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  • 1
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    Gearing up for the future: Exploring facilitators and barriers to inform clinical trial design in frontotemporal lobar degeneration
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S7 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S7 ( 2021-12)
    Abstract: Frontotemporal 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. Objective The objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD. Methods Advancing 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. Results 29% 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%). Conclusions Favorable 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S7
    DOI: 10.1002/alz.052495
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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    Demographic and psychosocial factors associated with the decision to learn mutation status in familial frontotemporal dementia and the impact of disclosure on mood
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S7 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S7 ( 2021-12)
    Abstract: Up 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. Method F‐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). Result Of 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. Conclusion The 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S7
    DOI: 10.1002/alz.050692
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 3
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    Diagnostic value of plasma P‐tau217 in frontotemporal dementia spectrum disorders
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Frontotemporal 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. Method Plasma 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 . Result The 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. Conclusion When 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.055763
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 4
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    Clinical value of CSF tau, p‐tau181, neurogranin and neurofilaments in familial frontotemporal lobar degeneration
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S4 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S4 ( 2021-12)
    Abstract: Blood 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. Method FLTD‐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 tau 181 (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. Result NfL (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. Conclusion CSF 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S4
    DOI: 10.1002/alz.052993
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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    Studying the natural history of frontotemporal lobar degeneration (FTLD): The ARTFL LEFFTDS longitudinal FTLD (ALLFTD) protocol : Neuropsychiatry and behavioral neurology: DLB and FTD — clinical manifestations
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S6 ( 2020-12)
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    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S6 ( 2020-12)
    Abstract: It is important to determine the natural history of sporadic and familial frontotemporal lobar degeneration (FTLD) and generate clinical, neuropsychological, neuroimaging and biofluid data for planning disease‐modifying trials. Method As part of the ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD; U19 AG063911) protocol, investigators at 19 centers in North America will enroll 2100 participants with FTLD over the next 5 years beginning in early 2020. Result As of 1/20/20, the ARTFL/LEFFTDS (A/L) Consortium had enrolled 1832 participants, including 850 in kindreds with familial FTLD (239 associated with mutations in MAPT , 192 in GRN , 370 in C9orf72 , 4 with mutations in both GRN and C9orf72 , and 45 with a mutation in a different gene or no mutation in any known FTLD‐associated gene). Over 500 participants have undergone 2 or more annual visits to date. MRI has been performed in 1105. Biofluid samples have also been collected, with blood (DNA, plasma, serum, mRNA, PBMC) in 1413 and CSF in 303. Over 60 manuscripts using A/L data or samples have been published to date. Five clinical trials involving A/L and ALLFTD participants are in progress or planned. The longitudinal arm in ALLFTD will enroll 500 of existing A/L and 600 future participants for annual assessments with similar methodology to A/L. An additional 1000 FTLD patients will undergo focused one‐time clinical evaluations and biofluid collection. Conclusion The data/samples from already‐enrolled and planned participants in ALLFTD and findings published to date underscore the utility of evaluating FTLD subjects. The absence of identifiable mutations in some with familial FTLD suggests that other genes are yet to be discovered. ALLFTD data will inform clinical trial design, and many participants will be eligible for future trials. The key data and samples in ALLFTD are available to interested investigators worldwide. Supported by: AG063911, AG045390, NS092089, AG016976, AG21886.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S6
    DOI: 10.1002/alz.045482
    Language: English
    Publisher: Wiley
    Publication Date: 2020
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    An examination of atypical primary progressive aphasia variants
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S6 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S6 ( 2021-12)
    Abstract: The 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. Method We 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. Result PAA 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. Conclusion The 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.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S6
    DOI: 10.1002/alz.055305
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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    [ 18 F]AV‐1451 tau‐PET and primary progressive aphasia
    Wiley ; 2018
    In:  Annals of Neurology Vol. 83, No. 3 ( 2018-03), p. 599-611
    Details
    In: Annals of Neurology, Wiley, Vol. 83, No. 3 ( 2018-03), p. 599-611
    Abstract: To assess [ 18 F]AV‐1451 tau‐PET (positron emission tomography) uptake patterns across the primary progressive aphasia (PPA) variants (logopenic, semantic, and agrammatic), examine regional uptake patterns of [ 18 F]AV‐1451 independent of clinical diagnosis, and compare the diagnostic utility of [ 18 F]AV‐1451, [ 18 F]‐fluorodeoxygluclose (FDG)‐PET and MRI (magnetic resonance imaging) to differentiate the PPA variants. Methods We performed statistical parametric mapping of [ 18 F]AV‐1451 across 40 PPA patients (logopenic‐PPA = 14, semantic‐PPA = 13, and agrammatic‐PPA = 13) compared to 80 cognitively normal, Pittsburgh compound B–negative controls, age and gender matched 2:1. Principal component analysis of regional [ 18 F]AV‐1451 tau‐PET standard uptake value ratio was performed to understand underlying patterns of [ 18 F]AV‐1451 uptake independent of clinical diagnosis. Penalized multinomial regression analyses were utilized to assess diagnostic utility. Results Logopenic‐PPA showed striking uptake throughout neocortex, particularly temporoparietal, compared to controls, semantic‐PPA, and agrammatic‐PPA. Semantic‐PPA and agrammatic‐PPA showed milder patterns of focal [ 18 F]AV‐1451 uptake. Semantic‐PPA showed elevated uptake (left 〉 right) in anteromedial temporal lobes, compared to controls and agrammatic‐PPA. Agrammatic‐PPA showed elevated uptake (left 〉 right) throughout prefrontal white matter and in subcortical gray matter structures, compared to controls and semantic‐PPA. The principal component analysis of regional [ 18 F]AV‐1451 indicated two primary dimensions, a severity dimension that distinguished logopenic‐PPA from agrammatic‐PPA and semantic‐PPA, and a frontal versus temporal contrast that distinguishes agrammatic‐PPA and semantic‐PPA cases. Diagnostic utility of [ 18 F]AV‐1451was superior to MRI and at least equal to FDG‐PET. Interpretation [ 18 F]AV‐1451binding characteristics differ across the PPA variants and were excellent at distinguishing between the variants. [ 18 F]AV‐1451binding characteristics were as good or better than other brain imaging modalities utilized in clinical practice, suggesting that [ 18 F]AV‐1451 may have clinical diagnostic utility in PPA. Ann Neurol 2018 Ann Neurol 2018;83:599–611
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v83.3
    DOI: 10.1002/ana.25183
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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    IC‐P‐083: DIAGNOSTIC UTILITY OF [18F]AV‐1451 PET, FDG‐PET AND MRI TO DIFFERENTIATE THE THREE VARIANTS OF PRIMARY PROGRESSIVE APHASIA
    Wiley ; 2018
    In:  Alzheimer's & Dementia Vol. 14, No. 7S_Part_1 ( 2018-07)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 14, No. 7S_Part_1 ( 2018-07)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Article
    DOI: 10.1016/j.jalz.2018.06.2147
    Language: English
    Publisher: Wiley
    Publication Date: 2018
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    Synthesizing Images of Tau Pathology from Images of Glucose Utilization
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: In vivo tau‐positron emission tomography (PET) is an attractive biomarker for Alzheimer’s disease (AD) diagnosis and treatment. However, tau‐PET is less widely available than other modalities. In this study, we tested cross‐modality synthesis of tau‐PET brain images from fluorodeoxyglucose F‐18 (FDG)‐PET using a deep convolutional neural network (CNN). Method Participants (n=1,192) who had brain FDG‐PET with 18 F‐FDG and tau‐PET with Flortaucipir (F‐18‐AV‐1451) were included for training and testing. This cohort spanned normal aging (ages 26‐98), pre‐clinical, and clinical AD and related disorders including the FTD and DLB spectrum. External validation was done using ADNI (n=288). The PET scans were co‐registered to the corresponding MRI and subsequently warped to Mayo Clinic Adult Lifespan Template (MCALT) space. Tau‐PET images were SUVR‐normalized to the cerebellar crus, and FDG to the pons. A 3D dense‐U‐net model was utilized as an architecture. Cross‐validation experiments were conducted using 5‐fold validations (60% training set, 20% validation set, and 20% test set) with mean squared error as the loss function. Result Our dense‐U‐net model successfully synthesized tau‐PET from metabolic images with good correlation and low prediction error for regional SUVRs (Figure 1A‐C). The model showed a robust prediction ability, performing accurately in an independent, external ADNI cohort (Figure 1D‐F). The model‐imputed tau‐PET significantly improved performance in classifying tau positivity (mean AUROC(±SD)=0.78±0.04 and 0.85±0.03 for FDG‐PET and synthesized tau‐PET, respectively) and diagnostic groups (cognitively unimpaired with abnormal amyloid‐PET vs. cognitively impaired with abnormal amyloid‐PET) compared to the original input FDG data (mean AUROC(±SD)=0.89±0.04, 0.85±0.05 0.91±0.04 for actual tau‐PET, FDG‐PET and synthesized tau‐PET, respectively) (Figure 2), suggesting enhanced clinical utility for metabolic images. The ADNI cohort also showed similar results (for tau positivity: AUROC=0.66 and 0.78 for FDG‐PET and synthesized tau‐PET, respectively; for CU A+ vs. CI A+: AUROC=0.86, 0.62, and 0.73 for actual tau‐PET, FDG‐PET, and synthesized tau‐PET; Figure 3). Conclusion We showed that using a CNN model to predict tau‐PET from FDG‐PET is feasible. The synthesized tau‐PET can augment the value of FDG‐PET, facilitating the multi‐modal diagnosis of AD.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.062011
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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    White matter health in the context of Alzheimer’s disease pathophysiology
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S5 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S5 ( 2022-12)
    Abstract: Multi‐compartment modelling of white matter (WM) microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) can provide information on WM health through the neurite (axons and dendrites) density index and free water measures. We hypothesized that cerebrovascular disease (CVD), Alzheimer’s disease (AD), and an FDG pattern suggestive of TDP‐43 proteinopathy would be associated with distinct NODDI readouts of WM damage which would be informative for identifying the substrate for cognitive impairment. Method We identified two independent cohorts with multi‐shell diffusion MRI, amyloid and tau PET, and cognitive assessments. One, were participants from the Mayo Clinic Study of Aging, a population‐based cohort of 347 elderly randomly sampled from the Olmsted county, Minnesota. The second were 61 amyloid positive AD participants from the Mayo AD Research Center. Result We observed an increase in free water and decrease in neurite density in the genu of the corpus callosum associated with vascular risk factors, which we refer to as vascular WM component (Figure 1) . Tau PET signal reflective of 3R/4R tau deposition was associated with worsening neurite density index in the temporal WM where we measured parahippocampal cingulum and inferior temporal WM bundles. Worsening temporal neurite density was associated with (antemortem confirmed) FDG TDP‐43 signature. Post‐mortem neuropathologic data on a small subset (n=9) of this sample lend support to our findings. In the population‐based cohort where vascular disease was more prevalent, the vascular WM component explained variability in global cognition (partial R 2 of free water and neurite density = 8.3%) and MMSE performance (8.2%) which was comparable to amyloid PET (7.4% for global cognition and 6.6% for memory) (Table 1) . In the AD dementia clinic‐based cohort, tau deposition was the greatest contributor to cognitive performance (9.6%), but there was also a non‐trivial contribution of the temporal WM component (8.5%) to cognitive performance. The differences observed between the two cohorts were reflective of their distinct clinical composition. Conclusion White matter microstructural damage assessed using advanced diffusion models may add significant value for distinguishing the underlying substrate (whether CVD versus neurodegenerative disease caused by tau deposition or TDP‐43 pathology) for cognitive impairment in older individuals.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S5
    DOI: 10.1002/alz.063199
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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