Small vascular and Alzheimer disease-related pathologic determinants of dementia in the oldest-old.

The relative contributions of Alzheimer disease (AD) and vascular lesion burden to the occurrence of cognitive decline are more difficult to define in the oldest-old than they are in younger cohorts. To address this issue, we examined 93 prospectively documented autopsy cases from 90 to 103 years with various degrees of AD lesions, lacunes, and microvascular pathology. Cognitive assessment was performed prospectively using the Clinical Dementia Rating scale. Neuropathologic evaluation included the Braak neurofibrillary tangle (NFT) and β-amyloid (Aβ) protein deposition staging and bilateral semiquantitative assessment of vascular lesions. Statistics included regression models and receiver operating characteristic analyses. Braak NFTs, Aβ deposition, and cortical microinfarcts (CMIs) predicted 30% of Clinical Dementia Rating variability and 49% of the presence of dementia. Braak NFT and CMI thresholds yielded 0.82 sensitivity, 0.91 specificity, and 0.84 correct classification rates for dementia. Using these threshold values, we could distinguish 3 groups of demented cases and propose criteria for neuropathologic definition of mixed dementia, pure vascular dementia, and AD in very old age. Braak NFT staging and severity of CMI allow for defining most of demented cases in the oldest-old. Most importantly, single cutoff scores for these variables that could be used in the future to formulate neuropathologic criteria for mixed dementia in this age group were identified.

Primary motor cortex involvement in Alzheimer disease.

In Alzheimer disease (AD) the involvement of entorhinal cortex, hippocampus, and associative cortical areas is well established. Regarding the involvement of the primary motor cortex the reported data are contradictory. In order to determine whether the primary motor cortex is involved in AD, the brains of 29 autopsy cases were studied, including, 17 cases with severe cortical AD-type changes with definite diagnoses of AD, 7 age-matched cases with discrete to moderate cortical AD-type changes, and 5 control cases without any AD-type cortical changes. Morphometric analysis of the cortical surface occupied by senile plaques (SPs) on beta-amyloid-immunostained sections and quantitative analysis of neurofibrillary tangles (NFTs) on Gallyas-stained sections was performed in 5 different cortical areas including the primary motor cortex. The percentage of cortical surface occupied by SPs was similar in all cortical areas, without significant difference and corresponded to 16.7% in entorhinal cortex, 21.3% in frontal associative, 16% in parietal associative, and 15.8% in primary motor cortex. The number of NFTs in the entorhinal cortex was significantly higher (41 per 0.4 mm2), compared with those in other cortical areas (20.5 in frontal, 17.9 in parietal and 11.5 in the primary motor cortex). Our findings indicate that the primary motor cortex is significantly involved in AD and suggest the appearance of motor dysfunction in late and terminal stages of the disease.

Du vieillissement cérébral à la maladie d'Alzheimer : vulnérabilité et plasticité

Sens de la mémoire... mémoire du sens chez l'adulte vieillissant - Les ressources adaptatives : de l'anticipation involontaire aux stratégies conscientes - Les ressources adaptatives : l'épreuve du vieillissement - Plasticité et dégénérescence des circuits cérébraux dans le vieillissement et la maladie d'Alzheimer - Facteurs de risque génétiques et mécanismes moléculaires dans la maladie d'Alzheimer - La mort neuronale : mécanismes d'un phénomène naturel ou pathologique - Facteurs de risque et de protection - Vieillissement cérébral pathologique : les pathologies démentielles - Prise en charge globale et thérapies actuelles de la démence de type Alzheimer - Regard anthropologique sur le veillissement cérébral et la maladie d'Alzheimer

Differential damage in the frontal cortex with aging, sporadic and familial Alzheimer's disease.

In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer's disease, we studied frontal pathological changes in young and old controls compared to cases with sporadic (AD) or familial Alzheimer's disease (FAD). We performed a semi-automatic computer assisted analysis of the distribution of beta-amyloid (Abeta) deposits revealed by Abeta immunostaining as well as of neurofibrillary tangles (NFT) revealed by Gallyas silver staining in Brodman areas 10 (frontal polar), 12 (ventro-infero-median) and 24 (anterior cingular), using tissue samples from 5 FAD, 6 sporadic AD and 10 control brains. We also performed densitometric measurements of glial fibrillary acidic protein, principal compound of intermediate filaments of astrocytes, and of phosphorylated neurofilament H and M epitopes in areas 10 and 24. All regions studied seem almost completely spared in normal old controls, with only the oldest ones exhibiting a weak percentage of beta-amyloid deposit and hardly any NFT. On the contrary, all AD and FAD cases were severely damaged as shown by statistically significant increased percentages of beta-amyloid deposit, as well as by a high number of NFT. FAD cases (all from the same family) had statistically more beta-amyloid and GFAP than sporadic AD cases in both areas 10 and 24 and statistically more NFT only in area 24. The correlation between the percentage of beta-amyloid and the number of NFT was significant only for area 24. Altogether, these data suggest that the frontal cortex can be spared by AD type lesions in normal aging, but is severely damaged in sporadic and still more in familial Alzheimer's disease. The frontal regions appear to be differentially vulnerable, with area 12 having the less amyloid burden, area 24 the less NFT and area 10 having both more amyloid and more NFT. This pattern of damage in frontal regions may represent a strong neuroanatomical support for the deterioration of attention and cognitive capacities as well as for the presence of emotional and behavioral troubles in AD patients.

Personality changes in patients with beginning Alzheimer disease

Objective: To investigate personality traits in patients with Alzheimer disease, compared with mentally healthy control subjects. We compared both current personality characteristics using structured interviews as well as current and previous personality traits as assessed by proxies.Method: Fifty-four patients with mild Alzheimer disease and 64 control subjects described their personality traits using the Structured Interview for the Five-Factor Model. Family members filled in the Revised NEO Personality Inventory, Form R, to evaluate their proxies' current personality traits, compared with 5 years before the estimated beginning of Alzheimer disease or 5 years before the control subjects.Results: After controlling for age, the Alzheimer disease group presented significantly higher scores than normal control subjects on current neuroticism, and significantly lower scores on current extraversion, openness, and conscientiousness, while no significant difference was observed on agreeableness. A similar profile, though less accentuated, was observed when considering personality traits as the patients' proxies remembered them. Diachronic personality assessment showed again significant differences between the 2 groups for the same 4 domains, with important personality changes only for the Alzheimer disease group.Conclusions: Group comparison and retrospective personality evaluation are convergent. Significant personality changes follow a specific trend in patients with Alzheimer disease and contrast with the stability generally observed in mentally healthy people in their personality profile throughout their lives. Whether or not the personality assessment 5 years before the current status corresponds to an early sign of Alzheimer disease or real premorbid personality differences in people who later develop Alzheimer disease requires longitudinal studies.

Indicativos de aplicabilidade das orientações de enfermagem no cotidiano de cuidadores de portadores de Alzheimer

Objetivamos descrever a orientação recebida pelo cuidador do portador de Alzheimer antes de sua participação no Pólo de Neurogeriatria; analisar a aplicabilidade das orientações recebidas no Pólo de Neurogeriatria no cotidiano do cuidado domiciliar; e identificar os mecanismos de enfrentamento e adaptação encontrados nesses cuidadores. Adotamos uma abordagem qualitativa, do tipo estudo de caso, descritivo-exploratório. Como técnica de coleta dos dados, utilizamos a entrevista semi-estruturada. Os sujeitos foram 15 cuidadores atendidos num Hospital Federal do Rio de Janeiro. Para tratamento dos dados, optou-se pela análise temática de conteúdo, obtendo-se três categorias: Orientações recebidas antes da participação no Pólo de Neurogeriatria; Orientações recebidas no Pólo de Neurogeriatria; Mecanismos de enfretamento e adaptação no contexto do cuidado familiar. Concluiu-se que os mecanismos de enfrentamento são utilizados para a adaptação à situação de sobrecarga, podendo ser amenizada pelo apoio educativo e emocional recebido nos grupos de orientação.

Stable complexes involving acetylcholinesterase and amyloid-ß-peptide change the biochemical properties of the enzyme and increase the neurotoxicity of Alzheimer's fibrils

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-beta peptide (Abeta) during its assembly into filaments, in agreement with its colocalization with the Abeta deposits of Alzheimer's brain. The association of the enzyme with nascent Abeta aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE-amyloid complexes is higher than that of the Abeta aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of Abeta fibrils and thus may determine the selective neuronal loss observed in Alzheimer's brain.

Nível de independência funcional e déficit cognitivo em idosos com doença de Alzheimer

Este estudo investigou a influência do nível de independência funcional dos idosos com doença de Alzheimer segundo escores da avaliação cognitiva. A população foi composta por 67 idosos atendidos no Ambulatório de Neurologia Comportamental do Hospital das Clínicas/Ribeirão Preto, avaliados em 2008, por meio de um questionário para dados sociodemográficos, Medida de Independência Funcional (MIF) e Mini-Exame do Estado Mental (MEEM). Observou-se que o déficit cognitivo influenciou o desempenho na realização das AVDs. A média da MIF para idosos sem déficit cognitivo foi 107,7 e para os com déficit, 63,2 (p<0,001). Na MIF motora, as médias foram 81,7 e 49,4 (p<0,001), e na MIF cognitiva 25,7 e 13,8 (p<0,001), respectivamente. Conhecer a redução da independência e da capacidade cognitiva é indispensável para manter o provimento das necessidades básicas da vida diária. O estudo pode subsidiar a prática do enfermeiro, melhorando a condição de vida do idoso e de sua família.

Influência da doença de Alzheimer na percepção de qualidade de vida do idoso

Este estudo tem por objetivo comparar a percepção geral e de cada dimensão de qualidade de vida (QV) de um grupo de idosos com Doença de Alzheimer (DA) (n=53) com as de um grupo semelhante quanto às variáveis sociodemográficas (n=53). As medidas de QV foram obtidas por meio da Escala de Avaliação da Qualidade de Vida na Doença de Alzheimer, e os dados foram digitados em um banco de dados no programa Statistical Program for Social Sciences, para a realização de análises estatísticas (descritivas, teste-t de Student, Mann-Whitney e Qui-Quadrado). Os resultados revelaram que todas as dimensões de QV medidas pelo instrumento eram estatisticamente inferiores no grupo de idosos com DA. Quanto aos escores totais de QV, a média obtida foi de 40,18 pontos para idosos sem DA e de 29,32 para idosos com DA, t(104) = 9,449, p<0,001. Estes resultados apontam que idosos com DA apresentam medidas de QV inferiores, sugerindo que a DA influencia negativamente na sua percepção da qualidade de vida.

Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.

Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events-mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model.

Predicting clinical scores from magnetic resonance scans in Alzheimer's disease.

Machine learning and pattern recognition methods have been used to diagnose Alzheimer's disease (AD) and mild cognitive impairment (MCI) from individual MRI scans. Another application of such methods is to predict clinical scores from individual scans. Using relevance vector regression (RVR), we predicted individuals' performances on established tests from their MRI T1 weighted image in two independent data sets. From Mayo Clinic, 73 probable AD patients and 91 cognitively normal (CN) controls completed the Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), and Auditory Verbal Learning Test (AVLT) within 3months of their scan. Baseline MRI's from the Alzheimer's disease Neuroimaging Initiative (ADNI) comprised the other data set; 113 AD, 351 MCI, and 122 CN subjects completed the MMSE and Alzheimer's Disease Assessment Scale-Cognitive subtest (ADAS-cog) and 39 AD, 92 MCI, and 32 CN ADNI subjects completed MMSE, ADAS-cog, and AVLT. Predicted and actual clinical scores were highly correlated for the MMSE, DRS, and ADAS-cog tests (P<0.0001). Training with one data set and testing with another demonstrated stability between data sets. DRS, MMSE, and ADAS-Cog correlated better than AVLT with whole brain grey matter changes associated with AD. This result underscores their utility for screening and tracking disease. RVR offers a novel way to measure interactions between structural changes and neuropsychological tests beyond that of univariate methods. In clinical practice, we envision using RVR to aid in diagnosis and predict clinical outcome.

Quantitative distribution of parvalbumin, calretinin, and calbindin D-28k immunoreactive neurons in the visual cortex of normal and Alzheimer cases.

The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons was studied with the help of an image analysis system (Vidas/Zeiss) in the primary visual area 17 and associative area 18 (Brodmann) of Alzheimer and control brains. In neither of these areas was there a significant difference between Alzheimer and control groups in the mean number of PV, CR, or CB immunoreactive neuronal profiles, counted in a cortical column going from pia to white matter. Significant differences in the mean densities (numbers per square millimeter of cortex) of PV, CR, and CB immunoreactive neuronal profiles were not observed either between groups or areas, but only between superficial, middle, and deep layers within areas 17 and 18. The optical density of the immunoreactive neuropil was also similar in Alzheimer and controls, correlating with the numerical density of immunoreactive profiles in superficial, middle, and deep layers. The frequency distribution of neuronal areas indicated significant differences between PV, CR, and CB immunoreactive neuronal profiles in both areas 17 and 18, with more large PV than CR and CB positive profiles. There were also significantly more small and less large PV and CR immunoreactive neuronal profiles in Alzheimer than in controls. Our data show that, although the brain pathology is moderate to severe, there is no prominent decrease of PV, CR and CB positive neurons in the visual cortex of Alzheimer brains, but only selective changes in neuronal perikarya.

Social capabilities in Alzheimer's patients

Patients with stage-I (very mild and mild) Alzheimer's disease were asked to participate in a Dictator Game, a type of game in which a subject has to decide how to allocate a certain amount of money between himself and another person. The game enables the experimenter to examine the influence of social norms and social preferences on the decision-making process. When the results of treatments involving Alzheimer's disease patients were compared with those of identical treatments involving patients with mild cognitive impairment or healthy control subjects, with similar ages and social backgrounds, no statistically significant difference was found. This finding suggests that stage-I Alzheimer's disease patients may be as capable of making decisions involving social norms and preferences as other individuals of their age. Whatever brain structures are affected by the disease, they do not appear to influence, at this early stage, the neural basis for cooperation-enhancing social interactions.