Prevalence, treatment, and neural correlates of apathy in different forms of dementia: a narrative review.

OBJECTIVES: The aim of this review is to provide an overview on prevalence and clinical tools for the diagnosis of apathy, as well as on neurophysiological and neuroimaging findings obtained from studies in patients with apathy in different forms of dementia, including Alzheimer's disease (AD), vascular (VaD) and mixed dementia, frontotemporal dementia (FTD), and Parkinson's disease dementia (PDD). METHODS: Randomized controlled trials, non-randomized controlled trials, controlled before-after studies, and interrupted time series from four databases (WebOfScience, Scopus, Pubmed, and PsycINFO) addressing apathy in adults or older people aged over 65 years of age affected by dementia were included. RESULTS: The prevalence of apathy was 26-82% for AD, 28.6-91.7 for VaD, 29-97.5% in PDD, and 54.8-88.0 in FTD. The assessment of apathy was not consistent in the reviewed studies. Methylphenidate was the most successful pharmacological treatment for apathy. Neurobiological studies highlighted the relationship between both structural and functional brain areas and the presence or severity of apathy. CONCLUSION: Apathy is a very common disorder in all types of dementia, although it is often underdiagnosed and undertreated. Further studies are needed to investigate its diagnosis and management. A consensus on the different evaluation scales should be achieved.

Prediction of rehabilitation induced motor recovery after stroke using a multi-dimensional and multi-modal approach.

Background: Stroke is a debilitating disease affecting millions of people worldwide. Despite the survival rate has significantly increased over the years, many stroke survivors are left with severe impairments impacting their quality of life. Rehabilitation programs have proved to be successful in improving the recovery process. However, a reliable model of sensorimotor recovery and a clear identification of predictive markers of rehabilitation-induced recovery are still needed. This article introduces the cross-modality protocols designed to investigate the rehabilitation treatment's effect in a group of stroke survivors. Methods/design: A total of 75 stroke patients, admitted at the IRCCS San Camillo rehabilitation Hospital in Venice (Italy), will be included in this study. Here, we describe the rehabilitation programs, clinical, neuropsychological, and physiological/imaging [including electroencephalography (EEG), transcranial magnetic stimulation (TMS), and magnetic resonance imaging (MRI) techniques] protocols set up for this study. Blood collection for the characterization of predictive biological biomarkers will also be taken. Measures derived from data acquired will be used as candidate predictors of motor recovery. Discussion/summary: The integration of cutting-edge physiological and imaging techniques, with clinical and cognitive assessment, dose of rehabilitation and biological variables will provide a unique opportunity to define a predictive model of recovery in stroke patients. Taken together, the data acquired in this project will help to define a model of rehabilitation induced sensorimotor recovery, with the final aim of developing personalized treatments promoting the greatest chance of recovery of the compromised functions.

Investigating the Effects of a Focal Muscle Vibration Protocol on Sensorimotor Integration in Healthy Subjects.

Background: The ability to perceive two tactile stimuli as asynchronous can be measured using the somatosensory temporal discrimination threshold (STDT). In healthy humans, the execution of a voluntary movement determines an increase in STDT values, while the integration of STDT and movement execution is abnormal in patients with basal ganglia disorders. Sensorimotor integration can be modulated using focal muscle vibration (fMV), a neurophysiological approach that selectively activates proprioceptive afferents from the vibrated muscle. Method: In this study, we investigated whether fMV was able to modulate STDT or STDT-movement integration in healthy subjects by measuring them before, during and after fMV applied over the first dorsalis interosseous, abductor pollicis brevis and flexor radialis carpi muscles. Results: The results showed that fMV modulated STDT-movement integration only when applied over the first dorsalis interosseous, namely, the muscle performing the motor task involved in STDT-movement integration. These changes occurred during and up to 10 min after fMV. Differently, fMV did not influence STDT at rest. We suggest that that fMV interferes with the STDT-movement task processing, possibly disrupting the physiological processing of sensory information. Conclusions: This study showed that FMV is able to modulate STDT-movement integration when applied over the muscle involved in the motor task. This result provides further information on the mechanisms underlying fMV, and has potential future implications in basal ganglia disorders characterized by altered sensorimotor integration.

Frailty and hyperactive delirium in hospitalized older patients with COVID-19: an insight from GeroCovid registry.

BACKGROUND: Delirium is an acute neuropsychiatric condition associated with unfavourable outcomes, frequent in older hospitalized people. In the context of the SARS-CoV-2 pandemic, few studies have specifically focused on the inflammatory status of older, frail patients with hyperactive delirium (HD) hospitalized for COVID-19. AIM: To identify biological correlates of HD at hospital admission and to assess the independent effect of delirium and physical frailty on in-hospital mortality. METHODS: Data were retrospectively extracted by the multicenter registry GeroCovid Observational Study. Individuals aged ≥ 60 years were included if the information on the presence of HD, frailty based on the modified Fried criteria and inflammatory status had been collected. The risk of mortality was evaluated using a Kaplan-Meier estimator, according to frailty and delirium. Logistic and restricted cubic-spline regressions were employed to assess the relationship between inflammatory markers and HD. RESULTS: Three-hundred-thirty-seven older adults were included in the analysis [mean age (SD) 77.1 (9.5) years, 50.1% females], and 11.5% presented with HD. A significant association of both PaO2/FiO2 ratio (p = 0.015) and serum lactate dehydrogenase (p = 0.04) with delirium was observed. By Cox multivariable regression, frail and non-frail patients with HD had a 4.42 and 2.85 higher mortality risk compared with non-frail, non-delirious patients. CONCLUSIONS: Hyperactive delirium at hospital admission is related with markers of lung failure among older adults, especially when physical frailty coexists. Delirium is associated with increased in-hospital mortality risk, which is doubled by the coexistence of physical frailty.

Health trajectories in older patients hospitalized for COVID-19: Results from the GeroCovid multicenter study.

BACKGROUND: COVID-19 has disproportionately affected older adults. Yet, healthcare trajectories experienced by older persons hospitalized for COVID-19 have not been investigated. This study aimed at estimating the probabilities of transitions between severity states in older adults admitted in COVID-19 acute wards and at identifying the factors associated with such dynamics. METHODS: COVID-19 patients aged ≥60 years hospitalized between March and December 2020 were involved in the multicentre GeroCovid project-acute wards substudy. Sociodemographic and health data were obtained from medical records. Clinical states during hospitalization were categorized on a seven-category scale, ranging from hospital discharge to death. Based on the transitions between these states, first, we defined patients' clinical course as positive (only improvements), negative (only worsening), or fluctuating (both improvements and worsening). Second, we focused on the single transitions between clinical states and estimated their probability (through multistage Markov modeling) and associated factors (with proportional intensity models). RESULTS: Of the 1024 included patients (mean age 78.1 years, 51.1% women), 637 (62.2%) had a positive, 66 (6.4%) had a fluctuating, and 321 (31.3%) had a negative clinical course. Patients with a fluctuating clinical course were younger, had better mobility and cognitive levels, fewer diseases, but a higher prevalence of cardiovascular disease and obesity. Considering the single transitions, the probability that older COVID-19 patients experienced clinical changes was higher within a 10-day timeframe, especially for milder clinical states. Older age, male sex, lower mobility level, multimorbidity, and hospitalization during the COVID-19 first wave (compared with the second one) were associated with an increased probability of progressing towards worse clinical states or with a lower recovery. CONCLUSION: COVID-19 in older inpatients has a complex and dynamic clinical course. Identifying individuals more likely to experience a fluctuating clinical course and sudden worsening may help organize healthcare resources and clinical management across settings at different care intensity levels.

Depression in People With Dementia and Caregiver Outcomes: Results From the European Right Time Place Care Study.

OBJECTIVE: To investigate the cross-sectional associations between depression in people with dementia and both caregiver burden and quality of life in 8 European countries, and to test these associations compared with the presence of other neuropsychiatric symptoms. DESIGN: Cross-sectional study. SETTING AND PARTICIPANTS: In total, 1223 dyads comprised of informal caregivers and people with dementia living in a community-dwelling setting, recruited from the Right Time Place Care study, a cohort survey from 8 European countries. MEASURES: To test the associations between depression (according to the Cornell Scale for Depression in Dementia) and informal caregiver burden (defined by the Zarit scale and hours of supervision in terms of Resource Utilization in Dementia), distress (defined by the Neuropsychiatric Inventory Questionnaire distress score), and quality of life (according to the visual analogue scale and 12-item General Health Questionnaire). RESULTS: Linear regressions showed an association between depression and main outcomes (Zarit scale: ß 3.7; P = .001; hours of supervision: ß 1.7; P = .004; Neuropsychiatric Inventory Questionnaire distress score: ß 1.2; P = .002). A similar association was found concerning psychological and overall well-being (12-item General Health Questionnaire: ß 1.8; P < .001; Euroqol Visual Analogue Scale: ß -4.1; P = .003). Both associations remained significant despite the presence of other NPS and after adjusting for confounders. CONCLUSIONS AND IMPLICATIONS: Further studies are needed to assess whether providing tailored strategies for optimizing diagnosis and managing of depression in people with dementia might improve caregiver quality of life and reduce their burden in the community-dwelling setting.

The association between apathy and frailty in older adults: a new investigation using data from the Mapt study.

INTRODUCTION: Apathy is a behavioral syndrome that has been suggested to share similar neuro-physiological pathways with frailty. OBJECTIVE: To investigate the cross-sectional association between apathy and frailty using original data from dementia-free, community-dwelling older adults. METHOD: A cross-sectional analysis was performed to test the association between frailty (according to Fried's frailty phenotype) and apathy (defined by three items from Geriatric Depression Scale) using data from MAPT, a 3-year, randomized, multicenter, placebo-controlled trial among community-dwelling, dementia-free participants (1.679 individuals with mean age of 75 years). RESULTS: The ordinal logistic regression showed that apathetic individuals had a two-fold more probability to be rated as frail (OR 2.20, 95% CI 1.7-2.9), when adjusting for confounders. Apathetic individuals display a two-fold more likelihood to be rated as pre-frail (RRR 2.1; 95% CI 1.5-2.8) and a three-fold higher probability to be rated as frail (RRR 3.5, 95% CI 1.8-6.9) compared to robust participants. CONCLUSION: Although data on the associations between apathy and frailty are scarce, these conditions potentially shares physiological mechanisms and were found to be closely associated. Temporal association between frailty and apathy deserve to be further investigated.

Arrhythmic Risk in Elderly Patients Candidates to Transcatheter Aortic Valve Replacement: Predictive Role of Repolarization Temporal Dispersion.

BACKGROUND/AIM: Degenerative aortic valve stenosis (AS) is associated to ventricular arrhythmias and sudden cardiac death, as well as mental stress in specific patients. In such a context, substrate, autonomic imbalance as well as repolarization dispersion abnormalities play an undoubted role. Aim of the study was to evaluate the increase of premature ventricular contractions (PVC) and complex ventricular arrhythmias during mental stress in elderly patients candidate to the transcatheter aortic valve replacement (TAVR). METHODS: In eighty-one elderly patients with AS we calculated several short-period RR- and QT-derived variables at rest, during controlled breathing and during mild mental stress, the latter being represented by a mini-mental state evaluation (MMSE). RESULTS: All the myocardial repolarization dispersion markers worsened during mental stress (p < 0.05). Furthermore, during MMSE, low frequency component of the RR variability increased significantly both as absolute power (LFRR) and normalized units (LFRRN U) (p < 0.05) as well as the low-high frequency ratio (LFRR/HFRR) (p < 0.05). Eventually, twenty-four (30%) and twelve (15%) patients increased significantly PVC and, respectively, complex ventricular arrhythmias during the MMSE administration. At multivariate logistic regression analysis, the standard deviation of QTend (QTesd), obtained at rest, was predictive of increased PVC (odd ratio: 1.54, 95% CI 1.14-2.08; p = 0.005) and complex ventricular arrhythmias (odd ratio: 2.31, 95% CI 1.40-3.83; p = 0.001) during MMSE. The QTesd showed the widest sensitive-specificity area under the curve for the increase of PVC (AUC: 0.699, 95% CI: 0.576-0.822, p < 0.05) and complex ventricular arrhythmias (AUC: 0.801, 95% CI: 0.648-0.954, p < 0.05). CONCLUSION: In elderly with AS ventricular arrhythmias worsened during a simple cognitive assessment, this events being a possible further burden on the outcome of TAVR. QTesd might be useful to identify those patients with the highest risk of ventricular arrhythmias. Whether the TAVR could led to a QTesd reduction and, hence, to a reduction of the arrhythmic burden in this setting of patients is worthy to be investigated.

Possible predictive role of electrical risk score on transcatheter aortic valve replacement outcomes in older patients: preliminary data.

OBJECTIVES: To evaluate the predicative power of the electrical risk score (ERS), a noninvasive and inexpensive test obtained by means of a standard 12-lead electrocardiogram (ECG), in a cohort of elderly patients who had undergone transcatheter aortic valve replacement (TAVR). METHODS: Survivors and non-survivors after TAVR at 1-year follow-up were compared in respect to the pre-procedural ERS as well as a number of other clinical and instrumental variables. ERS is composed of seven simple ECG markers: heart rate (>75 bpm); QRS duration (>110 ms); left ventricular hypertrophy (Sokolow-Lyon criteria); delayed QRS transition zone (≥ V4); frontal QRS-T angle (>90°); long QTBazett (>450 ms for men and >460 in women) or JTBazett (330 ms for men and >340 ms for women); and long Tpeak to Tend interval (Tp-e) (>89 ms). The trial was registered in ClinicalTrials.gov as NCT03145376. RESULTS: A total of 40 patients were evaluated. During the follow-up, the all-cause mortality rate was 25% (ten patients) with 15% of cardiovascular death (six patients). The ERS was the strongest predictor of all-cause (odds ratio 3.73, 95% CI: 1.44-9.66, P<0.05) or cardiovascular (odds ratio 3.95, 95% CI: 1.09-14.27, P<0.05) mortality. Receiver operating characteristic curves showed that ERS had the widest significant sensitivity-specificity area under the curve (AUC) predicting all-cause (AUC: 0.855, P<0.05) or cardiovascular mortality (AUC: 0.908, P<0.05). CONCLUSION: ERS seems to be a useful noninvasive tool able to stratify the risk of mortality in 1-year follow-up of TAVR patients. These findings, however, require larger trials to be confirmed.

Oscillatory behavior of P wave duration and PR interval in experimental congestive heart failure: a preliminary study.

OBJECTIVE: The relationship between the autonomic nervous system (ANS) modulation of the sinus node and heart rate variability has been extensively investigated. The current study sought to evaluate, in an animal experimental model of pacing-induced tachycardia congestive heart failure (CHF), a possible ANS influence on the P wave duration and PR interval oscillations. APPROACH: Short-term (5 min) time and frequency domain analysis has been obtained in six dogs for the following electrocardiographic intervals: P wave duration (P), from the onset to peak of P wave (P p), from the onset of P wave to the q onset (PR) and from the end of P wave to the onset of q wave (P e R). Direct vagal nerve activity (VNA), stellate ganglion nerve activity (SGNA) and electrocardiogram (ECG) intervals have been evaluated contextually by implantation of three bipolar recording leads. MAIN RESULTS: At the baseline, multiple regression analysis pointed out that VNA was strongly positively associated with the standard deviation of PP and P e R intervals (r 2:0.997, p < 0.05). The same variable was also positively associated with high-frequency (HF) of P expressed in normalized units, of P p, and of P e R (b: 0.001) (r 2: 0.993; p < 0.05). During CHF, most of the time and frequency domain variability significantly decreased from 20% to 50% in comparison to the baseline values (p < 0.05) and SGNA correlated inversely with the low frequency (LF) obtained from P e R (p < 0.05) and PR (p < 0.05) (r 2:0.899, p < 0.05). LF components, expressed in absolute and normalized power, obtained from all studied intervals, were reduced significantly during CHF. Any difference between the RR and PP spectral components was observed. SIGNIFICANCE: The data showed a significant relationship between ANS and atrial ECG variables, independent of the cycle duration. In particular, the oscillations were vagal mediated at the baseline, while sympathetic mediated during CHF. Whereas P wave variability might have a clinical utility in CHF management, it needs to be addressed in specific studies.

Transcranial direct current stimulation enhances soothing positive affect and vagal tone.

Transcranial Direct Current Stimulation (tDCS) is a promising tool for the treatment of depression and the dorsolateral prefrontal cortex (dlPFC) is often targeted when exploring tDCS effects on mood. However, the basic effects of tDCS on momentary emotions are inconsistent. We tested whether a single-session of anodal tDCS over the left temporal lobe (T3), topographically closer to the insular cortex than dlPFC, had effects on both vagally-mediated heart rate variability (HRV) and momentary affect in healthy participants. Thirty-four subjects underwent both sham and active tDCS in a counterbalanced random order. ECG was continuously recorded to derive both time and frequency domain HRV indexes. Before and after the tDCS protocol, participants completed momentary affect assessments. Results showed that HRV and soothing positive affectivity were both enhanced after a single-session of tDCS over T3, while negative and activating positive affect were not modulated by the stimulation. After controlling for sex, age, and levels of anxiety and depression a significant association emerged between increases in soothing positive affect and concomitant increases in vagally-mediated HRV. Deficits in soothing positive emotions have consistently been associated with psychopathology and psychotherapeutic approaches aimed to develop this type of emotionality have shown to improve psychological well-being. Thus, present exploratory results may impact future research investigating potential moderators (site of stimulation) and mediators (specificity for a determined type of momentary affect) of the effects of tDCS on psychopathological conditions such as depression.

Transcranial direct current stimulation improves the QT variability index and autonomic cardiac control in healthy subjects older than 60 years.

BACKGROUND: Noninvasive brain stimulation technique is an interesting tool to investigate the causal relation between cortical functioning and autonomic nervous system (ANS) responses. OBJECTIVE: The objective of this report is to evaluate whether anodal transcranial direct current stimulation (tDCS) over the temporal cortex influences short-period temporal ventricular repolarization dispersion and cardiovascular ANS control in elderly subjects. SUBJECTS AND METHODS: In 50 healthy subjects (29 subjects younger than 60 years and 21 subjects older than 60 years) matched for gender, short-period RR and systolic blood pressure spectral variability, QT variability index (QTVI), and noninvasive hemodynamic data were obtained during anodal tDCS or sham stimulation. RESULTS: In the older group, the QTVI, low-frequency (LF) power expressed in normalized units, the ratio between LF and high-frequency (HF) power, and systemic peripheral resistances decreased, whereas HF power expressed in normalized units and α HF power increased during the active compared to the sham condition (P<0.05). CONCLUSION: In healthy subjects older than 60 years, tDCS elicits cardiovascular and autonomic changes. Particularly, it improves temporal ventricular repolarization dispersion, reduces sinus sympathetic activity and systemic peripheral resistance, and increases vagal sinus activity and baroreflex sensitivity.