Future perspective and clinical applicability of the combined use of plasma phosphorylated tau 181 and neurofilament light chain in Subjective Cognitive Decline and Mild Cognitive Impairment.

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer's Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aß1-42, Aß1-42/1-40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP-) when they were A-, A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP- patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn's k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.

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.

Plasma GFAP, NfL and pTau 181 detect preclinical stages of dementia.

Background: Plasma biomarkers are preferable to invasive and expensive diagnostic tools, such as neuroimaging and lumbar puncture that are gold standard in the clinical management of Alzheimer's Disease (AD). Here, we investigated plasma Glial Fibrillary Acidic Protein (GFAP), Neurofilament Light Chain (NfL) and Phosphorylated-tau-181 (pTau 181) in AD and in its early stages: Subjective cognitive decline (SCD) and Mild cognitive impairment (MCI). Material and methods: This study included 152 patients (42 SCD, 74 MCI and 36 AD). All patients underwent comprehensive clinical and neurological assessment. Blood samples were collected for Apolipoprotein E (APOE) genotyping and plasma biomarker (GFAP, NfL, and pTau 181) measurements. Forty-three patients (7 SCD, 27 MCI, and 9 AD) underwent a follow-up (FU) visit after 2 years, and a second plasma sample was collected. Plasma biomarker levels were detected using the Simoa SR-X technology (Quanterix Corp.). Statistical analysis was performed using SPSS software version 28 (IBM SPSS Statistics). Statistical significance was set at p < 0.05. Results: GFAP, NfL and pTau 181 levels in plasma were lower in SCD and MCI than in AD patients. In particular, plasma GFAP levels were statistically significant different between SCD and AD (p=0.003), and between MCI and AD (p=0.032). Plasma NfL was different in SCD vs MCI (p=0.026), SCD vs AD (p<0.001), SCD vs AD FU (p<0.001), SCD FU vs AD (p=0.033), SCD FU vs AD FU (p=0.011), MCI vs AD (p=0.002), MCI FU vs AD (p=0.003), MCI FU vs AD FU (p=0.003) and MCI vs AD FU (p=0.003). Plasma pTau 181 concentration was significantly different between SCD and AD (p=0.001), MCI and AD (p=0.026), MCI FU and AD (p=0.020). In APOE ϵ4 carriers, a statistically significant increase in plasma NfL (p<0.001) and pTau 181 levels was found (p=0.014). Moreover, an association emerged between age at disease onset and plasma GFAP (p = 0.021) and pTau181 (p < 0.001) levels. Discussion and conclusions: Plasma GFAP, NfL and pTau 181 are promising biomarkers in the diagnosis of the prodromic stages and prognosis of dementia.

A systematic review of progranulin concentrations in biofluids in over 7,000 people-assessing the pathogenicity of GRN mutations and other influencing factors.

BACKGROUND: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. METHODS: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. RESULTS: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. CONCLUSIONS: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.

Distribution of the C9orf72 hexanucleotide repeat expansion in healthy subjects: a multicenter study promoted by the Italian IRCCS network of neuroscience and neurorehabilitation.

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population. Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing. Results: All samples carried hexanucleotide G4C2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats. Conclusion: This study describes the distribution of hexanucleotide G4C2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD.

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.

Parkinson-ALS with a novel MAPT variant.

The mutations on microtubule associated protein tau (MAPT) gene manifest clinically with behavioural frontotemporal dementia (FTD), parkinsonism, such as progressive supranuclear palsy and corticobasal degeneration, and rarely with amyotrophic lateral sclerosis (ALS). FTD-parkinsonism and FTD-ALS are clinical overlaps included in the spectrum of MAPT mutation's phenotypes. The mutations on MAPT gene cause the dysfunction of tau protein determining its accumulation in neurofibrillary tangles. Recent data describe frequently the co-occurrence of the aggregation of tau protein and α-synuclein in patients with parkinsonism and Parkinson disease (PD), suggesting an interaction of the two proteins in determining neurodegenerative process. The sporadic description of PD-ALS clinical complex, known as Brait-Fahn-Schwarz disease, supports the hypothesis of common neuropathological pathways between different disorders. Here we report the case of a 54-year-old Italian woman with idiopathic PD later complicated by ALS carrying a novel MAPT variant (Pro494Leu). The variant is characterized by an amino acid substitution and is classified as damaging for MAPT functions. The case supports the hypothesis of tau dysfunction as the basis of multiple neurodegenerative disorders.

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.

Understanding the interplay between APO E polymorphism and cognition in the Italian oldest old: results from the "Mugello study".

INTRODUCTION: Recent data suggest that the deleterious effect on general health and cognition of ε4 allele of Apolipoprotein E (ApoE) observed in the elderly population, may attenuate in extreme aging. This study aimed to describe the ApoE genotype distribution and its relationship with cognition in a group of nonagenarians living in the Mugello area, Italy. MATERIAL AND METHODS: Cognition was evaluated using the Mini-Mental-State-Examination (MMSE). DNA was extracted from blood samples to determine ApoE genotyping. Participants were classified into three ApoE groups (ε2, ε3, ε4). Logistic and linear regression models were created, to assess the relationship between ApoE genotype group and dementia diagnosis and cognitive performance, respectively. RESULTS: 169 subjects were included. ApoE ε3 was the most prevalent genotype (76.3%). Dementia prevalence was 26.6% and it was not associated with the presence of ApoE ε4. Participants of ε4 group were significantly more likely to have lower cognitive performances than ε2 and ε3, independently of a dementia diagnosis. DISCUSSION: Results support that ApoE genotype no longer plays a role in the health condition of the oldest old, however, an interaction is detectable between ApoE polymorphism and cognitive performances at this extreme age.

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.

The Frequency of Intermediate Alleles in Patients with Cerebellar Phenotypes.

Cerebellar syndromes are clinically and etiologically heterogeneous and can be classified as hereditary, neurodegenerative non-hereditary, or acquired. Few data are available on the frequency of each form in the clinical setting. Growing interest is emerging regarding the genetic forms caused by triplet repeat expansions. Alleles with repeat expansion lower than the pathological threshold, termed intermediate alleles (IAs), have been found to be associated with disease manifestation. In order to assess the relevance of IAs as a cause of cerebellar syndromes, we enrolled 66 unrelated Italian ataxic patients and described the distribution of the different etiology of their syndromes and the frequency of IAs. Each patient underwent complete clinical, hematological, and neurophysiological assessments, neuroimaging evaluations, and genetic tests for autosomal dominant cerebellar ataxia (SCA) and fragile X-associated tremor/ataxia syndrome (FXTAS). We identified the following diagnostic categories: 28% sporadic adult-onset ataxia, 18% cerebellar variant of multiple system atrophy, 9% acquired forms, 9% genetic forms with full-range expansion, and 12% cases with intermediate-range expansion. The IAs were six in the FMR1 gene, two in the gene responsible for SCA8, and one in the ATXN2 gene. The clinical phenotype of patients carrying the IAs resembles, in most of the cases, the one associated with full-range expansion. Our study provides an exhaustive description of the causes of cerebellar ataxia, estimating for the first time the frequency of IAs in SCAs- and FXTAS-associated genes. The high percentage of cases with IAs supports further screening among patients with cerebellar syndromes.

GRN Missense Variants and Familial Alzheimer's Disease: Two Case Reports.

BACKGROUND: Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer 's disease (AD) patients. OBJECTIVE: Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2, and APP). In addition, Microtubule-associated protein tau (MAPT) gene was studied too. All patients underwent an extensive neuropsychological battery. METHODS: Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records. RESULTS: Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect. CONCLUSIONS: Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD.

Multilayered Bioorthogonal SERS Nanoprobes Selectively Aggregating in Human Fluids: A Smart Optical Assay for ß-Amyloid Peptide Quantification.

Alzheimer's disease (AD) is a debilitating neurological condition characterized by cognitive decline, memory loss, and behavioral skill impairment, features that worsen with time. Early diagnosis will likely be the most effective therapy for Alzheimer's disease since it can ensure timely pharmacological treatments that can reduce the irreversible progression and delay the symptoms. Amyloid ß-peptide 1-42 (Aß (1-42)) is considered one of the key pathological AD biomarkers that is present in different biological fluids. However, Aß (1-42) detection still relies on colorimetric and enzyme-linked immunoassays as the gold standard characterized by low accuracy or high costs, respectively. In this context, optical detection techniques based on surface-enhanced Raman spectroscopy (SERS) through advanced nanoconstructs are promising alternatives for the development of novel rapid and low-cost methods for the targeting of Aß pathological biomarkers in fluids. Here, a multilayered nanoprobe constituted by bioorthogonal Raman reporters (RRs) embedded within two layers of gold nanoparticles (Au@RRs@AuNPs) has been developed and successfully validated for specific detection of Aß (1-42) in the human cerebrospinal fluid (CSF) with sensitivity down to pg/mL. The smart double-layer configuration enables us to exploit the outer gold NP surfaces for selective absorption of targeted peptide whose concentration controls the aggregation behavior of Au@RRs@AuNPs, proportionally reflected in Raman intensity changes, providing high specificity and sensitivity and representing a significant step ahead of the state of the art on SERS for clinical analyses.

The Huntington's Disease Gene in an Italian Cohort of Patients with Bipolar Disorder.

BACKGROUND AND OBJECTIVES: Huntington's disease (HD) is characterized by motor, cognitive and psychiatric manifestations and caused by an expansion of CAG repeats over 35 triplets on the huntingtin (HTT) gene. However, expansions in the range 27-35 repeats (intermediate allele) can be associated with pathological phenotypes. The onset of HD is conventionally defined by the onset of motor symptoms, but psychiatric disturbances can precede the motor phase by up to twenty years. The aims of the present study are to identify HD patients in the pre-motor phase of the disease among patients diagnosed with bipolar disorders and evaluate any differences between bipolar patients carrying the normal HTT allele and patients with the expanded HTT gene. METHODS: We assessed the HTT genotype in an Italian cohort of 69 patients who were affected by either type 1 or type 2 bipolar disorder. RESULTS: No patient was found to be a carrier of the pathological HTT allele, but 10% of bipolar subjects carried an intermediate allele. Carriers of the intermediate allele were older at the onset of psychiatric symptoms than non-carriers. CONCLUSION: The pathological HTT gene was not associated with bipolar disorder, while we found a higher frequency of the intermediate allele among the bipolar population with respect to healthy controls. The identification of this subset of bipolar subjects has implications for the clinical management of patients and their family members and promotes further investigation into possible pathological mechanisms common to both HD and bipolar disorder.

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis.

The hippocampus is a primary region affected in Alzheimer's disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis by comparing patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Proteomic analysis of the graft enabled the identification of pathways and network dysfunction in AD patient brain cells, associated with increased levels of Aß-42 and ß-sheet structures. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of early to end stage AD cellular pathogenesis. Our data showcase patient-based models to study the cell autonomous origin and progression of AD pathogenesis.

Plasma p-tau181 as a promising non-invasive biomarker of Alzheimer's Disease pathology in Subjective Cognitive Decline and Mild Cognitive Impairment.

INTRODUCTION: The aim of this study is to investigate the role of plasma phosphorylated tau (p-tau) 181 as a potential biomarker for Alzheimer's Disease (AD) pathology in the early stages of the disease, as a valuable marker for tauopathy. MATERIALS AND METHODS: Thirty-three Subjective Cognitive Decline (SCD), 32 Mild Cognitive Impairment (MCI) and 14 AD demented (AD-d) patients underwent plasma p-tau181 analysis with SiMoA assay. Twenty-six SCD, 32 MCI and 14 AD-d patients also underwent CSF biomarkers analysis (Aß1-42, Aß1-42/1-40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) when A+ was associated with 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. RESULTS: Plasma p-tau181 levels were higher in SCD AP+ than in SCD AP- (2.85 ± 0.53 vs 1.73 ± 0.64, p < 0.001), and in MCI AP+ than in MCI AP- (4.03 ± 1.07 vs 2.04 ± 0.87, p < 0.001). In a multivariate linear regression analysis, AP status was the only variable that influenced plasma p-tau181 (B = 1.670 [95% CI 1.097:2.244], p < 0.001). Plasma p-tau181 was highly accurate for discriminating between AP+ and AP- patients (AUC = 0.910). We identified a cut-off level of 2.69 pg/mL to distinguish between AP+ and AP- (sensibility 0.86, specificity 0.82, PPV 75.00% NPV 90.32%). CONCLUSIONS: Plasma p-tau181 levels were influenced by the presence of underlying AD pathology, independently from the cognitive status and were highly accurate in differentiating SCD-MCI patients who were carriers of AD pathology from non-carriers. Plasma p-tau181 might be a promising non-invasive biomarker of AD pathology at a very early stage.

PRedicting the EVolution of SubjectIvE Cognitive Decline to Alzheimer's Disease With machine learning: the PREVIEW study protocol.

BACKGROUND: As disease-modifying therapies (DMTs) for Alzheimer's disease (AD) are becoming a reality, there is an urgent need to select cost-effective tools that can accurately identify patients in the earliest stages of the disease. Subjective Cognitive Decline (SCD) is a condition in which individuals complain of cognitive decline with normal performances on neuropsychological evaluation. Many studies demonstrated a higher prevalence of Alzheimer's pathology in patients diagnosed with SCD as compared to the general population. Consequently, SCD was suggested as an early symptomatic phase of AD. We will describe the study protocol of a prospective cohort study (PREVIEW) that aim to identify features derived from easily accessible, cost-effective and non-invasive assessment to accurately detect SCD patients who will progress to AD dementia. METHODS: We will include patients who self-referred to our memory clinic and are diagnosed with SCD. Participants will undergo: clinical, neurologic and neuropsychological examination, estimation of cognitive reserve and depression, evaluation of personality traits, APOE and BDNF genotyping, electroencephalography and event-related potential recording, lumbar puncture for measurement of Aß42, t-tau, and p-tau concentration and Aß42/Aß40 ratio. Recruited patients will have follow-up neuropsychological examinations every two years. Collected data will be used to train a machine learning algorithm to define the risk of being carriers of AD and progress to dementia in patients with SCD. DISCUSSION: This is the first study to investigate the application of machine learning to predict AD in patients with SCD. Since all the features we will consider can be derived from non-invasive and easily accessible assessments, our expected results may provide evidence for defining cost-effective and globally scalable tools to estimate the risk of AD and address the needs of patients with memory complaints. In the era of DMTs, this will have crucial implications for the early identification of patients suitable for treatment in the initial stages of AD. TRIAL REGISTRATION NUMBER (TRN): NCT05569083.

Degradation of EEG microstates patterns in subjective cognitive decline and mild cognitive impairment: Early biomarkers along the Alzheimer's Disease continuum?

Alzheimer's disease (AD) pathological changes may begin up to decades earlier than the appearance of the first symptoms of cognitive decline. Subjective cognitive decline (SCD) could be the first pre-clinical sign of possible AD, which might be followed by mild cognitive impairment (MCI), the initial stage of clinical cognitive decline. However, the neural correlates of these prodromic stages are not completely clear yet. Recent studies suggest that EEG analysis tools characterizing the cortical activity as a whole, such as microstates and cortical regions connectivity, might support a characterization of SCD and MCI conditions. Here we test this approach by performing a broad set of analyses to identify the prominent EEG markers differentiating SCD (n = 57), MCI (n = 46) and healthy control subjects (HC, n = 19). We found that the salient differences were in the temporal structure of the microstates patterns, with MCI being associated with less complex sequences due to the altered transition probability, frequency and duration of canonic microstate C. Spectral content of EEG, network connectivity, and spatial arrangement of microstates were instead largely similar in the three groups. Interestingly, comparing properties of EEG microstates in different cerebrospinal fluid (CSF) biomarkers profiles, we found that canonic microstate C displayed significant differences in topography in AD-like profile. These results show that the progression of dementia might be associated with a degradation of the cortical organization captured by microstates analysis, and that this leads to altered transitions between cortical states. Overall, our approach paves the way for the use of non-invasive EEG recordings in the identification of possible biomarkers of progression to AD from its prodromal states.