RESUMEN
Functional magnetic resonance imaging research employing regional homogeneity (ReHo) analysis has uncovered aberrant local brain connectivity in individuals with mild cognitive impairment (MCI) and Alzheimer's disease (AD) in comparison with healthy controls. However, the precise localization, extent, and possible overlap of these aberrations are still not fully understood. To bridge this gap, we applied a novel meta-analytic and Bayesian method (minimum Bayes Factor Activation Likelihood Estimation, mBF-ALE) for a systematic exploration of local functional connectivity alterations in MCI and AD brains. We extracted ReHo data via a standardized MEDLINE database search, which included 35 peer-reviewed experiments, 1,256 individuals with AD or MCI, 1,118 healthy controls, and 205 x-y-z coordinates of ReHo variation. We then separated the data into two distinct datasets: one for MCI and the other for AD. Two mBF-ALE analyses were conducted, thresholded at "very strong evidence" (mBF ≥ 150), with a minimum cluster size of 200 mm³. We also assessed the spatial consistency and sensitivity of our Bayesian results using the canonical version of the ALE algorithm. For MCI, we observed two clusters of ReHo decrease and one of ReHo increase. Decreased local connectivity was notable in the left precuneus (Brodmann area - BA 7) and left inferior temporal gyrus (BA 20), while increased connectivity was evident in the right parahippocampal gyrus (BA 36). The canonical ALE confirmed these locations, except for the inferior temporal gyrus. In AD, one cluster each of ReHo decrease and increase were found, with decreased connectivity in the right posterior cingulate cortex (BA 30 extending to BA 23) and increased connectivity in the left posterior cingulate cortex (BA 31). These locations were confirmed by the canonical ALE. The identification of these distinct functional connectivity patterns sheds new light on the complex pathophysiology of MCI and AD, offering promising directions for future neuroimaging-based interventions. Additionally, the use of a Bayesian framework for statistical thresholding enhances the robustness of neuroimaging meta-analyses, broadening its applicability to small datasets.
RESUMEN
The glymphatic system is an emerging target in neurodegenerative disorders. Here, we investigated the activity of the glymphatic system in genetic frontotemporal dementia with a diffusion-based technique called diffusion tensor image analysis along the perivascular space. We investigated 291 subjects with symptomatic or presymptomatic frontotemporal dementia (112 with chromosome 9 open reading frame 72 [C9orf72] expansion, 119 with granulin [GRN] mutations and 60 with microtubule-associated protein tau [MAPT] mutations) and 83 non-carriers (including 50 young and 33 old non-carriers). We computed the diffusion tensor image analysis along the perivascular space index by calculating diffusivities in the x-, y- and z-axes of the plane of the lateral ventricle body. Clinical stage and blood-based markers were considered. A subset of 180 participants underwent cognitive follow-ups for a total of 640 evaluations. The diffusion tensor image analysis along the perivascular space index was lower in symptomatic frontotemporal dementia (estimated marginal mean ± standard error, 1.21 ± 0.02) than in old non-carriers (1.29 ± 0.03, P = 0.009) and presymptomatic mutation carriers (1.30 ± 0.01, P < 0.001). In mutation carriers, lower diffusion tensor image analysis along the perivascular space was associated with worse disease severity (ß = -1.16, P < 0.001), and a trend towards a significant association between lower diffusion tensor image analysis along the perivascular space and higher plasma neurofilament light chain was reported (ß = -0.28, P = 0.063). Analysis of longitudinal data demonstrated that worsening of disease severity was faster in patients with low diffusion tensor image analysis along the perivascular space at baseline than in those with average (P = 0.009) or high (P = 0.006) diffusion tensor image analysis along the perivascular space index. Using a non-invasive imaging approach as a proxy for glymphatic system function, we demonstrated glymphatic system abnormalities in the symptomatic stages of genetic frontotemporal dementia. Such measures of the glymphatic system may elucidate pathophysiological processes in human frontotemporal dementia and facilitate early phase trials of genetic frontotemporal dementia.
RESUMEN
BACKGROUND: The Genetic Frontotemporal Initiative Staging Group has proposed clinical criteria for the diagnosis of prodromal frontotemporal dementia (FTD), termed mild cognitive and/or behavioral and/or motor impairment (MCBMI). The objective of the study was to validate the proposed research criteria for MCBMI-FTD in a cohort of genetically confirmed FTD cases against healthy controls. METHODS: A total of 398 participants were enrolled, 117 of whom were carriers of an FTD pathogenic variant with mild clinical symptoms, while 281 were non-carrier family members (healthy controls (HC)). A subgroup of patients underwent blood neurofilament light (NfL) levels and anterior cingulate atrophy assessment. RESULTS: The core clinical criteria correctly classified MCBMI vs HC with an AUC of 0.79 (p < 0.001), while the addition of either blood NfL or anterior cingulate atrophy significantly increased the AUC to 0.84 and 0.82, respectively (p < 0.001). The addition of both markers further increased the AUC to 0.90 (p < 0.001). CONCLUSIONS: The proposed MCBMI criteria showed very good classification accuracy for identifying the prodromal stage of FTD.