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.

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.

Alzheimer's Disease CSF Biomarker Profiles in Idiopathic Normal Pressure Hydrocephalus.

Patients with idiopathic normal pressure hydrocephalus (iNPH) frequently show pathologic CSF Aß42 levels, comparable with Alzheimer's Disease (AD). Nevertheless, the clinical meaning of these findings has not been fully explained. We aimed to assess the role of AD CSF biomarkers (Aß42, Aß42/Aß40, p-tau, t-tau) in iNPH. To this purpose, we enrolled 44 patients diagnosed with iNPH and 101 with AD. All the patients underwent CSF sampling. We compared CSF biomarker levels in iNPH and AD: Aß42 levels were not different between iNPH and AD, while Aß42/Aß40, p-tau, and t-tau were significantly different and showed excellent accuracy in distinguishing iNPH and AD. A multiple logistic regression analysis showed that Aß42/Aß40 was the variable that most contributed to differentiating the two groups. Furthermore, iNPH patients with positive Aß42/Aß40 had higher p-tau and t-tau than iNPH patients with negative Aß42/Aß40. Those iNPH patients who showed cognitive impairment had lower Aß42/Aß40 and higher p-tau than patients without cognitive impairment. We concluded that positive CSF Aß42 with negative Aß42/Aß40, p-tau, and t-tau is a typical CSF profile of iNPH. On the contrary, positive Aß42/Aß40 in iNPH patients, especially when associated with positive p-tau, may lead to suspicion of a coexistent AD pathology.

Huntingtin gene intermediate alleles influence the progression from subjective cognitive decline to mild cognitive impairment: A 14-year follow-up study.

BACKGROUND AND PURPOSE: Huntingtin (HTT) is a gene containing a key region of CAG repeats. HTT alleles containing from 27 to 35 CAG repeats are termed intermediate alleles (IAs). We aimed to assess the effect of IAs on progression of cognitive impairment in patients with subjective cognitive decline (SCD). METHODS: We included 106 patients with SCD. All the patients underwent neuropsychological assessments and blood sample collection at baseline. Patients were followed up for a median (interquartile range) time of 13.75 (8.17) years. We genotyped APOE and HTT at the end of the follow-up. RESULTS: Eleven out of 106 patients (10.38%, 95% confidence interval [CI] 4.57-16.18) were carriers of IAs (IA+ ). During the follow-up, 44 patients (41.51%, 95% CI 32.13-50.89) progressed to mild cognitive impairment (MCI; p-SCD group), while 62 patients (58.49%, 95% CI 49.11-67.87) did not (np-SCD group). Rate of progression to MCI was associated with IAs, age at baseline, and APOE ɛ4. We dichotomized age at baseline (<60 years = younger patients [YP], >60 years = older patients [OP]) and then classified patients into four groups: YP/IA- , YP/IA+ , OP/IA-  and OP/IA+ . The OP/IA+  group had a higher proportion of patients with progression from SCD to MCI (85.71%, 95% CI 59.79-100) as compared to the YP/IA-  group (28.57%, 95% CI 13.60-43.54, χ2  = 15.25; p < 0.001) and the OP/IA-  group (45.00%, 95% CI 32.41-57.59, χ2  = 7.903; p = 0.005). We classified patients according to APOE and IA as: ɛ4- /IA- , ɛ4- /IA+ , ɛ4+ /IA- , ɛ4+ /IA+ . The proportion of patients with progression in the ɛ4+ /IA+  group (100%) was higher as compared to the ɛ4- /IA-  group (33.33%, 95% CI 21.96-44.71, χ2  = 14.43; p < 0.001) and ɛ4+ /IA-  (55.56%, 95% CI 36.81-74.30, χ2  = 4.60; p = 0.032). CONCLUSIONS: Intermediate alleles interact with age and APOE ɛ4, increasing the risk of progression to MCI in SCD patients.

Dual Effect of PER2 C111G Polymorphism on Cognitive Functions across Progression from Subjective Cognitive Decline to Mild Cognitive Impairment.

BACKGROUND: Periodic circadian protein homolog 2 (PER2) has a role in the intracellular signaling pathways of long-term potentiation and has implications for synaptic plasticity. We aimed to assess the association of PER2 C111G polymorphism with cognitive functions in subjective cognitive decline (SCD). METHODS: Forty-five SCD patients were included in this study. All participants underwent extensive neuropsychological investigation, analysis of apolipoprotein E (APOE) and PER2 genotypes, and neuropsychological follow-up every 12 or 24 months for a mean time of 9.87 ± 4.38 years. RESULTS: Nine out of 45 patients (20%) were heterozygous carriers of the PER2 C111G polymorphism (G carriers), while 36 patients (80%) were not carriers of the G allele (G non-carriers). At baseline, G carriers had a higher language composite score compared to G non-carriers. During follow-up, 15 (34.88%) patients progressed to mild cognitive impairment (MCI). In this group, we found a significant interaction between PER2 G allele and follow-up time, as carriers of G allele showed greater worsening of executive function, visual-spatial ability, and language composite scores compared to G non-carriers. CONCLUSIONS: PER2 C111G polymorphism is associated with better language performance in SCD patients. Nevertheless, as patients progress to MCI, G allele carriers showed a greater worsening in cognitive performance compared to G non-carriers. The effect of PER2 C111G polymorphism depends on the global cognitive status of patients.

Matching Clinical Diagnosis and Amyloid Biomarkers in Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: The aims of this study were to compare the diagnostic accuracy, sensitivity, specificity, and positive and negative predictive values (PPV, NPV) of different cerebrospinal fluid (CSF) amyloid biomarkers and amyloid-Positron Emission Tomography (PET) in patients with a clinical diagnosis of Alzheimer's disease (AD) and Frontotemporal Dementia (FTD); to compare concordance between biomarkers; and to provide an indication of their use and interpretation. METHODS: We included 148 patients (95 AD and 53 FTD), who underwent clinical evaluation, neuropsychological assessment, and at least one amyloid biomarker (CSF analysis or amyloid-PET). Thirty-six patients underwent both analyses. One-hundred-thirteen patients underwent Apolipoprotein E (ApoE) genotyping. RESULTS: Amyloid-PET presented higher diagnostic accuracy, sensitivity, and NPV than CSF Aß1-42 but not Aß42/40 ratio. Concordance between CSF biomarkers and amyloid-PET was higher in FTD patients compared to AD cases. None of the AD patients presented both negative Aß biomarkers. CONCLUSIONS: CSF Aß42/40 ratio significantly increased the diagnostic accuracy of CSF biomarkers. On the basis of our current and previous data, we suggest a flowchart to guide the use of biomarkers according to clinical suspicion: due to the high PPV of both amyloid-PET and CSF analysis including Aß42/40, in cases of concordance between at least one biomarker and clinical diagnosis, performance of the other analysis could be avoided. A combination of both biomarkers should be performed to better characterize unclear cases. If the two amyloid biomarkers are both negative, an underlying AD pathology can most probably be excluded.

Influence of ApoE Genotype and Clock T3111C Interaction with Cardiovascular Risk Factors on the Progression to Alzheimer's Disease in Subjective Cognitive Decline and Mild Cognitive Impairment Patients.

BACKGROUND: Some genes could interact with cardiovascular risk factors in the development of Alzheimer's disease. We aimed to evaluate the interaction between ApoE ε4 status, Clock T3111C and Per2 C111G polymorphisms with cardiovascular profile in Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI). METHODS: We included 68 patients who underwent clinical evaluation; neuropsychological assessment; ApoE, Clock and Per2 genotyping at baseline; and neuropsychological follow-up every 12-24 months for a mean of 13 years. We considered subjects who developed AD and non-converters. RESULTS: Clock T3111C was detected in 47% of cases, Per2 C111G in 19% of cases. ApoE ε4 carriers presented higher risk of heart disease; Clock C-carriers were more frequently smokers than non C-carriers. During the follow-up, 17 patients progressed to AD. Age at baseline, ApoE ε 4 and dyslipidemia increased the risk of conversion to AD. ApoE ε4 carriers with history of dyslipidemia showed higher risk to convert to AD compared to ApoE ε4- groups and ApoE ε4+ without dyslipidemia patients. Clock C-carriers with history of blood hypertension had a higher risk of conversion to AD. CONCLUSIONS: ApoE and Clock T3111C seem to interact with cardiovascular risk factors in SCD and MCI patients influencing the progression to AD.