Real-word application of the AT(N) classification and disease-modifying treatment eligibility in a hospital-based cohort.

BACKGROUND AND OBJECTIVES: The AT(N) classification system stratifies patients based on biomarker profiles, including amyloid-beta deposition (A), tau pathology (T), and neurodegeneration (N). This study aims to apply the AT(N) classification to a hospital-based cohort of patients with cognitive decline and/or dementia, within and outside the Alzheimer's disease (AD) continuum, to enhance our understanding of the multidimensional aspects of AD and related disorders. Furthermore, we wish to investigate how many cases from our cohort would be eligible for the available disease modifying treatments, such as aducanemab and lecanemab. METHODS: We conducted a retrospective evaluation of 429 patients referred to the Memory Center of IRCCS San Raffaele Hospital in Milan. Patients underwent clinical/neuropsychological assessments, lumbar puncture, structural brain imaging, and positron emission tomography (FDG-PET). Patients were stratified according to AT(N) classification, group comparisons were performed and the number of eligible cases for anti-ß amyloid monoclonal antibodies was calculated. RESULTS: Sociodemographic and clinical features were similar across groups. The most represented group was A + T + N + accounting for 38% of cases, followed by A + T - N + (21%) and A - T - N + (20%). Although the clinical presentation was similar, the A + T + N + group showed more severe cognitive impairment in memory, language, attention, executive, and visuospatial functions compared to other AT(N) groups. Notably, T + patients demonstrated greater memory complaints compared to T - cases. FDG-PET outperformed MRI and CT in distinguishing A + from A - patients. Although 61% of the observed cases were A + , only 17% of them were eligible for amyloid-targeting treatments. DISCUSSION: The AT(N) classification is applicable in a real-world clinical setting. The classification system provided insights into clinical management and treatment strategies. Low cognitive performance and specific regional FDG-PET hypometabolism at diagnosis are highly suggestive for A + T + or A - T + profiles. This work provides also a realistic picture of the proportion of AD patients eligible for disease modifying treatments emphasizing the need for early detection.

EEG Correlates in the 3 Variants of Primary Progressive Aphasia.

BACKGROUND AND OBJECTIVES: The 3 clinical presentations of primary progressive aphasia (PPA) reflect heterogenous neuropathology, which is difficult to be recognized in vivo. Resting-state (RS) EEG is promising for the investigation of brain electrical substrates in neurodegenerative conditions. In this study, we aim to explore EEG cortical sources in the characterization of the 3 variants of PPA. METHODS: This is a cross-sectional, single-center, memory center-based cohort study. Patients with PPA and healthy controls were consecutively recruited at the Neurology Unit, IRCCS San Raffaele Scientific Institute (Milan, Italy). Each participant underwent an RS 19-channel EEG. Using standardized low-resolution brain electromagnetic tomography, EEG current source densities were estimated at voxel level and compared among study groups. Using an RS functional MRI-driven model of source reconstruction, linear lagged connectivity (LLC) values within language and extra-language brain networks were obtained and analyzed among groups. RESULTS: Eighteen patients with logopenic PPA variant (lvPPA; mean age = 72.7 ± 6.6; % female = 52.4), 21 patients with nonfluent/agrammatic PPA variant (nfvPPA; mean age = 71.7 ± 8.1; % female = 66.6), and 9 patients with semantic PPA variant (svPPA; mean age = 65.0 ± 6.9; % female = 44.4) were enrolled in the study, together with 21 matched healthy controls (mean age = 69.2 ± 6.5; % female = 57.1). Patients with lvPPA showed a higher delta density than healthy controls (p < 0.01) and patients with nfvPPA (p < 0.05) and svPPA (p < 0.05). Patients with lvPPA also displayed a greater theta density over the left posterior hemisphere (p < 0.01) and lower alpha2 values (p < 0.05) over the left frontotemporal regions than controls. Patients with nfvPPA showed a diffuse greater theta density than controls (p < 0.05). LLC was altered in all patients relative to controls (p < 0.05); the alteration was greater at slow frequency bands and within language networks than extra-language networks. Patients with lvPPA also showed greater LLC values at theta band than patients with nfvPPA (p < 0.05). DISCUSSION: EEG findings in patients with PPA suggest that lvPPA-related pathology is associated with a characteristic disruption of the cortical electrical activity, which might help in the differential diagnosis from svPPA and nfvPPA. EEG connectivity was disrupted in all PPA variants, with distinct findings in disease-specific PPA groups. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that EEG analysis can distinguish PPA due to probable Alzheimer disease from PPA due to probable FTD from normal aging.

Potential Cardiologic Protective Effects of Acetylcholinesterase Inhibitors in Patients With Mild to Moderate Dementia.

In patients with mild to moderate dementia, acetylcholinesterase inhibitors (AChE-I) are used to improve cognitive functions, but bradycardia, conduction abnormalities, and hypotension are possible side effects because of the peripheral muscarinic M2 receptor stimulation. This study aimed to evaluate the main cardiologic clinical outcomes in patients with dementia who are on AChE-I. In this retrospective, monocentric, observational cohort study, 2 groups were considered: (1) patients with dementia because of the typical and atypical forms of Alzheimer disease treated with AChE-I and (2) cognitively unimpaired, matched control group. The primary end point was a composite of cardiovascular death, nonfatal acute myocardial infarction, myocardial revascularization, occurrence of stroke and/or transient ischemic attacks, and hospitalization for heart failure occurring during a mean of 3.1 years of follow-up. The secondary end points were each individual component of the primary end point, total mortality, noncardiovascular death, and incidence of pacemaker implant. Each group included 221 patients who were homogeneous in terms of age, gender, and main cardiovascular risk factors. Major adverse cardiovascular events occurred in 24 patients with dementia (2.1 per 100 patient-years) compared with 56 in control group (5.0 per 100 patient-years), p = 0.036. Even if not significant, the difference was mainly driven by myocardial revascularization (3.2% vs 6.8%) and hospitalization for heart failure (4.5% vs 14.5%). As expected, noncardiovascular mortality was significantly higher in the treatment group (13.6% vs 2.7% p = 0.006). No significant difference between the groups was observed in terms of other secondary outcomes. In conclusion, in patients with dementia, the use of AChE-I may be protective for cardiovascular outcomes, especially in reducing heart failure hospitalization and myocardial revascularization.

Plasma neurofilament light chain levels and cognitive testing as predictors of fast progression in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is characterized by a heterogeneous course. Predicting a fast rather than a slow decline over time is crucial to both provide a reliable prognosis and elaborate stricter enrolment criteria in clinical trials. Here we searched for independent predictors of cognitive decline rate to assess the risk of fast disease progression already at baseline. METHODS: Fifty-three subjects with an "in-vivo biomarker confirmed" diagnosis of AD were included. Neuropsychological assessment, plasma neurofilaments (NfL) concentrations and, in a subsample of 23 patients, brain magnetic resonance imaging were available. Patients were labelled FAST or SLOW depending on the Mini-Mental State Examination (MMSE) points lost per year (FAST if more than 3 points). We adopted single logistic regression models to search for independent predictors of FAST progression. RESULTS: At baseline no differences were found between FAST and SLOW subgroups in demographics, MMSE scores, vascular burden and medial temporal lobe atrophy measurements. Higher plasma NfL concentrations and worse scores at semantic verbal fluency (SVF) and clock drawing test (CDT) were independent predictors of FAST decline, after controlling for age, education, sex and baseline disease severity stage. The regression model combining all the predictors correctly classified 80% of patients overall. The risk of FAST decline was 81.2% if all the three predictors were abnormal (i.e., SVF ≤21.5, CDT ≤5.5, NfL ≥22.19). CONCLUSIONS: An easily applicable algorithm, including plasma NfL measurement and two neuropsychological tests worldwide adopted in clinical practice (SVF and CDT), may allow clinicians to reliably stratify AD patients in relation to the risk of fast cognitive decline.

Resting-state electroencephalographic biomarkers of Alzheimer's disease.

OBJECTIVE: We evaluated the value of resting-state EEG source biomarkers to characterize mild cognitive impairment (MCI) subjects with an Alzheimer's disease (AD)-like cerebrospinal fluid (CSF) profile and to track neurodegeneration throughout the AD continuum. We further applied a resting-state functional MRI (fMRI)-driven model of source reconstruction and tested its advantage in terms of AD diagnostic accuracy. METHODS: Thirty-nine consecutive patients with AD dementia (ADD), 86 amnestic MCI, and 33 healthy subjects enter the EEG study. All ADD subjects, 37 out of 86 MCI patients and a distinct group of 53 healthy controls further entered the fMRI study. MCI subjects were divided according to the CSF phosphorylated tau/ß amyloid-42 ratio (MCIpos: ≥ 0.13, MCIneg: < 0.13). Using Exact low-resolution brain electromagnetic tomography (eLORETA), EEG lobar current densities were estimated at fixed frequencies and analyzed. To combine the two imaging techniques, networks mostly affected by AD pathology were identified using Independent Component Analysis applied to fMRI data of ADD subjects. Current density EEG analysis within ICA-based networks at selected frequency bands was performed. Afterwards, graph analysis was applied to EEG and fMRI data at ICA-based network level. RESULTS: ADD patients showed a widespread slowing of spectral density. At a lobar level, MCIpos subjects showed a widespread higher theta density than MCIneg and healthy subjects; a lower beta2 density than healthy subjects was also found in parietal and occipital lobes. Evaluating EEG sources within the ICA-based networks, alpha2 band distinguished MCIpos from MCIneg, ADD and healthy subjects with good accuracy. Graph analysis on EEG data showed an alteration of connectome configuration at theta frequency in ADD and MCIpos patients and a progressive disruption of connectivity at alpha2 frequency throughout the AD continuum. CONCLUSIONS: Theta frequency is the earliest and most sensitive EEG marker of AD pathology. Furthermore, EEG/fMRI integration highlighted the role of alpha2 band as potential neurodegeneration biomarker.

Repetitive Transcranial Magnetic Stimulation With H-Coil Coupled With Cycling for Improving Lower Limb Motor Function After Stroke: An Exploratory Study.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been recognized as a promising intervention for the treatment of post-stroke motor deficits. Here, we explore safety, feasibility, and potential effectiveness of high-frequency rTMS (HF-rTMS) delivered with the Hesed coil (H-coil) during active cycling on paretic lower extremity (LE) motor function in chronic stroke. MATERIALS AND METHODS: Twelve subjects with a first-ever stroke were recruited in this double-blind, placebo controlled, crossover study. Eleven sessions of HF-rTMS (40 2s-trains of 20 Hz at 90% resting leg motor threshold) were delivered over the LE motor areas using the H-coil during active cycling for three weeks. Each subject underwent both real and sham rTMS treatments separated by a four-week washout period, in a random sequence. Vital signs were recorded before and after each rTMS session. Any discomfort related to stimulation and side effects were recorded. LE function was also evaluated with Fugl-Meyer assessment (FMA-LE), spasticity was assessed with modified-Ashworth scale and measures of gait speed and endurance (10-meter and 6-min walk tests, respectively) were recorded. RESULTS: No participant reported serious adverse effects. During real rTMS, 4 of 12 subjects reported mild side effects including transitory dizziness and muscle twitches on shoulder, so that intensity of stimulation initially set at 90% of RMT was reduced to 80% of RMT on average in these four subjects. Only real treatment was associated with a significant and sustained improvement in FMA-LL (67% responders vs. 9% of the sham). Spasticity significantly ameliorated only after the real rTMS. Real treatment did not offer advantages on walking timed measures when compared with sham. CONCLUSIONS: This exploratory study suggests that bilateral HF-rTMS combined with cycling is safe and potentially effective in ameliorating paretic LE motor function and spasticity, rather than gait speed or endurance, in chronic stroke.

Biomarker-based stability in limbic-predominant amnestic mild cognitive impairment.

BACKGROUND: The amnestic presentation of mild cognitive impairment (aMCI) represents the most common prodromal stage of Alzheimer's disease (AD) dementia. There is, however, some evidence of aMCI with typical amnestic syndrome but showing long-term clinical stability. The ability to predict stability or progression to dementia in the aMCI condition is important, particularly for the selection of candidates in clinical trials. We aimed to establish the role of in vivo biomarkers, as assessed by cerebrospinal fluid (CSF) measures and [18 F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, in predicting prognosis in a large aMCI cohort. METHODS: We conducted a retrospective study, including 142 aMCI subjects who had a long follow-up (4-19 years), baseline CSF data and [18 F]FDG-PET scans individually assessed by validated voxel-based procedures, classifying subjects into either limbic-predominant or AD-like hypometabolism patterns. RESULTS: The two aMCI cohorts were clinically comparable at baseline. At follow-up, the aMCI group with a limbic-predominant [18 F]FDG-PET pattern showed clinical stability over a very long follow-up (8.20 ± 3.30 years), no decline in Mini-Mental State Examination score, and only 7% conversion to dementia. Conversely, the aMCI group with an AD-like [18 F]FDG-PET pattern had a high rate of dementia progression (86%) over a shorter follow-up (6.47 ± 2.07 years). Individual [18 F]FDG-PET hypometabolism patterns predicted stability or conversion with high accuracy (area under the curve = 0.89), sensitivity (0.90) and specificity (0.89). In the limbic-predominant aMCI cohort, CSF biomarkers showed large variability and no prognostic value. CONCLUSIONS: In a large series of clinically comparable subjects with aMCI at baseline, the specific [18 F]FDG-PET limbic-predominant hypometabolism pattern was associated with clinical stability, making progression to AD very unlikely. The identification of a biomarker-based benign course in aMCI subjects has important implications for prognosis and in planning clinical trials.

Neuro-Retina Might Reflect Alzheimer's Disease Stage.

BACKGROUND: Alzheimer's disease (AD) pathological hallmarks were found in retinas of AD patients. Several studies showed a significant reduction of neuro-retina thickness measured through optical coherence tomography (OCT) in AD patients, but possible correlations between retina morphology, cognition, and cerebrospinal fluid (CSF) AD biomarkers (Aß42, t-tau, and p-tau) have been poorly investigated so far. OBJECTIVE: In the present cross-sectional study, we measured the thickness of neuro-retinal layers through OCT searching for possible correlations with patients' cognitive performances and CSF AD biomarkers. METHODS: 137 consecutive subjects [43 with AD, 37 with mild cognitive impairment (MCI), and 57 healthy controls (HC)], received an OCT scan acquisition to measure the peripapillary retinal nerve fiber layer (RNFL) thickness. In a subsample of 21 AD, 18 MCI, and 18 HC, the macular volume of ganglion cell layer (GCL), inner plexiform layer (IPL), and inner nuclear layer was computed. A comprehensive neuropsychological assessment and CSF AD biomarkers' concentrations were available in AD and MCI patients. RESULTS: Peripapillary RNFL, global, and in superior quadrant was significantly thinner in AD and MCI patients when compared to HC, while macular GCL volume was significantly reduced only in AD. RNFL thickness in nasal and inferior quadrants was correlated with single CSF AD biomarker concentrations, but no differences were found in retina morphology depending on the presence of a CSF profile typical for AD. Memory performances were positively associated with GCL and IPL volume. CONCLUSION: Our findings might propose OCT as a reliable and easy to handle tool able to detect neuro-retinal atrophy in AD in relation with cognitive performances.

CSF p-tau/Aß42 ratio and brain FDG-PET may reliably detect MCI "imminent" converters to AD.

PURPOSE: To know whether mild cognitive impairment (MCI) patients will develop Alzheimer's disease (AD) dementia in very short time or remain stable is of crucial importance, also considering new experimental drugs usually tested within very short time frames. Here we combined cerebrospinal fluid (CSF) AD biomarkers and a neurodegeneration marker such as brain FDG-PET to define an objective algorithm, suitable not only to reliably detect MCI converters to AD dementia but also to predict timing of conversion. METHODS: We included 77 consecutive MCI patients with neurological/neuropsychological assessment, brain 18F-FDG-PET and CSF analysis available at diagnosis and a neuropsychological/neurological evaluation every 6 months for a medium- to a long-term follow-up (at least 2 and up to 8 years). Binomial logistic regression models and Kaplan-Meier survival analyses were performed to determine the best biomarker (or combination of biomarkers) in detecting MCI converters to AD dementia and then, among the converters, those who converted in short time frames. RESULTS: Thirty-five out of 77 MCI patients (45%) converted to AD dementia, with an average conversion time since MCI diagnosis of 26.07 months. CSF p-tau/Aß42 was the most accurate predictor of conversion from MCI to AD dementia (82.9% sensitivity; 90% specificity). CSF p-tau/Aß42 and FDG-PET-positive MCIs converted to AD dementia significantly earlier than the CSF-positive-only MCIs (median conversion time, 17.1 vs 31.3 months). CONCLUSIONS: CSF p-tau/Aß42 ratio and brain FDG-PET may predict both occurrence and timing of MCI conversion to full-blown AD dementia. MCI patients with both biomarkers suggestive for AD will likely develop an AD dementia shortly, thus representing the ideal target for any new experimental drug requiring short periods to be tested for.

The combined effects of microglia activation and brain glucose hypometabolism in early-onset Alzheimer's disease.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) is characterized by young age of onset (< 65 years), severe neurodegeneration, and rapid disease progression, thus differing significantly from typical late-onset Alzheimer's disease. Growing evidence suggests a primary role of neuroinflammation in AD pathogenesis. However, the role of microglia activation in EOAD remains a poorly explored field. Investigating microglial activation and its influence on the development of synaptic dysfunction and neuronal loss in EOAD may contribute to the understanding of its pathophysiology and to subject selection in clinical trials. In our study, we aimed to assess the amount of neuroinflammation and neurodegeneration and their relationship in EOAD patients, through positron emission tomography (PET) measures of microglia activation and brain metabolic changes. METHODS: We prospectively enrolled 12 EOAD patients, classified according to standard criteria, who underwent standard neurological and neuropsychological evaluation, CSF analysis, brain MRI, and both [18F]-FDG PET and [11C]-(R)-PK11195 PET. Healthy controls databases were used for statistical comparison. [18F]-FDG PET brain metabolism in single subjects and as a group was assessed by an optimized SPM voxel-wise single-subject method. [11C]-PK11195 PET binding potentials were obtained using reference regions selected with an optimized clustering procedure followed by a parametric analysis. We performed a topographic interaction analysis and correlation analysis in AD-signature metabolic dysfunctional regions and regions of microglia activation. A network connectivity analysis was performed using the interaction regions of hypometabolism and [11C]-PK11195 PET BP increases. RESULTS: EOAD patients showed a significant and extended microglia activation, as [11C]-PK11195 PET binding potential increases, and hypometabolism in typical AD-signature brain regions, i.e., temporo-parietal cortex, with additional variable frontal and occipital hypometabolism in the EOAD variants. There was a spatial concordance in the interaction areas and significant correlations between the two biological changes. The network analysis showed a disruption of frontal connectivity induced by the metabolic/microglia effects. CONCLUSION: The severe microglia activation characterizing EOAD and contributing to neurodegeneration may be a marker of rapid disease progression. The coupling between brain glucose hypometabolism and local immune response in AD-signature regions supports their biological interaction.

Repetitive Transcranial Magnetic Stimulation With H-Coil in Alzheimer's Disease: A Double-Blind, Placebo-Controlled Pilot Study.

Focal repetitive transcranial magnetic stimulation (rTMS) has been applied to improve cognition in Alzheimer's disease (AD) with conflicting results. We applied rTMS in AD in a pilot placebo-controlled study using the H2-coil. H-coils are suitable for targeting wider neuronal structures compared with standard focal coils, in particular the H2-coil stimulates simultaneously the frontal-parietal-temporal lobes bilaterally. Thirty patients (mean age 70.9 year, SD 8.1; mean MMSE score 16.9, SD 5.5) were randomized to sham or real 10 Hz rTMS stimulation with the H2-coil. Each patient underwent 3 sessions/week for 4 weeks, followed by 4 weeks with maintenance treatment (1 session/week). Primary outcome was improvement of ADAS-cog at 4 and 8 weeks compared with baseline. A trend toward an improved ADAS-cog score over time was observed for patients undergoing real rTMS, with actively treated patients experiencing a mean decrease of -1.01 points at the ADAS-Cog scale score per time point (95% CIs -0.02 to -3.13, p < 0.04). This trend was no longer evident 2 months after the end of treatment. Real rTMS showed no significant effect on MMSE and BDI changes over time. These preliminary findings suggest that rTMS with H-coil is feasible and safe in patients with probable AD and might provide beneficial, even though transient, effects on cognition. This study prompts larger studies in the early stages of AD, combining rTMS and cognitive rehabilitation. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04562506.

Brain metabolic signatures across the Alzheimer's disease spectrum.

PURPOSE: Given the challenges posed by the clinical diagnosis of atypical Alzheimer's disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [18F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI). METHODS: We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11 months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions. RESULTS: W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [18F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up. CONCLUSIONS: The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.

A new electrophysiological non-invasive method to assess retinocortical conduction time in the Dark Agouti rat through the simultaneous recording of electroretinogram and visual evoked potential.

PURPOSE: To develop a non-invasive method exploiting simultaneous recording of epidermal visual evoked potential (VEP) and epicorneal electroretinogram (ERG) to study retinocortical function and to evaluate its reliability and repeatability over time. METHODS: Female wild-type DA rats were anesthetized with ketamine/xylazine (40/5 mg/kg). Epidermal VEP (Ag/AgCl cup electrode on scalp) and epicorneal ERG (gold ring electrode on eye surface) were recorded simultaneously in response to flash stimulation. RESULTS: ANOVA for repeated measures showed that peak times of ERG b-wave and of VEP N1 and P2 were stable across 6 weekly time-points, as well as the corresponding amplitudes. Mean retinocortical time from b-wave to N1 (RCT1) was 7.6 ms and remained comparable across the 6 time-points. Mean retinocortical time from b-wave to P2 (RCT2) was 28.7 ms and did not show significant variations over time. Coefficient of variation (CoV%) and CoV% adjusted for sample size, namely relative standard error (RSE%), were calculated as indexes of repeatability. Good RSE% over time was obtained (< 5% for b-wave, N1 and P2 peak times; < 20% and < 7% for RCT1 and RCT2, respectively). CONCLUSIONS: Simultaneous recording of ERG and VEP has been previously achieved through invasive methods requiring surgery. Here, we present a new non-invasive method, which allowed to obtain peak and retinocortical times that were constant across a long period and had a good repeatability over time. This method will ensure not only a gain in animal welfare, but will also avoid stress and eye or brain lesions which can interfere with experimental variables.

Two distinct pathological substrates associated with MMSE-pentagons item deficit in DLB and AD.

INTRODUCTION: Dementia with Lewy Bodies (DLB) is characterized by a prominent deficit in visuospatial abilities. Visuospatial impairment is also detectable in the course of Alzheimer's dementia (AD). However, visuospatial impairment presents some differences in these two conditions, suggesting pathological involvement of distinct brain circuits. Recent studies applied a new method to score the Mini Mental State Examination (MMSE) pentagon copy subtest, namely the Qualitative Scoring Pentagon Test (QSPT), which is a sensitive measure of visuospatial abilities. Using [18F]fluorodeoxy-glucose positron emission tomography (FDG-PET), we assessed the relationship between in vivo brain metabolic dysfunction and visuospatial deficits, in terms of QSPT total value, in DLB and AD. MATERIALS AND METHODS: Sixty Patients were diagnosed as DLB (n = 35) and AD (n = 25) dementia according with the standard research diagnostic criteria. Each patient underwent a FDG-PET scan as support for the final diagnosis. Patients underwent an extended neuropsychological evaluation, including MMSE, language, memory, executive functions and visuospatial abilities tests. The MMSE QSPT scoring was calculated following the methods by Caffarra et al. (2013). Offline voxel-wise correlation analysis between QSPT total scores and FDG-PET brain metabolism was then performed, correcting for MMSE, sex and disease duration. RESULTS: Both groups presented reduced visuospatial performances, as assessed by QSPT scores. DLB compared to AD showed a statistically significant difference in QSPT rotation parameter (p = 0.022). In DLB, worse performance at QSPT total score, i.e. more severe visuospatial impairment, correlated with brain occipital hypometabolism (i.e. lateral occipital cortex, calcarine cortex, fusiform and lingual gyri). In AD, worse performance at QSPT total score correlated with brain hypometabolism in the right parietal cortex (i.e. superior and inferior parietal cortex and angular gyrus). DISCUSSION: These findings reveal that visuospatial deficits may derive from distinct brain alterations in AD and DLB. We propose that the inabilities to perform correctly the QSPT task is related to altered visuoperceptual process in DLB, and visuospatial process in AD. This is consistent with our results showing hypometabolism in brain system related to visuoperceptual processing, namely the occipital cortex in DLB, and visuospatial processing, namely parietal cortex in AD.

The CSF p-tau181/Aß42 Ratio Offers a Good Accuracy "In Vivo" in the Differential Diagnosis of Alzheimer's Dementia.

BACKGROUND: The incoming disease-modifying therapies against Alzheimer's disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-ß 42 (Aß42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption. METHODS: We measured CSF AD biomarkers' concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings. RESULTS: A p-tau181/Aß42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aß42 ratio, thus determining an increase in CSF accuracy. CONCLUSION: The p-tau181/Aß42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.

Functional and morphological changes of the retinal vessels in Alzheimer's disease and mild cognitive impairment.

Imaging and histopathological studies have demonstrated that structural changes of the retina affect subjects with Alzheimer's disease (AD) or mild cognitive impairment (MCI). The aim of this study was to quantitatively investigate the retinal vessels in these disorders, using dynamic vessel analyzer (DVA) and optical coherence tomography angiography (OCTA) analysis. Twelve subjects with AD, 12 subjects with MCI, and 32 gender- and age-matched controls were prospectively enrolled. Mean ± SD age was 72.9 ± 7.2 years in the AD group, 76.3 ± 6.9 years in the MCI group, and 71.6 ± 5.9 years in the control group (p = 0.104). In the DVA dynamic analysis, the arterial dilation was decreased in the AD group (0.77 ± 2.06%), in the comparison with the control group (3.53 ± 1.25%, p = 0.002). The reaction amplitude was decreased both in AD (0.21 ± 1.80%, <0.0001) and MCI (2.29 ± 1.81%, p = 0.048) subjects, compared with controls (3.86 ± 1.94%). OCTA variables did not differ among groups. In the Pearson correlation analysis, amyloid ß level in the cerebrospinal fluid was directly correlated with the arterial dilation (R = 0.441, p = 0.040) and reaction amplitude (R = 0.580, p = 0.005). This study demonstrate that Alzheimer's and MCI subjects are characterized by a significant impairment of the retinal neurovascular coupling. This impairment is inversely correlated with the level of amyloid ß in the cerebrospinal fluid.

Automated classification of Alzheimer's disease and mild cognitive impairment using a single MRI and deep neural networks.

We built and validated a deep learning algorithm predicting the individual diagnosis of Alzheimer's disease (AD) and mild cognitive impairment who will convert to AD (c-MCI) based on a single cross-sectional brain structural MRI scan. Convolutional neural networks (CNNs) were applied on 3D T1-weighted images from ADNI and subjects recruited at our Institute (407 healthy controls [HC], 418 AD, 280 c-MCI, 533 stable MCI [s-MCI]). CNN performance was tested in distinguishing AD, c-MCI and s-MCI. High levels of accuracy were achieved in all the classifications, with the highest rates achieved in the AD vs HC classification tests using both the ADNI dataset only (99%) and the combined ADNI + non-ADNI dataset (98%). CNNs discriminated c-MCI from s-MCI patients with an accuracy up to 75% and no difference between ADNI and non-ADNI images. CNNs provide a powerful tool for the automatic individual patient diagnosis along the AD continuum. Our method performed well without any prior feature engineering and regardless the variability of imaging protocols and scanners, demonstrating that it is exploitable by not-trained operators and likely to be generalizable to unseen patient data. CNNs may accelerate the adoption of structural MRI in routine practice to help assessment and management of patients.

Optic nerve involvement in experimental autoimmune encephalomyelitis to homologous spinal cord homogenate immunization in the dark agouti rat.

Dark-Agouti rats were immunized with spinal cord homogenate to develop Experimental Autoimmune Encephalomyelitis, a model of multiple sclerosis. We assessed motor signs and recorded VEPs for five or eight weeks with epidural or epidermal electrodes, respectively, with final histopathology of optic nerves (ONs). Injected rats exhibited motor deficits a week after immunization. VEP delays arose from the 2nd to the 5th week, when a recovery occurred in epidermal-recorded rats. ON damage appeared in epidural-, but not in epidermal-recorded rats, probably due to a remyelination process. VEP could be exploited as neurophysiological marker to test novel treatments against neurodegeneration involving ONs.

Prevalence of amyloid-ß pathology in distinct variants of primary progressive aphasia.

OBJECTIVE: To estimate the prevalence of amyloid positivity, defined by positron emission tomography (PET)/cerebrospinal fluid (CSF) biomarkers and/or neuropathological examination, in primary progressive aphasia (PPA) variants. METHODS: We conducted a meta-analysis with individual participant data from 1,251 patients diagnosed with PPA (including logopenic [lvPPA, n = 443], nonfluent [nfvPPA, n = 333], semantic [svPPA, n = 401], and mixed/unclassifiable [n = 74] variants of PPA) from 36 centers, with a measure of amyloid-ß pathology (CSF [n = 600], PET [n = 366], and/or autopsy [n = 378]) available. The estimated prevalence of amyloid positivity according to PPA variant, age, and apolipoprotein E (ApoE) ε4 status was determined using generalized estimating equation models. RESULTS: Amyloid-ß positivity was more prevalent in lvPPA (86%) than in nfvPPA (20%) or svPPA (16%; p < 0.001). Prevalence of amyloid-ß positivity increased with age in nfvPPA (from 10% at age 50 years to 27% at age 80 years, p < 0.01) and svPPA (from 6% at age 50 years to 32% at age 80 years, p < 0.001), but not in lvPPA (p = 0.94). Across PPA variants, ApoE ε4 carriers were more often amyloid-ß positive (58.0%) than noncarriers (35.0%, p < 0.001). Autopsy data revealed Alzheimer disease pathology as the most common pathologic diagnosis in lvPPA (76%), frontotemporal lobar degeneration-TDP-43 in svPPA (80%), and frontotemporal lobar degeneration-TDP-43/tau in nfvPPA (64%). INTERPRETATION: This study shows that the current PPA classification system helps to predict underlying pathology across different cohorts and clinical settings, and suggests that age and ApoE genotype should be considered when interpreting amyloid-ß biomarkers in PPA patients. Ann Neurol 2018;84:737-748.

The brain metabolic signature of visual hallucinations in dementia with Lewy bodies.

Visual hallucinations (VH) are a core clinical feature of dementia with Lewy bodies (DLB), but their specific neural substrate remains elusive. We used 18F-FDG-PET to study the neural dysfunctional signature of VH in a group of 38 DLB patients (mean age±SD 72.9 ± 7.5) with available anamnestic records, cognitive and neurological examination and NeuroPsychiatric Inventory assessing VH. We tested the voxel-wise correlation between 18F-FDG-PET hypometabolism and VH NPI scores at the whole-group level, then adopting inter-regional correlation analysis to explore the resting-state networks (RSNs) metabolic connectivity in DLB patients with and without visual hallucinations, as compared to N = 38 age-matched healthy controls (HCs) (mean age±SD 71.5 ± 6.9). At the whole-group level, we found a negative correlation between VH NPI scores and 18F-FDG-PET hypometabolism in the right occipito-temporal cortex (p < .001 uncorrected, p < .05 Family-Wise Error cluster-corrected). Then, splitting the group according to VH presence, we found that DLB non-hallucinators presented a pattern of connectivity seeding from this occipito-temporal cluster and extending to the ventral visual stream. At difference, the DLB hallucinators showed a metabolic connectivity pattern limited to the occipital-dorsal parietal regions. As for RSNs, both the DLB subgroups showed a markedly reduced extent of attention and visual networks compared to HCs, with a variable alteration in the topography. DLB-VH patients showed a more pronounced shrinkage of the primary visual network, which was disconnected from the higher visual hubs, at difference with both HC and DLB non-hallucinators. These findings suggest that an altered brain metabolic connectivity within and beyond visual systems may promote VH in DLB. These results support the most recent neurocognitive models interpreting VH as the result of an inefficient recruitment of the ventral visual stream and of a large-scale multi-network derangement.