Kantarci, Kejal

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.

PurposeAdvanced MRS protocols improve data quality and reproducibility relative to vendor‐provided protocols; however, they are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high‐quality spectroscopic data without local MRS expertise.MethodsFirst, a B0 shimming protocol was selected for automation by comparing 3 widely used B0 algorithms (2 vendor protocols and FAST(EST)MAP). Next, voxel‐based B0 and B1 calibrations were incorporated into the consensus‐recommended semi‐LASER sequence and combined with an automated VOI prescription tool, a recently developed method for automated voxel prescription. The efficiency of collecting single‐voxel data from a clinical cohort (N = 40) with the automated protocol (calibration time and fraction of usable datasets) was compared with the nonautomated semi‐LASER protocol (N = 35) whereby all prescan calibrations were executed manually in the academic hospital setting with rotating MR technologists in the neuroradiology unit.ResultsA multi‐iteration FAST(EST)MAP protocol resulted in narrower water linewidths than vendor’s B0 shim protocols for data acquired from 6 brain locations (p < 1e‐5) and was selected for automation. The automated B0 and B1 calibrations resulted in a time saving of ~4.5 minutes per voxel relative to the same advanced protocol executed manually. All spectra acquired with the automated protocol were usable, whereas only 86% of those collected with the manual protocol were usable and spectral quality was more variable.ConclusionThe plug‐and‐play advanced MRS protocol allows automated acquisition of high‐quality MRS data with high success rate and consistency on a clinical 3T platform.

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.

AbstractBackgroundResearch on menopausal hormone therapy (MHT) for the reduction/prevention of cognitive decline or Alzheimer’s disease has been inconsistent. The Women’s Health Initiative Memory Study (WHIMS) revealed elevated incident cognitive impairment for women starting MHT after age >65 with oral conjugated equine estrogens (o‐CEE) treatment, especially among women with diabetes. Subsequently, the Cognitive and Affective substudy of the Kronos Early Estrogen Prevention Study (KEEPS‐Cog) found that MHT initiated soon after menopause caused neither cognitive benefit nor harm. Waist‐to‐hip ratio (WHR) is a measure of central adiposity and a surrogate marker for insulin resistance/prediabetes. To explore effects of MHT in insulin‐resistant states, in younger women, we analyzed WHR as a predictor of cognitive response to MHT in KEEPS‐Cog.MethodsKEEPS‐Cog randomized women less than 36‐months postmenopause to oCEE, transdermal 17‐β‐estradiol (tE2) or placebo for 48 months. Cognitive tests, completed at baseline, 18, 36, and 48 months post‐randomization were summarized as factor scores representing four cognitive domains: verbal learning and memory (VLM), auditory attention and working memory (AAWM), visual attention and executive function (VAEF), and speeded language and mental flexibility (SLMF). WHR, measured at screening and months 12, 36, and 48 was modeled as a time‐varying moderator of MHT on cognitive function over time. Education was included as a time‐invariant covariate.ResultsWHR decreased throughout the study in both the tE2 and oCEE groups compared to placebo. WHR was also inversely associated with all cognitive parameters at baseline. The inverse relationship of WHR on SLMF was significant at baseline and month 18, but decreased at month 48. The inverse relationship of WHR on VLM increased significantly over time. Models including interaction effects were significant for oCEE x WHR effects at months 18, 36, and 48 on SLMF, indicating better performance in MHT vs placebo arms. No other interaction effects were significant.ConclusionsWHR decreased with MHT, and was consistently associated with VLM through 4 years of MHT. Further, women on oCEE performed better on SLMF tasks at a given WHR. Differences between KEEPS‐Cog and WHIMS findings may be related to the timing of MHT administration, and effects on central adiposity/insulin resistance/prediabetes.

AbstractBackgroundNeocortical tau can be present in over half of patients with Lewy body disease at autopsy, and may influence the timing of when a diagnosis of Dementia with Lewy bodies (DLB) can be made. We examined whether the core features, onset age and latency of probable DLB diagnosis differ by pathological subgroups.MethodAll patients (n=176) met clinical criteria for probable DLB, underwent autopsy and were classified as transitional or diffuse Lewy body disease (TLBD, DLBD). The TLBD and DLBD groups were further subdivided based on the absence of neocortical tangles represented by a low (L) Braak NFT stage of 0‐III or by the presence of neocortical tangles represented by a high (H) Braak NFT stage of IV‐VI. Onset age and latency from cognitive symptom onset to probable DLB were compared for TLBD‐L (n=30), DLBD‐L (n=47), DLBD‐H (n=78) and TLBD‐H (n=21).ResultThe TLBD‐H group met criteria for DLB at an older age (median 76 years) compared to TLBD‐L, DLBD‐L or DLBD‐H groups (median age 70 years, p<0.001). The latency to probable DLB from cognitive onset was shortest for TLBD‐L and DLBD‐L (median < 1 year), which was shorter than DLBD‐H (median 2 years; p=0.016), each of which were shorter than TLBD‐H (median 7.3 years; p<0.001). RBD was more common in men (79% men vs. 40% women, p<0.001) and in patients without neocortical tangles (86% vs. 57%, p<0.001). Patients with RBD met criteria for probable DLB at a younger age than those without a history of RBD (median 69 years vs. 76 years, p<0.001). Men had a shorter latency to probable DLB than women (median 1.0 year vs. 2.8 years, p<0.01), but this was related to RBD status that was more common in men.ConclusionPresence of RBD in both sexes led to a younger onset age and shorter latency to diagnosis of probable DLB. Patients with more widespread tau relative to α‐synuclein pathology (TLBD‐H) were older when probable DLB was diagnosed compared to those with so‐called pure Lewy body disease (TLBD‐L, DLBD‐L) or those with diffuse α‐synuclein and tau pathology (DLBD‐H).

AbstractBackgroundThe Mayo Clinic Study of Aging and Alzheimer’s Disease Research Center used GE scanners exclusively for MRI from 2005‐2017, employing consistent imaging parameters throughout. In 2017 the MRI protocol was updated and migrated to Siemens Prisma scanners; 113 participants were scanned with each configuration. The GE protocol included a 2D FLAIR. The Siemens protocol includes 3D FLAIR and T2‐weighted images. Both vendor protocols included a 3D T1. Experience with multi‐center trials suggests such changes may introduce systematic variations.MethodsGE scanning was carried out on 3T scanners with 12 channel phased array head coils. Siemens Prisma scanning was carried out with 64 channel head/neck coils. Imaging sequences and parameters are given in Table 1. We used the MCALT template and priors to perform standard six‐class segmentation on T1‐weighted (T1w) images. SPM12 unified segmentation supports the simultaneous use of multiple input contrasts; segmentation of multi‐contrast inputs was done using eight tissue classes including deep grey and white matter hyperintensity (WMH) priors. For a given MRI study (either GE or Siemens) all images were registered and resampled to the study’s T1w image. Two‐channel (T1+FLAIR) segmentation was performed on GE scans. Two and three‐channel segmentations were performed on Siemens scans. Comparisons included total intracranial volume, total tissue volume and total grey matter volumes, as well as hippocampal volumes and grey matter volume in a temporal lobe meta‐ROI.ResultsFour participants were excluded for poor image quality: one poor GE T1w quality, one poor Siemens T1, T2 and FLAIR quality, and two poor Siemens T2 quality. Comparisons were made among 109 participants aged 34–97 (Table 2). By visual assessment, adding T2‐weighted images always improved intracranial volume correctness. Using the combination of single‐channel GE and three‐channel Siemens generally improved cross‐vendor agreement on grey matter volumes with the exceptions of hippocampal and intracranial volume estimates.ConclusionRequiring multiple input channels increases the likelihood that the result of a study being excluded. Combining T1w, FLAIR and T2w images allows the delineation of WMH and deep grey matter probability outputs but may introduce differences in GM volumes.

AbstractBackgroundOptimizing software to measure Flortaucipir (AV‐1451) tau PET SUVR change‐over‐time is crucial for longitudinal observational studies and potential trials of anti‐tau agents. Ideal measurements should have good repeatability (low noise), and should clearly separate clinical cognitive groups.MethodWe compared 456 software methods varying in their use of: two major packages, each with cross‐sectional and longitudinal variants (FreeSurfer and an in‐house pipeline using SPM12, MCALT, and ANTs); three temporal‐lobe target regions (each with/without adjacent WM); seven reference regions; five PVC methods; and two statistics (mean vs. median). We used linear mixed‐effects models to compare methods using scans from 88 Mayo Clinic participants (46 cognitively impaired, 42 impaired, excluding those with symptoms inconsistent with the AD pathology imaged by Flortaucipir), each with three visits with PET and MRI. From these models, we calculated two criteria for each pipeline: relative measurement error (residual from the linear mixed model), and the t‐statistic for testing differences in group‐wise rates of change (which has a Cohen’s d interpretation of effect size for longitudinal data). We plotted both criteria orthogonally, then ranked methods overall according to the average of their ranks on both individual criteria.ResultMethods using the entorhinal cortex target region performed poorly in both criteria (Figure 1). The top 10 methods by the combined criteria (top‐left in Figure 2) all used the Mayo SPM12‐based pipeline with an eroded supratentorial WM (eSWM) or composite (eSWM + pons + cerebellum) reference region. Among them, 9/10 used the longitudinal variant, 8/10 used 2‐compartment PVC, and 7/10 used median. Altogether, our results favored SUVR methods with a longitudinal design (simultaneously calculating all time‐points), a temporal‐lobe meta‐ROI including adjacent WM, a composite reference region, 2‐class voxel‐based (Meltzer) PVC, and median statistics. Methods using GTM‐Tau PVC (Baker et al., Data in Brief, 2017) had the highest group separation but relatively large measurement error, giving them ranks 197 and 199 out of 456 with the joint (average rank) criteria.ConclusionCompared with popular FreeSurfer‐based methods (ranks 176, 258; Figure 2), our top‐ranked approaches approximately halved error in SUVR measurements while maintaining or improving group separation.

AbstractIntroductionWe examined the temporal sequence of the core features in probable dementia with Lewy bodies (DLB).MethodsIn 488 patients with probable DLB, the onset of each core feature and time to diagnosis was determined for men and women, and a pathologic subgroup (n = 209).ResultsREM sleep behavior disorder (RBD) developed before the other core features in men and women. Men were more likely to have RBD and were diagnosed with probable DLB earlier than women. Visual hallucinations developed after the other core features in men, but in women, they appeared earlier and concurrently with fluctuations and parkinsonism. Women were older and more cognitively impaired at first visit, were less likely to have RBD, more likely to be diagnosed with probable DLB later than men, and more likely to have neocortical tangles.DiscussionAn earlier latency to probable DLB was associated with men, RBD, and Lewy body disease without neocortical tangles.

A rare APOE variant APOE3 -Jac reduces self-aggregation and promotes healthy brain aging.