This narrative review explores the current landscape of blood biomarkers in Frontotemporal dementia (FTD). Neurofilament light chain (NfL) may be useful in the differentiation of behavioral variant FTD from primary psychiatric disorders (PPDs) or dementia with Lewy bodies (DLB). In prodromal FTD and presymptomatic mutation carriers (GRN, MAPT, C9orf72), elevated NfL may herald pheno-conversion to full-blown dementia. Baseline NfL correlates with steeper neuroanatomical changes and cognitive, behavioral and functional decline, making NfL promising in monitoring disease progression. Phosphorylated neurofilament heavy chain (pNfH) levels have a potential limited role in the demarcation of the conversion stage to full-blown FTD. Combined NfL and pNfH measurements may allow a wider stage stratification. Total tau levels lack applicability in the framework of FTD. p-tau, on the other hand, is of potential value in the discrimination of FTD from Alzheimer’s dementia. Progranulin concentrations could serve the identification of GRN mutation carriers. Glial fibrillary acidic protein (GFAP) may assist in the differentiation of PPDs from behavioral variant FTD and the detection of GRN mutation carriers (additional research is warranted). Finally, TAR DNA-binding protein-43 (TDP-43) appears to be a promising diagnostic biomarker for FTD. Its potential in distinguishing TDP-43 pathology from other FTD-related pathologies requires further research.

Functional near-infrared spectroscopy (fNIRS) is an innovative neuroimaging method that offers several advantages over other commonly used modalities. This narrative review investigated the potential contribution of this method to the study of neurodegenerative disorders. Thirty-four studies involving patients with Alzheimer’s disease (AD), mild cognitive impairment (MCI), frontotemporal dementia (FTD), Parkinson’s disease (PD), or amyotrophic lateral sclerosis (ALS) and healthy controls were reviewed. Overall, it was revealed that the prefrontal cortex of individuals with MCI may engage compensatory mechanisms to support declining brain functions. A rightward shift was suggested to compensate for the loss of the left prefrontal capacity in the course of cognitive decline. In parallel, some studies reported the failure of compensatory mechanisms in MCI and early AD; this lack of appropriate hemodynamic responses may serve as an early biomarker of neurodegeneration. One article assessing FTD demonstrated a heterogeneous cortical activation pattern compared to AD, indicating that fNIRS may contribute to the challenging distinction of these conditions. Regarding PD, there was evidence that cognitive resources (especially executive function) were recruited to compensate for locomotor impairments. As for ALS, fNIRS data support the involvement of extra-motor networks in ALS, even in the absence of measurable cognitive impairment.

In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer’s disease—AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD—APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive–neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.

Background/Objectives: Multiple system atrophy (MSA) presents a challenging diagnosis due to its clinical overlap with other neurodegenerative disorders, especially other α-synucleinopathies. The main purpose of this systematic review and meta-analysis was to assess neurofilament light chain (NfL) differences in the CSF and blood of patients with MSA versus the healthy control group (HC), patients with Parkinson’s disease (PD) and patients with Lewy body dementia (LBD). Secondarily, the diagnostic metrics of CSF and circulating NfL in MSA versus HC, PD, LBD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were discussed. Methods: MEDLINE and EMBASE were thoroughly searched for relevant case-control studies. Standardized mean differences (SMDs) were calculated separately for CSF and blood NfL per comparison. Statistical heterogeneity was assessed based on the Q and I^2 statistics. Results: Twenty-five relevant studies were retrieved. Quantitative syntheses revealed elevated CSF and circulating NfL levels in individuals with MSA versus HC [SMD = 1.80 (95%CI = 1.66, 1.94) and SMD = 2.00 (95%CI = 1.36, 2.63), respectively] versus PD [SMD = 1.65 (95%CI = 1.26, 2.03) and SMD = 1.63 (95%CI = 0.84, 2.43), respectively] as well as versus LBD [SMD = 1.17, (95%CI = 0.71, 1.63) and SMD = 0.65 (95%CI = 0.30, 1.00), respectively]. Diagnostic accuracy was outstanding for CSF and blood NfL in MSA versus HC and PD, and it was moderate in MSA versus LBD. On the other hand, it was suboptimal in MSA vs. PSP and CBD. Conclusions: Both CSF and circulating NfL levels are elevated in MSA compared to HC, PD and LBD. To achieve optimal diagnostic properties, further work is required in the standardization of processes and the establishment of reference NfL intervals and/or thresholds.

Objective:We aimed to examine associations between neuropsychiatric symptoms (NPS) and white matter hyperintensities (WMH) status in older adults without dementia under the hypothesis that WMH increased the odds of having NPS.Design:Longitudinal analysis of data acquired from the National Alzheimer’s Coordinating Center Uniform Data Set.Settings:Data were derived from 46 National Institute on Aging - funded Alzheimer’s Disease Research Centers.Participants:NACC participants aged ≥50 years with available data on WMH severity with a diagnosis of mild cognitive impairment (MCI) or who were cognitively unimpaired (CU) were studied. Among 4617 CU participants, 376 had moderate and 54 extensive WMH. Among 3170 participants with MCI, 471 had moderate and 88 had extensive WMH.Measurements: Using Cardiovascular Health Study (CHS) scores, WMH were coded as no to mild (CHS score: 0-4), moderate (score: 5-6) or extensive (score: 7-8). NPS were quantified on the Neuropsychiatric Inventory Questionnaire. Binary logistic regression models estimated the odds of reporting each of 12 NPS by WMH status separately for individuals with MCI or who were CU.Results:Compared to CU individuals with no to mild WMH, the odds of having elation [9.87,(2.63-37.10)], disinhibition [4.42,(1.28-15.32)], agitation [3.51,(1.29-9.54)] or anxiety [2.74,(1.28-5.88)] were higher for the extensive WMH group, whereas the odds of having disinhibition were higher for the moderate WMH group [1.94,(1.05-3.61)]. In the MCI group, he odds of NPS did not vary by WMH status.Conclusions:Extensive WMH were associated with higher odds of NPS in CU older adults but not in those with MCI.

Choroid plexus (CP) can be seen as a watchtower of the central nervous system (CNS) that actively regulates CNS homeostasis. A growing body of literature suggests that CP alterations are involved in the pathogenesis of multiple sclerosis (MS) but the underlying mechanisms remain elusive. CPs are enlarged and inflamed in relapsing-remitting (RRMS) but also in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) stages, far beyond MS diagnosis. Increases in the choroid plexus/total intracranial volume (CP/TIV) ratio have been robustly associated with increased lesion load, higher translocator protein (TSPO) uptake in normal-appearing white matter (NAWM) and thalami, as well as with higher annual relapse rate and disability progression in highly active RRMS individuals, but not in progressive MS. The CP/TIV ratio has only slightly been correlated with magnetic resonance imaging (MRI) findings (cortical or whole brain atrophy) and clinical outcomes (EDSS score) in progressive MS. Therefore, we suggest that plexus volumetric assessments should be mainly applied to the early disease stages of MS, whereas it should be taken into consideration with caution in progressive MS. In this review, we attempt to clarify the pathological significance of the temporal CP volume (CPV) changes in MS and highlight the pitfalls and limitations of CP volumetric analysis.