Real-life management of patients with mild cognitive impairment: an Italian survey.

BACKGROUND: Mild cognitive impairment (MCI) is a syndrome with heterogeneous underlying causes and different rates of disease progression, whose clinical heterogeneity leads to a wide variation in diagnostic and therapeutic approaches in clinical practice. The lack of uniform practical recommendations on diagnostic workup and treatment for MCI patients hinders optimal management of these patients, worsening their prognosis. Standardized guidelines for the investigation and follow-up of MCI are therefore urgently required. AIM: Aim of our study was to assess the diagnostic and therapeutic approach to MCI patients in the setting of Italian Memory Clinics. METHODS: A survey was delivered to a sample of Italian neurologists through two different phases: a first exploratory phase recording general information about the usual clinical management of patients with MCI, and a subsequent operative phase assessing the practical diagnostic and therapeutic decisions taken in a real life setting to manage subjects with MCI. RESULTS: A total of 121 neurologists participated to the first phase of the survey and 203 patients were enrolled in the second phase. Information gathered in the first phase of the survey highlighted a non-uniform use of diagnostic criteria and procedures for MCI, as well as a very heterogeneous therapeutic strategy among Italian neurologists. In the second phase, recorded data on diagnostic and therapeutic approach confirmed the large variability observed in the first phase of the survey. CONCLUSIONS: The results of our study reflect a suboptimal management of MCI patients in Italy and highlight the need of standardized diagnostic and therapeutic approaches for this condition.

Data-driven analysis of regional brain metabolism in behavioral frontotemporal dementia and late-onset primary psychiatric diseases with frontal lobe syndrome: A PET/MRI study.

Late-onset primary psychiatric disease (PPD) and behavioral frontotemporal dementia (bvFTD) present with a similar frontal lobe syndrome. We compare brain glucose metabolism in bvFTD and late-onset PPD and investigate the metabolic correlates of cognitive and behavioral disturbances through FDG-PET/MRI. We studied 37 bvFTD and 20 late-onset PPD with a mean clinical follow-up of three years. At baseline evaluation, metabolism of the dorsolateral, ventrolateral, orbitofrontal regions and caudate could classify the patients with a diagnostic accuracy of 91% (95% CI: 0.81-0.98%). 45% of PPD showed low-grade hypometabolism in the anterior cingulate and/or parietal regions. Frontal lobe metabolism was normal in 32% of genetic bvFTD and bvFTD with motor neuron signs. Hypometabolism of the frontal and caudate regions could help in distinguishing bvFTD from PPD, except in cases with motor neuron signs and/or genetic bvFTD for which brain metabolism may be less informative.

Detection of TDP-43 seeding activity in the olfactory mucosa from patients with frontotemporal dementia.

INTRODUCTION: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis. METHODS: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants. RESULTS: TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P < 0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected. DISCUSSION: TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients.

MRI abnormalities in Creutzfeldt-Jakob disease and other rapidly progressive dementia.

OBJECTIVE: To investigate brain MRI abnormalities in a cohort of patients with rapidly progressive dementia (RPD) with and without a diagnosis of Creutzfeldt-Jakob disease (CJD). METHODS: One hundred and seven patients with diagnosis of prion disease (60 with definite sCJD, 33 with probable sCJD and 14 with genetic prion disease) and 40 non-prion related RPD patients (npRPD) underwent brain MRI including DWI and FLAIR. MRIs were evaluated with a semiquantitative rating score, which separately considered abnormal signal extent and intensity in 22 brain regions. Clinical findings at onset, disease duration, cerebrospinal-fluid 14-3-3 and t-tau protein levels, and EEG data were recorded. RESULTS: Among patients with definite/probable diagnosis of CJD or genetic prion disease, 2/107 had normal DWI-MRI: in one patient a 2-months follow-up DWI-MRI showed CJD-related changes while the other had autopsy-proven CJD despite no DWI abnormalities 282 days after clinical onset. CJD-related cortical changes were detected in all lobes and involvement of thalamus was common. In the npRPD groups, 6/40 patients showed DWI alterations that clustered in three different patterns: (1) minimal/doubtful signal alterations (limbic encephalitis, dementia with Lewy bodies); (2) clearly suggestive of alternative diagnoses (status epilepticus, Wernicke or metabolic encephalopathy); (3) highly suggestive of CJD (mitochondrial disease), though cortical swelling let exclude CJD. CONCLUSIONS: In the diagnostic work-up of RPD, negative/doubtful DWI makes CJD diagnosis rather unlikely, while specific DWI patterns help differentiating CJD from alternative diagnoses. The pulvinar sign is not exclusive of the variant form.

Episodic Memory in Amnestic Behavioral Frontotemporal Dementia and Alzheimer's Disease.

Behavioral frontotemporal dementia (bvFTD) may present with episodic memory deficits. In 38 patients with bvFTD and 61 with Alzheimer's disease (AD) specific measures of verbal memory (learning curves and serial position effects) were studied through the Rey Auditory Verbal Learning test. Forty-two percent of bvFTD showed deficits of delayed recall memory similar to that found in AD including the serial position effects. Amnestic bvFTD had more severe atrophy in the left mesial temporal lobe than non-amnestic bvFTD. AD-like memory deficits are not infrequent in bvFTD and may be in part related to mesial temporal lobe atrophy.

Case report: Multiple disconnection patterns revealed by a multi-modal analysis explained behavior after a focal frontal damage.

Introduction: There is overwhelming evidence that focal lesions cause structural, metabolic, functional, and electrical disconnection of regions directly and indirectly connected with the site of injury. Unfortunately, methods to study disconnection (positron emission tomography, structural and functional magnetic resonance imaging, electroencephalography) have been applied primarily in isolation without capturing their interaction. Moreover, multi-modal imaging studies applied to focal lesions are rare. Case report: We analyzed with a multi-modal approach the case of a patient presenting with borderline cognitive deficits across multiple domains and recurrent delirium. A post-surgical focal frontal lesion was evident based on the brain anatomical MRI. However, we were able to acquire also simultaneous MRI (structural and functional) and [18F]FDG using a hybrid PET/MRI scan along with EEG recordings. Despite the focality of the primary anatomical lesion, structural disconnection in the white matter bundles extended far beyond the lesion and showed a topographical match with the cortical glucose hypometabolism seen both locally and remotely, in posterior cortices. Similarly, a right frontal delta activity near/at the region of structural damage was associated with alterations of distant occipital alpha power. Moreover, functional MRI revealed even more widespread local and distant synchronization, involving also regions not affected by the structural/metabolic/electrical impairment. Conclusion: Overall, this exemplary multi-modal case study illustrates how a focal brain lesion causes a multiplicity of disconnection and functional impairments that extend beyond the borders of the anatomical irrecoverable damage. These effects were relevant to explain patient's behavior and may be potential targets of neuro-modulation strategies.

Redefinition of dementia care in Italy in the era of amyloid-lowering agents for the treatment of Alzheimer's disease: an expert opinion and practical guideline.

No disease-modifying therapies are currently available for Alzheimer's disease (AD) in Europe. Current evidence from clinical trials testing anti-beta amyloid (Aß) 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-Aß 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-Aß mAbs were discussed.

How both positive and burdensome caregiver experiences are associated with care recipient cognitive performance: Evidence from the National Health and Aging Trends Study and National Study of Caregiving.

Introduction: Being an informal caregiver to a person with chronic disease, including persons living with dementia (PLWD), is a big role to take on and many caregivers experience both substantial burden and emotional reward related to caregiving. Care recipient factors (e.g., behavioral symptoms) are associated with caregiver experience. However, the relationship between caregiver and care recipient is bidirectional, so it is likely that caregiver factors impact the care recipient, though few studies have investigated this. Methods: In the 2017 round of the National Health and Aging Trends Study (NHATS) and National Study of Caregiving (NSOC), we studied 1,210 care dyads--170 PLWD dyads and 1,040 without dementia dyads. Care recipients completed immediate and delayed word list memory tasks, the Clock Drawing Test, and a self-rated memory rating, while caregivers were interviewed about their caregiving experiences using a 34-item questionnaire. Using principal component analysis, we created a caregiver experience score with three components-Practical Care Burden, Positive Care Experiences, and Emotional Care Burden. We then investigated the cross-sectional association between caregiver experience components and care recipient cognitive test performance using linear regression models adjusted for age, sex, education, race, and depressive and anxiety symptoms. Results: Among PLWD dyads, a higher caregiver Positive Care Experiences score was associated with better care recipient performance on the delayed word recall (B = 0.20, 95% CI 0.05, 0.36) and Clock Draw (B = 0.12, 95% CI 0.01, 0.24) tests while higher Emotional Care Burden score was associated with worse self-rated memory score (B = -0.19, 95% CI -0.39, -0.003). Among participants without dementia, higher Practical Care Burden score was associated with poorer care recipient performance on the immediate (B = -0.07, 95% CI -0.12, -0.01) and delayed (B = -0.10, 95% CI -0.16, -0.05) word recall tests. Discussion: These findings support the concept that caregiving is bidirectional within the dyad and that positive variables can positively impact both members of the dyad. This suggests that caregiving interventions should target the caregiver and recipient both individually and as a unit, with the goal of holistically improving outcomes for both.

Patients with Alzheimer's disease dementia show partially preserved parietal 'hubs' modeled from resting-state alpha electroencephalographic rhythms.

Introduction: Graph theory models a network by its nodes (the fundamental unit by which graphs are formed) and connections. 'Degree' hubs reflect node centrality (the connection rate), while 'connector' hubs are those linked to several clusters of nodes (mainly long-range connections). Methods: Here, we compared hubs modeled from measures of interdependencies of between-electrode resting-state eyes-closed electroencephalography (rsEEG) rhythms in normal elderly (Nold) and Alzheimer's disease dementia (ADD) participants. At least 5 min of rsEEG was recorded and analyzed. As ADD is considered a 'network disease' and is typically associated with abnormal rsEEG delta (<4 Hz) and alpha rhythms (8-12 Hz) over associative posterior areas, we tested the hypothesis of abnormal posterior hubs from measures of interdependencies of rsEEG rhythms from delta to gamma bands (2-40 Hz) using eLORETA bivariate and multivariate-directional techniques in ADD participants versus Nold participants. Three different definitions of 'connector' hub were used. Results: Convergent results showed that in both the Nold and ADD groups there were significant parietal 'degree' and 'connector' hubs derived from alpha rhythms. These hubs had a prominent outward 'directionality' in the two groups, but that 'directionality' was lower in ADD participants than in Nold participants. Discussion: In conclusion, independent methodologies and hub definitions suggest that ADD patients may be characterized by low outward 'directionality' of partially preserved parietal 'degree' and 'connector' hubs derived from rsEEG alpha rhythms.

Subjective experience of time in dementia with Lewy bodies during COVID-19 lockdown.

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.

Positive Aspects of Caregiving Are Associated With Lower Risk of Frailty and Sleep Disruption in the National Study of Caregiving.

Background and Objectives: Older adult caregivers have compounded risk for adverse health outcomes; however, evidence investigating the association between caregiving and frailty has been limited. In the National Study of Caregiving (NSOC), we examined the cross-sectional association between caregiving experiences and frailty and sleep disruption. Research Design and Methods: We included 621 caregivers aged 65 and older from the 2011 NSOC round. They completed a phone interview, including 36 items about caregiving. Using principal component analysis, we identified 3 caregiving components: general burden, positive emotions, and financial-led burden. Frailty was assessed via low energy, shrinking, weakness, reduced activity, and poor self-rated health. Sleep disruption was assessed with 2 questions regarding sleep interruption and trouble falling back asleep. Results: In models adjusted for age, sex, education, depression and anxiety symptoms, and medical conditions, positive emotions were associated with a reduced relative risk of frailty (relative risk [RR] = 0.94, 95% confidence interval [CI] 0.90, 0.99) while general burden (proportional odds ratio [POR] = 1.96, 95% CI 1.30, 2.93) and financial-led burden (POR = 1.94, 95% CI 1.22, 3.06) were associated with sleep interruption. Discussion and Implications: Caregiver burden was associated with increased frailty and sleep interruption. Positive emotions were associated with decreased frailty risk. Interventions aimed at reducing the burden and increasing positive emotions in caregivers may improve frailty outcomes.

A Multimodal Neuroimaging and Neuropsychological Study of Visual Hallucinations in Alzheimer's Disease.

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.

A comparison of advanced semi-quantitative amyloid PET analysis methods.

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 < 0.05). 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.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

Depression, Anxiety and Sleep Alterations in Caregivers of Persons With Dementia After 1-Year of COVID-19 Pandemic.

BACKGROUND: Social isolation due to COVID-19 pandemic has an important psychological impact particularly in persons with dementia and their informal caregivers. AIM: To assess frequency and severity of long-term stress-related symptoms in caregivers of patients with dementia 1-year after the beginning of COVID-19 pandemic and to identify predictors of psychological outcomes. METHODS: Eighty-five caregivers were involved in a longitudinal study with 1-year follow-up during pandemic in Italy. At baseline in April 2020 a telephone interview assessed socio-demographic characteristics of caregivers and self-perception of distress symptoms. After 1 year, between March and April 2021, the same standardized interview was delivered to the caregivers' sample. In addition, scales assessing levels of depression and anxiety (DASS-21), sleep disturbances (PSQI) and coping strategies (COPE-NVI) were administered to the caregivers and to 50 age and sex-matched non-caregivers subjects. Linear regression analysis was performed to investigate the power of baseline variables to predict long-term psychological outcomes. RESULTS: After 1 year of pandemic frequency of caregivers' stress-related symptoms increased respect to baseline: depression (60 vs. 5, 9%; p < 0.001), anxiety (45, 9 vs. 29, 4%; p = 0.035), irritability (49, 4 vs. 24, 7%; p < 0.001), and anguish (31, 7 vs. 10, 6%; p < 0.001). Frequency of severe depression was higher in caregivers than in non-caregivers (p = 0.002) although mean levels of depression were comparable in the two groups. Long-term higher depression was predicted by a model built on baseline information (r2 = 0.53, p < 0.001) where being female (t = -3.61, p < 0.001), having lower education (t = -2.15, p = 0.04), presence of feelings of overwhelm (t = 2.29, p = 0.02) and isolation (t = 2.12, p = 0.04) were significant predictors. Female sex was also predictive of anxiety (t = -2.7, p = 0.01) and poor sleep quality (t = -2.17, p = 0.03). DISCUSSION: At 1 year follow-up caregivers of patients with dementia reported higher prevalence of all stress-related symptoms respect to the acute phase of lockdown, particularly depression. Long-lasting stressful conditions may cause exhaustion of resilience factors and increased depression. Planning interventions should support caregivers to enable them to continue with their role during pandemic.