Data-driven subtypes of mixed semantic-logopenic primary progressive aphasia: Linguistic features, biomarker profiles and brain metabolic patterns.

Mixed primary progressive aphasia (mPPA) accounts for a substantial proportion of primary progressive aphasia (PPA) cases. However, the lack of a standardised definition of this condition has resulted in misclassification of PPA cases. In this study, we enrolled 55 patients diagnosed with PPA, comprising 12 semantic variant (svPPA), 23 logopenic variant (lvPPA), and 20 mPPA cases with linguistic characteristics consistent with both svPPA and lvPPA (s/lvPPA). All patients underwent language assessments, evaluation of Alzheimer's disease biomarkers (via cerebrospinal fluid analysis or Amyloid-PET), and 18F-FDG-PET brain scans. An agglomerative hierarchical clustering (AHC) analysis based on linguistic characteristics revealed two distinct clusters within the s/lvPPA group: cluster k1 (n = 10) displayed an AD-like biomarker profile, with lower levels of Aß42 and Aß42/Aß40 ratio, along with higher levels of t-tau and p-tau compared to cluster k2 (n = 10). Interestingly, k1 exhibited linguistic features that were similar to those of svPPA. Both clusters exhibited extensive temporoparietal hypometabolism. These findings support the hypothesis that a subgroup of s/lvPPA may represent a clinical manifestation of AD-related PPA.

Disentangling empathy impairment along Alzheimer's disease continuum: From subjective cognitive decline to Alzheimer's dementia.

Little is known about empathy changes from the early stages of Alzheimer's Disease (AD) continuum. The aim of this study is to investigate empathy across AD spectrum from Subjective Cognitive Decline (SCD) to Mild Cognitive Impairment (MCI) and AD dementia (AD-d). Forty-five SCD, 83 MCI and 80 AD-d patients were included. Empathy was assessed by Interpersonal Reactivity Index (IRI) (Perspective Taking - PT, Fantasy - FT, Empathic Concern - EC, and Personal Distress - PD), rated by caregivers before (T0) and after (T1) cognitive symptoms' onset. IRI was also administered to SCD patients to have a self-reported empathy evaluation. Facial emotion recognition was assessed by Ekman-60 Faces Test. Twenty-two SCD, 54 MCI and 62 AD-d patients underwent CSF biomarkers analysis and were classified as carriers of AD pathology (AP+) when they were A+/T+ (regardless of N), or non-carriers (AP-) when they were A- (regardless of T and N), or A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Cerebral FDG-PET SPM analysis was used to explore neural correlates underlying empathy deficits. PD scores significantly increased from T0 to T1 in SCD, MCI and AD-d (p < .001), while PT scores decreased in MCI and in AD-d (p < .001). SCD AP+ showed a greater increase in PD scores over time (ΔPD T0 - T1) than SCD AP- (p < .001). SCD self-reported PT scores were lower than those of general Italian population (14.94 ± 3.94, 95% C.I. [13.68-16.20] vs 17.70 ± 4.36, 95% C.I. [17.30-18.10]). In AD continuum (SCD AP+, MCI AP+, AD-d), a positive correlation was detected between PT-T1 and brain metabolism in left posterior cingulate gyrus, precuneus and right frontal gyri; a negative correlation was found between ΔPT and brain metabolism in bilateral posterior cingulate gyri. PT may be subtly involved since the preclinical phase of AD. Changes over time of PD are influenced by the underlying Alzheimer's pathology and could potentially serve as an early AD neuropsychological marker.

The role of plasma neurofilament light chain and glial fibrillary acidic protein in subjective cognitive decline and mild cognitive impairment.

INTRODUCTION AND AIM: NfL and GFAP are promising blood-based biomarkers for Alzheimer's disease. However, few studies have explored plasma GFAP in the prodromal and preclinical stages of AD. In our cross-sectional study, our aim is to investigate the role of these biomarkers in the earliest stages of AD. MATERIALS AND METHODS: We enrolled 40 patients (11 SCD, 21 MCI, 8 AD dementia). All patients underwent neurological and neuropsychological examinations, analysis of CSF biomarkers (Aß42, Aß42/Aß40, p-tau, t-tau), Apolipoprotein E (APOE) genotype analysis and measurement of plasma GFAP and NfL concentrations. Patients were categorized according to the ATN system as follows: normal AD biomarkers (NB), carriers of non-Alzheimer's pathology (non-AD), prodromal AD, or AD with dementia (AD-D). RESULTS: GFAP was lower in NB compared to prodromal AD (p = 0.003, d = 1.463) and AD-D (p = 0.002, d = 1.695). NfL was lower in NB patients than in AD-D (p = 0.011, d = 1.474). NfL demonstrated fair accuracy (AUC = 0.718) in differentiating between NB and prodromal AD, with a cut-off value of 11.65 pg/mL. GFAP showed excellent accuracy in differentiating NB from prodromal AD (AUC = 0.901) with a cut-off level of 198.13 pg/mL. CONCLUSIONS: GFAP exhibited excellent accuracy in distinguishing patients with normal CSF biomarkers from those with prodromal AD. Our results support the use of this peripheral biomarker for detecting AD in patients with subjective and objective cognitive decline.

Plasma neurofilament light chain predicts Alzheimer's disease in patients with subjective cognitive decline and mild cognitive impairment: A cross-sectional and longitudinal study.

BACKGROUND AND PURPOSE: We aimed to evaluate the accuracy of plasma neurofilament light chain (NfL) in predicting Alzheimer's disease (AD) and the progression of cognitive decline in patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). METHODS: This longitudinal cohort study involved 140 patients (45 with SCD, 73 with MCI, and 22 with AD dementia [AD-D]) who underwent plasma NfL and AD biomarker assessments (cerebrospinal fluid, amyloid positron emission tomography [PET], and 18 F-fluorodeoxyglucose-PET) at baseline. The patients were rated according to the amyloid/tau/neurodegeneration (A/T/N) system and followed up for a mean time of 2.72 ± 0.95 years to detect progression from SCD to MCI and from MCI to AD. Forty-eight patients (19 SCD, 29 MCI) also underwent plasma NfL measurements 2 years after baseline. RESULTS: At baseline, plasma NfL detected patients with biomarker profiles consistent with AD (A+/T+/N+ or A+/T+/N-) with high accuracy (area under the curve [AUC] 0.82). We identified cut-off values of 19.45 pg/mL for SCD and 20.45 pg/mL for MCI. During follow-up, nine SCD patients progressed to MCI (progressive SCD [p-SCD]), and 14 MCI patients developed AD dementia (progressive MCI [p-MCI]). The previously identified cut-off values provided good accuracy in identifying p-SCD (80% [95% confidence interval 65.69: 94.31]). The rate of NfL change was higher in p-MCI (3.52 ± 4.06 pg/mL) compared to non-progressive SCD (0.81 ± 1.25 pg/mL) and non-progressive MCI (-0.13 ± 3.24 pg/mL) patients. A rate of change lower than 1.64 pg/mL per year accurately excluded progression from MCI to AD (AUC 0.954). CONCLUSION: Plasma NfL concentration and change over time may be a reliable, non-invasive tool to detect AD and the progression of cognitive decline at the earliest stages of the disease.