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.

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.

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.

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.

Diagnostic Performance of an Eye-Tracking Assisted Visual Inference Language Test in the Assessment of Cognitive Decline due to Alzheimer's Disease.

BACKGROUND: The assessment of language changes associated with visual search impairment can be an important diagnostic tool in the Alzheimer's disease (AD) continuum. OBJECTIVE: Investigate the performance of an eye-tracking assisted visual inference language task in differentiating subjects with mild cognitive impairment (MCI) or AD dementia from cognitively unimpaired older adults (controls). METHODS: We assessed a group of 95 older adults (49 MCI, 18 mild dementia due to AD, and 28 controls). The subjects performed the same task under multiple experimental conditions which generate correlated responses that need to be taken into account. Thus, we performed a non-parametric repeated measures ANOVA model for verbal answers, and a linear mixed model (LMM) or its generalized version for the analysis of eye tracking variables. RESULTS: Significant differences were found in verbal answers across all diagnostic groups independently of type of inference, i.e., logic or pragmatic. Also, eye-tracking parameters were able to discriminate AD from MCI and controls. AD patients did more visits to challenge stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011), more visits to the correct response stimulus (Control-AD, -1.363, SE = 0.383, p = 0.002; MCI-AD, -0.946, SE = 0.349, p = 0.022), more fixations on distractors (Control-AD, -4.580, SE = 1.172, p = 0.001; MCI-AD, -2.940, SE = 1.070, p = 0.020), and a longer time to first fixation on the correct response stimulus (Control-AD, -0.622, SE = 0.190, p = 0.004; MCI-AD, -0.514, SE = 0.173, p = 0.011). CONCLUSION: The analysis of oculomotor behavior along with language assessment protocols may increase the sensitivity for detection of subtle deficits in the MCI-AD continuum, representing an important diagnostic tool.

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).

Whole-brain DTI parameters associated with tau protein and hippocampal volume in Alzheimer's disease.

The causes of the neurodegenerative processes in Alzheimer's disease (AD) are not completely known. Recent studies have shown that white matter (WM) damage could be more severe and widespread than whole-brain cortical atrophy and that such damage may appear even before the damage to the gray matter (GM). In AD, Amyloid-beta (Aß42 ) and tau proteins could directly affect WM, spreading across brain networks. Since hippocampal atrophy is common in the early phase of disease, it is reasonable to expect that hippocampal volume (HV) might be also related to WM integrity. Our study aimed to evaluate the integrity of the whole-brain WM, through diffusion tensor imaging (DTI) parameters, in mild AD and amnestic mild cognitive impairment (aMCI) due to AD (with Aß42 alteration in cerebrospinal fluid [CSF]) in relation to controls; and possible correlations between those measures and the CSF levels of Aß42 , phosphorylated tau protein (p-Tau) and total tau (t-Tau). We found a widespread WM alteration in the groups, and we also observed correlations between p-Tau and t-Tau with tracts directly linked to mesial temporal lobe (MTL) structures (fornix and hippocampal cingulum). However, linear regressions showed that the HV better explained the variation found in the DTI measures (with weak to moderate effect sizes, explaining from 9% to 31%) than did CSF proteins. In conclusion, we found widespread alterations in WM integrity, particularly in regions commonly affected by the disease in our group of early-stage disease and patients with Alzheimer's disease. Nonetheless, in the statistical models, the HV better predicted the integrity of the MTL tracts than the biomarkers in CSF.

Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment

Objectives: To re-evaluate a sample of older adults enrolled in a randomized controlled trial of lithium for amnestic mild cognitive impairment (MCI) after 11 to 15 years, re-assessing their current (or last available) global cognitive and functional state. Methods: We recalled all former participants of the Lithium-MCI trial conducted by our group between 2009 and 2012 to perform a single-blinded, cross-sectional evaluation of their global clinical state to compare the long-term outcome of those who received lithium vs. those who received placebo. Results: Of the original sample (n=61), we were able to reach 36 participants (59% of retention), of whom 22 had previously received lithium (61% of the recall sample) and 14 (39%) had received placebo. Since 30.5% of the recalled sample was deceased, psychometric data were collected only for 69.5% of the participants. We found statistically significant differences in current mean Mini Mental State Examination score according to previous treatment group (25.5 [SD, 5.3] vs. 18.3 [SD, 10.9], p = 0.04). The lithium group also had better performance in the phonemic Verbal Fluency Test than the control group (34.4 [SD, 14.4] vs. 11.6 [SD, 10.10], p < 0.001). Differences in these measures also had large effect sizes, as shown by Cohen's d values of 0.92 and 1.78, respectively. Conclusion: This data set suggests that older adults with amnestic MCI who had been treated with lithium during a previous randomized controlled trial had a better long-term global cognitive outcome than those from a matched sample who did not receive the intervention.

Cholinesterase Inhibitors Response Might Be Related to Right Hippocampal Functional Connectivity in Mild Alzheimer's Disease.

Background: The response to cholinesterase inhibitors (ChEIs) treatment is variable in patients with Alzheimer's disease (AD). Patients and physicians would benefit if these drugs could be targeted at those most likely to respond in a clinical setting. Therefore, this study aimed to evaluate the ability of cerebrospinal fluid (CSF) AD biomarkers, hippocampal volumes, and Default Mode Network functional connectivity to predict clinical response to ChEIs treatment in mild AD. Methods: We followed up on 39 mild AD patients using ChEIs at therapeutic doses. All subjects underwent clinical evaluation, neuropsychological assessment, magnetic resonance imaging examination, and CSF biomarkers quantification at the first assessment. The Mini-Mental Status Examination (MMSE) was used to measure the global cognitive status before and after the follow-up. "Responders" were considered as those who have remained stable or improved the MMSE score between evaluations and "Nonresponders" as those who have worsened the MMSE score. We performed univariate and multivariate logistic regressions to predict the clinical response from each biomarker. Results: About 35.89% of patients were classified as "Responders" to ChEIs treatment after the follow-up. The multivariate model with measures of Right Hippocampus (RHIPPO), adjusted for gender and interval between assessments, was significant (odds ratio: 1.09 [95% confidence interval, 1.00-1.19], p = 0.0392). This model achieved an accuracy of 77.60%. Conclusion: Our findings suggest that the functional connectivity of RHIPPO might be an early imaging biomarker to predict clinical response to ChEIs drugs in mild AD. Impact statement The functional connectivity of the right hippocampus showed a direct relationship with the clinical response to cholinesterase inhibitors (ChEIs) treatment in patients with mild Alzheimer's disease. Transposing our findings to clinical settings could allow physicians to prescribe ChEIs for patients for whom treatment would be most beneficial.

Revisiting global cognitive and functional state 13 years after a clinical trial of lithium for mild cognitive impairment.

OBJECTIVES: To re-evaluate a sample of older adults enrolled in a randomized controlled trial of lithium for amnestic mild cognitive impairment (MCI) after 11 to 15 years, re-assessing their current (or last available) global cognitive and functional state. METHODS: We recalled all former participants of the Lithium-MCI trial conducted by our group between 2009 and 2012 to perform a single-blinded, cross-sectional evaluation of their global clinical state to compare the long-term outcome of those who received lithium vs. those who received placebo. RESULTS: Of the original sample (n=61), we were able to reach 36 participants (59% of retention), of whom 22 had previously received lithium (61% of the recall sample) and 14 (39%) had received placebo. Since 30.5% of the recalled sample was deceased, psychometric data were collected only for 69.5% of the participants. We found statistically significant differences in current mean Mini Mental State Examination score according to previous treatment group (25.5 [SD, 5.3] vs. 18.3 [SD, 10.9], p = 0.04). The lithium group also had better performance in the phonemic Verbal Fluency Test than the control group (34.4 [SD, 14.4] vs. 11.6 [SD, 10.10], p < 0.001). Differences in these measures also had large effect sizes, as shown by Cohen's d values of 0.92 and 1.78, respectively. CONCLUSION: This data set suggests that older adults with amnestic MCI who had been treated with lithium during a previous randomized controlled trial had a better long-term global cognitive outcome than those from a matched sample who did not receive the intervention.

Discourse abilities in euthymic elderly patients with bipolar disorder: a preliminary study / Habilidades discursivas em pacientes idosos com transtorno afetivo bipolar: estudo preliminar

ABSTRACT 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).

RESUMO 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).

Electroconvulsive therapy for treating patients with agitation and related behavioral disorders due to dementia: a systematic review / Eletroconvulsoterapia no tratamento de pacientes com agitação e outros distúrbios de comportamento devido à demência: uma revisão sistemática

ABSTRACT 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.

RESUMO 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; 51-98 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.

Diagnosis of Alzheimer's disease: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology.

This paper presents the consensus of the Scientific Department of Cognitive Neurology and Aging from the Brazilian Academy of Neurology on the diagnostic criteria for Alzheimer's disease (AD) in Brazil. The authors conducted a literature review regarding clinical and research criteria for AD diagnosis and proposed protocols for use at primary, secondary, and tertiary care levels. Within this clinical scenario, the diagnostic criteria for typical and atypical AD are presented as well as clinical, cognitive, and functional assessment tools and complementary propaedeutics with laboratory and neuroimaging tests. The use of biomarkers is also discussed for both clinical diagnosis (in specific conditions) and research.

Este artigo apresenta o consenso realizado pelo Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia sobre os critérios diagnósticos da Doença de Alzheimer (DA) no Brasil. Foi realizada uma revisão da literatura e dos critérios clínicos e de pesquisa para DA, sendo propostos protocolos para o diagnóstico de DA em níveis de atenção primária, secundária e terciária. Dentro deste cenário clínico, são apresentados os critérios diagnósticos para DA típica e atípica, além de instrumentos de avaliação clínica, cognitiva e funcional; bem como propedêutica complementar com exames laboratoriais e de neuroimagem. A utilização de biomarcadores é também apresentada, tanto para o diagnóstico clínico em situações específicas quanto para pesquisa.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease.

OBJECTIVE: Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer's disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer's disease. METHODS: We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer's disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping. RESULTS: We found that the probable Alzheimer's disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration. CONCLUSIONS: Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Evaluation of 10-minute post-injection 11C-PiB PET and its correlation with 18F-FDG PET in older adults who are cognitively healthy, mildly impaired, or with probable Alzheimer's disease

Objective: Positron emission tomography (PET) allows in vivo evaluation of molecular targets in neurodegenerative diseases, such as Alzheimer's disease. Mild cognitive impairment is an intermediate stage between normal cognition and Alzheimer-type dementia. In vivo fibrillar amyloid-beta can be detected in PET using [11C]-labeled Pittsburgh compound B (11C-PiB). In contrast, [18F]fluoro-2-deoxy-d-glucose (18F-FDG) is a neurodegeneration biomarker used to evaluate cerebral glucose metabolism, indicating neuronal injury and synaptic dysfunction. In addition, early cerebral uptake of amyloid-PET tracers can determine regional cerebral blood flow. The present study compared early-phase 11C-PiB and 18F-FDG in older adults without cognitive impairment, amnestic mild cognitive impairment, and clinical diagnosis of probable Alzheimer's disease. Methods: We selected 90 older adults, clinically classified as healthy controls, with amnestic mild cognitive impairment, or with probable Alzheimer's disease, who underwent an 18F-FDG PET, early-phase 11C-PiB PET and magnetic resonance imaging. All participants were also classified as amyloid-positive or -negative in late-phase 11C-PiB. The data were analyzed using statistical parametric mapping. Results: We found that the probable Alzheimer's disease and amnestic mild cognitive impairment group had lower early-phase 11C-PiB uptake in limbic structures than 18F-FDG uptake. The images showed significant interactions between amyloid-beta status (negative or positive). However, early-phase 11C-PiB appears to provide different information from 18F-FDG about neurodegeneration. Conclusions: Our study suggests that early-phase 11C-PiB uptake correlates with 18F-FDG, irrespective of the particular amyloid-beta status. In addition, we observed distinct regional distribution patterns between both biomarkers, reinforcing the need for more robust studies to investigate the real clinical value of early-phase amyloid-PET imaging.

Treatment of depression in the elderly with repetitive transcranial magnetic stimulation using theta-burst stimulation: Study protocol for a randomized, double-blind, controlled trial.

Introduction: Transcranial magnetic stimulation (TMS) is a consolidated procedure for the treatment of depression, with several meta-analyses demonstrating its efficacy. Theta-burst stimulation (TBS) is a modification of TMS with similar efficacy and shorter session duration. The geriatric population has many comorbidities and a high prevalence of depression, but few clinical trials are conducted specifically for this age group. TBS could be an option in this population, offering the advantages of few side effects and no pharmacological interactions. Therefore, our aim is to investigate the efficacy of TBS in geriatric depression. Clinical trial registration: [https://clinicaltrials.gov/ct2/], identifier [NCT04842929].

Impact of Cognitive Demand on Eye Movement Pattern in Patients with Alzheimer's Disease.

BACKGROUND: Eye-movement behavior has been used as a reliable tool to identify cognitive and behavioral patterns in individuals with different neuropsychiatric disorders including Alzheimer's disease (AD). Most studies in the field have been dedicated to evaluating eye-movement behavior during cognitive tasks in different protocols using multiple parameters. OBJECTIVE: We aimed to evaluate the differences of eye-movement behavior in healthy subjects, subjects with mild cognitive impairment (MCI), and those with AD in a simple color task with and without cognitive demand. METHODS: 91 subjects: 18 AD, 47 MCI, and 26 healthy controls had their oculomotor parameters assessed during baseline (no cognitive demand involved) and during a simple computational color memory task using an eye-tracker. RESULTS: Baseline showed statistically different and heterogeneous results between normal cognition and MCI groups. Familiarization phase of the task could not discriminate between groups in any of the analyzed parameters. AD subjects made longer fixations and visits on distractors, and more frequent fixations and visits on the target areas than other groups during the response phase. CONCLUSION: Eye-tracking time-related parameters differentiate AD subjects from other groups under cognitive demand even in a simple color memory task.

Diagnóstico da doença de Alzheimer: recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia / Diagnosis of Alzheimer's disease: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology

RESUMO Este artigo apresenta o consenso realizado pelo Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia sobre os critérios diagnósticos da Doença de Alzheimer (DA) no Brasil. Foi realizada uma revisão da literatura e dos critérios clínicos e de pesquisa para DA, sendo propostos protocolos para o diagnóstico de DA em níveis de atenção primária, secundária e terciária. Dentro deste cenário clínico, são apresentados os critérios diagnósticos para DA típica e atípica, além de instrumentos de avaliação clínica, cognitiva e funcional; bem como propedêutica complementar com exames laboratoriais e de neuroimagem. A utilização de biomarcadores é também apresentada, tanto para o diagnóstico clínico em situações específicas quanto para pesquisa.

ABSTRACT This paper presents the consensus of the Scientific Department of Cognitive Neurology and Aging from the Brazilian Academy of Neurology on the diagnostic criteria for Alzheimer's disease (AD) in Brazil. The authors conducted a literature review regarding clinical and research criteria for AD diagnosis and proposed protocols for use at primary, secondary, and tertiary care levels. Within this clinical scenario, the diagnostic criteria for typical and atypical AD are presented as well as clinical, cognitive, and functional assessment tools and complementary propaedeutics with laboratory and neuroimaging tests. The use of biomarkers is also discussed for both clinical diagnosis (in specific conditions) and research.

Functional Connectome Analysis in Mild Cognitive Impairment: Comparing Alzheimer's Disease Continuum and Suspected Non-Alzheimer Pathology.

Introduction: Research in brain resting-state functional connectivity (FC) analysis in mild cognitive impairment (MCI) has conflicting results. This work intends to find differences in resting-state FC of 2 groups of MCI subjects due to Alzheimer's disease (MCI-AD) continuum or to suspected non-Alzheimer pathology (MCI-SNAP). Materials and Methods: Ninety-two subjects older than 55 years were enrolled. MCI and controls were grouped using clinical dementia rating and neuropsychological data. Cerebrospinal fluid biomarkers were collected from MCI subjects, resulting in 32 MCI-AD, 25 MCI-SNAP, and 35 controls. A region of interest (ROI)-to-ROI analysis was carried out looking at inter- and intranetwork interactions selecting the following networks: default mode network (DMN), salience network (SN), visuospatial network (VN), and executive network. Pearson correlation coefficients, converted to Z-scores, were compared by T-tests with alpha set to 0.05, and false discovery rate corrected. Results: Groups were similar in age, education, and demographic measures, there were no differences in neuropsychological data between the MCI groups. The ROI-to-ROI analysis of MCI-AD versus MCI-SNAP showed no differences. MCI-AD versus controls showed decreased FC between ROIs of the SN and between ROIs from SN and VN. MCI-SNAP versus controls showed increased FC between an ROI of DMN and VN. Discussion: SN, DMN, and VN are multimodal networks with high value/high cost and may be more vulnerable to AD pathogenic processes. SN and VN were affected in the MCI-AD group, with maintained anticorrelation between DMN and VN. This may indicate subthreshold DMN dysfunction. The result in MCI-SNAP, although discrete, reflects a rearrangement of brain FC, as DMN and VN are expected to be anticorrelated. More research is necessary to confirm these findings.