitive decline in mild cognitive impairment (MCI). We sought to examine whether changes in WM integrity differed among empirically derived subtypes of incident MCI.MethodParticipants included 66 individuals with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) previously identified via cluster analysis as having one of four MCI subtypes: subtle cognitive impairment (SCI; n = 13, mean age 78; 15% women), amnestic (n = 24; mean age 79; 54% women), dysnomic (n = 8; mean age 79; 38% women), and dysexecutive (n = 21; mean age 82; 33% women). All participants completed 3T MRI at the time of the MCI diagnosis. We compared the MCI subtypes to 100 cognitively unimpaired (CU) participants (mean age 77; 49% women). We used tract‐based spatial statistics to examine voxel‐level differences in fractional anisotropy (FA). We also fit a linear regression model to regional FA data from the corpus callosum (CC), the major interhemispheric WM connection, to quantify the relative differences in WM damage.ResultAll MCI subtypes except the subtle cognitive impairment group had widespread decreased FA. Relative to CU, the amnestic cluster showed decreased FA in the CC (genu), cingulum, fornix and uncinate fasciculus (UF); the dysnomic cluster showed decreased FA in the CC (genu, splenium), fornix, UF, anterior thalamic radiation (ATR), and corticospinal tract (CST); and the dysexecutive group showed decreased FA in the CC (genu, body, splenium), cingulum, UF, ATR, CST, and superior longitudinal fasciculus. The dysexecutive cluster had the most severe bilateral involvement among all MCI subtypes. The regional analysis showed that the amnestic, dysnomic, and dysexecutive groups (but not the subtle cognitive impairment group) had significantly lower FA of the CC compared to CU (p<0.001; Figure 1).ConclusionWe found widespread WM degeneration in the commissural and long association fibers in amnestic, dysnomic, and dysexecutive incident MCI subtypes. The extent of CC damage seen in Figure 1. confirmed the voxel‐level results and suggests that interhemispheric WM disconnection is relevant to the development of MCI.