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.

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.

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.

Treatment of dementia: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology.

There is currently no cure for neurodegenerative or vascular dementias, but some pharmacological and non-pharmacological interventions may contribute to alleviate symptoms, slow disease progression and improve quality of life. Current treatment approaches are based on etiology, symptom profile and stage of dementia. This manuscript presents recommendations on pharmacological and non-pharmacological treatments of dementia due to Alzheimer's disease, vascular cognitive impairment, frontotemporal dementia, Parkinson's disease dementia, and dementia with Lewy bodies.

Atualmente não há tratamento curativo para as demências neurodegenerativas ou para a demência vascular, mas algumas intervenções farmacológicas e não farmacológicas podem contribuir para aliviar os sintomas, retardar a progressão da doença e melhorar a qualidade de vida. As abordagens terapêuticas atuais são baseadas na etiologia, no perfil dos sintomas e no estágio da demência. Neste artigo apresentamos recomendações sobre os tratamentos farmacológicos e não farmacológicos da demência devida à doença de Alzheimer, comprometimento cognitivo vascular, demência frontotemporal, demência da doença de Parkinson e demência com corpos de Lewy.

Tratamento da demência: recomendações do Departamento Científico de Neurologia Cognitiva e do Envelhecimento da Academia Brasileira de Neurologia / Treatment of dementia: recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology

RESUMO Atualmente não há tratamento curativo para as demências neurodegenerativas ou para a demência vascular, mas algumas intervenções farmacológicas e não farmacológicas podem contribuir para aliviar os sintomas, retardar a progressão da doença e melhorar a qualidade de vida. As abordagens terapêuticas atuais são baseadas na etiologia, no perfil dos sintomas e no estágio da demência. Neste artigo apresentamos recomendações sobre os tratamentos farmacológicos e não farmacológicos da demência devida à doença de Alzheimer, comprometimento cognitivo vascular, demência frontotemporal, demência da doença de Parkinson e demência com corpos de Lewy.

ABSTRACT There is currently no cure for neurodegenerative or vascular dementias, but some pharmacological and non-pharmacological interventions may contribute to alleviate symptoms, slow disease progression and improve quality of life. Current treatment approaches are based on etiology, symptom profile and stage of dementia. This manuscript presents recommendations on pharmacological and non-pharmacological treatments of dementia due to Alzheimer's disease, vascular cognitive impairment, frontotemporal dementia, Parkinson's disease dementia, and dementia with Lewy bodies.

Decision tree-based classification as a support to diagnosis in the Alzheimer's disease continuum using cerebrospinal fluid biomarkers: insights from automated analysis

Objective: Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimer's disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. Methods: A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment [MCI], and 82 healthy controls) were assessed for CSF concentrations of Aβ1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays; biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. Results: The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. Conclusion: Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Decision tree-based classification as a support to diagnosis in the Alzheimer's disease continuum using cerebrospinal fluid biomarkers: insights from automated analysis.

OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers add accuracy to the diagnostic workup of cognitive impairment by illustrating Alzheimer's disease (AD) pathology. However, there are no universally accepted cutoff values for the interpretation of AD biomarkers. The aim of this study is to determine the viability of a decision-tree method to analyse CSF biomarkers of AD as a support for clinical diagnosis. METHODS: A decision-tree method (automated classification analysis) was applied to concentrations of AD biomarkers in CSF as a support for clinical diagnosis in older adults with or without cognitive impairment in a Brazilian cohort. In brief, 272 older adults (68 with AD, 122 with mild cognitive impairment [MCI], and 82 healthy controls) were assessed for CSF concentrations of Aß1-42, total-tau, and phosphorylated-tau using multiplexed Luminex assays; biomarker values were used to generate decision-tree algorithms (classification and regression tree) in the R statistical software environment. RESULTS: The best decision tree model had an accuracy of 74.65% to differentiate the three groups. Cluster analysis supported the combination of CSF biomarkers to differentiate AD and MCI vs. controls, suggesting the best cutoff values for each clinical condition. CONCLUSION: Automated analyses of AD biomarkers provide valuable information to support the clinical diagnosis of MCI and AD in research settings.

Neuropsychiatric symptoms and cerebrovascular risk in non-demented elders: cross-sectional study using the mild behavioural impairment checklist (MBI-C).

BACKGROUND: Neuropsychiatric symptoms (NPS) may represent early clinical manifestations of evolving brain diseases. Studies underpin the occurrence of NPS in the context of mild cognitive impairment (MCI) and prodromal Alzheimer's disease, where symptoms referred to as 'mild behavioural impairment' (MBI) have been shown to predict conversion to dementia and to hasten cognitive/functional decline. However, the association between NPS and cerebrovascular risk factors has been poorly investigated, despite the high prevalence of the latter among individuals with MCI. The aim of the present study was to investigate the association between MBI and cerebrovascular risk in a clinical sample of non-demented elders. METHODS: Sixty-five MCI and 15 cognitively unimpaired older adults were cross-sectionally assessed with the Mild Behavioural Impairment Checklist (MBI-C), using the cut-off score > 6.5 to define positive screening. Participants were submitted to the Hachinski Ischaemic Score (HIS) to account for cerebrovascular symptoms, vascular risk, and related comorbidities. Neuroimaging scans (magnetic resonance imaging and/or 18F-fluorodeoxyglucose-positron emission tomography) and apolipoprotein E genotype were obtained. RESULTS: Positive associations were found between total MBI-C scores and increasing number of comorbidities present (0-2 comorbidities), but not with three comorbidities. Two domains of the MBI-C-impulse dyscontrol and social inappropriateness-followed the same trend of the MBI-C total score, with higher scores with the increasing numbers of comorbidities. No significant associations were found between MBI symptoms and HIS or cerebrovascular burden in neuroimaging assessment. CONCLUSION: We found weak associations between MBI-C total score and the presence of comorbidities with cerebrovascular risk, but not with structural or functional neuroimaging abnormalities or HIS. This finding may represent that the presence of comorbidities adds limited risk to the occurrence of MBI in this sample of non-demented elders.

Medical cannabinoids for treatment of neuropsychiatric symptoms in dementia: a systematic review.

INTRODUCTION: Neuropsychiatric symptoms are an integral component of the natural history of dementia, occurring from prodromal to advanced stages of the disease process and causing increased burden and morbidity. Clinical presentations are pleomorphic and clinical management often requires combinations of pharmacological and non-pharmacological interventions. However, limited efficacy and a non-negligible incidence of adverse psychotropic drug events emphasize the need for novel therapeutic options. OBJECTIVES: To review the evidence supporting use of medical cannabinoids for treatment of neuropsychiatric symptoms (NPS) of dementia. METHODS: We conducted a systematic review of the medical literature to examine scientific publications reporting use of medical cannabinoids for treatment of NPS. Medical Subject Headings (MeSH) were used to search for relevant publications and only papers reporting original clinical information were included. A secondary search was performed within selected publications to capture relevant citations that were not retrieved by the systematic review. The papers selected were categorized according to the level of evidence generated by the studies in relation to this clinical application, i.e. (1) controlled clinical trials; (2) open-label or observational studies; and (3) case reports. RESULTS: Fifteen publications with original clinical data were retrieved: five controlled clinical trials, three open-label/observational studies, and seven case reports. Most studies indicated that use of medical cannabinoids engendered favorable outcomes for treatment of NPS related to moderate and advanced stages of dementia, particularly agitation, aggressive behavior, sleep disorder, and sexual disinhibition. CONCLUSION: Medical cannabinoids constitute a promising pharmacological approach to treatment of NPS with preliminary evidence of benefit in at least moderate to severe dementia. Controlled trials with longitudinal designs and larger samples are required to examine the long-term efficacy of these drugs in different types and stages of dementia, in addition to their adverse events and risk of interactions with other drugs. Many pharmacological details are yet to be determined, such as dosing, treatment duration, and concentrations of active compounds (e.g., cannabidiol [CBD]/ Δ9-tetrahydrocannabinol [THC] ratio) in commercial preparations of medical cannabinoids.

Adjunctive Therapy to Manage Neuropsychiatric Symptoms in Moderate and Severe Dementia: Randomized Clinical Trial Using an Outpatient Version of Tailored Activity Program.

BACKGROUND: Neuropsychiatric symptoms (NPS) such as aggression, apathy, agitation, and wandering may occur in up to 90%of dementia cases. International guidelines have suggested that non-pharmacological interventions are as effective as pharmacological treatments, however without the side effects and risks of medications. An occupational therapy method, called Tailored Activity Program (TAP), was developed with the objective to treat NPS in the elderly with dementia and has been shown to be effective. OBJECTIVE: Evaluate the efficacy of the TAP method (outpatient version) in the treatment of NPS in individuals with dementia and in the burden reduction of their caregivers. METHODS: This is a randomized, double-blind, controlled clinical trial for the treatment of NPS in dementia. Outcome measures consisted of assessing the NPS of individuals with dementia, through the Neuropsychiatric Inventory-Clinician rating scale (NPI-C), and assessing the burden on their caregivers, using the Zarit Scale. All the participants were evaluated pre-and post-intervention. RESULTS: 54 individuals with dementia and caregivers were allocated to the experimental (n = 28) and control (n = 26) groups. There was improvement of the following NPS in the experimental group: delusions, agitation, aggressiveness, depression, anxiety, euphoria, apathy, disinhibition, irritability, motor disturbance, and aberrant vocalization. No improvement was observed in hallucinations, sleep disturbances, and appetite disorders. The TAP method for outpatient settings was also clinically effective in reducing burden between caregivers of the experimental group. CONCLUSION: The use of personalized prescribed activities, coupled with the caregiver training, may be a clinically effective approach to reduce NPS and caregiver burden of individuals with dementia.

Heterogeneity of Cerebrospinal Fluid Biomarkers Profiles in Individuals with Distinct Levels of Cognitive Decline: A Cross-Sectional Study.

BACKGROUND: Decreased cerebrospinal fluid (CSF) concentrations of the amyloid-ß (Aß), along with increased total (T-tau) and phosphorylated tau protein (P-tau), are widely accepted as core biomarkers of Alzheimer's disease (AD) pathology. Nonetheless, there are a few remaining caveats that still preclude the full incorporation of AD biomarkers into clinical practice. OBJECTIVE: To determine the frequency of clinical-biological mismatches in a clinical sample of older adults with varying degrees of cognitive impairment. METHODS: 204 participants were enrolled for a cross-sectional assessment and allocated into diagnostic groups: probable AD (n = 60, 29.4%); MCI (n = 84, 41.2%); or normal cognition (NC, n = 60, 29.4%). CSF concentrations of Aß42, T-tau, and 181Thr-P-tau were determined, and Aß42/P-tau ratio below 9.53 was used as a proxy of AD pathology. The AT(N) classification was further used as a framework to ascertain the biological evidence of AD. RESULTS: The majority (73.7%) of patients in the AD group had the Aß42/P-tau ratio below the cut-off score for AD, as opposed to a smaller proportion in the MCI (42.9%) and NC (23.3%) groups. In the latter, 21 subjects (35%) were classified as A+, 28 (46.7%) as T+, and 23 (38.3%) as N + . In the AD group, 66.7%of the cases were classified as A+, 78.3%as T+, and 80%as N+. CONCLUSION: Analysis of CSF biomarkers was able to discriminate between AD, MCI, and NC. However, clinical-biological mismatches were observed in a non-negligible proportion of cases.

Mental Health Status of Psychogeriatric Patients During the 2019 New Coronavirus Disease (COVID-19) Pandemic and Effects on Caregiver Burden.

Introduction: There is a growing awareness about the noxious effects of the 2019 Coronavirus Disease (COVID-19) pandemic on the mental health of the elderly. However, there is limited information from clinically driven research. The objectives of the present study were to examine the magnitude of psychiatric symptoms and to determine their association with caregiver distress, in a cross-section of community-dwelling older adults and a subsample of aging adults with Down syndrome (DS) attending a psychogeriatric service in São Paulo, Brazil. Method: Telephone-based interviews and electronically filled self-assessment questionnaires were used to collect information from patients and caregivers, addressing their impressions and concerns about the pandemic and related effects on the patient's emotional state and behavior. Clinical information was obtained from hospital charts, medical records, and psychometric tests administered through telephone interviews [Hospital Anxiety and Depression Scale (HADS) and Neuropsychiatric Inventory Questionnaire (NPI-Q)]. Results: We included 100 consecutive participants, comprising 71 older adults with psychogeriatric/neurocognitive disorders and 29 aging adults with DS. Higher HADS and NPI-Q scores were significantly associated with caregiver distress (p < 0.05) in both groups. Correlation analyses indicated strong, positive associations between caregiver burden and scores in HADS anxiety (HADS-A) and HADS depression (HADS-D) scales in the subsamples of euploid and DS subjects. Higher NPI-Q scores in the former group were also correlated with caregiver distress, with stronger associations for neuropsychiatric symptoms. Similar findings were observed among DS subjects. ANOVA tests indicated significant associations between NPI-Q scores and caregiver distress among dementia patients, as well as with HADS scores. Similar results were found after multiple linear regressions; as such, among the elderly subsample, higher scores in HADS-A (p = 0.002) and HADS-D (p = 0.001) predict a significant impact on caregiver burden (p < 0.00001, R 2 0.46); taking into consideration caregiver burden as a dependent variable and NPI-Q total score as an independent variable, we obtained significant strong prediction values for either DS (p < 0.00001, R 2 0.95) or elderly adults (p < 0.00001, R 2 0.88). Conclusion: During the COVID-19 pandemic, patients with neurocognitive disorders present with clinically relevant neuropsychiatric symptoms, with significant impact on caregiver distress. Apathy, aberrant motor behavior, sleep disorders, and psychoses were the main psychopathological domains, which had determined caregiver burden worsening.

Early diagnosis and treatment of Alzheimers disease: new definitions and challenges

The prevalence of Alzheimer's disease (AD), a progressive neurodegenerative disorder, is expected to more than double by 2050. Studies on the pathophysiology of AD have been changing our understanding of this disorder and setting a new scenario for drug development and other therapies. Concepts like the "amyloid cascade" and the "continuum of AD," discussed in this article, are now well established. From updated classifications and recommendations to advances in biomarkers of AD, we aim to critically assess the literature on AD, addressing new definitions and challenges that emerged from recent studies on the subject. Updates on the status of major clinical trials are also given, and future perspectives are discussed.

Cognitive impairment in remitted late-life depression is not associated with Alzheimer's disease-related CSF biomarkers.

BACKGROUND: Cognitive impairment is a common feature of late-life depression (LLD). Early studies using Alzheimer's disease (AD) biomarkers inferred a biological link between AD pathology and LLD, but recent findings have challenged this association. The aim of this investigation was to determine a panel of AD-related cerebrospinal fluid (CSF) biomarkers in a cross-section of elders with mild cognitive impairment (MCI) with and without LLD. METHODS: Subjects comprised 102 older adults: 27 with 'pure' amnestic MCI (aMCI), 53 with major depression and cognitive impairment - encompassing 22 late-onset (LOD) and 31 early-onset depression (EOD), and 22 euthymic elders without cognitive impairment (controls). Participants underwent lumbar puncture for determination of CSF concentrations of Aß1-42, T-tau, and P-tau. Cut-off scores for suspected AD were: Aß1-42 < 416p g/mL, P-tau > 36.1 pg/mL and Aß/P-tau ratio < 9.53 (O. V. Forlenza et al. 2015). Statistical analyses consisted of analyses of variance (ANOVA), analyses of covariance (ANCOVA), Bonferroni post-hoc tests, and Pearson's chi-squared tests. RESULTS: ANCOVA (age and schooling as covariates) displayed statistically significant results with respect to CSF biomarkers' profiles regardless of the socio-demographic divergencies previously identified by one-way ANOVA. Mean Aß1-42 values (pg/mL) were: aMCI, 360.3 (p < 0.001); LOD, 486.6 (p < 0.001); EOD, 494.2 (p < 0.001); controls, 528.3 (p < 0.001); p< 0.05. Mean Aß1-42/P-tau ratio: aMCI, 7.9 (p < 0.001); LOD 14.2 (p < 0.001); EOD, 15.3 (p < 0.001); controls, 17.1 (p < 0.001); p < 0.05. Post-hoc tests indicated that patients with aMCI showed significant differences in biomarker profile compatible with AD signature. LIMITATION: The main limitation is the relatively small sample. CONCLUSION: Our findings suggest that, distinctively from aMCI, cognitive impairment in LLD is not associated with AD's CSF pathological signature.

Passive antiamyloid immunotherapy for Alzheimer's disease.

PURPOSE OF REVIEW: Antiamyloid therapy of Alzheimer's disease tackles the overproduction and clearance of the amyloid-beta peptide (Aß). Immunotherapeutic compounds were tested in large-scale trials. We revisit the recent literature focusing on randomized-controlled trials (RCT) using monoclonal anti-Aß antibodies. RECENT FINDINGS: Forty-three articles on anti-Aß passive immunotherapy for Alzheimer's disease were published between January 2016 and October 2019 regarding 17 RCTs: 13 phase III trials using the monoclonal antibodies bapineuzumab, solanezumab, gantenerumab, crenezumab, and aducanumab; three phase II with crenezumab and aducanumab; and one phase I trial with BAN2401. Studies resulted largely negative considering the effect of the treatment on primary and secondary outcome variables. The incidence of the most important adverse effect, amyloid-related imaging abnormalities (ARIAs) ranged between 0.2 and 22%, in treatment groups. Primary endpoints were not met in eight trials, and five trials were discontinued prior to completion. SUMMARY: Passive immunotherapy RCTs failed to show clinically relevant effects in patients with clinically manifest or prodromal dementia. The high incidence of ARIAs indicates that the risk of adverse events may outweigh the benefits of these interventions. Ongoing studies must determine the benefit of such interventions in preclinical Alzheimer's disease, addressing the effect of antiamyloid immunotherapy in samples of asymptomatic carriers of autosomal-dominant mutations related to early-onset Alzheimer's disease.

Early diagnosis and treatment of Alzheimer's disease: new definitions and challenges.

The prevalence of Alzheimer's disease (AD), a progressive neurodegenerative disorder, is expected to more than double by 2050. Studies on the pathophysiology of AD have been changing our understanding of this disorder and setting a new scenario for drug development and other therapies. Concepts like the "amyloid cascade" and the "continuum of AD," discussed in this article, are now well established. From updated classifications and recommendations to advances in biomarkers of AD, we aim to critically assess the literature on AD, addressing new definitions and challenges that emerged from recent studies on the subject. Updates on the status of major clinical trials are also given, and future perspectives are discussed.

Recommendations for the Nonpharmacological Treatment of Apathy in Brain Disorders.

Apathy is a common neuropsychiatric syndrome observed across many neurocognitive and psychiatric disorders. Although there are currently no definitive standard therapies for the treatment of apathy, nonpharmacological treatment (NPT) is often considered to be at the forefront of clinical management. However, guidelines on how to select, prescribe, and administer NPT in clinical practice are lacking. Furthermore, although new Information and Communication Technologies (ICT) are beginning to be employed in NPT, their role is still unclear. The objective of the present work is to provide recommendations for the use of NPT for apathy, and to discuss the role of ICT in this domain, based on opinions gathered from experts in the field. The expert panel included 20 researchers and healthcare professionals working on brain disorders and apathy. Following a standard Delphi methodology, experts answered questions via several rounds of web-surveys, and then discussed the results in a plenary meeting. The experts suggested that NPT are useful to consider as therapy for people presenting with different neurocognitive and psychiatric diseases at all stages, with evidence of apathy across domains. The presence of a therapist and/or a caregiver is important in delivering NPT effectively, but parts of the treatment may be performed by the patient alone. NPT can be delivered both in clinical settings and at home. However, while remote treatment delivery may be cost and time-effective, it should be considered with caution, and tailored based on the patient's cognitive and physical profile and living conditions.

A survey on the prevalence of apathy in elderly people referred to specialized memory centers.

BACKGROUND: Apathy is a pervasive neuropsychiatric syndrome in people with neurocognitive and psychiatric disorders. The diagnostic criteria for apathy (DCA) have been revised in 2018. OBJECTIVES: Employing the 2018 DCA, in the present study, we investigated in groups of elderly subjects suffering from different neuropsychiatric disorders (a) the apathy prevalence; (b) the most commonly affected apathy dimensions (behavior/cognition, emotion, and social interaction); (c) the sensitivity and specificity of those dimensions for apathy diagnosis; and (d) the concurrent validity of 2018 DCA compared with the 2009 DCA. METHODS: This multicenter survey included 166 subjects. Each center checked the presence of apathy in subjects belonging to the following DSM-5 diagnoses: mild neurocognitive disorders (mild NCDs); major NCDs; affective disorders (Aff D); and subjective cognitive decline (SCD). RESULTS: The frequency of apathy varied significantly based on the diagnostic groups (0% of subjects with apathy in the SCD group; 25% in the mild NCD group; 77% in the major NCD group; and 57% in the Aff. D group). All subjects with apathy fulfilled the criteria for the behavior/cognition dimension, 73.1% fulfilled the criteria for the emotion dimension, and 97.4% fulfilled the criteria for the social interaction dimension. Behavior/cognition showed the highest sensitivity, the copresence of emotion and social interaction the highest specificity. The concordance between the 2009 and the 2018 DCA indicated an almost perfect agreement. CONCLUSIONS: These results are consistent with previous reports and confirm that the social interaction dimension added to the 2018 DCA is present in most of subjects with apathy referred to specialized memory centers.

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.