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.

Heterogeneity and overlap in the continuum of linguistic profile of logopenic and semantic variants of primary progressive aphasia: a Profile Analysis based on Multidimensional Scaling study.

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce. METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [18F] FDG-PET. Correlations were performed between metabolic and behavioral data. RESULTS: Patients' profiles were distributed across a continuum. All PPA, but two, presented a lexical retrieval impairment, in terms of reduced production of verbs and nouns. svPPA patients occupied a fairly clumped space along the continuum, showing a preponderant semantic deficit, which correlated to fusiform gyrus hypometabolism, while only few presented working memory deficits. Adjacently, lvPPA + presented a semantic impairment combined with phonological deficits, which correlated with metabolism in the anterior fusiform gyrus and posterior middle temporal gyrus. Starting from the shared phonological deficit side, a large portion of the space was occupied by all lvPPA, showing a combination of phonological, lexical, and working memory deficits, with the latter correlating with posterior temporo-parietal hypometabolism. Mixed PPA did not show unique profile, distributing across the space. DISCUSSION: Different clinical PPA entities exist but overlaps are frequent. Identifying shared and unique clinical markers is critical for research and clinical practice. Further research is needed to identify the role of genetic and pathological factors in such distribution, including also higher sample size of less represented groups.

Personalized modeling of Alzheimer's disease progression estimates neurodegeneration severity from EEG recordings.

INTRODUCTION: Early identification of Alzheimer's disease (AD) is necessary for a timely onset of therapeutic care. However, cortical structural alterations associated with AD are difficult to discern. METHODS: We developed a cortical model of AD-related neurodegeneration accounting for slowing of local dynamics and global connectivity degradation. In a monocentric study we collected electroencephalography (EEG) recordings at rest from participants in healthy (HC, n = 17), subjective cognitive decline (SCD, n = 58), and mild cognitive impairment (MCI, n = 44) conditions. For each patient, we estimated neurodegeneration model parameters based on individual EEG recordings. RESULTS: Our model outperformed standard EEG analysis not only in discriminating between HC and MCI conditions (F1 score 0.95 vs 0.75) but also in identifying SCD patients with biological hallmarks of AD in the cerebrospinal fluid (recall 0.87 vs 0.50). DISCUSSION: Personalized models could (1) support classification of MCI, (2) assess the presence of AD pathology, and (3) estimate the risk of cognitive decline progression, based only on economical and non-invasive EEG recordings. Highlights: Personalized cortical model estimating structural alterations from EEG recordings.Discrimination of Mild Cognitive Impairment (MCI) and Healthy (HC) subjects (95%)Prediction of biological markers of Alzheimer's in Subjective Decline (SCD) Subjects (87%)Transition correctly predicted for 3/3 subjects that converted from SCD to MCI after 1y.

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.

Primary progressive aphasia: six questions in search of an answer.

Here, we review recent progress in the diagnosis and management of primary progressive aphasia-the language-led dementias. We pose six key unanswered questions that challenge current assumptions and highlight the unresolved difficulties that surround these diseases. How many syndromes of primary progressive aphasia are there-and is syndromic diagnosis even useful? Are these truly 'language-led' dementias? How can we diagnose (and track) primary progressive aphasia better? Can brain pathology be predicted in these diseases? What is their core pathophysiology? In addition, how can primary progressive aphasia best be treated? We propose that pathophysiological mechanisms linking proteinopathies to phenotypes may help resolve the clinical complexity of primary progressive aphasia, and may suggest novel diagnostic tools and markers and guide the deployment of effective therapies.

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.

Depressive Symptoms Moderate the Association Between Functional Level at Admission to Intensive Post-Stroke Rehabilitation and Effectiveness of the Intervention.

INTRODUCTION: Previous studies showed that depression acts as an independent factor in functional recovery after stroke. In a prospective cohort of patients admitted to intensive inpatient rehabilitation after a stroke, we aimed to test depression as a moderator of the relationship between the functional level at admission and the effectiveness of rehabilitation at discharge. METHODS: All patients admitted to within 30 days from an ischemic or hemorrhagic stroke to 4 intensive rehabilitation units were prospectively screened for eligibility to a multicenter prospective observational study. Enrolled patients underwent an evidence-based rehabilitation pathway. We used clinical data collected at admission (T0) and discharge (T1). The outcome was the effectiveness of recovery at T1 on the modified Barthel Index (proportion of achieved over potential functional improvement). Moderation analysis was performed by using the PROCESS macro for SPSS using the bootstrapping procedure. RESULTS: Of 278 evaluated patients, 234 were eligible and consented to enrolment; 81 patients were able to answer to the Hospital Anxiety and Depression Scale (HADS) and were included in this analysis. The relationship between the functional status at admission and rehabilitation effectiveness was significant only in persons with fewer depressive symptoms; depression (HADS cut-off score: 5.9) moderated this relationship (P = .047), independent from age and neurological impairment. CONCLUSIONS: Our results suggest that depression moderates between the functional status at admission and the functional recovery after post-stroke rehabilitation. This approach facilitates the identification of subgroups of individuals who may respond differently to stroke rehabilitation based on depression.

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.

Comparing two picture naming tasks in primary progressive aphasia: Insights from behavioural and neural results.

Picture naming tests are widely used to evaluate language impairments in neurodegenerative diseases, especially in Primary Progressive Aphasia (PPA). The available tests differ for many factors affecting the performance, e.g. format of stimuli and their psycholinguistic properties. We aim to identify the most appropriate naming test to be used on PPA according to the clinical and research demands. We investigated the behavioural characteristics, i.e. proportion of correct responses and error type, and their neural correlates in two Italian naming tests, CaGi naming (CaGi) and naming subtest of the Screening for Aphasia in NeuroDegeneration battery (SAND), administered to 52 PPA patients who underwent an FDG-PET scan. We analysed the effectiveness of the tests in distinguishing PPA versus controls and among PPA variants, considering the psycholinguistic variables affecting performance. We explored the brain metabolic correlates of behavioural performance in the tests. SAND, differently from CaGi, has time limits for the response and its items are less frequent and acquired later. SAND and CaGi differed in terms of number of correct responses and error profile, suggesting a higher difficulty to name SAND items compared to CaGi. Semantic errors predominated in CaGi, while anomic and semantic errors were equally frequent in SAND. Both tests distinguished PPA from controls, but SAND outperformed CaGi in discriminating among PPA variants. FDG-PET imaging revealed a shared metabolic involvement of temporal areas associated with lexico-semantic processing, encompassing anterior fusiform, temporal pole, and extending to posterior fusiform in sv-PPA. Concluding, a picture naming test with response time limit and items which are less frequent and acquired later in life, as SAND, may be effective at highlighting subtle distinctions between PPA variants, improving the diagnosis. Conversely, a naming test without time limit for the response, as CaGi, may be useful for a better characterization of the nature of the naming impairment at the behavioural level, eliciting more naming errors than anomia, possibly helping in the development of rehabilitation protocols.

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.

Differences and Similarities in Empathy Deficit and Its Neural Basis between Logopenic and Amnesic Alzheimer's Disease.

The aims of the study were to assess empathy deficit and neuronal correlates in logopenic primary progressive aphasia (lv-PPA) and compare these data with those deriving from amnesic Alzheimer's disease (AD). Eighteen lv-PPA and thirty-eight amnesic AD patients were included. Empathy in both cognitive and affective domains was assessed by Informer-rated Interpersonal Reactivity Index (perspective taking, PT, and fantasy, FT, for cognitive empathy; empathic concern, EC, and personal distress, PD, for affective empathy) before (T0) and after (T1) cognitive symptoms' onset. Emotion recognition was explored through the Ekman 60 Faces Test. Cerebral FDG-PET was used to explore neural correlates underlying empathy deficits. From T0 to T1, PT scores decreased, and PD scores increased in both lv-PPA (PT z = -3.43, p = 0.001; PD z = -3.62, p < 0.001) and in amnesic AD (PT z = -4.57, p < 0.001; PD z = -5.20, p < 0.001). Delta PT (T0-T1) negatively correlated with metabolic disfunction of the right superior temporal gyrus, fusiform gyrus, and middle frontal gyrus (MFG) in amnesic AD and of the left inferior parietal lobule (IPL), insula, MFG, and bilateral superior frontal gyrus (SFG) in lv-PPA (p < 0.005). Delta PD (T0-T1) positively correlated with metabolic disfunction of the right inferior frontal gyrus in amnesic AD (p < 0.001) and of the left IPL, insula, and bilateral SFG in lv-PPA (p < 0.005). Lv-PPA and amnesic AD share the same empathic changes, with a damage of cognitive empathy and a heightening of personal distress over time. The differences in metabolic disfunctions correlated with empathy deficits might be due to a different vulnerability of specific brain regions in the two AD clinical presentations.

Loss of speech and functional impairment in Alzheimer's disease-related primary progressive aphasia: predictive factors of decline.

We aimed to identify features associated with different disease trajectories in Alzheimer's disease (AD)-related primary progressive aphasia (PPA). We considered 23 patients diagnosed with AD-related PPA. All patients underwent neuropsychological evaluation, 18F-Fluorodeoxyglucose-PET brain scan, CSF biomarkers measurement and APOE genotype analysis at baseline and underwent neurological follow-up for a mean time of 3 years. Patients who progressed to total loss of speech (TLoS+) had greater impairment in writing and higher t-tau concentration as compared to TLoS- patients. Patients who progressed to loss of functional autonomy (LoFA+) had greater impairment in single-word comprehension as compared to patients who maintained autonomy in self-care. Furthermore, 18F-FDG-PET SPM analyses revealed different brain metabolic patterns between TLoS+ and TLoS- and between LoFA+ and LoFA-. In conclusion, linguistic profile, CSF t-tau and brain metabolic pattern might be useful tools to predict progression to total loss of speech and loss of functional autonomy in AD-related PPA patients.

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.

Intermediate alleles of HTT: A new pathway in longevity.

Centenarians are the best example of successful aging, reaching extreme longevity escaping age-related diseases. Genome sequencing studies provided evidence for genetic factors linked to heathy long life, including genes related to age-dependent diseases. HTT (Huntingtin) gene is linked to Huntington's Disease, but also associated to longevity in capuchins and mice. HTT Intermediate alleles (IAs) are defined as CAG repeat expansion between 27 and 35. According to recent data IAs might increase Alzheimer's Disease risk, but also might have a neuroprotective effect and can confer an advantage in brain development. Here, we investigated, for the first time, the possible implication of HTT IAs in extreme longevity and their possible association in cognitive decline. We analysed the distribution of IAs in Italian Centenarians (n = 143) and compared with pathological controls with cognitive decline (n = 232, including 80 Alzheimer's Disease, 78 Frontotemporal Dementia and 74 Subjective Cognitive Decline patients) and healthy controls (n = 104). Our data show a statistically significant higher frequency of IAs in Centenarians with respect to pathological controls with cognitive decline (p = .031; OR = 2.3097 95% CI 1.0591 to 5.0371), with a percentage of 11.2 respect to 5.4 respectively. The highest presence of IAs in Centenarians confirms and extends in humans a possible implication of HTT gene in exceptional lifespan and in brain development with a neuroprotective effect.

Unravelling neural correlates of empathy deficits in Subjective Cognitive Decline, Mild Cognitive Impairment and Alzheimer's Disease.

Empathy is the ability to understand (cognitive empathy) and to feel (affective empathy) what others feel. The aim of the study was to assess empathy deficit and neuronal correlates in Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI) and Alzheimer's Disease (AD) dementia. Twenty-four SCD, 41 MCI and 46 CE patients were included. Informer-rated Interpersonal Reactivity Index was used to explore cognitive (Perspective Taking-PT, Fantasy-FT) and affective (Empathic Concern-EC, Personal Distress-PD) empathy, before (T0) and after (T1) cognitive symptoms' onset. Emotion recognition ability was tested through Ekman-60 Faces Test. Cerebral FDG-PET SPM analysis was used to explore neural correlates underlying empathy deficits. FT-T1 scores were lower in AD compared to SCD (13.0 ± 8.0 vs 19.1 ± 4,7 p = 0.008), PD-T1 score were higher in AD compared to MCI and to SCD (27.00 ± 10.00 vs 25.3 ± 5.9 vs 20.5 ± 5.6, p = 0.001). A positive correlation was found between PT-T1 and metabolic disfunction of right middle gyrus (MFG) in MCI and AD. In AD group, a positive correlation between PT-T1 and insula and superior temporal gyrus (STG) metabolism was detected. A negative correlation was found between PD-T1 and superior parietal lobule metabolism in MCI, and between PD-T1 and STG metabolism in AD. Impairment of cognitive empathy starts at MCI stage. Increase of PD starts from preclinical phases and seems to be to be dissociated from cognitive decline. Loss of PT is related to a progressive involvement starting from right MFG in prodromal stage, extending to insula and STG in dementia. Heightened emotional contagion is probably related to derangement of mirror neurons systems in parietal regions in prodromal stages, and to impairment of temporal emotion inhibition system in advanced phases. Further studies are needed to clarify if alterations in emotional contagion might be a predictive feature of a cognitive decline driven by AD.

CAG Repeats Within the Non-pathological Range in the HTT Gene Influence Personality Traits in Patients With Subjective Cognitive Decline: A 13-Year Follow-Up Study.

Objective: HTT is a gene containing a key region of CAG repeats. When expanded beyond 39 repeats, Huntington disease (HD) develops. HTT genes with <35 repeats are not associated with HD. The biological function of CAG repeat expansion below the non-pathological threshold is not well understood. In fact higher number of repeats in HTT confer advantageous changes in brain structure and general intelligence, but several studies focused on establishing the association between CAG expansions and susceptibility to psychiatric disturbances and to other neurodegenerative disease than HD. We hypothesized that HTT CAG repeat length below the pathological threshold might influence mood and personality traits in a longitudinal sample of individuals with Subjective Cognitive Decline. Methods: We included 54 patients with SCD. All patients underwent an extensive neuropsychological battery at baseline, APOE genotyping and analysis of HTT alleles. We used the Big Five Factors Questionnaire (BFFQ) and Hamilton Depression Rating Scale (HDRS), respectively, to assess personality traits of patients and depression at baseline. Patients who did not progress to Mild Cognitive Impairment (MCI) had at least 5-year follow-up time. Results: In the whole sample, CAG repeat number in the shorter HTT allele was inversely correlated with conscientiousness (Pearson = -0.364, p = 0.007). There was no correlation between HDRS and CAG repeats. During the follow-up, 14 patients [25.93% (95% C.I. = 14.24-37.61)] progressed to MCI (MCI+) and 40 [74.07% (95% C.I. = 62.39-85.76)] did not (MCI-). When we performed the same analysis in the MCI+ group we found that: CAG repeat length on the shorter allele was inversely correlated with energy (Pearson = 0.639, p = 0.014) and conscientiousness (Pearson = -0.695, p = 0.006). CAG repeat length on the longer allele was inversely correlated with conscientiousness (Pearson = -0.901, p < 0.001) and directly correlated with emotional stability (Pearson = 0.639, p = 0.014). These associations were confirmed also by multivariate analysis. We found no correlations between BFFQ parameters and CAG repeats in the MCI- group. Discussion: Personality traits and CAG repeat length in the intermediate range have been associated with progression of cognitive decline and neuropathological findings consistent with AD. We showed that CAG repeat lengths in the HTT gene within the non-pathological range influence personality traits.

Plasma neurofilament light chain as a biomarker of Alzheimer's disease in Subjective Cognitive Decline and Mild Cognitive Impairment.

INTRODUCTION: Neurofilament light chain (NfL) is becoming increasingly notable in neurological diseases including AD, and it has been suggested as a new peripherical biomarker of neurodegeneration. We aimed to compare plasma NfL levels among Subjective Cognitive Decline (SCD), Mild Cognitive Impairment (MCI), and AD patients and to evaluate relationships between NfL and CSF biomarkers and neuropsychological scores. MATERIALS AND METHODS: We enrolled 110 patients (34 SCD, 53 MCI, and 23 AD), who underwent clinical and neuropsychological evaluation, APOE genotyping, and plasma NfL analysis. Ninety-one patients underwent at least one amyloid burden biomarker (CSF and/or amyloid PET); 86 patients also underwent CSF phosphorylated-tau (p-tau) and total-tau (t-tau) measurement. Patients were classified as A + if they presented at least one positive amyloid biomarker or A- if not. RESULTS: NfL levels were significantly increased in AD and MCI compared to SCD patients. These differences depend on A status, e.g., SCD A + had lower NfLs than MCI A + but comparable with MCI A-. Similarly, MCI A + had higher NfL levels than MCI A-, but comparable with AD. NfL levels correlated with p-tau in SCD, with all CSF biomarkers in MCI patients. No correlations were found in AD subgroup. In SCD, NfL levels were negatively correlated with memory test scores. CONCLUSIONS: Plasma NfL levels might be a promising biomarker for neurodegeneration to discriminate cognitive decline due to AD from other conditions causing cognitive impairment in prodromal stages. Considering correlations with CSF p-tau and memory tests in SCD, NfL might be a useful peripheral biomarker also in preclinical phases of AD.