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  • 1
    Online Resource
    Online Resource
    Tracking neurodegeneration in frontotemporal dementia and Alzheimer’s disease: A comparative study of plasma tau and neurofilament light chain : Biomarkers (non‐neuroimaging): Blood based biomarkers
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S5 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Abstract: The comparative clinical utility of plasma Tau and neurofilament light chain (NfL) in frontotemporal lobar degeneration syndromes (FTLD‐S) and Alzheimer’s disease (AD) was determined. Method We measured plasma Tau and NfL with Simoa in 265 participants: 167 FTLD‐S, 43 AD and 55 healthy controls (HC), including 82 pathology‐proven cases (50 FTLD‐Tau, 18 FTLD‐TDP, 2 FTLD‐FUS and 12 AD) and 98 participants with amyloid PET. We compared cross‐sectional and longitudinal biomarker concentrations between groups, and studied their correlation with baseline clinical measures of disease severity and cortical thickness and their ability to predict disease progression and survival. Result Plasma NfL, but not plasma Tau, discriminated between FTLD‐S, AD and HC (AUC = .97, 95% CI .95 – .99, p 〈 .001 for FTLD‐S vs HC, and AUC = .94, 95 CI .89 ‐ .98, p 〈 .001 for AD vs HC). In pathologically‐confirmed cases, plasma NfL levels were higher in FTLD‐TDP (85.6 ± 46 pg/mL), compared to FTLD‐Tau (50.4 ± 26 pg/mL), after accounting for age, and disease severity ( p 〈 .001; partial η 2 = .20). High plasma NfL, but not plasma Tau, predicted disease progression in both FTLD‐S (2.3 points increase in CDRsb per log NfL ng/mL increase per time interval, 95% CI 0.4 – 4, FDR‐corrected, p =.007) and AD (2.9 points increase in CDRsb per log NfL ng/mL increase per time interval, 95% CI 0.2 – 5.6, FDR‐corrected, p = .035) and shorter survival (Log‐Rank = 14.4, p 〈 .001) in FLTD‐S. Plasma NfL, but not plasma Tau, correlated with reduced cortical thickness in frontal regions in FLTD‐S and temporoparietal regions in AD. The combination of plasma NfL with plasma Tau did not improve the diagnostic prognostic performance of plasma NfL alone. Conclusion Plasma Tau has limited diagnostic and prognostic value. Plasma NfL discriminates FTLD and AD from healthy individuals and is associated with disease progression in FTLD and AD and may be have important clinical value for prognostic purposes.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S5
    DOI: 10.1002/alz.040015
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2211627-8
    detail.hit.zdb_id: 2201940-6
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  • 2
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    Online Resource
    Neuropsychiatric abnormalities in familial frontotemporal dementia: Findings from the LEFFTDS Cohort : Neuropsychiatry and behavioral neurology: Neuropsychiatric symptoms in MCI and dementia
    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: The LEFFTDS Consortium involves investigators at 8 centers in North America evaluating individuals in kindreds with mutations in microtubule associated protein tau ( MAPT ), progranulin ( GRN ), or chromosome 9 open reading frame 72 ( C9orf72 ) genes using a standardized battery of measures. Participants are evaluated annually. We sought to determine possible correlations between FTLD disease progression and neuropsychiatric features. Method The Neuropsychiatric Inventory Questionnaire (NPI‐Q) scale is an informant‐based instrument that measures the presence and severity of 12 neuropsychiatric features in patients with dementia. The NPI‐Q was completed at each LEFFTDS visit. The individual NPI questions and total score were analyzed in those with CDR® Dementia Staging Instrument PLUS National Alzheimer Coordinating Center Frontotemporal Lobar Degeneration (CDR®+ NACC FTLD) ratings of 0 (i.e., clinically normal), 0.5 (i.e., questionably/minimally abnormal), 1, 2, and 3. Result The 472 participants enrolled to date with a baseline (Visit 1) assessment have the following characteristics: 261 (55.5%) female, mean age 48 (range 18‐80) years, mean education 16 (range 11‐22) years, and 275 participants with a CDR®+NACC FTLD=0 (58%) and known genetic status. Participants with a CDR®+NACC FTLD=0 plus a genetic mutation were compared to those without a mutation and found to have increased severity of apathy (mean score of 0.116 versus 0.035, p=0.0302). Regardless of the specific mutation, those with a CDR®+NACC FTLD=0.5 were reported to have increased severity of apathy, disinhibition, and irritability. For most domains, mean NPI‐Q severity scores increase between groups up to CDR®+NACC FTLD=2. Depression increases in severity up to CDR®+NACC FTLD=1, whereas apathy severity continues to increase with increasing disease severity through CDR®+NACC FTLD=3. Twenty participants converted from CDR®+NACC FTLD 0 to 〉 0 between their baseline and most recent visit; apathy severity almost tripled in these participants. For those that converted, disinhibition, irritability, and NPI total score were different between baseline and most recent visit (Wilcoxon signed rank test, p 〈 0.05). Conclusion Key neuropsychiatric features measured by the NPI‐Q demonstrate differences in apathy severity between clinically normal mutation vs non‐mutation carriers. Key domains differ at different levels of FTLD severity and show dynamic changes with increasing level of FTLD severity. Supported by AG063911, AG045390, NS092089, AG016976.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S6
    DOI: 10.1002/alz.045505
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2211627-8
    detail.hit.zdb_id: 2201940-6
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  • 3
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    Online Resource
    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
    detail.hit.zdb_id: 2211627-8
    detail.hit.zdb_id: 2201940-6
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  • 4
    Online Resource
    Online Resource
    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
    detail.hit.zdb_id: 2211627-8
    detail.hit.zdb_id: 2201940-6
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