Recently, the synaptic proteins neurogranin (Ng) and α-synuclein (α-Syn) have attracted scientific interest as potential biomarkers for synaptic dysfunction in neurodegenerative diseases. In this study, we measured the CSF Ng and α-Syn concentrations in patients affected by AD (n = 69), non-AD neurodegenerative disorders (n-AD = 50) and non-degenerative disorders (n-ND, n = 98). The concentrations of CSF Ng and α-Syn were significantly higher in AD than in n-AD and n-ND. Moreover, the Aβ42/Ng and Aβ42/α-Syn ratios showed statistically significant differences between groups and discriminated AD patients from n-AD patients, better than Ng or α-Syn alone. Regression analyses showed an association of higher Ng concentrations with MMSE < 24, pathological Aβ 42/40 ratios, pTau, tTau and the ApoEε4 genotype. Aβ 42/Ng was associated with MMSE < 24, an AD-related FDG-PET pattern, the ApoEε4 genotype, pathological Aβ 42 levels and Aβ 42/40 ratios, pTau, and tTau. Moreover, APO-Eε4 carriers showed higher Ng concentrations than non-carriers. Our results support the idea that the Aβ 42/Ng ratio is a reliable index of synaptic dysfunction/degeneration able to discriminate AD from other neurological conditions.

The involvement of β-amyloid (Aβ) in the pathogenesis of amyotrophic lateral sclerosis (ALS) has been widely discussed and its role in the disease is still a matter of debate. Aβ accumulates in the cortex and the anterior horn neurons of ALS patients and seems to affect their survival. To clarify the role of cerebrospinal fluid (CSF) Aβ 1–42 and Aβ 42/40 ratios as a potential prognostic biomarker for ALS, we performed a retrospective observational study on a cohort of ALS patients who underwent a lumbar puncture at the time of the diagnosis. CSF Aβ 1–40 and Aβ 1–42 ratios were detected by chemiluminescence immunoassay and their values were correlated with clinical features. We found a significant correlation of the Aβ 42/40 ratio with age at onset and Mini Mental State Examination (MMSE) scores. No significant correlation of Aβ 1–42 or Aβ 42/40 ratios to the rate of progression of the disease were found. Furthermore, when we stratified patients according to Aβ 1–42 concentration and the Aβ 42/40 ratio, we found that patients with a lower Aβ 42/40 ratio showed a shorter survival. Our results support the hypothesis that Aβ 1–42 could be involved in some pathogenic mechanism of ALS and we suggest the Aβ 42/40 ratio as a potential prognostic biomarker.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and a leading cause of dementia. One major challenge for clinicians is accurately assessing the rate of disease progression (RoP) early in the diagnostic process, which is crucial for patient management and clinical trial stratification. This study evaluated the role of cerebrospinal fluid biomarkers—Aβ42, t-Tau, pTau, Neurogranin (Ng), and Neurofilament light-chain (NF-L)—in predicting RoP at the time of AD diagnosis. We included 56 AD patients and monitored cognitive impairment using MMSE scores at diagnosis and during six-month follow-up visits. RoP scores were calculated based on these assessments. Our correlation analyses revealed significant associations between RoP and pTau, Aβ42/Ng ratio, and NF-L levels. When patients were stratified by median RoP values into low-to-moderate (L-M: 2) groups, those in the U-M group had notably higher CSF NF-L levels compared to the L-M group. Logistic regression analysis further demonstrated that elevated CSF NF-L levels were predictive of a faster RoP. These findings highlight the potential of CSF NF-L as a prognostic biomarker for rapid disease progression in AD. By identifying patients at risk for accelerated cognitive decline, CSF NF-L could significantly enhance early intervention strategies and improve patient management in clinical settings.

Introduction: Several studies have investigated the specific neural correlates of trans people, highlighting mixed results. This study aimed to compare the presence of specific functional connectivity and differences in cognitive profile and hormone levels in trans men diagnosed with gender dysphoria (GD), and a homogeneous group of cisgender men and cisgender women. Methods: A total of 42 participants (19 trans men, 11 cisgender men, and 12 cisgender women) underwent a resting state fMRI and were measured for blood levels of testosterone, estradiol, and progesterone. A neuropsychological battery evaluated executive functions, attention, visual-perceptual ability, verbal fluency, manual preference, and general intelligence. Results: Trans men showed weaker functional connectivity in the precentral gyrus, subcallosal cortex, paracingulate gyrus, temporal pole, and cingulate gyrus than cisgender men (p < 0.01). Trans men performed worse than cisgender men in verbal and visuospatial working memory but similarly to cisgender women (p < 0.05). In trans men, functional connectivity of the precentral gyrus correlated positively with testosterone (r = 0.459, p = 0.064) and negatively with estradiol (r = −0.654, p = 0.004) and progesterone blood levels (r = −0.475, p = 0.054). The cluster involving the subcallosal cortex showed a positive correlation with testosterone (r = 0.718, p = 0.001), and a negative correlation with estradiol (r = −0.602, p = 0.011). The functional connectivity from a cluster involving the paracingulate gyrus showed a positive correlation with testosterone (r = 0.592, p = 0.012). Conclusions: This study highlights the importance of overpassing the binary model by underlining the presence of neural pathways that could represent the peculiarity of the neural profile of people with GD.

Background: Alzheimer’s disease (AD) shows highly variable progression rates among individuals. Plasma neurofilament light chain (NfL) has emerged as a potential biomarker of neurodegeneration. Objectives: this study aimed to evaluate the predictive value of plasma NfL in estimating the rate of clinical progression (RoP) in AD. Methods: we retrospectively analyzed 87 AD patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We stratified patients into two groups based on the median RoP, which was calculated from longitudinal Mini-Mental State Examination (MMSE) score evaluations: slow decliners (SD) and fast decliners (FD). We then compared plasma NfL levels between the two groups and examined their relationship with the progression rate. Results: patients with faster decline rates had higher levels of NfL. Logistic regression (LR) analysis revealed a strong correlation between plasma NfL levels and disease progression rates. Furthermore, a multivariate model incorporating Aβ42 levels improved predictive accuracy. Conclusions: these findings suggest that plasma NfL could serve as a valuable biomarker for monitoring the progression of Alzheimer’s disease, identifying patients at greater risk of rapid decline, and optimizing therapeutic strategies and clinical management. Future studies on larger cohorts will be essential to confirm and further explore these observations.

Background/Objectives: Amyloid-PET is accurate but costly and capacity-limited. Blood-based biomarkers (BBMs), particularly plasma p-tau217, offer a scalable alternative for triaging patients. Objective of this study is to evaluate the diagnostic accuracy and clinical utility of plasma p-tau217 as a pre-screening tool for amyloid-PET positivity, identifying operating thresholds for rule-out and rule-in strategies. Methods: We analyzed 1681 participants from the ADNI cohort with concurrent plasma biomarkers (Fujirebio Lumipulse assays) and ¹⁸F-florbetapir PET. The primary outcome was discrimination of amyloid-PET positivity (Centiloid > 20). We compared p-tau217 alone against multivariable models (including Aβ42/40, GFAP, NfL, APOE) using Area Under the Curve (AUC) and Decision Curve Analysis (DCA). Two clinical thresholds were defined: a high-sensitivity “rule-out” cut-off (≥95% sensitivity) and a Youden-optimal “balanced” cut-off. These were validated using stratified bootstrap resampling. Results: Of 1681 participants, 679 (40.4%) were amyloid-positive. In the full sample, plasma p-tau217 alone achieved an AUC of 0.902 (95% CI 0.885–0.918). Operating thresholds were derived on a development split and applied to an independent validation split (N = 505). In the validation cohort, the high-sensitivity threshold (0.106 pg/mL) yielded 94.6% sensitivity and 93.7% NPV, effectively ruling out amyloid pathology. The Youden threshold (0.177 pg/mL) offered 78.9% sensitivity and 86.0% specificity. DCA demonstrated net benefit for p-tau217 screening over “PET all” strategies across clinically relevant probability ranges. Conclusions: Plasma p-tau217 provides high discrimination and clinically interpretable operating points for prioritizing confirmatory PET. Implementing a p-tau217-first strategy could significantly reduce unnecessary imaging without compromising diagnostic safety.