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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). 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. 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. 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.

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.

Co-existence of Alzheimer's disease (AD) in normal pressure hydrocephalus (NPH) is a frequent finding, thus a common pathophysiological basis between AD and NPH has been postulated. We measured CSF amyloid-β 42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) concentrations in a sample of 294 patients with different types of dementia and 32 subjects without dementia. We then compared scores on neuropsychological tests of NPH patients with pathological and normal CSF Aβ42 values. Aβ42 levels were significantly lower in NPH than in control patients, with no significant differences between AD and NPH. On the contrary, t-tau and p-tau levels were significantly lower in NPH than in AD, with no differences between NPH and controls. NPH patients with pathological Aβ42 levels did not perform worse than NPH patients with normal Aβ42 levels in any cognitive domains. Our data seem to support the hypothesis of amyloid accumulation in brains of NPH patients. Nevertheless, amyloid does not seem to play a pathogenetic role in the development of cognitive deficits in NPH.

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.

Background: Mild cognitive impairment (MCI) is a heterogeneous syndrome resulting from Alzheimer's disease (AD) as well as to non-AD and non-neurodegenerative conditions. A subset of patients with amnestic MCI (aMCI) present with an unusually long-lasting course, a slow rate of clinical neuropsychological progression, and evidence of focal involvement of medial temporal lobe structures. In the present study, we explored positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a sample of subjects with aMCI with such clinical features in order to provide in vivo evidence to improve disease characterisation in this subgroup.Methods: Thirty consecutive subjects with aMCI who had long-lasting memory impairment (more than 4 years from symptom onset) and a very slow rate of cognitive progression were included. All subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolic imaging. A measure of cerebral amyloid load, by PET and/or CSF, was obtained in 26 of 30 subjects. The mean clinical follow-up was 58.3 ± 10.1 months.Results: No patient progressed to dementia during the follow-up. The typical AD FDG-PET pattern of temporoparietal hypometabolism was not present in any of the subjects. In contrast, a selective medial temporal lobe hypometabolism was present in all subjects, with an extension to frontolimbic regions in some subjects. PET imaging showed absent or low amyloid load in the majority of samples. The values were well below those reported in prodromal AD, and they were slightly elevated in only two subjects, consistent with the CSF β-amyloid (1–42) protein values. Notably, no amyloid load was present in the hippocampal structures.Conclusions: FDG-PET and amyloid-PET together with CSF findings questioned AD pathology as a unique neuropathological substrate in this aMCI subgroup with long-lasting disease course. The possibility of alternative pathological conditions, such as argyrophilic grain disease, primary age-related tauopathy or age-related TDP-43 proteinopathy, known to spread throughout the medial temporal lobe and limbic system structures should be considered in these patients with MCI.

Purpose: Visual evoked potentials (VEPs) are a powerful tool to evaluate nervous conduction along the visual pathways, both in humans and in animal models. Traditionally, epidural screw electrodes are used to record VEPs in preclinical research. Here we tested the feasibility in the preclinical setting of the same noninvasive technique used for clinical VEP acquisition, by using epidermal cup electrodes with no surgical procedures. Methods: Monocular flash VEPs were recorded bilaterally under sevoflurane anesthesia once a week for 6 weeks in 14 dark Agouti rats, 7 with implanted epidural screws and 7 with epidermal 6 mm Ø Ag/AgCl cups. Results: VEP traces obtained with the two techniques were morphologically comparable. There were no significant differences in latency of the main visual component between screw-recorded VEPs (sVEPs) and cup-recorded VEPs (cVEPs). Amplitude values with epidermal cups were significantly lower than those with epidural screws. Both techniques provided latencies and amplitudes which were stable over time. Furthermore, with regard to latency both methods ensured highly repeatable measurements over time, with epidermal cups even providing slightly better results. On the other hand, considering amplitudes, cVEPs and sVEPs provided fairly acceptable repeatability. Conclusions: Epidermal cup electrodes can provide comparable results to those obtained with the “gold standard” epidural screws, while representing a simpler and less invasive technique to test nervous conduction along the visual pathways in the preclinical setting.