Neuropsychiatric symptoms and ApoE genotype in older adults without dementia: a cross-sectional study.

BACKGROUND: The ApoE genotype and neuropsychiatric symptoms (NPS) are known risk factors for cognitive decline in older adults. However, the interaction between these variables is still unclear. The aim of this study was to determine the association between the presence of the ApoE ε4 allele and the occurrence of NPS in older adults without dementia. METHODS: In this cross-sectional investigation we determined the apolipoprotein E (ApoE) genotype of 74 older adults who were either cognitively normal (20.3% / Clinician Dementia Rating Scale (CDR): 0) or had mild cognitive impairment (MCI: 79.7% / CDR: 0.5). We used a comprehensive cognitive assessment protocol, and NPS were estimated by the Neuropsychiatric Inventory-Clinician Rating Scale (NPI-C), Mild Behavioural Impairment-Checklist (MBI-C), Hamilton Rating Scale for Depression (HAM-D), and Apathy Inventory. RESULTS: ApoE ε4 carriers had higher MBI-C total scores than ApoE ε4 noncarriers. Correlations between NPS and ApoE genotype were observed for two NPI-C domains, although in opposite directions: the ApoE ε4 allele was associated with a 1.8 unit decrease in the estimated aberrant motor disturbance score and with a 1.3 unit increase in the estimated appetite/eating disorders score. All fitted models were significant, except for the one fitted for the domain delusions from the NPI-C. Among individuals with amnestic MCI, ε4 carriers presented higher depression score (HAM-D) than noncarriers; in turn, ε4 noncarriers exhibited higher aggression score (NPI-C) than ε4 carriers. CONCLUSIONS: Our analyses showed associations between NPS and the presence of the ApoE ε4 allele in two NPI-C domains, despite the sample size. Furthermore, compared to noncarriers, the presence of the ApoE ε4 correlated positively with appetite/eating disorders and negatively with aberrant motor disturbance domain. Examination of the amnestic MCI group displayed significant, although weak, associations. Therefore, ε4 carriers exhibited higher depression scores according to the HAM-D scale compared to ε4 noncarriers. Conversely, ε4 noncarriers had higher scores in the aggression domain of the NPI-C than ε4 carriers.

Differences in structural and functional default mode network connectivity in amyloid positive mild cognitive impairment: a longitudinal study.

PURPOSE: Default mode network (DMN) has emerged as a potential biomarker of Alzheimer's disease (AD); however, it is not clear whether it can differentiate amnestic mild cognitive impairment with altered amyloid (aMCI-Aß +) who will evolve to AD. We evaluated if structural and functional connectivity (FC), hippocampal volumes (HV), and cerebrospinal fluid biomarkers (CSF-Aß42, p-Tau, and t-Tau) can differentiate aMCI-Aß + converters from non-converters. METHODS: Forty-eight individuals (18 normal controls and 30 aMCI subjects in the AD continuum - with altered Aß42 in the CSF) were followed up for an average of 13 months. We used MultiAtlas, UF2C, and Freesurfer software to evaluate diffusion tensor imaging, FC, and HV, respectively, INNOTEST® kits to measure CSF proteins, and neuropsychological tests. Besides, we performed different MANOVAs with further univariate analyses to differentiate groups. RESULTS: During follow-up, 8/30 aMCI-Aß + converted (26.6%) to AD dementia. There were no differences in multivariate analysis between groups in CSF biomarkers (p = 0.092) or at DMN functional connectivity (p = 0.814). aMCI-Aß + converters had smaller right HV than controls (p = 0.013), and greater right cingulum parahippocampal bundle radial diffusivity than controls (p < 0.001) and non-converters (p = 0.036). CONCLUSION: In this exploratory study, structural, but not functional, DMN connectivity alterations may differentiate aMCI-Aß + subjects who converted to AD dementia.

Hippocampal subregional volume changes in elders classified using positron emission tomography-based Alzheimer's biomarkers of ß-amyloid deposition and neurodegeneration.

Changes in hippocampal subfield volumes (HSV) along the Alzheimer's disease (AD) continuum have been scarcely investigated to date in elderly subjects classified based on the presence of ß-amyloid aggregation and signs of neurodegeneration. We classified patients (either sex) with mild dementia compatible with AD (n = 35) or amnestic mild cognitive impairment (n = 39), and cognitively unimpaired subjects (either sex; n = 26) using [11 C]PIB-PET to assess ß-amyloid aggregation (A+) and [18 F]FDG-PET to account for neurodegeneration ((N)+). Magnetic resonance imaging-based automated methods were used for HSV and white matter hyperintensity (WMH) measurements. Significant HSV reductions were found in A+(N)+ subjects in the presubiculum/subiculum complex and molecular layer, related to worse memory performance. In both the A+(N)+ and A+(N)- categories, subicular volumes were inversely correlated with the degree of Aß deposition. The A-(N)+ subgroup showed reduced HSV relative to the A-(N)- subgroup also in the subiculum/presubiculum. Combining all (N)- subjects, HSV were lower in subjects presenting significant cognitive decline irrespective of A+/A- classification (controlling for WMH load); these between-group differences were detected again in the presubiculum, but also involved the CA4 and granular layer. These findings demonstrate that differential HSV reductions are detectable both in (N)+ and (N)- categories along the AD continuum, and are directly related to the severity of cognitive deficits. HSV reductions are larger both in A+(N)+ and A+(N)- subjects in direct proportion to the degree of Aß deposition. The meaningful HSV reductions detected in the A-(N)+ subgroup highlights the strength of biomarker-based classifications outside of the classical AD continuum.

Deficits in short-term memory binding are detectable in individuals with brain amyloid deposition in the absence of overt neurodegeneration in the Alzheimer's disease continuum.

The short-term memory binding (STMB) test involves the ability to hold in memory the integration between surface features, such as shapes and colours. The STMB test has been used to detect Alzheimer's disease (AD) at different stages, from preclinical to dementia, showing promising results. The objective of the present study was to verify whether the STMB test could differentiate patients with distinct biomarker profiles in the AD continuum. The sample comprised 18 cognitively unimpaired (CU) participants, 30 mild cognitive impairment (MCI) and 23 AD patients. All participants underwent positron emission tomography (PET) with Pittsburgh compound-B labelled with carbon-11 ([11C]PIB) assessing amyloid beta (Aß) aggregation (A) and 18fluorine-fluorodeoxyglucose ([18F]FDG)-PET assessing neurodegeneration (N) (A-N- [n = 35]); A+N- [n = 11]; A+ N+ [n = 19]). Participants who were negative and positive for amyloid deposition were compared in the absence (A-N- vs. A+N-) of neurodegeneration. When compared with the RAVLT and SKT memory tests, the STMB was the only cognitive task that differentiated these groups, predicting the group outcome in logistic regression analyses. The STMB test showed to be sensitive to the signs of AD pathology and may represent a cognitive marker within the AD continuum.

Brain PET amyloid and neurodegeneration biomarkers in the context of the 2018 NIA-AA research framework: an individual approach exploring clinical-biomarker mismatches and sociodemographic parameters.

PURPOSE: [18F]FDG-PET and [11C]PIB-PET are validated as neurodegeneration and amyloid biomarkers of Alzheimer's disease (AD). We used a PET staging system based on the 2018 NIA-AA research framework to compare the proportion of amyloid positivity (A+) and hypometabolism ((N)+) in cases of mild probable AD, amnestic mild cognitive impairment (aMCI), and healthy controls, incorporating an additional classification of abnormal [18F]FDG-PET patterns and investigating the co-occurrence of such with A+, exploring [18F]FDG-PET to generate hypotheses in cases presenting with clinical-biomarker "mismatches." METHODS: Elderly individuals (N = 108) clinically classified as controls (N = 27), aMCI (N = 43) or mild probable AD (N = 38) were included. Authors assessed their A(N) profiles and classified [18F]FDG-PET neurodegenerative patterns as typical or non-typical of AD, performing re-assessments of images whenever clinical classification was in disagreement with the PET staging (clinical-biomarker "mismatches"). We also investigated associations between "mismatches" and sociodemographic and educational characteristics. RESULTS: AD presented with higher rates of A+ and (N)+. There was also a higher proportion of A+ and (N)+ individuals in the aMCI group in comparison to controls, however without statistical significance regarding the A staging. There was a significant association between amyloid positivity and AD (N)+ hypometabolic patterns typical of AD. Non-AD (N)+ hypometabolism was seen in all A- (N)+ cases in the mild probable AD and control groups and [18F]FDG-PET patterns classified such individuals as "SNAP" and one as probable frontotemporal lobar degeneration. All A- (N)- cases in the probable AD group had less than 4 years of formal education and lower socioeconomic status (SES). CONCLUSION: The PET-based staging system unveiled significant A(N) differences between AD and the other groups, whereas aMCI and controls had different (N) staging, explaining the cognitive impairment in aMCI. [18F]FDG-PET could be used beyond simple (N) staging, since it provided alternative hypotheses to cases with clinical-biomarker "mismatches." An AD hypometabolic pattern correlated with amyloid positivity. Low education and SES were related to dementia in the absence of biomarker changes.

Correction to: Brain PET amyloid and neurodegeneration biomarkers in the context of the 2018 NIA-AA research framework: an individual approach exploring clinical-biomarker mismatches and sociodemographic parameters.

In the last paragraph of the subsession "Recruitment of the study population and clinical Evaluation" (Material and methods session).

An intervention to reduce neuropsychiatric symptoms and caregiver burden in dementia: Preliminary results from a randomized trial of the tailored activity program-outpatient version.

OBJECTIVE: To evaluate the efficacy of the tailored activity program-outpatient version (TAP-O) and to reduce neuropsychiatric symptoms (NPS) in patients with dementia and caregiver burden compared with a control group (psychoeducation intervention). METHODS: Twenty-one persons with dementia and their caregivers were recruited and randomized. The intervention group received TAP-O, designed for outpatients with dementia and their caregivers. TAP-O consisted of eight sessions in which an occupational therapist assessed the patient's abilities and interests; prescribed tailored activities; and educated caregivers about dementia, NPS, and how to implement meaningful activities in the daily routine. The control group received eight sessions of a psychoeducation intervention about dementia and NPS. RESULTS: Compared with controls, patients receiving TAP-O had a significant decrease in hallucination (P = 0.04), agitation (P = 0.03), anxiety (P = 0.02), aggression (P = 0.01), sleep disorder (P = 0.02), aberrant motor behavior (P = 0.02), and in caregiver burden (P = 0.003). CONCLUSIONS: Findings suggest that TAP-O may be an effective nonpharmacological strategy to reduce NPS of outpatients with dementia and to minimize caregiver burden.

Protein levels of ADAM10, BACE1, and PSEN1 in platelets and leukocytes of Alzheimer's disease patients.

The clinical diagnosis of Alzheimer's disease (AD) is a probabilistic formulation that may lack accuracy particularly at early stages of the dementing process. Abnormalities in amyloid-beta precursor protein (APP) metabolism and in the level of APP secretases have been demonstrated in platelets, and to a lesser extent in leukocytes, of AD patients, with conflicting results. The aim of the present study was to compare the protein level of the APP secretases A-disintegrin and metalloprotease 10 (ADAM10), Beta-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PSEN1) in platelets and leukocytes from 20 non-medicated older adults with AD and 20 healthy elders, and to determine the potential use of these biomarkers to discriminate cases of AD from controls. The protein levels of all APP secretases were significantly higher in platelets compared to leukocytes. We found statistically a significant decrease in ADAM10 (52.5%, p < 0.0001) and PSEN1 (32%, p = 0.02) in platelets from AD patients compared to controls, but not in leukocytes. Combining all three secretases to generate receiver-operating characteristic (ROC) curves, we found a good discriminatory effect (AD vs. controls) when using platelets (the area under the curve-AUC-0.90, sensitivity 88.9%, specificity 66.7%, p = 0.003), but not in leukocytes (AUC 0.65, sensitivity 77.8%, specificity 50.0%, p = 0.2). Our findings indicate that platelets represent a better biological matrix than leukocytes to address the peripheral level of APP secretases. In addition, combining the protein level of ADAM10, BACE1, and PSEN1 in platelets, yielded a good accuracy to discriminate AD from controls.

Intranetwork and internetwork connectivity in patients with Alzheimer disease and the association with cerebrospinal fluid biomarker levels.

BACKGROUND: In the last decade, many studies have reported abnormal connectivity within the default mode network (DMN) in patients with Alzheimer disease. Few studies, however, have investigated other networks and their association with pathophysiological proteins obtained from cerebrospinal fluid (CSF). METHODS: We performed 3 T imaging in patients with mild Alzheimer disease, patients with amnestic mild cognitive impairment (aMCI) and healthy controls, and we collected CSF samples from the patients with aMCI and mild Alzheimer disease. We analyzed 57 regions from 8 networks. Additionally, we performed correlation tests to investigate possible associations between the networks' functional connectivity and the protein levels obtained from the CSF of patients with aMCI and Alzheimer disease. RESULTS: Our sample included 41 patients with Alzheimer disease, 35 with aMCI and 48 controls. We found that the main connectivity abnormalities in those with Alzheimer disease occurred between the DMN and task-positive networks: these patients presented not only a decreased anticorrelation between some regions, but also an inversion of the correlation signal (positive correlation instead of anticorrelation). Those with aMCI did not present statistically different connectivity from patients with Alzheimer disease or controls. Abnormal levels of CSF proteins were associated with functional disconnectivity between several regions in both the aMCI and mild Alzheimer disease groups, extending well beyond the DMN or temporal areas. LIMITATIONS: The presented data are cross-sectional in nature, and our findings are dependent on the choice of seed regions used. CONCLUSION: We found that the main functional connectivity abnormalities occur between the DMN and task-positive networks and that the pathological levels of CSF biomarkers correlate with functional connectivity disruption in patients with Alzheimer disease.

Apolipoprotein E genotype is not associated with cognitive impairment in older adults with bipolar disorder.

OBJECTIVES: Cognitive decline is part of the long-term outcome for many individuals with bipolar disorder (BD). The ε4 allele (APOE*4) of apolipoprotein E (APOE) is a well-established risk factor for dementia in Alzheimer's disease (AD). However, its contribution to the risk of cognitive deterioration in BD has not yet been determined. Our aim was to analyze the APOE genotype association with cognitive status in a sample of older adults with BD and compare this to the association in individuals with AD, individuals with mild cognitive impairment (MCI), and healthy controls. METHODS: Participants (n = 475) were allocated to four groups: individuals with BD (n = 77), those with AD (n = 211), those with MCI (n = 43), and healthy controls (n = 144) according to clinical and neuropsychological assessment. APOE was genotyped by real-time polymerase chain reaction. Tukey's honest significant difference test and Pearson's chi-squared test were used to compare diagnostic groups. RESULTS: Subjects with BD were similar to controls with respect to the distribution of the APOE genotype (p = 0.636) and allele frequencies (p = 0.481). Significant differences were found when comparing the AD group to the BD group or to controls (APOE genotype: p < 0.0002; allele frequencies: p < 0.001). APOE*4 was significantly increased in the AD group when compared to the BD group (p = 0.031) and controls (p < 0.0001). The cognitively impaired BD subgroup (Mini-Mental State Examination below the cutoff score and/or neuropsychological assessment compatible with MCI) had a statistically significant higher frequency of APOE*2 compared to the AD group (p = 0.003). CONCLUSIONS: APOE*4 is not associated with the diagnosis of BD and does not impact the occurrence of dementia in BD. Given the distinct clinical and biological features of cognitive impairment in BD, we hypothesized that dementia in BD is unrelated to AD pathological mechanisms.

Association of neuropsychiatric syndromes with global clinical deterioration in Alzheimer's disease patients.

BACKGROUND: Data on the relationship between behavioral disturbances in Alzheimer's disease (AD) and global clinical deterioration is still controversial. The purpose of this study was to explore potential correlations of neuropsychiatric syndromes with global clinical deterioration in patients with AD, with particular consideration on severity levels of dementia. METHODS: AD patients (n = 156) aged 76.7 years from Brazilian clinical centers were assessed to diagnose the five neuropsychiatric syndromes measured by the Neuropsychiatric Inventory-Clinician rating scale (NPI-C): psychosis, agitation, affective, apathy, and sleep. These syndromes were then analyzed for their correlation with the Global Deterioration Scale (GDS). To analyze the association of neuropsychiatric syndromes with the GDS, considering the total sample and patients grouped by dementia severity levels, we applied the coefficient of multiple correlation (Ryy), adjusted multiple linear regression, and the coefficient of determination (R2yx). We tested the significance of correlation coefficients using the Student t-test for simple correlations (a single independent variable) and analysis of variance (ANOVA) for multiple correlations. ANOVA was also used to compare means of demographic and some clinical variables at different levels of dementia. RESULTS: For the total sample, apathy and agitation syndromes were most strongly correlated (0.74; 0.72, respectively) with clinical deterioration according to the GDS, followed by psychosis (0.59), affective (0.45), and sleep syndromes (0.34). Agitation significantly correlated with mild and moderate dementia (CDR 1: 0.45; and CDR 2: 0.69, respectively). At CDR 2, agitation and affective syndromes were most strongly correlated (0.69; 0.59, respectively) with clinical deterioration while at CDR 3, the apathy syndrome was most strongly correlated with clinical deterioration (0.52). CONCLUSIONS: Agitation, apathy, and affective disorders were the syndromes most strongly correlated with global deterioration in AD patients, becoming more evident at severe stages of dementia.

Reduced activities of phospholipases A2 in platelets of drug-naïve bipolar disorder patients.

OBJECTIVE: Phospholipases A2 (PLA2 ) comprise a family of hydrolytic enzymes that cleave membrane phospholipids and play a key role in cellular homeostasis. Alterations in enzymatic activity have been hypothesized in bipolar disorder (BD). Recent studies suggest that PLA2 activity in platelets may reflect PLA2 activity in the brain. The aim of this study was to determine PLA2 activity in platelets of BD patients. METHODS: We determined the activity of PLA2 subtypes [extracellular, calcium-dependent PLA2 (sPLA2 ), intracellular, calcium-dependent PLA2 (cPLA2 ), and intracellular, calcium-independent PLA2 (iPLA2 )] by a radioenzymatic method in platelets from 20 patients with BD (15 drug-naïve and five drug-free) and from 16 age- and gender-matched healthy controls. RESULTS: We found that iPLA2 , cPLA2 , and sPLA2 activities were lower in drug-naïve patients with BD when compared to the control group (p = 0.017, p < 0.001, and p < 0.001, respectively). CONCLUSIONS: Reduced PLA2 activity at the early stage of BD may disrupt brain function and increase the risk for the disease. Moreover, epidemiological studies show that patients with BD have a fivefold increased risk for developing Alzheimer's disease. Because patients with Alzheimer's disease also have reduced PLA2 activity, the present finding of reduced PLA2 in the BD group may be related to the risk factor for these individuals developing Alzheimer's disease in advanced age.

Caregiver report versus clinician impression: disagreements in rating neuropsychiatric symptoms in Alzheimer's disease patients.

BACKGROUND: The measurement of neuropsychiatric symptoms (NPS) in dementia is often based on caregiver report. Challenges associated with providing care may bias the caregiver's recognition and reporting of symptoms. Given potential problems associated with caregiver report, clinicians may improve measurement by drawing from a wider array of available data and by applying clinical judgment. OBJECTIVE: The objective of this study is to evaluate potential disagreements between caregiver report and clinician impression when rating psychopathological manifestations from the same patient with dementia. METHODS: Three hundred twelve participants (156 patients with Alzheimer's disease [AD] and 156 caregivers) were studied using the Neuropsychiatric Inventory-Clinician Rating Scale. We considered disagreement to be present when caregiver ratings were significantly higher or lower (p < 0.05) than NPS ratings by clinicians of the same patient. To evaluate whether disagreements were related to dementia severity, we repeated comparisons across levels defined by the clinical dementia rating. RESULTS: The most common disagreements involved ratings of agitation, depression, anxiety, apathy, irritability, and aberrant motor behavior especially in patients with mild dementia. There were fewer discrepancies in moderate or severe dementia. The most consistent disagreements involved global ratings of depression where caregiver scores ranged from +22.5 higher to -4.5 lower than clinician rating. CONCLUSIONS: Caregivers may have incomplete perception of patient NPS mainly in mild dementia. NPS ratings might be confounded by cultural beliefs, sometimes leading caregiver to interpret symptoms as part of "normal" aging.

Long-Term Lithium Treatment Increases cPLA2 and iPLA2 Activity in Cultured Cortical and Hippocampal Neurons.

BACKGROUND: Experimental evidence supports the neuroprotective properties of lithium, with implications for the treatment and prevention of dementia and other neurodegenerative disorders. Lithium modulates critical intracellular pathways related to neurotrophic support, inflammatory response, autophagy and apoptosis. There is additional evidence indicating that lithium may also affect membrane homeostasis. OBJECTIVE: To investigate the effect of lithium on cytosolic phospholipase A2 (PLA2) activity, a key player on membrane phospholipid turnover which has been found to be reduced in blood and brain tissue of patients with Alzheimer's disease (AD). METHODS: Primary cultures of cortical and hippocampal neurons were treated for 7 days with different concentrations of lithium chloride (0.02 mM, 0.2 mM and 2 mM). A radio-enzymatic assay was used to determine the total activity of PLA2 and two PLA2 subtypes: cytosolic calcium-dependent (cPLA2); and calcium-independent (iPLA2). RESULTS: cPLA2 activity increased by 82% (0.02 mM; p = 0.05) and 26% (0.2 mM; p = 0.04) in cortical neurons and by 61% (0.2 mM; p = 0.03) and 57% (2 mM; p = 0.04) in hippocampal neurons. iPLA2 activity was increased by 7% (0.2 mM; p = 0.04) and 13% (2 mM; p = 0.05) in cortical neurons and by 141% (0.02 mM; p = 0.0198) in hippocampal neurons. CONCLUSION: long-term lithium treatment increases membrane phospholipid metabolism in neurons through the activation of total, c- and iPLA2. This effect is more prominent at sub-therapeutic concentrations of lithium, and the activation of distinct cytosolic PLA2 subtypes is tissue specific, i.e., iPLA2 in hippocampal neurons, and cPLA2 in cortical neurons. Because PLA2 activities are reported to be reduced in Alzheimer's disease (AD) and bipolar disorder (BD), the present findings provide a possible mechanism by which long-term lithium treatment may be useful in the prevention of the disease.

Lithium and disease modification: A systematic review and meta-analysis in Alzheimer's and Parkinson's disease.

The role of lithium as a possible therapeutic strategy for neurodegenerative diseases has generated scientific interest. We systematically reviewed and meta-analyzed pre-clinical and clinical studies that evidenced the neuroprotective effects of lithium in Alzheimer's (AD) and Parkinson's disease (PD). We followed the PRISMA guidelines and performed the systematic literature search using PubMed, EMBASE, Web of Science, and Cochrane Library. A total of 32 articles were identified. Twenty-nine studies were performed in animal models and 3 studies were performed on human samples of AD. A total of 17 preclinical studies were included in the meta-analysis. Our analysis showed that lithium treatment has neuroprotective effects in diseases. Lithium treatment reduced amyloid-ß and tau levels and significantly improved cognitive behavior in animal models of AD. Lithium increased the tyrosine hydroxylase levels and improved motor behavior in the PD model. Despite fewer clinical studies on these aspects, we evidenced the positive effects of lithium in AD patients. This study lends further support to the idea of lithium's therapeutic potential in neurodegenerative diseases.

Non-invasive sound wave brain stimulation with Transcranial Pulse Stimulation (TPS) improves neuropsychiatric symptoms in Alzheimer's disease.

BACKGROUND: This study explores Transcranial Pulse Stimulation (TPS) as a potential non-invasive treatment for Alzheimer's disease (AD), focusing on its impact on cognitive functions and behavioral symptoms. METHODS: In a prospective, one-arm open-label trial, ten patients with mild to moderate dementia due to AD were assessed using the Alzheimer's Disease Assessment Scale (ADAS-Cog), Neuropsychiatric Inventory (NPI), Pfeffer Functional Activities Questionnaire, and Zarit Caregiver Burden Interview. Assessments occurred at 30- and 90-days post-treatment. The TPS protocol consisted of 10 sessions over five weeks, using the Neurolith® device to deliver 6000 focused shockwave pulses at 0.25 mJ/mm2 and a frequency of 4 Hz. RESULTS: TPS significantly reduced neuropsychiatric symptoms, with NPI scores decreasing by 23.9 points (95% CI: -39.19 to -8.61, p = 0.0042) after 30 days, and by 18.9 points (95% CI: -33.49 to -2.91, p = 0.022) after 90 days. These changes had large effect sizes (Cohen's dz = 1.43 and dz = 0.94, respectively). A decreasing trend was observed in the ADAS-Cog score (-3.6, 95% CI: -7.18 to 0.00, p = 0.05) after 90 days, indicating a potential reduction in cognitive impairment, though not statistically significant. CONCLUSION: The preliminary results indicate that TPS treatment leads to significant improvement in neuropsychiatric symptoms in AD patients, showing promise as a therapeutic approach for AD. Further research is needed to fully establish its effectiveness, especially concerning cognitive functions.

Data-driven, cross-disciplinary collaboration: lessons learned at the largest academic health center in Latin America during the COVID-19 pandemic.

Introduction: The COVID-19 pandemic has prompted global research efforts to reduce infection impact, highlighting the potential of cross-disciplinary collaboration to enhance research quality and efficiency. Methods: At the FMUSP-HC academic health system, we implemented innovative flow management routines for collecting, organizing and analyzing demographic data, COVID-related data and biological materials from over 4,500 patients with confirmed SARS-CoV-2 infection hospitalized from 2020 to 2022. This strategy was mainly planned in three areas: organizing a database with data from the hospitalizations; setting-up a multidisciplinary taskforce to conduct follow-up assessments after discharge; and organizing a biobank. Additionally, a COVID-19 curated collection was created within the institutional digital library of academic papers to map the research output. Results: Over the course of the experience, the possible benefits and challenges of this type of research support approach were identified and discussed, leading to a set of recommended strategies to enhance collaboration within the research institution. Demographic and clinical data from COVID-19 hospitalizations were compiled in a database including adults and a minority of children and adolescents with laboratory confirmed COVID-19, covering 2020-2022, with approximately 350 fields per patient. To date, this database has been used in 16 published studies. Additionally, we assessed 700 adults 6 to 11 months after hospitalization through comprehensive, multidisciplinary in-person evaluations; this database, comprising around 2000 fields per subject, was used in 15 publications. Furthermore, thousands of blood samples collected during the acute phase and follow-up assessments remain stored for future investigations. To date, more than 3,700 aliquots have been used in ongoing research investigating various aspects of COVID-19. Lastly, the mapping of the overall research output revealed that between 2020 and 2022 our academic system produced 1,394 scientific articles on COVID-19. Discussion: Research is a crucial component of an effective epidemic response, and the preparation process should include a well-defined plan for organizing and sharing resources. The initiatives described in the present paper were successful in our aim to foster large-scale research in our institution. Although a single model may not be appropriate for all contexts, cross-disciplinary collaboration and open data sharing should make health research systems more efficient to generate the best evidence.

The Brazilian version of the Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity in dementia.

BACKGROUND: Patients with dementia may be unable to describe their symptoms, and caregivers frequently suffer emotional burden that can interfere with judgment of the patient's behavior. The Neuropsychiatric Inventory-Clinician rating scale (NPI-C) was therefore developed as a comprehensive and versatile instrument to assess and accurately measure neuropsychiatric symptoms (NPS) in dementia, thereby using information from caregiver and patient interviews, and any other relevant available data. The present study is a follow-up to the original, cross-national NPI-C validation, evaluating the reliability and concurrent validity of the NPI-C in quantifying psychopathological symptoms in dementia in a large Brazilian cohort. METHODS: Two blinded raters evaluated 312 participants (156 patient-knowledgeable informant dyads) using the NPI-C for a total of 624 observations in five Brazilian centers. Inter-rater reliability was determined through intraclass correlation coefficients for the NPI-C domains and the traditional NPI. Convergent validity included correlations of specific domains of the NPI-C with the Brief Psychiatric Rating Scale (BPRS), the Cohen-Mansfield Agitation Index (CMAI), the Cornell Scale for Depression in Dementia (CSDD), and the Apathy Inventory (AI). RESULTS: Inter-rater reliability was strong for all NPI-C domains. There were high correlations between NPI-C/delusions and BPRS, NPI-C/apathy-indifference with the AI, NPI-C/depression-dysphoria with the CSDD, NPI-C/agitation with the CMAI, and NPI-C/aggression with the CMAI. There was moderate correlation between the NPI-C/aberrant vocalizations and CMAI and the NPI-C/hallucinations with the BPRS. CONCLUSION: The NPI-C is a comprehensive tool that provides accurate measurement of NPS in dementia with high concurrent validity and inter-rater reliability in the Brazilian setting. In addition to universal assessment, the NPI-C can be completed by individual domains.

Electroconvulsive therapy for treating patients with agitation and related behavioral disorders due to dementia: a systematic review.

Behavioral disturbances are clinically relevant in patients with dementia, and pharmacological regimens to mitigate these symptoms have provided limited results. Proven to be effective in several psychiatric conditions, electroconvulsive therapy is a potentially beneficial strategy for treating severe agitation due to dementia. Objective: This review aimed to examine the publications on the efficacy, safety and tolerability of electroconvulsive therapy in treating patients with agitation due to dementia. Methods: We performed a systematic analysis on the electroconvulsive therapy to treat patients with dementia and coexisting severe agitation. Articles were classified according to the level of evidence based on methodological design. Patients received an acute course of electroconvulsive therapy, often followed by maintenance intervention. Results: We selected 19 studies (156 patients; 64.1% women; 51-98 years old), which met the inclusion criteria: one case-control study by chart analysis (level of evidence 2); one open-label study (level of evidence 3); three historical/retrospective chart analyses (level of evidence 4); and 14 case series/reports (level of evidence 5). No randomized, sham-controlled clinical trials (level of evidence 1) were identified, which represents the main methodological weakness. Some patients had postictal delirium, cardiovascular decompensation and cognitive changes, lasting for a short time. Conclusions: Overall, patients achieved significant improvement in agitation. However, the main finding of the present review was the absence of methodological design based on randomized and sham-controlled clinical trials. Despite methodological limitations and side effects requiring attention, electroconvulsive therapy was considered a safe and effective treatment of patients with severe agitation and related behavioral disorders due to dementia.

Distúrbios comportamentais são clinicamente relevantes em pacientes com demência, e regimes farmacológicos para mitigar esses sintomas têm proporcionado resultados limitados. Comprovadamente eficaz em diversas condições psiquiátricas, a eletroconvulsoterapia é uma estratégia potencialmente benéfica para o tratamento de pacientes com agitação grave na demência. Objetivos: Esta revisão examina as publicações sobre eficácia, segurança e tolerabilidade da eletroconvulsoterapia no tratamento de pacientes com agitação na demência. Métodos: Realizamos uma análise sistemática da eletroconvulsoterapia no tratamento de pacientes com demência e agitação grave. Os artigos foram classificados quanto ao nível de evidência com base no delineamento metodológico. Os pacientes receberam um curso agudo de eletroconvulsoterapia, frequentemente seguido de manutenção. Resultados: Foram selecionados 19 estudos (156 pacientes; 64,1% mulheres; 51­98 anos): um estudo caso-controle desenvolvido com base na análise de prontuários (nível de evidência 2); um estudo aberto (nível de evidência 3); três estudos de análise retrospectiva de prontuários (nível de evidência 4); e 14 séries/relatos de casos (nível de evidência 5). Não foram identificados ensaios clínicos randomizados e controlados com placebo (nível de evidência 1), fator que representa a principal fragilidade metodológica. No entanto, o principal achado da presente revisão consistiu na ausência de desenho metodológico baseado em ensaios clínicos randomizados e controlados com placebo. Em geral, os efeitos colaterais foram transitórios e bem tolerados. Alguns pacientes apresentaram delirium pós-ictal, descompensação cardiovascular e alterações cognitivas por períodos breves. Conclusões: No geral, os pacientes obtiveram melhora significativa na agitação. No entanto, o principal achado da presente revisão foi a ausência de delineamento metodológico baseado em ensaios clínicos randomizados e controlados com placebo. Apesar das limitações metodológicas e dos efeitos adversos, a eletroconvulsoterapia foi considerada um tratamento seguro e eficaz em pacientes com agitação grave e com outros distúrbios comportamentais clinicamente relevantes na demência.

Discourse abilities in euthymic elderly patients with bipolar disorder: a preliminary study.

Cognitive impairment has been well described in euthymic patients with bipolar disorder (BD), as well as in elderly patients. Language disturbances are less studied, and several inconsistencies are reported in the literature. Most language studies focus on verbal fluency and semantic alterations, with a lack of studies addressing discursive abilities in BD. Objective: The aim of this study was to evaluate discourse abilities in euthymic elderly individuals with BD. Methods: We studied 19 euthymic elderly patients with BD and a control group of non-BD, which performed a cognitive assessment of attention, memory, executive functions, and visual abilities. All participants produced a description from the Cookie Theft Picture in oral and written modalities that was analyzed according to micro- and macrolinguistic aspects. Generalized linear models were performed to compare intergroup linguistic performance and to determine whether any cognitive domain was associated with linguistic outcomes. Results: The BD group produced more cohesion errors in the oral and written modalities (p=0.016 and p=0.011, respectively) and fewer thematic units in the oral modality (p=0.027) than the control group. Conclusions: BD patients presented minimal changes in the descriptive discourse task. The BD group produced more cohesion errors than the control group in the oral (p=0.016) and written discourse (p=0.011); also, the BD group produced fewer thematic units than controls in the oral discourse (p=0.027).

Déficits cognitivos têm sido descritos em pacientes com transtorno bipolar (TB) em fase eutímica, bem como em idosos. Alterações linguísticas são menos estudadas, e os achados de literatura são inconsistentes. A maioria dos estudos em linguagem baseia-se em avaliações de fluência verbal e alterações semânticas, havendo escassez de trabalhos que abordem as habilidades discursivas no TB. Objetivo: Avaliar as habilidades discursivas em indivíduos idosos eutímicos com TB. Métodos: Estudamos 19 pacientes idosos eutímicos com TB e um grupo de idosos sem TB e cognitivamente saudáveis, que realizaram avaliação cognitiva da atenção, memória, funções executivas e habilidades visuoespaciais. Todos os participantes produziram uma descrição da Prancha do Roubo dos Biscoitos nas modalidades oral e escrita, que foram analisadas de acordo com aspectos micro e macrolinguísticos. Análises por meio de modelos lineares generalizados foram realizados para comparar o desempenho linguístico entre os grupos e para determinar se algum domínio cognitivo estava associado a esse desempenho. Resultados: O grupo TB produziu mais erros de coesão nas modalidades oral e escrita (p=0,016 e p=0,011, respectivamente) e menos unidades temáticas na modalidade oral (p=0,027) do que o grupo controle. Conclusão: Os pacientes com TB apresentaram alterações leves na tarefa discursiva. O grupo TB produziu maior número de erros de coesão do que o grupo controle no discurso oral (p=0,016) e escrito (p=0,011). Além disso, o grupo TB produziu menor número de unidades temáticas do que os controles na tarefa de discurso oral (p=0,027).