Minimally invasive biomarkers are urgently needed to detect molecular pathology in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we show that plasma extracellular vesicles (EVs) contain quantifiable amounts of TDP-43 and full-length tau, which allow the quantification of 3-repeat (3R) and 4-repeat (4R) tau isoforms. Plasma EV TDP-43 levels and EV 3R/4R tau ratios were determined in a cohort of 704 patients, including 37 genetically and 31 neuropathologically proven cases. Diagnostic groups comprised patients with TDP-43 proteinopathy ALS, 4R tauopathy progressive supranuclear palsy, behavior variant FTD (bvFTD) as a group with either tau or TDP-43 pathology, and healthy controls. EV tau ratios were low in progressive supranuclear palsy and high in bvFTD with tau pathology. EV TDP-43 levels were high in ALS and in bvFTD with TDP-43 pathology. Both markers discriminated between the diagnostic groups with area under the curve values >0.9, and between TDP-43 and tau pathology in bvFTD. Both markers strongly correlated with neurodegeneration, and clinical and neuropsychological markers of disease severity. Findings were replicated in an independent validation cohort of 292 patients including 34 genetically confirmed cases. Taken together, the combination of EV TDP-43 levels and EV 3R/4R tau ratios may aid the molecular diagnosis of FTD, FTD spectrum disorders and ALS, providing a potential biomarker to monitor disease progression and target engagement in clinical trials.

Objective To determine whether following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer disease (AD), we analyzed cross-sectional data from the German DZNE-Longitudinal Cognitive Impairment and Dementia Study. Method The sample (n = 512, mean age 69.5 ± 5.9 years) included 169 cognitively normal participants and individuals at higher AD risk (53 with relatives with AD, 209 with subjective cognitive decline, and 81 with mild cognitive impairment). We defined MeDi adherence according to the food frequency questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI, and cognitive performance was assessed with an extensive neuropsychological battery. AD-related biomarkers (β-amyloid_42/40 [Aβ_42/40] ratio, phosphorylated tau 181 [pTau181]) in CSF were assessed in n = 226 individuals. We analyzed the associations between MeDi and outcomes with linear regression models controlling for several covariates. In addition, we applied hypothesis-driven mediation and moderation analysis. Results Higher MeDi adherence related to larger mediotemporal gray matter volume (p < 0.05 family-wise error corrected), better memory (β ± SE = 0.03 ± 0.02; p = 0.038), and less amyloid (Aβ_42/40 ratio, β ± SE = 0.003 ± 0.001; p = 0.008) and pTau181 (β ± SE = −1.96 ± 0.68; p = 0.004) pathology. Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations among Aβ_42/40 ratio, pTau181, and mediotemporal atrophy. Results were consistent correcting for APOE-ε4 status. Conclusion Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. They suggest that these associations might be explained by a decrease of amyloidosis and tau pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications.

Background and Objectives: To determine the relevance of minor neuropsychological deficits (MNPD) in patients with subjective cognitive decline (SCD) with regard to CSF levels of Alzheimer’s disease (AD) biomarkers, cognitive decline and clinical progression to mild cognitive impairment (MCI). Methods: This study included clinical SCD patients and SCD free, healthy control (HC) participants with available baseline CSF and/or longitudinal cognitive data from the observational DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study. We defined MNPD as a performance of at least 0.5SD below the mean on a demographically adjusted total score derived from the Consortium to Establish a Registry for Alzheimer’s Disease Neuropsychological Assessment Battery. We compared SCD patients with MNPD and those without MNPD with regard to CSF amyloid-β (Aβ)42/Aβ40, phosphorylated tau (p-tau₁₈₁)_, total tau and Aβ42/p-tau₁₈₁ levels, longitudinal cognitive composite trajectories and risk of clinical progression to incident MCI (follow-up M±SD: 40.6±23.7 months). Additionally, we explored group differences between SCD and HC in those without MNPD. Results: In our sample (N = 672, mean age: 70.7±5.9 years, 50% female), SCD patients with MNPD (n = 55, 12.5% of SCD group) showed significantly more abnormal CSF biomarker levels, increased cognitive decline and a higher risk of progression to incident MCI (HR: 4.07, 95%CI: 2.46-6.74) compared to SCD patients without MNPD (n = 384). MNPD had a positive predictive value of 57.0% (95%CI: 38.5-75.4) and a negative predictive value of 86.0% (95%CI: 81.9-90.1) for the progression of SCD to MCI within three years. SCD patients without MNPD showed increased cognitive decline and a higher risk of incident MCI compared to HC participants without MNPD (n = 215; HR: 4.09, 95%CI: 2.07-8.09), while AD biomarker levels did not differ significantly between these groups. Discussion: Our results suggest that MNPD are a risk factor for AD related clinical progression in cognitively normal patients seeking medical counseling due to SCD. As such, the assessment of MNPD could be useful for individual clinical prediction and for AD risk stratification in clinical trials. However, SCD remains a risk factor for future cognitive decline even in the absence of MNPD.

Zusammenfassung: Gedächtnisambulanzen sind spezialisierte und multidisziplinäre Einrichtungen zur (Früh-)Erkennung demenzieller Erkrankungen, welche zwar unterschiedliche institutionelle Rahmenbedingungen und inhaltliche Schwerpunkte aufweisen, die aber auch viele Gemeinsamkeiten haben in Bezug auf diagnostische Abläufe und therapeutisches Handeln. Für die neuropsychologische Diagnostik als Kernelement der Demenzdiagnostik liegen zahlreiche etablierte Testverfahren vor, einheitliche Standards für die Auswahl und Anwendung geeigneter Verfahren wurden jedoch in Deutschland bisher nicht formuliert. Eine Onlineumfrage unter 28 Zentren des Deutschen Netzwerks Gedächtnisambulanzen e. V. (DNG) stellt den aktuellen Stand der klinischen Praxis in der neuropsychologischen Demenzdiagnostik in diesen Gedächtnisambulanzen dar und zeigt mittels Empfehlungen Ansätze zu einer möglichen Harmonisierung im Vorgehen auf.