Botha, Hugo

Abstract Mild cognitive impairment with the core clinical features of dementia with Lewy bodies is recognized as a prodromal stage of dementia with Lewy bodies. Although grey matter atrophy has been demonstrated in prodromal dementia with Lewy bodies, longitudinal rates of atrophy during progression to probable dementia with Lewy bodies are unknown. We investigated the regional patterns of cross-sectional and longitudinal rates of grey matter atrophy in prodromal dementia with Lewy bodies, including those who progressed to probable dementia with Lewy bodies. Patients with mild cognitive impairment with at least one core clinical feature of dementia with Lewy bodies (mean age = 70.5; 95% male), who were enrolled in the Mayo Clinic Alzheimer’s Disease Research Center and followed for at least two clinical evaluations and MRI examinations, were included (n = 56). A cognitively unimpaired control group (n = 112) was matched 2:1 to the patients with mild cognitive impairment by age and sex. Patients either remained stable (n = 28) or progressed to probable dementia with Lewy bodies (n = 28) during a similar follow-up period and pathologic confirmation was available in a subset of cases (n = 18). Cross-sectional and longitudinal rates of grey matter atrophy were assessed using voxel-based and atlas-based region of interest analyses. At baseline, prodromal dementia with Lewy bodies was characterized by atrophy in the nucleus basalis of Meynert both in those who remained stable and those who progressed to probable dementia with Lewy bodies (P < 0.05 false discovery rate corrected). Increase in longitudinal grey matter atrophy rates were widespread, with greatest rates of atrophy observed in the enthorhinal and parahippocampal cortices, temporoparietal association cortices, thalamus and the basal ganglia, in mild cognitive impairment patients who progressed to probable dementia with Lewy bodies at follow-up (P < 0.05 false discovery rate corrected). Rates of inferior temporal atrophy were associated with greater rates of worsening on the clinical dementia rating–sum of boxes. Seventeen of the 18 (94%) autopsied cases had Lewy body disease. Results show that atrophy in the nucleus basalis of Meynert is a feature of prodromal dementia with Lewy bodies regardless of proximity to progression to probable dementia with Lewy bodies. Longitudinally, grey matter atrophy progresses in regions with significant cholinergic innervation, in alignment with clinical disease progression, with widespread and accelerated rates of atrophy in patients who progress to probable dementia with Lewy bodies. Given the prominent neurodegeneration in the cholinergic system, patients with prodromal dementia with Lewy bodies may be candidates for cholinesterase inhibitor treatment.

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.

AbstractBackgroundIn animal models of Alzheimer’s disease (AD), aerobic exercise favorably modified the accumulation, degradation, and removal of Aβ and tau. However, human mechanistic randomized controlled trials (RCTs) are limited with mixed findings on hippocampal volume and biofluid Aβ and tau. Hence, an objective of the FIT‐AD Trial was to examine the effects of 6‐month aerobic exercise on magnetic resonance imaging (MRI) biomarkers in community‐dwelling older adults with AD dementia.MethodThe FIT‐AD Trial was a pilot RCT that first qualified participants for the main exercise study eligibility and then for MRI. Participants were randomized to moderate intensity cycling or low intensity stretching for 20‐50 minutes, 3 times a week for six months on a 2:1 ratio with three age strata (66‐75, 76‐85, and 85+ years of age) and followed up for another six months. MRI biomarkers included hippocampal volume, temporal meta‐regions of interest cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ) measured at baseline, six months, and 12 months.ResultSixty participants met MRI eligibility, but one was excluded when this participant’s baseline MRI failed quality control. Among the 59 remaining participants, 38 were randomized to cycling and 21 to stretching. The sample characteristics (n=59) were 77.3±6.3 years old with 15.6±2.9 years of education and 53% men. Both groups experienced significant declines in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and cortical thickness (0.94% vs. 1.54%) over six months and over 12 months (hippocampal volume: 4.47% vs. 3.84%; cortical thickness: 2.27% vs. 1.79%). These declines didn’t differ between groups. WMH volume increased significantly, but the cycling group increased >50% less than stretching (10.9% vs. 24.5% over six months [f=4.47, p=.04]; 12.1% vs. 27.6% over 12 months [f=5.88, p=.02]). NFQ didn’t change significantly over time nor differed between group.ConclusionAerobic exercise may reduce hippocampal volume and cortical thickness declines during the intervention period; however, its effects are likely to be small and dose‐dependent and reverse after the intervention stops. Aerobic exercise is effective on reducing WMH progression but has no effect on NFQ.

AbstractBackgroundIn longitudinal tau (flortaucipir) positron emission tomography (PET), a reliable method to detect a tau accumulation while minimizing a random variability is crucial. Variability can be a problem especially in the early stages of tau pathology in which only small regions and low levels of accumulation may exist relative to the range of random noise fluctuation.MethodWe recruited 76 participants who had serial scans for a total of 234 tau PET scans. In this cohort we tested a PET signal measurement method we developed called the “overlap index” (OI). The OI was calculated by identifying voxels that have elevated tau PET signal that overlap on two successive tau PET scans in the same participant (Figure 1). This analysis procedure tests the hypothesis that voxel‐wise, elevated‐uptake consistency might be more sensitive for early detection of tau tangles than standard ROI based measures. We compared OI to ROI based measures for early detection of increasing tau PET signal and detection clinical progression. A meta ROI used in this analysis included the amygdala, entorhinal cortex, fusiform, parahippocampal, and inferior temporal and middle temporal gyri.ResultOI showed regional progression of tau in the temporal lobe followed by increases throughout the brain at relatively low standardized uptake value ratio (SUVr) levels (Figure 2A and B). The topographical pattern of OI was in agreement in some respects with the sequential appearance of tau aggregation (Figure 2B and C). The high‐OI group (OI>0.5) had a significantly higher ΔSUVr compared to the low‐OI group (OI<0.5) (Figure 3A and B). OI identified subjects that did or didn’t have tau accumulation within meta SUVr subgroups even when below the meta ROI SUVr threshold. OI was associated with early clinical disease stage progression vs meta‐ROI SUVr measures (Figure 3C‐E).ConclusionIn this study, we found that OI tau PET measurement was able to quantify voxel‐wise consistency using a set of serial scans. OI may detect earlier tau tangle accumulation and earlier disease progression than standard SUVr measurements in tau PET.

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.

AbstractBackgroundIndividuals with Primary Progressive Apraxia of Speech (PPAOS) have AOS as the initial and predominant symptom. Many develop aphasia and/or dysarthria later in the disease course. Past research has shown that patients with neurodegenerative AOS experience reduced participation in communication that is further exacerbated by co‐occurring language deficits. Previous studies suggest measures of disease severity do not necessarily correlate with measures of participation restrictions. The aim of this study was to describe changes in communication limitations in these patients over a one‐year interval, measured by 1) the patient via the Communicative Participation Item Bank (CPIB) and 2) the speech‐language pathologist via ASHA's Functional Communication Measures (FCMs) and an adapted Motor Speech Disorder (MSD) severity rating and determine if there are significant changes in these and other objective speech and language measures (e.g. Western Aphasia Battery‐Revised Aphasia Quotient, Apraxia of Speech Rating Scale‐3).MethodSeventeen patients (10 male) with progressive AOS were seen for a second visit approximately one year following the first visit. The measures collected at each visit were statistically compared. Correlations were calculated between the participation ratings and other clinical assessment measures at each visit and qualitatively compared.ResultThere were statistically significant differences in AOS and aphasia severity between visits. There were significant changes in clinical assessments, MSD severity rating, and all ASHA FCMs between visits, but not the CPIB. Comparison of correlations suggest the relationships among clinical and participation measures may change over time.ConclusionThe findings of this study support the use of patient reported outcome measures, like the CPIB, as they may better reflect the patient experience and associated changes in day‐to‐day functioning when other measures may simply index the progression of the disease.

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.

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.

AbstractBackgroundLogopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) have distinct patterns of hypometabolism and atrophy. However, these clinical syndromes overlap: visuospatial impairment has been documented in LPA and aphasia in PCA. Rey‐Osterrieth Complex Figure – Copy (Rey‐O Copy) performance is correlated with parietal‐occipital atrophy in LPA. We explore visuospatial impairment on the Rey‐O Copy in LPA and PCA with the Mayo Older Americans Normative Studies (MOANS; which uses Meyers & Meyers criteria) and the Boston Qualitative Scoring System (BQSS). We also examine the proportion of visuospatial impairment in LPA, an under‐appreciated phenomenon, compared to PCA wherein it is fundamental.MethodPatients with LPA (n=25) or PCA (n=23) were recruited by the Neurodegenerative Research Group. Patients underwent comprehensive neuropsychological testing (including Rey‐O Copy) at baseline visit. Cut‐offs of T‐score=40 (BQSS) or scaled score=7 (MOANS) were used based on normative data. Proportions of patients with low performance were examined across LPA and PCA groups. Individual logistic regressions and AUROC analyses were then conducted to quantify differences in visuospatial impairment in LPA and PCA with both scoring systems. Identical analyses were conducted using raw scores corrected for age and sex, to avoid confounds of adjustments in normative data.ResultLPA and PCA groups were comparable on age, sex, and disease duration (LPA Median = 2.7 years, IQR=1.9‐3.5; PCA Median = 3.6 years, IQR=1.5‐4.9); p=.823). Surprisingly, 52‐72% of LPA participants demonstrated impaired performance across scoring systems, relative to 96% of the PCA group identified by both scoring systems. Odds ratios (OR) for the Rey‐O Copy MOANS (OR = 1.59; p=.008) and BQSS Copy Presence and Accuracy index (CPA; OR = 1.13, p=.002) were significant, persisting for age‐ and sex‐ controlled raw scores, suggesting the odds of a PCA diagnosis increased with decrement on Rey‐O Copy. AUROC values ranged from 0.77 to 0.88 across these indices.ConclusionA substantial number of LPA participants showed visuospatial impairment, despite initial primary language complaints. Differentiation of diagnostic groups by the Rey‐O is likely underscored by relatively uniform, profound, visuospatial impairment in PCA with more variability in LPA. However, the degree of visuospatial impairment overlaps remarkably across diagnoses.