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No disease-modifying therapies are currently available for Alzheimer’s disease (AD) in Europe. Current evidence from clinical trials testing anti-beta amyloid (Aβ) monoclonal antibodies (mAbs) in patients with early AD, though, suggests a likely marketing authorization in the next years. Since the implementation of disease-modifying therapies for AD in the clinical practice will evidently require a huge change of dementia care in all countries, a group of prominent AD clinical experts in Italy met to discuss patients’ selection and management strategies. The current diagnostic–therapeutic standard of care in Italy was taken as the starting point. The prescription of new therapies cannot ignore the definition of a biological diagnosis through the assessment of both amyloid- and tau-related biomarkers. The high risk/benefit ratio of anti-Aβ immunotherapies, moreover, needs a highly specialized diagnostic work-up and a thorough exclusion criteria assessment, which should be provided by a neurology specialist. The Expert Panel also suggests a reorganization of the Centers for dementia and cognitive decline in Italy into 3 levels of increasing complexity: community center, first- and second-level center. Tasks and requirements for each level were defined. Finally, specific characteristics of a center deputed to prescribe anti-Aβ mAbs were discussed.

Purpose To date, there is no consensus on how to semi-quantitatively assess brain amyloid PET. Some approaches use late acquisition alone (e.g., ELBA, based on radiomic features), others integrate the early scan (e.g., TDr, which targets the area of maximum perfusion) and structural imaging (e.g., WMR, that compares kinetic behaviour of white and grey matter, or SI based on the kinetic characteristics of the grey matter alone). In this study SUVr, ELBA, TDr, WMR, and SI were compared. The latter — the most complete one — provided the reference measure for amyloid burden allowing to assess the efficacy and feasibility in clinical setting of the other approaches. Methods We used data from 85 patients (aged 44–87) who underwent dual time-point PET/MRI acquisitions. The correlations with SI were computed and the methods compared with the visual assessment. Assuming SUVr, ELBA, TDr, and WMR to be independent measures, we linearly combined them to obtain more robust indices. Finally, we investigated possible associations between each quantifier and age in amyloid-negative patients. Results Each quantifier exhibited excellent agreement with visual assessment and strong correlation with SI (average AUC = 0.99, ρ = 0.91). Exceptions to this were observed for subcortical regions with ELBA and WMR (ρELBA = 0.44, ρWMR = 0.70). The linear combinations showed better performances than the individual methods. Significant associations were observed between TDr, WMR, SI, and age in amyloid-negative patients (p Conclusion Among the other methods, TDr came closest to the reference with less implementation complexity. Moreover, this study suggests that combining independent approaches gives better results than the individual procedure, so efforts should focus on multi-classifier systems for amyloid PET. Finally, the ability of techniques integrating blood perfusion to depict age-related variations in amyloid load in amyloid-negative subjects demonstrates the goodness of the estimate.

Background: Recurrent complex visual hallucinations (VHs) are common in dementia with Lewy bodies (DLB). Previous investigations suggest that VHs are associated with connectivity changes within and...

Visual hallucinations (VH) are common in dementia with Lewy bodies (DLB), and are among the core symptoms for its clinical diagnosis. VH have been associated with cognitive alterations, although research findings in this area are still limited. The present study aimed at investigating the cognitive correlates of VH in DLB, and the baseline neuropsychological features predicting the future development of VH. A cross sectional study compared the cognitive profile of 18 DLB patients with VH with that of 32 DLB without VH. A longitudinal study involved 34 DLB patients with no VH at baseline, among whom 17 developed VH and 17 remained without VH at follow-up. Logistic regression analyses were carried out to investigate what baseline cognitive variables independently predicted the development of VH at follow-up. DLB patients with VH had worse performance on the copy of the Rey complex figure, assessing visual construction/perception, than those without VH in the cross-sectional study (p = .001). Significant impairments in attention and visual memory delayed recall were also present. Baseline performance on the immediate prose memory was the only significant predictor of VH development in the longitudinal study (p = .03). DLB patients are more at risk of developing VH if presenting more severe immediate verbal memory impairment, and this might be related to a combination of (a) DMN-related dysfunctions, (b) impairment in medial temporal lobe-related functions, and (c) frontal abilities including long-term encoding of information and working memory. Differences between hallucinating and non-hallucinating patients in visual construction/perception, typical of DLB symptomatology, may be essential for VH to emerge in individuals with an at risk cognitive profile.

Peripherin (PRPH), a type III intermediate filament, assembles with neurofilaments in neurons of the peripheral nervous system, including lower motor neurons (LMN). To evaluate the role of PRPH in LMN degeneration, we assessed PRPH and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and serum of 91 patients with motor neuron diseases (MND) and 69 controls. Overall, we found PRPH to be more concentrated in serum than in CSF. Serum PRPH resulted significantly increased in MND patients but it was unrelated to CSF‐NfL or survival in the amyotrophic lateral sclerosis (ALS) subset. PRPH might represent a marker of LMN involvement.

Background: Hallucinations in Alzheimer’s disease (AD) have been linked to more severe cognitive and functional decline. However, research on visual hallucinations (VH), the most common type of hallucinations in AD, is limited. Objective: To investigate the cognitive and cerebral macrostructural and metabolic features associated with VH in AD. Methods: Twenty-four AD patients with VH, 24 with no VH (NVH), and 24 cognitively normal (CN) matched controls were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Differences in regional gray matter (GM) volumes and cognitive performance were investigated with whole brain voxel-based morphometry analyses of MRI structural brain scans, and analyses of neuropsychological tests. Glucose metabolic changes were explored in a sub-sample of patients who had FDG-PET scans available. Results: More severe visuoconstructive and attentional deficits were found in AD VH compared with NVH. GM atrophy and hypometabolism were detected in occipital and temporal areas in VH patients in comparison with CN. On the other hand, NVH patients had atrophy and hypometabolism mainly in temporal areas. No differences in GM volume and glucose metabolism were found in the direct comparison between AD VH and NVH. Conclusion: In addition to the pattern of brain abnormalities typical of AD, occipital alterations were observed in patients with VH compared with CN. More severe visuoconstructive and attentional deficits were found in AD VH when directly compared with NVH, and might contribute to the emergence of VH in AD.

Background Functional neurological disorders (FND) are disabling medical conditions commonly seen in neurological practice. Neurologists play an essential role in managing FND, from establishing a diagnosis to coordination of multidisciplinary team-based treatment for patients. With this study, we investigated the knowledge and the clinical experience of Italian neurologists in managing patients with FND. Methods Members of the Italian Society of Neurology were invited via e-mail to participate in this ad hoc online survey; 492 questionnaires were returned completed. Results The term “Functional neurological disorders” in reference to FND was used more frequently than other psychological (e.g., psychogenic or conversion), or descriptive terms (e.g., non-organic or stress-related). When speaking with patients, the respondents stated that they preferred explaining symptoms based on abnormal functioning of the nervous system than discussing mental illness and that they would refer their patient to a psychologist rather than to a psychiatrist. Few considered that physiotherapy and psychiatric interventions are useful approaches to treating FND. Some believed that patients simulate their symptoms. Conclusions Overall, the responses suggest that knowledge about scientific advances in FND is somewhat sparse. A psychiatric-centered view of FND opens the way to an approach in which neurobiological and psychological aspects constitute essential factors of the condition. In this context, professional education could improve understanding of FND and optimize patient management.

Older adult caregivers have compounded risk for adverse health outcomes; however, evidence investigating the association between the spectrum of the caregiving experience and frailty has been limited. In the National Study of Caregiving, we examined the cross-sectional association between caregiving experiences and both frailty and sleep disruption outcomes among caregivers. We included 621 caregivers aged 65+ who completed a phone interview, including 36 items about caregiving. Using principal component analysis, we identified three caregiving components: general burden, financial burden, and positive emotions. Frailty was assessed via low energy, shrinking, weakness, reduced activity, and poor self-rated health. Sleep disruption was assessed with two questions regarding sleep interruption and trouble falling back asleep. In age- and sex-adjusted ordinal regression models, general burden was associated with frailty (OLO=1.21, 95% CI 1.12, 1.30) and trouble falling back asleep (OLO=1.08, 95% CI 1.00, 1.17); financial burden (OLO=1.15, 95% CI 1.02, 1.31) was associated with frailty. General (OLO=1.99, 95% CI 1.38, 2.88) and financial (OLO=1.98, 95% CI 1.25, 3.14) burden were associated with sleep interruption in the fully adjusted model. Positive emotions were associated with lower odds of both frailty (OLO=0.86, 95% CI 0.74, 0.99) and sleep interruption (OLO=0.75, 95% CI 0.58, 0.98). Caregiver burden was associated with greater risk of frailty in age- and sex- adjusted models and sleep interruption when further accounting for sociodemographic and health factors. Positive emotions of caregiving were associated with decreased risk of these outcomes.

Around half of the patients with Guillain-Barré syndrome (GBS) present autonomic dysfunction requiring admission to intensive care unit in up to a quarter of patients. Treatment of GBS consists of plasma exchange (PE) and intravenous immunoglobulins (IVIG). Posterior reversible encephalopathy syndrome (PRES) consists in a reversible subcortical vasogenic brain edema caused by endothelial damage triggered by abrupt blood pressure changes. We report on a woman who presented with PRES in the course of GBS treated first with IVIG, and then with PE. The present report underlines the challenge that the clinicians face when these two rare syndromes concur. The literature is not helpful considering that both blood pressure fluctuations and IVIG are reported to be involved in the pathogenesis of PRES. In the present letter, both pathogenic mechanisms and clinical management considerations are discussed.

Objectives: Visual hallucinations (VH) are common in Lewy body disease (LBD), and have been associated with cognitive and structural brain alterations. Evidence so far concerns mainly Parkinson’s disease (PD), but little is known about symptom-specific pathophysiological mechanisms across the LBD spectrum, especially related to the presence of dementia. The aim of the present pilot study was to investigate the neuroanatomical, and neuropsychological characteristics related to VH in two forms of LBD, namely dementia with Lewy bodies (DLB) and PD without dementia. Methods: Whole brain voxel-based morphometry (VBM) analyses on 3D MRI acquired structural brain scans, and neuropsychological testing were performed on 28 clinically diagnosed DLB (11 with VH, 17 NVH), and 24 PD (9 with VH, and 15 NVH) patients. In order to assess differences in gray matter (GM) regional volumes, and cognitive performance, hallucinating patients for each group were compared with corresponding non-hallucinating ones. Results: DLB patients with VH presented significantly worse visual attention deficits compared to those without, which persisted even when controlling for visual perception. Whole brain VBM analysis revealed decreased GM volume in DLB with VH in the right superior and medial frontal gyri, putamen, caudate nucleus and insula. Subcortical regional volumes were also significantly associated with visual attention performance. Hallucinating PD patients, instead, presented more severe executive dysfunction, but VBM showed no volumetric differences between the two PD subgroups. Post hoc region of interest analyses revealed striatal GM loss in PD with VH. Conclusion: Frontal and striatal GM atrophy may contribute to the emergence of VH in DLB, which may be fostered by the more severe attention deficits. Striatal GM loss and executive dysfunction, instead, appeared to underlie VH in PD without dementia.

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We investigated in a longitudinal multicenter cohort study functional cortical connectivity changes along the course of frontotemporal dementia (FTD) and Alzheimer’s disease (AD) from the prodromal stage of the diseases. Electroencephalography (EEG) was recorded in 18 FTD and 18 AD patients at the prodromal stage of dementia, at dementia onset, and 3 years after dementia onset. Twenty healthy controls (HC) underwent EEG recordings at the same time interval as the patients. Mutual information (MI) analysis measured the strength of functional network connectivity. FTD and AD patients showed greater MI at the prodromal stage of dementia (FTD vs. HC P = 2 × 10−8; AD vs. HC P = 4 × 10–3). Local connectivity was higher in left and right frontal areas of FTD (P = 7 × 10−5 and 0.03) and in left and right posterior areas in AD (P = 3 × 10−5 and 5 × 10−5) versus HC. We showed cortical hyperconnectivity at the prodromal stage of dementia in areas involved in the specific pathological process of FTD (frontal regions) and AD (posterior regions). Hyperconnectivity disappeared during follow-up, thus suggesting that it is an early electrophysiological feature of dementia, potentially useful to identify prodromal FTD and AD.

Dementia in Lewy Body Diseases (Parkinson’s disease and dementia with Lewy Bodies) affects progression of disabilities, quality of life and well-being. Understanding its pathogenetic mechanisms is critical to properly implement disease-modifying strategies. It has been hypothesized that synuclein- and amyloid-pathology act synergistically aggravating cognitive decline in elderly patients but their precise contribution to dementia is debated. In this study, we aimed at exploring if presence of amyloid deposits influences clinical, cognitive and neuroanatomical correlates of mental decline in a cohort of 40 Parkinson’s disease patients with normal cognition (n = 5), mild cognitive impairment (n = 22), and dementia (n = 13) as well as in Dementia with Lewy Bodies (n = 10). Patients underwent simultaneous 3 T PET/MRI with [18F]-flutemetamol and were assessed with an extensive baseline motor and neuropsychological examination, which allowed level II diagnosis of mild cognitive impairment and dementia. The role of amyloid positivity on each cognitive domain, and on the rate of conversion to dementia at 1-year follow-up was explored. A Kaplan Meier and the Log Rank (Mantel–Cox) test were used to assess the pairwise differences in time-to-develop dementia in Parkinson’s disease patients with and without significant amyloidosis. Furthermore, the presence of an Alzheimer’s dementia-like morphological pattern was evaluated using visual and automated assessment of T1-weighted and T2-weighted MRI images. We observed similar percentage of amyloid deposits in Parkinson’s disease dementia and dementia with Lewy Bodies cohorts (50% in each group) with an overall prevalence of 34% of significant amyloid depositions in Lewy Body Diseases. PET amyloid positivity was associated with worse global cognition (Montreal Cognitive Assessment and Mini Mental State Examination), executive and language difficulties. At 12-month follow-up, amyloid positive Parkinson’s disease patients were more likely to have become demented than those without amyloidosis. Moreover, there was no difference in the presence of an Alzheimer’s disease-like atrophy pattern and in vascular load (at Fazekas scale) between Lewy Body Diseases with and without significant amyloid deposits. Our findings suggest that in Lewy Body Diseases, amyloid deposition enhances cognitive deficits, particularly attention-executive and language dysfunctions. However, the large number of patients without significant amyloid deposits among our cognitively impaired patients indicates that synuclein pathology itself plays a critical role in the development of dementia in Lewy Body Diseases., Biundo et al. used PET/3TMRI to study amyloidosis influence on cognition and conversion to dementia in Lewy Body disorders. A similar percentage of patients were amyloid-β negative, but general cognition was more severe and conversion to dementia was faster in amyloid-β positive. Amyloid-β contributes to cognitive decline in Lewy Body disorders., Graphical Abstract Graphical Abstract

Dementia with Lewy bodies (DLB) is a neurodegenerative disease characterized by cognitive, behavioral and motor symptoms and has a more challenging clinical management and poorer prognosis compared to other forms of dementia. The experience of lockdown leads to negative psychological outcomes for fragile people such as elderly with dementia, particularly for DLB, causing a worsening of cognitive and neuropsychiatric symptoms. Since an individual’s feeling of time passage is strongly related to their cognitive and emotional state, it is conceivable to expect alterations of this construct in people with DLB during such a difficult period. We therefore assessed the subjective experience of the passage of time for present and past time intervals (Subjective Time Questionnaire, STQ) during the lockdown due to coronavirus disease (COVID−19) in 22 patients with DLB (17 of which were re-tested in a post-lockdown period) and compared their experience with that of 14 caregivers with similar age. Patients showed a significantly slower perception of present and past time spent under lockdown restrictions. We argue that these alterations might be related to the distinctive features of DLB and their exacerbation recorded by the patients’ caregivers during the period of lockdown, though our results show that the patients’ experience of time passage in a post-lockdown period remained similarly slow. Overall, we show an impairment of the subjective perception of time passage in DLB tested during the COVID-19 lockdown. Supplementary Information The online version contains supplementary material available at 10.1007/s12144-021-01811-7.

Trazodone is indicated for the treatment of Major Depressive Disorder (MDD), often associated with anxiety, insomnia, agitation, nervousness, or irritability.The aim of this review was to summarise the pharmacological proper- ties of trazodone in improving depressive symptoms in elderly patients and in patients with neurological comorbidities, for whom secondary depression is often present.Five different pharmaceutical formulations of trazodone are available: intravenous or intramuscular liquid solution, immediate-release tablets (I.R.), oral drops, prolonged-release tablets (P.R.), and extended-release Contramid® tablets (COAD). The initial dose of trazodone should range from 75 to 100 mg/day. For COAD formulation, the starting recom- mended dose is 150 mg once daily. In elderly patients, trazodone may be administered at very low dosages (25-50 mg/day for I.R. formula- tion, and 50-100 mg for the P.R. or E.R. formulations). The maximum daily dose should not exceed 300 mg/day, split over two administra- tions across the day.In elderly patients, trazodone has reported excellent results, keeping high-quality standards for safety and tolerability. It can help to improve insomnia and anxiety without resorting to benzodiazepines. In patients with neurological conditions, trazodone helps to treat anxiety-depres- sive symptoms. In patients with Alzheimer’s disease or frontotemporal dementia, trazodone can help to handle behavioural symptoms, also acting as a putative neuroprotective agent.Trazodone is well tolerated. Somnolence/sedation, dizziness, consti- pation, and blurred vision are common side effects with an incidence slightly greater than 5%. Orthostatic hypotension and headache are relatively common side effects.The great availability of formulations allows to personalise trazodone administration according to patient profile characteristics.

Functional alterations of the visual attention networks in a setting of impaired visual information processing have a role in the genesis of visual hallucinations (VH) in dementia with Lewy bodies (DLB). This multimodal MRI study aims at exploring structural and functional basis of VH.23 DLB patients (10 with and 13 without VH) and 13 healthy controls were studied. They underwent MRI with T1-w sequences to measure cortical thickness, DTI for whole-brain and single tract microstructural properties and rs-fMRI of the default mode, dorsal and ventral attention, and visual networks.In DLB with VH, whole-brain DTI revealed a lower fractional anisotropy and a greater mean diffusivity in the right frontal and temporo-parietal white matter tracts. Tracts dissection showed lower fractional anisotropy in the right inferior and superior (ventral part) longitudinal fasciculi (ILF and SLF) (p .05, corrected), and greater mean diffusivity (p .05). The extent of white matter microstructural alterations involving the right ILF and SLF correlated with the severity of VH (r = .55, p .01; r = .42, p .05, respectively), and with performance in the visual attention task (r = -.56 and r = -.61; p .01, respectively). Cortical thickness in the projection areas of the right SLF was significantly reduced (p .05). Patients with VH also showed an altered functional connectivity in the ventral attention network, connected by the ventral portion of the SLF (p .05).Our findings suggest that a combination of microstructural and functional alterations involving the attention networks in the right hemisphere may be important in the genesis of VH.

Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic literature review was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs-fMRI. We included studies investigating connectivity in presymptomatic (pre-HD) and manifest HD gene carriers compared to healthy controls, implementing seed-based connectivity, independent component analysis, regional property, and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre-HD, showing disease stage-dependent changes. Cognitive networks underlying executive and attentional functions showed divergent anterior-posterior alterations, possibly reflecting compensatory mechanisms. The involvement of these networks in pre-HD is still unclear. In conclusion, aberrant connectivity of the sensory-motor network is observed in the early stage of HD while, as pathology spreads, other networks might be affected, such as the visual and executive/attentional networks. Moreover, sensory-motor and executive networks exhibit hyper- and hypo-connectivity patterns following different spatiotemporal trajectories. These findings could potentially help to implement future huntingtin-lowering interventions. ispartof: HUMAN BRAIN MAPPING vol:41 issue:1 pages:256-269 ispartof: location:United States status: published