Pharmacogenetics of angiotensin modulators according to APOE-ϵ4 alleles and the ACE insertion/deletion polymorphism in Alzheimer's disease.

OBJECTIVE: In Alzheimer's disease (AD), angiotensin II receptor blockers (ARBs) could reduce cerebrovascular dysfunction, while angiotensin-converting enzyme inhibitors (ACEis) might increase brain amyloid-ß by suppressing effects of the angiotensin-converting enzyme 1, an amyloid-ß-degrading enzyme. However, ACEis could benefit patients with AD by reducing the amyloidogenic processing of the amyloid precursor protein, by central cholinergic and anti-inflammatory mechanisms, and by peripheral modulation of glucose homeostasis. We aimed to investigate whether the ACE insertion/deletion polymorphism is associated with clinical changes in patients with AD, while considering apolipoprotein E (APOE)-ϵ4 carrier status and blood pressure response to angiotensin modulators. METHODS: Consecutive outpatients with late-onset AD were screened with cognitive tests and anthropometric measurements, while their caregivers were queried for functional and caregiver burden scores. Prospective pharmacogenetic associations were estimated for 1 year, taking APOE-ϵ4 carrier status and genotypes of the ACE insertion/deletion polymorphism into account, along with treatment with ACEis or ARBs. RESULTS: For 193 patients (67.4% women, 53.4% APOE-ϵ4 carriers), the ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p = 0.281), while arterial hypertension was prevalent in 80.3% (n = 124 used an ACEi, n = 21 used an ARB). ARBs benefitted mostly APOE-ϵ4 carriers concerning caregiver burden variations, cognitive and functional decline. ACEis benefitted APOE-ϵ4 non-carriers concerning cognitive and functional decline due to improved blood pressure control in addition to possible central mechanisms. The ACE insertion/deletion polymorphism led to variable response to angiotensin modulators concerning neurological outcomes and blood pressure variations. CONCLUSION: Angiotensin modulators may be disease-modifiers in AD, while genetic stratification of samples is recommended in clinical studies.

Looking Behind the Curtain: Patient Stratification According to Genetic or Demographic Factors May Yield Unexpected Results in Studies of Neurodegenerative Diseases.

Amyloid-PET studies of neurodegenerative diseases may yield inconclusive findings due to lacking stratification according to genetic or demographic variants. APOEɛ4 alleles are the major variants to increase disease susceptibility and cause earlier onset and more behavioral features in patients with late-onset Alzheimer's disease, but have no linear effects on cognitive or functional decline; thus, sample stratification according to APOEɛ4 carrier status may be the best option. Interactions among APOEɛ4 alleles, sex, and age on amyloid-ß deposition may reveal even more innovative findings with sufficiently large samples, suggesting variable genomic effects of cognitive reserve, sex differences, and cerebrovascular risk on neurodegeneration.

Behavioural effects of the ACE insertion/deletion polymorphism in Alzheimer's disease depend upon stratification according to APOE-ϵ4 carrier status.

Introduction: The inherited risk of late-onset Alzheimer's disease (AD) is genetically determined. We aimed to examine associations of genetic variants of APOE and ACE with age at AD onset and with neuropsychiatric symptoms according to each dementia stage.Methods: Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, and the 10-item Neuropsychiatric Inventory, and genotyped for rs7412 and rs429358 (APOE haplotypes, Real-Time Polymerase Chain Reactions), and the ACE insertion/deletion polymorphism (Polymerase Chain Reactions). Combined genetic variants of APOE and ACE were associated with age at dementia onset, and with neuropsychiatric symptoms in each dementia stage (adjusted for sex and age at dementia onset).Results: Over two-thirds of the 238 patients were women, whereas the mean age at dementia onset was 73.82 ± 6.2 years-old. APOE-ϵ4/ϵ4 carriers had earlier dementia onset (p<.001). The ACE insertion/deletion polymorphism was in Hardy-Weinberg equilibrium (p=.37) but was not associated with age at dementia onset, regardless of APOE-ϵ4 carrier status. The only results that survived corrections for false discovery rates were higher scores of dysphoria for APOE-ϵ4 carriers (n=122) who also carried ACE deletion/deletion (p=.031). No results survived corrections for false discovery rates for APOE-ϵ4 non-carriers (n=116).Conclusions: Though only the APOE-ϵ4/ϵ4 haplotype affected AD onset, effects of the ACE insertion/deletion polymorphism over behavioural features might differ according to APOE-ϵ4 carrier status in genetic associations.

Swallowing in behavioral variant frontotemporal dementia.

BACKGROUND: Swallowing and feeding problems may occur with the progression of behavioral variant frontotemporal dementia (bvFTD) and can impair the anticipatory and oral preparatory phases of swallowing. OBJECTIVE: To characterize swallowing problems and the feeding situation of patients with bvFTD and to correlate the swallowing problems with functionality, executive functions, cognitive and behavioral features. METHODS: Consecutive outpatients with bvFTD in mild, moderate and severe dementia stages were recruited along with their caregivers. Patients and caregivers were screened with the following scales: "Mini-Mental State Examination", "Severe Mini-Mental State Examination", "FTLD-modified Clinical Dementia Rating", "Neuropsychiatric Inventory", "Frontal Assessment Battery", "Index of Independence in Activities of Daily Living", "Swallowing Rating Scale" and "Assessment of Feeding and Swallowing Difficulties in Dementia". RESULTS: Overall, thirty patients with bvFTD were included along with their caregivers. Patients with bvFTD showed feeding and swallowing difficulties such as: messy to eat, passivity, coughing and choking, difficulty with some food consistencies and with specific food. Swallowing problems in bvFTD correlated with impaired functionality (p<0.05) and cognition (p<0.05), executive dysfunction (p<0.01) and behavioral features (p<0.01). Caregivers had great difficulty in managing the feeding situation during mealtime, with different characteristics in each dementia stage. CONCLUSION: Patients with bvFTD had inappropriate speed eating, passivity, coughing and choking starting in the mild dementia stage, and these problems worsen in the severe stage. Such difficulties affected caregiver performance during mealtime. The correlations indicated that swallowing difficulties tend to follow cognitive and behavioral decline in patients with bvFTD.

Swallowing in behavioral variant frontotemporal dementia / Deglutição na variante comportamental da demência frontotemporal

ABSTRACT Background: Swallowing and feeding problems may occur with the progression of behavioral variant frontotemporal dementia (bvFTD) and can impair the anticipatory and oral preparatory phases of swallowing. Objective: To characterize swallowing problems and the feeding situation of patients with bvFTD and to correlate the swallowing problems with functionality, executive functions, cognitive and behavioral features. Methods: Consecutive outpatients with bvFTD in mild, moderate and severe dementia stages were recruited along with their caregivers. Patients and caregivers were screened with the following scales: "Mini-Mental State Examination", "Severe Mini-Mental State Examination", "FTLD-modified Clinical Dementia Rating", "Neuropsychiatric Inventory", "Frontal Assessment Battery", "Index of Independence in Activities of Daily Living", "Swallowing Rating Scale" and "Assessment of Feeding and Swallowing Difficulties in Dementia". Results: Overall, thirty patients with bvFTD were included along with their caregivers. Patients with bvFTD showed feeding and swallowing difficulties such as: messy to eat, passivity, coughing and choking, difficulty with some food consistencies and with specific food. Swallowing problems in bvFTD correlated with impaired functionality (p<0.05) and cognition (p<0.05), executive dysfunction (p<0.01) and behavioral features (p<0.01). Caregivers had great difficulty in managing the feeding situation during mealtime, with different characteristics in each dementia stage. Conclusion: Patients with bvFTD had inappropriate speed eating, passivity, coughing and choking starting in the mild dementia stage, and these problems worsen in the severe stage. Such difficulties affected caregiver performance during mealtime. The correlations indicated that swallowing difficulties tend to follow cognitive and behavioral decline in patients with bvFTD.

RESUMO Introdução: Os problemas na situação de alimentação e deglutição podem ocorrer com a progressão da variante comportamental da demência frontotemporal (DFT-vc) e alterar as fases antecipatória e preparatória oral da deglutição. Objetivo: Caracterizar os problemas de deglutição e a situação de alimentação de pacientes com DFT-vc e correlacionar os problemas de deglutição com a funcionalidade, funções executivas, aspectos cognitivos e comportamentais. Métodos: Foram recrutados pacientes ambulatoriais com DFT-vc nas fases leve, moderada e grave da demência, e seus respectivos cuidadores. Os pacientes e cuidadores foram avaliados com as escalas: "Mini-Exame do Estado Mental", "Mini-Exame do Estado Mental Grave", "Escala de Avaliação Clínica da Demência Modificada - DFT", "Inventário Neuropsiquiátrico", "Bateria de Avaliação Frontal", "Índice de Independência nas Atividades da Vida Diária", "Escala Funcional de Avaliação da Deglutição" e "Avaliação das Dificuldades de Alimentação e Deglutição na Demência". Resultados: Foram incluídos 30 pacientes com DFT-vc, e seus cuidadores. Pacientes com DFT-vc apresentaram dificuldades de alimentação e deglutição como: confusão na alimentação, passividade, tosse e asfixia, dificuldades com algumas consistências alimentares e alimentos específicos. Problemas de deglutição na DFT-vc correlacionaram-se com funcionalidade prejudicada (p<0,05) e cognição (p<0,05), disfunção executiva (p<0,01) e características comportamentais (p<0,01). Os cuidadores tiveram grande dificuldade em gerenciar a situação de alimentação diante de diferentes problemas em cada fase da demência. Conclusão: Pacientes com DFT-vc apresentaram velocidade de alimentação inapropriada, passividade, tosse e engasgos já na fase leve da doença, com piora na fase grave. As correlações indicaram que as alterações de deglutição tendem a seguir o declínio cognitivo e comportamental na DFT-vc.

Neurological impressions on the organization of language networks in the human brain.

BACKGROUND: More than 95% of right-handed individuals, as well as almost 80% of left-handed individuals, have left hemisphere dominance for language. The perisylvian networks of the dominant hemisphere tend to be the most important language systems in human brains, usually connected by bidirectional fibres originated from the superior longitudinal fascicle/arcuate fascicle system and potentially modifiable by learning. Neuroplasticity mechanisms take place to preserve neural functions after brain injuries. Language is dependent on a hierarchical interlinkage of serial and parallel processing areas in distinct brain regions considered to be elementary processing units. Whereas aphasic syndromes typically result from injuries to the dominant hemisphere, the extent of the distribution of language functions seems to be variable for each individual. METHOD: Review of the literature Results: Several theories try to explain the organization of language networks in the human brain from a point of view that involves either modular or distributed processing or sometimes both. The most important evidence for each approach is discussed under the light of modern theories of organization of neural networks. CONCLUSIONS: Understanding the connectivity patterns of language networks may provide deeper insights into language functions, supporting evidence-based rehabilitation strategies that focus on the enhancement of language organization for patients with aphasic syndromes.

Balance impairment does not necessarily coexist with gait apraxia in mild and moderate Alzheimer's disease.

OBJECTIVES: To assess correlations among gait apraxia, balance impairment and cognitive performance in mild (AD1, n = 30) and moderate (AD2, n = 30) AD. METHOD: The following evaluations were undertaken: gait apraxia (Assessment Walking Skills); balance performance (Berg Balance Scale); Clinical Dementia Rating and Mini-mental State Examination (MMSE). RESULTS: While disregarding AD subgroups, Berg Balance Scale and the MMSE correlated significantly with Assessment Walking Skills and 23% of all subjects scored below its cut-off. After stratification, Berg Balance Scale correlated significantly with Assessment Walking Skills in both AD subgroups, and with the MMSE only in AD1. CONCLUSIONS: Balance impairment does not necessarily coexist with gait apraxia. Gait apraxia is more prevalent in moderate AD when compared with mild AD.

Balance impairment does not necessarily coexist with gait apraxia in mild and moderate Alzheimer's disease / Comprometimento do equilíbrio e apraxia da marcha não necessariamente coexistem na doença de Alzheimer leve e moderada

ABSTRACT Currently, there are no studies reporting how much balance impairment coexists with gait apraxia in mild and moderate Alzheimer’s disease (AD). Objectives To assess correlations among gait apraxia, balance impairment and cognitive performance in mild (AD1, n = 30) and moderate (AD2, n = 30) AD. Method The following evaluations were undertaken: gait apraxia (Assessment Walking Skills); balance performance (Berg Balance Scale); Clinical Dementia Rating and Mini-mental State Examination (MMSE). Results While disregarding AD subgroups, Berg Balance Scale and the MMSE correlated significantly with Assessment Walking Skills and 23% of all subjects scored below its cut-off. After stratification, Berg Balance Scale correlated significantly with Assessment Walking Skills in both AD subgroups, and with the MMSE only in AD1. Conclusions Balance impairment does not necessarily coexist with gait apraxia. Gait apraxia is more prevalent in moderate AD when compared with mild AD.

RESUMO Apraxia da marcha e desequilíbrio são condições subinvestigadas na doença de Alzheimer (DA) leve e moderada. Objetivo Verificar a correlação da apraxia da marcha com desequilíbrio e cognição em 30 idosos com DA leve (DA1) e 30 idosos com DA moderada (DA2). Método Foram feitas as seguintes avaliações: apraxia da marcha (Assessment Walking Skills); equilíbrio (Berg Balance Scale); Clinical Dementia Rating e Mini-exame do estado mental – MEEM. Resultados Desconsiderando-se os grupos, Berg Balance Scale e MEEM correlacionaram-se significativamente com a Assessment Walking Skills, enquanto 23% dos participantes pontuaram abaixo da note de corte da mesma. Considerando-se os grupos, Berg Balance Scale correlacionou-se significativamente com a Assessment Walking Skills em ambos os grupos, embora o MEEM o tenha feito apenas em DA1. Conclusões Desequilíbrio e apraxia da marcha não necessariamente coexistem com apraxia da marcha. Prevalência de apraxia da marcha foi maior na DA moderada do que na DA leve.

Caregiver awareness of cerebrovascular risk of patients with dementia due to Alzheimer's disease in São Paulo: Brazil / Conhecimento dos cuidadores acerca do risco cerebrovascular de pacientes com síndrome demencial da doençade Alzheimer em São Paulo: Brasil

Background Proper control of cerebrovascular risk is essential to prevent cognitive change in dementia due to Alzheimer’s disease (AD). Objective To investigate whether caregiver awareness to control cerebrovascular risk impacts the lifestyles of patients with AD. Methods Consecutive outpatients with AD were assessed for demographic features, Clinical Dementia Rating scores, cerebrovascular risk, pharmacotherapy, dietary therapy and practice of physical activities. Patients and caregivers were inquired on awareness of the importance of measures to control cerebrovascular risk. Chi-square test was employed for statistics, significance at ρ < 0.05. Results A total of 217 patients were included; whereas 149 caregivers (68.7%) were aware of the need to control cerebrovascular risk, only 11 patients (5.1%) simultaneously practiced physical activities and received pharmacological treatment and dietary therapy. Patients with hypertension and diabetes mellitus were more likely to receive dietary therapy (ρ = 0.007). Male patients were more engaged in physical activities (ρ = 0.018). Patients in earlier AD stages exercised (ρ = 0.0003) and received pharmacological treatment more often (ρ = 0.0072). Caregiver awareness of the need to control cerebrovascular risk was higher when patients had hypertension (ρ = 0.024) and/or hypercholesterolemia (ρ = 0.006), and influenced adherence to dietary therapy (ρ = 0.002) and to pharmacological treatment (ρ = 0.001). Discussion Caregiver awareness of the need to control cerebrovascular risk has positive impacts for patients with AD.

Contexto O risco cerebrovascular é fundamental na etiologia da demência da doença de Alzheimer (DA), sendo importante seu controle adequado. Objetivo Investigar se o conhecimento dos cuidadores sobre o controle do risco cerebrovascular tem impacto sobre a saúde de pacientes com DA. Métodos Pacientes consecutivos com DA foram avaliados quanto a dados demográficos, Clinical Dementia Rating, risco cerebrovascular, tratamento farmacológico, dietoterapia e prática de atividades físicas. Pacientes e cuidadores foram questionados quanto à importância de medidas para controle do risco cerebrovascular. Chi-quadrado foi empregado na análise estatística, significância com ρ < 0,05. Resultados No total, 217 pacientes foram incluídos; enquanto 149 cuidadores (68,7%) conheciam a necessidade de controle do risco cerebrovascular, somente 11 pacientes (5,1%) simultaneamente praticavam exercícios e recebiam tratamento farmacológico e dietoterápico. Pacientes com hipertensão arterial e diabetes mellitus tinham maiores chances de receber dietotetapia (ρ = 0,007). Homens estavam mais engajados em atividades físicas (ρ = 0,018). Pacientes em estágios precoces da DA praticavam exercícios (ρ = 0,0003) e recebiam farmacoterapia mais frequentemente (ρ = 0,0072). O conhecimento dos cuidadores acerca do controle do risco cerebrovascular era maior quando os pacientes tinham hipertensão arterial (ρ = 0,024) e/ou dislipidemia (ρ = 0,006), e influenciou a adesão à dietoterapia (ρ = 0,002) e à farmacoterapia (ρ = 0,001). Conclusão O conhecimento dos cuidadores acerca do risco cerebrovascular tem impactos positivos para pacientes com DA.

Educational bias in the assessment of severe dementia: Brazilian cutoffs for severe Mini-Mental State Examination.

UNLABELLED: Cognitive assessment in advanced stages of Alzheimer's disease (AD) is limited by the imprecision of most instruments. OBJECTIVE: To determine objective cognitive responses in moderate and severe AD patients by way of the Severe Mini-Mental State Examination (SMMSE), and to correlate performances with Mini-Mental State Examination (MMSE) scores. METHOD: Consecutive outpatients in moderate and severe stages of AD (Clinical Dementia Rating 2.0 or 3.0) were evaluated and compared according to MMSE and SMMSE scores. RESULTS: Overall 400 patients were included, 67.5% females, mean age 76.6±6.7 years-old. There was no significant impact of age or gender over MMSE or SMMSE scores. Mean schooling was 4.4±2.5 years, impacting SMMSE scores (p=0.008). Scores on MMSE and SMMSE were significantly correlated (F-ratio=690.6325, p<0.0001). CONCLUSION: The SMMSE is influenced by schooling, but not by age or gender, and is an accurate test for assessment of moderate and severe AD.

Educational bias in the assessment of severe dementia: Brazilian cutoffs for severe Mini-Mental State Examination / Viés educacional na avaliação da demência grave: pontos de corte brasileiros para o Miniexame do Estado Mental grave

Cognitive assessment in advanced stages of Alzheimer’s disease (AD) is limited by the imprecision of most instruments. Objective: To determine objective cognitive responses in moderate and severe AD patients by way of the Severe Mini-Mental State Examination (SMMSE), and to correlate performances with Mini-Mental State Examination (MMSE) scores. Method: Consecutive outpatients in moderate and severe stages of AD (Clinical Dementia Rating 2.0 or 3.0) were evaluated and compared according to MMSE and SMMSE scores. Results: Overall 400 patients were included, 67.5% females, mean age 76.6±6.7 years-old. There was no significant impact of age or gender over MMSE or SMMSE scores. Mean schooling was 4.4±2.5 years, impacting SMMSE scores (p=0.008). Scores on MMSE and SMMSE were significantly correlated (F-ratio=690.6325, p<0.0001). Conclusion: The SMMSE is influenced by schooling, but not by age or gender, and is an accurate test for assessment of moderate and severe AD. .

A avaliação cognitiva na doença de Alzheimer (DA) avançada é insuficiente pela imprecisão dos instrumentos. Objetivo: Determinar respostas cognitivas objetivas em pacientes com DA moderada e grave por meio do Mini-Exame do Estado Mental Grave (MEEM-g) e correlacionar o seu desempenho com o Mini-Exame do Estado Mental (MEEM). Método: Pacientes consecutivos com DA moderada e grave (Clinical Dementia Rating – CDR: 2.0 e 3.0) foram avaliados e comparados conforme seus intervalos nos testes MEEM e MEEM-g. Resultados: Dentre 400 pacientes incluídos, 67,5% foram mulheres, com média de idade 76.6±6.7 anos. Não houve impacto significativo de gênero ou idade nas pontuações do MEEM ou MEEM-g. A escolaridade média foi de 4.4±2.5 anos, impactando nos escores do MEEM-g (p=0.008). Pontuações no MEEM e MEEM-g correlacionaram-se significativamente (F-ratio=690.6325, p<0.0001). Conclusão: O MEEM-g sofre influência da escolaridade, mas não de idade ou gênero, contribuindo para a precisão na avaliação da DA moderada ou grave. .

A topographic study on the evaluation of speech and language in the acute phase of a first stroke / Um estudo topográfico da avaliação de fala e linguagem na fase aguda de um primeiro infarto cerebral

Evaluation of speech and language may help in localization of site and extension of brain lesions, particularly in the absence of other neurological signs or radiologically defined injuries. OBJECTIVE: To verify what language tasks are best correlated to which brain regions, in order to develop a test for neurologists in emergency settings. METHOD: Thirty-seven adult first-stroke patients were submitted to cognitive and language tests, and then paired with thirty-seven healthy controls. Patients underwent CT and/or MRI for topographic correlation with test results (p<0.05). RESULTS: All tests were able to distinguish patients from controls, but only word/sentence repetition, naming, ideomotor praxis and, non-significantly, comprehension and counting 1-20 predicted left hemisphere lesions. Repetition was related to perisylvian structures, comprehension to the posterior portion of the middle cerebral artery territory, and fluency to frontal lesions, while naming was accurate only for lesion side. CONCLUSION: Language and cognitive tasks can help in the localization of acute stroke lesions.

Avaliação de fala e linguagem pode ajudar na localização do sítio e da extensão de lesões cerebrais, especialmente quando ausentes outros sinais neurológicos ou radiológicos. OBJETIVO: Verificar quais tarefas linguísticas se correlacionam melhor com quais regiões cerebrais, a fim de desenvolver um teste para uso pelos neurologistas em emergências. MÉTODO: 37 pacientes e 37 controles pareados passaram por avaliação linguístico-cognitiva. Pacientes foram submetidos a TC e/ou RM para correlação topográfica com os resultados da avaliação (p<0,05). RESULTADOS: Todos os testes diferenciaram pacientes de controles, mas apenas os de repetição de palavras/sentenças, nomeação, praxia ideomotora e, de forma não-significativa, compreensão e contagem 1-20 puderam predizer lesões no hemisfério esquerdo. Os testes de repetição estavam relacionados com estruturas perisylvianas, compreensão com a porção posterior do território da artéria cerebral média, e fluência com regiões frontais, enquanto os de nomeação localizavam apenas o lado das lesões. CONCLUSÃO: Testes linguístico-cognitivos podem ajudar a localizar infartos cerebrais agudos.

Global aphasia as a predictor of mortality in the acute phase of a first stroke.

OBJECTIVE: To establish whether vascular aphasic syndromes can predict stroke outcomes. METHOD: Thirty-seven adults were evaluated for speech and language within 72 hours after a single first-ever ischemic brain lesion, in blind association to CT and/or MR. RESULTS: Speech or language disabilities were found in seven (87.5%) of the eight deceased patients and twenty-six (89.7%) of the twenty-nine survivors. Global aphasia was identified in eleven patients, all with left hemisphere lesions (nine mute; five deceased), consisting on a risk factor for death in the acute stroke phase (ρ=0.022). Age (z=1.65; ρ>0.09), thrombolysis (ρ=0.591), infarct size (ρ=0.076) and side (ρ=0.649) did not significantly influence survival. Absence of aphasia did not predict a better evolution, regardless of the affected hemisphere. Prevalence of cardiovascular risk factors was similar for all patient groups. CONCLUSION: Global aphasia in acute stroke can adversely affect prognosis, translated into impairment of dominant perisylvian vascular territories, with mutism as an important semiological element.