The Advisory Group on Risk Evidence Education for Dementia: Multidisciplinary and Open to All.

The brain changes of Alzheimer's disease and other degenerative dementias begin long before cognitive dysfunction develops, and in people with subtle cognitive complaints, clinicians often struggle to predict who will develop dementia. The public increasingly sees benefits to accessing dementia risk evidence (DRE) such as biomarkers, predictive algorithms, and genetic information, particularly as this information moves from research to demonstrated usefulness in guiding diagnosis and clinical management. For example, the knowledge that one has high levels of amyloid in the brain may lead one to seek amyloid reducing medications, plan for disability, or engage in health promoting behaviors to fight cognitive decline. Researchers often hesitate to share DRE data, either because they are insufficiently validated or reliable for use in individuals, or there are concerns about assuring responsible use and ensuring adequate understanding of potential problems when one's biomarker status is known. Concerns include warning people receiving DRE about situations in which they might be compelled to disclose their risk status potentially leading to discrimination or stigma. The Advisory Group on Risk Evidence Education for Dementia (AGREEDementia) welcomes all concerned with how best to share and use DRE. Supporting understanding in clinicians, stakeholders, and people with or at risk for dementia and clearly delineating risks, benefits, and gaps in knowledge is vital. This brief overview describes elements that made this group effective as a model for other health conditions where there is interest in unfettered collaboration to discuss diagnostic uncertainty and the appropriate use and communication of health-related risk information.

Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions.

Psychotic phenomena are among the most severe and disruptive symptoms of dementias and appear in 30% to 50% of patients. They are associated with a worse evolution and great suffering to patients and caregivers. Their current treatments obtain limited results and are not free of adverse effects, which are sometimes serious. It is therefore crucial to develop new treatments that can improve this situation. We review available data that could enlighten the future design of clinical trials with psychosis in dementia as main target. Along with an explanation of its prevalence in the common diseases that cause dementia, we present proposals aimed at improving the definition of symptoms and what should be included and excluded in clinical trials. A review of the available information regarding the neurobiological basis of symptoms, in terms of pathology, neuroimaging, and genomics, is provided as a guide towards new therapeutic targets. The correct evaluation of symptoms is transcendental in any therapeutic trial and these aspects are extensively addressed. Finally, a critical overview of existing pharmacological and non-pharmacological treatments is made, revealing the unmet needs, in terms of efficacy and safety. Our work emphasizes the need for better definition and measurement of psychotic symptoms in dementias in order to highlight their differences with symptoms that appear in non-dementing diseases such as schizophrenia. Advances in neurobiology should illuminate the development of new, more effective and safer molecules for which this review can serve as a roadmap in the design of future clinical trials.

Associations of Cerebrovascular Metabolism Genotypes With Neuropsychiatric Symptoms and Age at Onset of Alzheimer's Disease Dementia

Objective: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer’s disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. Methods: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. Results: Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. Conclusion: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.

Associations of cerebrovascular metabolism genotypes with neuropsychiatric symptoms and age at onset of Alzheimer's disease dementia.

OBJECTIVE:: To study associations of cerebrovascular metabolism genotypes and haplotypes with age at Alzheimer's disease dementia (AD) onset and with neuropsychiatric symptoms according to each dementia stage. METHODS:: Consecutive outpatients with late-onset AD were assessed for age at dementia onset and Neuropsychiatric Inventory scores according to Clinical Dementia Rating scores, apolipoprotein E gene (APOE) haplotypes, angiotensin-converting enzyme gene (ACE) variants rs1800764 and rs4291, low-density lipoprotein cholesterol receptor gene (LDLR) variants rs11669576 and rs5930, cholesteryl ester transfer protein gene (CETP) variants I422V and TaqIB, and liver X receptor beta gene (NR1H2) polymorphism rs2695121. RESULTS:: Considering 201 patients, only APOE-ɛ4 carriers had earlier dementia onset in multiple correlations, as well as less apathy, more delusions, and more aberrant motor behavior. Both ACE polymorphisms were associated with less intense frontally mediated behaviors. Regarding LDLR variants, carriers of the A allele of rs11669576 had less anxiety and more aberrant motor behavior, whereas carriers of the A allele of rs5930 had less delusions, less anxiety, more apathy, and more irritability. CETP variants that included G alleles of I422V and TaqIB were mostly associated with less intense frontally mediated behaviors, while severely impaired carriers of the T allele of rs2695121 had more anxiety and more aberrant motor behavior. CONCLUSION:: Though only APOE haplotypes affected AD onset, cerebrovascular metabolism genotypes were associated with differences in several neuropsychiatric manifestations of AD.

Predictors of Cognitive and Functional Decline in Patients With Alzheimer Disease Dementia From Brazil.

Little is known on how risk factors for Alzheimer disease (AD) dementia affect disease progression, much less for populations with low mean schooling, whereas the transcription of APOE may be regulated by nongenetic factors. In this 44-month cohort study, 214 consecutive outpatients with late-onset AD were assessed for rates of cognitive and functional decline by way of Clinical Dementia Rating and Mini-Mental State Examination (MMSE) scores, keeping blinded assessment of APOE haplotypes. Subjects were evaluated for sex, schooling, age of dementia onset, and cerebrovascular risk factors (including Framingham risk scores). Of the 214 patients, there were 146 (68.2%) women and 113 (52.8%) APOE4+ carriers. The mean age of AD onset was 73.4±6.5 years-old, negatively correlated with time to Clinical Dementia Rating >1.0 (ß=-0.132; ρ<0.001), MMSE=20 (ß=-0.105; ρ<0.001), and MMSE=15 (ß=-0.124; ρ=0.003), more significantly for women and APOE4+ carriers. Mean schooling was 4.18±3.7 years, correlated with time to MMSE=20 and MMSE=15 for women and APOE4+ carriers. Body mass index was correlated with time to MMSE=20 only for men (ρ=0.006). The 10-year coronary heart disease risk was correlated with time to MMSE=20 only for APOE4+ carriers (ρ=0.015). These outcomes suggest interactions among genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes over mechanisms of neurodegeneration.

Contrasts Between Patients With Lewy Body Dementia Syndromes and APOE-ε3/ε3 Patients With Late-onset Alzheimer Disease Dementia.

INTRODUCTION: Neuropsychiatric and epidemiological patterns may compensate for insufficient specificity of diagnostic criteria of Lewy body dementia (LBD) syndromes in differential analysis with Alzheimer disease (AD) dementia. We aimed to compare and distinguish demographic and neuropsychiatric features between LBD and APOE-ε3/ε3 late-onset AD. METHODS: A total of 39 consecutive patients with Parkinson disease dementia or dementia with Lewy bodies were matched with 39 APOE-ε3/ε3 patients with late-onset AD according to sex and Mini-Mental State Examination scores, and evaluated for education, age at disease onset, lifetime sanitary conditions, anthropometric measures, alcohol use, smoking, history of head trauma or bacterial infections, family history of neurodegenerative diseases, caregiver burden, functional independence, cognitive decline, neuropsychiatric symptoms, and pharmacological treatment. RESULTS: Family history of parkinsonism and worse motor performance were more prevalent in Parkinson disease dementia, also impacting sleep satisfaction and physical self-maintenance. Patients with AD had higher systolic blood pressure, were more independent, and had better performance in visuospatial tasks and calculations, whereas patients with LBD were more oriented and previously lived longer in rural areas without sanitation. Among neuropsychiatric symptoms, hallucinations, apathy, dysphoria, anxiety, and aberrant motor behavior were the most significant for discrimination amidst dementia diagnoses. CONCLUSIONS: Functional performance, visuospatial skills, and behavioral symptoms are helpful for differential diagnoses between LBD and AD. Cerebrovascular risk might be more important for AD pathogenesis, whereas environmental factors might impact development of LBD.

Is there correlation between cognition and functionality in severe dementia? the value of a performance-based ecological assessment for Alzheimer's disease.

OBJECTIVE: Besides significant cognitive decline, patients in later stages of Alzheimer's disease (AD) also present global functional impairment, usually reported by their caregivers. This study searched for preserved activities of daily living by investigating correlations among specific instruments for severe dementia with a performance-based functional scale. METHOD: A sample of 95 moderate to severe AD patients and their caregivers underwent a neuropsychological battery consisting of screening tools, the Functional Assessment Staging Test (FAST), the Severe Mini-Mental State Examination (MMSEsev) and a performance-based ecological scale, the Performance Test of Activities of Daily Living (PADL). RESULTS: Consistent findings emerged from the comparisons among tests. PADL showed significant statistical correlation with MMSEsev (ρ<0.001), according to FAST subdivisions. CONCLUSION: Upon suspicion of unreliable caregiver reports, ecological scales may be useful for disease staging. Variable degrees of functionality and cognition may be present even in later stages of AD, requiring proper assessment.

Is there correlation between cognition and functionality in severe dementia? The value of a performance-based ecological assessment for Alzheimer’s disease / Há correlação entre cognição e funcionalidade na demência grave? Utilidade da avaliação ecológica baseada no desempenho para a doença de Alzheimer

Objective Besides significant cognitive decline, patients in later stages of Alzheimer's disease (AD) also present global functional impairment, usually reported by their caregivers. This study searched for preserved activities of daily living by investigating correlations among specific instruments for severe dementia with a performance-based functional scale. Method A sample of 95 moderate to severe AD patients and their caregivers underwent a neuropsychological battery consisting of screening tools, the Functional Assessment Staging Test (FAST), the Severe Mini-Mental State Examination (MMSEsev) and a performance-based ecological scale, the Performance Test of Activities of Daily Living (PADL). Results Consistent findings emerged from the comparisons among tests. PADL showed significant statistical correlation with MMSEsev (ρ<0.001), according to FAST subdivisions. Conclusion Upon suspicion of unreliable caregiver reports, ecological scales may be useful for disease staging. Variable degrees of functionality and cognition may be present even in later stages of AD, requiring proper assessment. .

Objetivo Além do significativo declínio cognitivo, pacientes em estágios avançados da doença de Alzheimer (DA) também apresentam prejuízo funcional global. Este estudo investigou atividades de vida diária correlacionando teste específico para a demência grave, com escala funcional baseada no desempenho. Método 95 pacientes com DA foram submetidos a uma bateria neuropsicológica composta por instrumentos de rastreio, a escala Functional Assessment Staging Test (FAST), o Mini-exame do Estado Mental grave (MEEMg) e escala ecológica baseada no desempenho: a Performance Test of Activities of Daily Living (PADL). Resultados Achados consistentes emergiram da comparação entre os instrumentos. De acordo com as subdivisões da escala FAST, a PADL apresentou significativa correlação estatística com o MEEMg (ρ<0.001). Conclusão Na suspeita de relato pouco confiável por parte do cuidador, escalas ecológicas podem ser úteis no estadiamento da doença. Igualmente à cognição, variados graus de funcionalidade estão presentes mesmo em fases avançadas da DA, exigindo avaliação adequada. .

Short-term prognosis for speech and language in first stroke patients.

OBJECTIVE: To evaluate the factors that can influence evolution of communication after a first stroke. METHOD: Thirty-seven adult patients were evaluated for speech and language within 72 hours after a single first-ever ischemic brain injury and later on. Patients who were comatose, with decompensated systemic diseases, or history of chronic alcoholism or illicit drug use were not included. Brain CT and/or 2T-MR exams were solicited for topographic correlation. Size of infarct was classified as large or small according to the TOAST classification. RESULTS: Patients who survived had lesser chances of presenting with aphasia or dysarthria 3 months after the stroke if the infarct size was small (p=0.017). Gender, age, schooling, aphasia subtype, infarct side and topography were non-significant in our sample. Subjects with global aphasia or lone cortical dysarthria had a slower evolution. CONCLUSION: Brain injury size was the most influential factor for neurological outcome at 3 months post-stroke.

Short-term prognosis for speech and language in first stroke patients / Prognóstico em curto prazo para fala e linguagem em pacientes acometidos de infarto cerebral único

OBJECTIVE: To evaluate the factors that can influence evolution of communication after a first stroke. METHOD: Thirty-seven adult patients were evaluated for speech and language within 72 hours after a single first-ever ischemic brain injury and later on. Patients who were comatose, with decompensated systemic diseases, or history of chronic alcoholism or illicit drug use were not included. Brain CT and/or 2T-MR exams were solicited for topographic correlation. Size of infarct was classified as large or small according to the TOAST classification. RESULTS: Patients who survived had lesser chances of presenting with aphasia or dysarthria 3 months after the stroke if the infarct size was small (p=0.017). Gender, age, schooling, aphasia subtype, infarct side and topography were non-significant in our sample. Subjects with global aphasia or lone cortical dysarthria had a slower evolution. CONCLUSION: Brain injury size was the most influential factor for neurological outcome at 3 months post-stroke.

OBJETIVO: Avaliar os fatores que podem influenciar o desempenho neurolinguístico após um primeiro acidente vascular cerebral isquêmico. MÉTODO: Foram avaliados 37 pacientes quanto a fala e linguagem dentro de 72 horas após um primeiro infarto cerebral e posteriormente. Pacientes comatosos, com doenças sistêmicas descompensadas, história de etilismo crônico ou uso de drogas ilícitas não foram incluídos. TC e/ou RMN-2T cerebrais foram solicitadas para correlação topográfica. Utilizou-se a classificação TOAST para o tamanho do infarto (grande ou pequeno). RESULTADOS: Sobreviventes tiveram menores chances de apresentarem-se afásicos ou disártricos 3 meses após o evento agudo caso o infarto fosse pequeno (p=0.017). Gênero, idade, escolaridade, subtipo de afasia, lado e topografia da lesão cerebral não foram fatores estatisticamente significativos. Pacientes portadores de afasia global ou disartria cortical isolada evoluíram mais lentamente. CONCLUSÃO: O tamanho da lesão cerebral foi o fator mais influente para o desempenho neurolinguístico 3 meses após o evento agudo.