Estudo exploratório de alterações na linguagem em pacientes com Alzheimer em indivíduos com baixa escolaridade

O presente trabalho descreve características da linguagem, em especial de alguns dos aspectos discursivos, de idosos com envelhecimento saudável, com declínio cognitivo senil, ou com doença de Alzheimer leve e moderada. Foram avaliados um total de 44 idosos sendo 22 saudáveis, 4 com declínio cognitivo senil, 9 com doença de Alzheimer leve e 9 com doença de Alzheimer moderada, classificados pelos critérios do CDR. Foram aplicados os testes neuropsicológicos do mini exame do estado mental, nomeação de Boston resumido, fluência verbal e narrativa por confronto visual (figura do roubo dos bolinhos). Foram estimados os desempenhos nos testes selecionados e aplicada a avaliação dos relatos pelos critérios propostos por Groves-Wright (2004) assim como foi feita a tipificação da narrativa. Tratamento estatístico paramétrico determinou os valores de média, erro-padrão e o nível de significância das diferenças entre as médias foi fixado para valores de p<0.05. Em seguida foi realizado inventário e análise do léxico e das categorias gramaticas das narrativas, e realizada análise paramétrica a partir dos escores Z, através do programa STABLEX. Encontrou-se que a fluência verbal semântica é melhor nos idosos saudáveis quando comparados aos com declínio cognitivo leve. As narrativas mostraram diferenças estatisticamente significantes entre os idosos saudáveis e os com declínio cognitivo leve nas análises de frequência de uso do vocabulário e das categorias gramaticais como um todo, e também entre saudáveis e todos os demais grupos nas análises de cada uma das categorias gramaticais. A análise do vocabulário e das categorias gramaticais permitiu identificar comprometimentos da função narrativa medida pelo tipo de vocabulário e pelas categorias gramaticais preferidas ou rejeitadas. Os resultados contribuem para distinguir as características da narrativa de idosos saudáveis, daquelas de idosos com declínio cognitivo leve ou com Alzheimer leve ou moderado, apontando alterações que possivelmente são indicadores precoces que podem ser usados para avaliar o curso temporal da doença.

Efeitos do exercício físico multimodal nas concentrações plasmáticas de biomarcadores, funções cognitivas e funcionalidade em pacientes com doença de Alzheimer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

New treatment strategies for Alzheimer's disease: is there a hope?

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease, and corresponds to the most common cause of dementia worldwide. Although not fully understood, the pathophysiology of AD is largely represented by the neurotoxic events triggered by the beta-amyloid cascade and by cytoskeletal abnormalities subsequent to the hyperphosphorylation of microtubule-associated Tau protein in neurons. These processes lead respectively to the formation of neuritic plaques and neurofibrillary tangles, which are the pathological hallmarks of the disease. Clinical benefits of the available pharmacological treatment for AD with antidementia drugs (namely cholinesterase inhibitors and memantine) are unquestionable, although limited to a temporary, symptomatic support to cognitive and related functions. Over the past decade, substantial funding and research have been dedicated to the search and development of new pharmaceutical compounds with disease-modifying properties. The rationale of such approach is that by tackling key pathological processes in AD it may be possible to attenuate or even change its natural history. In the present review, we summarize the available evidence on the new therapeutic approaches that target amyloid and Tau pathology in AD, focusing on pharmaceutical compounds undergoing phase 2 and phase 3 randomized controlled trials.

Equilíbrio, funções executivas e quedas de idosos com demência de Alzheimer: um estudo longitudinal

Falls among older people is a major clinical problem due to its high incidence, with consequent implications for the health and care costs. Elderly patients with dementia of Alzheimer type (AD) are more susceptible to falls due to the impairment of executive functions and gait, with the risk of falls 3 times higher than non-demented elderly. This study used a longitudinal design and aimed to analyze the effects of a regular and systematized physical activity program on the frequency of falls in patients with AD. Additionally, we aimed to correlate the frequency of falls with the executive functions and equilibrium, after and before the physical activity program. The study included 21 patients with clinical diagnosis of AD, divided into two groups: control group (CG), composed of 11 subjects not engaged in any systematized physical activity and training group (TG): 10 seniors who participated in the Cinesioterapia Functional and Cognitive in Elderly with Alzheimer's disease program (PRO-CDA). The physical activity program lasted four months, with weekly frequency of three times, with each session lasting 60 minutes. Were administered the Mini-Mental State Examination (MMSE) to assess cognitive functioning and global score of the Clinical Dementia Rating (CDR) to classify the severity of dementia. For the evaluation of executive functions were used the Clock Drawing Test (TDR) and Frontal Assessment Battery (FAB). In addition, we used the Functional Balance Scale, Berg test (EEFB) and Timed Up-and-Go (TUG) to assess the equilibrium and risk of falls. Falls were recorded by means of a questionnaire, which included the number of falls in the last four months. Analyzing the results, it was observed that TG obtained significant improvements in equilibrium and in executive functions, highlighting the beneficial effects of physical activity in these variables... (Complete abstract click electronic access below)

Der Einfluss der Zellalterung auf die pathobiochemischen Prozesse von Morbus Alzheimer und weiteren neurodegenerativen Erkrankungen

Die am häufigsten auftretende altersassoziierte neurodegenerative Krankheit ist die Alzheimer Demenz. Ein mit entscheidender Schritt bei der Entstehung der Alzheimer Erkrankung ist wahrscheinlich die Produktion des Aβ-Peptids durch proteolytische Spaltung das Amyloid-Vorläuferproteins APP. In der vorliegenden Arbeit wurde die altersabhängige Prozessierung des Amyloid-Vorläuferproteins (APP) in Fibroblasten von Hautbiopsien von Familiärer Alzheimer-, Trisomie21 und Niemann-Pick Typ C-Krankheit untersucht. Die in dieser Arbeit verwendeten Fibroblasten wurden bis zum Erreichen des zellulären Wachstumsstopps (replikative Seneszenz) seriell passagiert und die Untersuchungen erfolgten an Zellen aufsteigender PDL. Dabei zeigte sich, dass, unabhängig von dem durch die Krankheit vorliegenden genetischen biochemischen Hintergrund, die APP-Prozessierung im Laufe der Zellalterung progressiv verringert wird. Die altersabhängig ansteigenden Cholesterinspiegel führten zu einer Reduktion der APP-Reifung und infolge dessen nahmen sowohl die intrazellulären APP-Spaltfragmente (C99, C83 und AICD) als auch die extrazellulären APP-Fragmente (sAPPα, sAPP) ab. Ebenso konnte gezeigt werden, dass die γ-Sekretase-Aktivität abnimmt. Dies war verbunden mit einem Rückgang der Proteinspiegel von Nicastrin und Presenilin, beides Komponenten des γ-Sekretase-Komplexes. Obwohl die Proteinexpression der α-Sekretase ADAM10 altersassoziiert konstant blieb, nahm die α-Sekretase-Aktivität mit steigendem Lebensalter ab. Erste Untersuchungen zeigten, dass die NAD+-abhängige Histon-Deacetylase SIRT1 eine wichtige Rolle im Bezug auf die α-Sekretase-Aktivität spielen könnte. Im Gegensatz zu den Abnahmen der α- und γ-Sekretase-Aktivitäten konnte eine erhöhte Aktivität der β-Sekretase in seneszenten Zellen beobachtet werden. Die mRNA-Menge und Proteinspiegel der ß-Sekretase BACE1 blieben dabei unverändert. Des Weiteren zeigte sich eine Zunahme der β-Sekretase-Aktivität bei Behandlung von jungen Zellen mit konditioniertem Medium seneszenter Zellen. Da sensezente Zellen einem Proliferationsstopp in der G1-Phase unterliegen, wurde der Einfluss des Zellzyklus-Inhibitors Aphidicolin auf die β-Sekretase untersucht. Hier wurde sowohl in IMR90 Fibroblasten als auch in Neuroblastoma-Zellen N2a eine Zunahme der β-Sekretase-Aktivität nach Zugabe der Inhibitoren beobachtet. Auch kommt es im Zuge der Alterung zu einer verstärkten Expression inflammatorischer Zytokine, die mit der Entstehung von Aβ-Peptiden in Verbindung gebracht werden. Deshalb wurde der Einfluss von Zytokinen auf die β-Sekretase-Aktivität untersucht. Die Zugabe von Interferon-γ und Interleukin 6 führte bei jungen IMR90-Zellen zu einem Anstieg der β-Sekretase-Aktivität, während bei alten Zellen keine Änderung zu verzeichnen war.

Gamma-secretase modulators and inhibitors in Alzheimer's disease: influence of genetic background on efficacy and mechanism of action

According to the amyloid hypothesis, Alzheimer’s disease (AD) is caused by aberrant production or clearance of the amyloid-β (Aβ) peptides, and in particular of the longer more aggregation-prone Aβ42. The Aβ peptides are generated through successive proteolytic cleavage of the amyloid precursor protein (APP) by the β-site APP cleaving enzyme (BACE) and γ-secretase. γ-secretase produces Aβ peptides with variable C-termini ranging from Aβ34 to Aβ48, presumably by sequential trimming of longer into shorter peptides. γ-secretase is a multiprotein complex consisting of at least four different proteins and the presenilin proteins (PS1 or PS2) contain the catalytic center of the complex. In 2001 several non-steroidal anti-inflammatory drugs were identified as the founding members of a new class of γ-secretase modulators (GSMs) that can selectively reduce production of Aβ42. Concomitantly, these GSMs increase Aβ38 production indicating closely coordinated generation of Aβ42 and Aβ38 and a potential precursor-product relationship between these peptides. GSMs seem to exert their activity by direct modulation of γ-secretase. Support for this hypothesis is drawn from the finding that some PS mutations associated with early-onset familial AD (FAD) can modulate the cellular response to GSMs and to γ-secretase inhibitors (GSIs), which inhibit production of all Aβ peptides and are known to directly interact with PS. A particularly interesting FAD PS mutation is PS1-ΔExon9, a complex deletion mutant that blocks endoproteolysis of PS1 and renders cells completely non-responsive to GSMs. Studies presented in this thesis show that the diminished response of PS1-ΔExon9 to GSMs is mainly caused by its lack of endoproteolytic cleavage. Furthermore, we were able to demonstrate that a reduced response to GSMs and GSIs is not limited to PS1-ΔExon9 but is a common effect of aggressive FAD-associated PS1 mutations. Surprisingly, we also found that while the Aβ42 response to GSMs is almost completely abolished by these PS1 mutations, the accompanying Aβ38 increase was indistinguishable to wild-type PS1. Finally, the reduced response to GSIs was confirmed in a mouse model with transgenic expression of an aggressive FAD-associated PS1 mutation as a highly potent GSI failed to reduce Aβ42 levels in brain of these mice. Taken together, our findings provide clear evidence for independent generation of Aβ42 and Aβ38 peptides, and argue that the sequential cleavage model might be an oversimplification of the molecular mechanism of γ-secretase. Most importantly, our results highlight the significance of genetic background in drug discovery efforts aimed at γ-secretase, and indicate that the use of cellular models with transgenic expression of FAD-associated PS mutations might confound studies of the potency and efficacy of GSMs and GSIs. Therefore, such models should be strictly avoided in the ongoing preclinical development of these promising and potentially disease-modifying therapeutics for AD.

Recognition of familiar and unfamiliar music in normal aging and Alzheimer's disease

We tested normal young and elderly adults and elderly Alzheimer’s disease (AD) patients on recognition memory for tunes. In Experiment 1, AD patients and age-matched controls received a study list and an old/new recognition test of highly familiar, traditional tunes, followed by a study list and test of novel tunes. The controls performed better than did the AD patients. The controls showed the “mirror effect” of increased hits and reduced false alarms for traditional versus novel tunes, whereas the patients false-alarmed as often to traditional tunes as to novel tunes. Experiment 2 compared young adults and healthy elderly persons using a similar design. Performance was lower in the elderly group, but both younger and older subjects showed the mirror effect. Experiment 3 produced confusion between preexperimental familiarity and intraexperimental familiarity by mixing traditional and novel tunes in the study lists and tests. Here, the subjects in both age groups resembled the patients of Experiment 1 in failing to show the mirror effect. Older subjects again performed more poorly, and they differed qualitatively from younger subjects in setting stricter criteria for more nameable tunes. Distinguishing different sources of global familiarity is a factor in tune recognition, and the data suggest that this type of source monitoring is impaired in AD and involves different strategies in younger and older adults.

Consensus 2012 sur le diagnostic et le traitement des patients atteints de démence en Suisse

Le consensus 2012 sur le diagnostic et le traitement des patients atteints de démence en Suisse a été élaboré par une conférence d’experts qui s’est déroulée du 23 au 25 mars 2012 à Lucerne. Après revue des données scientifiques récentes, les auteurs ont rédigé un projet qui a été soumis à de nombreux experts de la démence en Suisse dans le cadre d’une procédure de consultation. Après adaptation et révisions du document initial en fonction des remarques exprimées, l’ensemble des spécialistes consultés et les membres du groupe d’experts adhèrent expressément aux prises de position énoncées dans ce document. La conférence d’experts a été financée par le Forum Alzheimer Suisse.

Can a novel computerized cognitive screening test provide additional information for early detection of Alzheimer's disease?

BACKGROUND: Virtual reality testing of everyday activities is a novel type of computerized assessment that measures cognitive, executive, and motor performance as a screening tool for early dementia. This study used a virtual reality day-out task (VR-DOT) environment to evaluate its predictive value in patients with mild cognitive impairment (MCI). METHODS: One hundred thirty-four patients with MCI were selected and compared with 75 healthy control subjects. Participants received an initial assessment that included VR-DOT, a neuropsychological evaluation, magnetic resonance imaging (MRI) scan, and event-related potentials (ERPs). After 12 months, participants were assessed again with MRI, ERP, VR-DOT, and neuropsychological tests. RESULTS: At the end of the study, we differentiated two subgroups of patients with MCI according to their clinical evolution from baseline to follow-up: 56 MCI progressors and 78 MCI nonprogressors. VR-DOT performance profiles correlated strongly with existing predictive biomarkers, especially the ERP and MRI biomarkers of cortical thickness. CONCLUSIONS: Compared with ERP, MRI, or neuropsychological tests alone, the VR-DOT could provide additional predictive information in a low-cost, computerized, and noninvasive way.

THE MOLECULAR INTERACTION BETWEEN TYPE II DIABETES AND ALZHEIMER’S DISEASE THROUGH CROSS-SEEDING OF PROTEIN MISFOLDING

With the population of the world aging, the prominence of diseases such as Type II Diabetes (T2D) and Alzheimer’s disease (AD) are on the rise. In addition, patients with T2D have an increased risk of developing AD compared to age-matched individuals, and the number of AD patients with T2D is higher than among aged-matched non-AD patients. AD is a chronic and progressive dementia characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), neuronal loss, brain inflammation, and cognitive impairment. T2D involves the dysfunctional use of pancreatic insulin by the body resulting in insulin resistance, hyperglycemia, hyperinsulinemia, pancreatic beta cell (β-cell) death, and other complications. T2D and AD are considered protein misfolding disorders (PMDs). PMDs are characterized by the presence of misfolded protein aggregates, such as in T2D pancreas (islet amyloid polypeptide - IAPP) and in AD brain (amyloid– Aβ) of affected individuals. The misfolding and accumulation of these proteins follows a seeding-nucleation model where misfolded soluble oligomers act as nuclei to propagate misfolding by recruiting other native proteins. Cross-seeding occurs when oligomers composed by one protein seed the aggregation of a different protein. Our hypothesis is that the pathological interactions between T2D and AD may in part occur through cross-seeding of protein misfolding. To test this hypothesis, we examined how each respective aggregate (Aβ or IAPP) affects the disparate disease pathology through in vitro and in vivo studies. Assaying Aβ aggregates influence on T2D pathology, IAPP+/+/APPSwe+/- double transgenic (DTg) mice exhibited exacerbated T2D-like pathology as seen in elevated hyperglycemia compared to controls; in addition, IAPP levels in the pancreas are highest compared to controls. Moreover, IAPP+/+/APPSwe+/- animals demonstrate abundant plaque formation and greater plaque density in cortical and hippocampal areas in comparison to controls. Indeed, IAPP+/+/APPSwe+/- exhibit a colocalization of both misfolded proteins in cerebral plaques suggesting IAPP may directly interact with Aβ and aggravate AD pathology. In conclusion, these studies suggest that cross-seeding between IAPP and Aβ may occur, and that these protein aggregates exacerbate and accelerate disease pathology, respectively. Further mechanistic studies are necessary to determine how these two proteins interact and aggravate both pancreatic and brain pathologies.

Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology

Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid β (Aβ) peptide, the major constituent of AD plaques. We expressed human APP751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes Aβ deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of Aβ in the pathogenesis of the disease.

Designed protein tetramer zipped together with a hydrophobic Alzheimer homology: A structural clue to amyloid assembly

Limited solubility and precipitation of amyloidogenic sequences such as the Alzheimer peptide (β-AP) are major obstacles to a molecular understanding of protein fibrillation and deposition processes. Here we have circumvented the solubility problem by stepwise engineering a β-AP homology into a soluble scaffold, the monomeric protein S6. The S6 construct with the highest β-AP homology crystallizes as a tetramer that is linked by the β-AP residues forming intermolecular antiparallel β-sheets. This construct also shows increased coil aggregation during refolding, and a 14-mer peptide encompassing the engineered sequence forms fibrils. Mutational analysis shows that intermolecular association is linked to the overall hydrophobicity of the sticky sequence and implies the existence of “structural gatekeepers” in the wild-type protein, that is, charged side chains that prevent aggregation by interrupting contiguous stretches of hydrophobic residues in the primary sequence.

Enhanced pathologic properties of Dutch-type mutant amyloid beta-protein.

Cerebrovascular amyloid beta-protein (Abeta) deposition is a pathological feature of several related disorders including Alzheimer disease and hereditary cerebral hemorrhage with amyloidosis Dutch-type (HCHWA-D). HCHWA-D is caused by a point mutation in the gene that encodes the Abeta precursor and results in a Glu --> Gln substitution at position 22 of Abeta. In comparison to Alzheimer disease, the cerebrovascular Abeta deposition in HCHWA-D is generally more severe, often resulting in intracerebral hemorrhage when patients reach 50 years of age. We recently reported that Abeta(1-42), but not the shorter Abeta(1-40) induces pathologic responses in cultured human leptomeningeal smooth muscle cells including cellular degeneration that is accompanied by a marked increase in the levels of cellular Abeta precursor and soluble Abeta peptide. In the present study, we show that the HCHWA-D mutation converts the normally nonpathologic Abeta(1-40) into a highly pathologic form of the peptide for cultured human leptomeningeal smooth muscle cells. These findings suggest that these altered functional properties of HCHWA-D mutated Abeta may contribute to the early and often severe cerebrovascular pathology that is the hallmark of this disorder.

Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis.

Extracellular deposition of amyloid fibrils is responsible for the pathology in the systemic amyloidoses and probably also in Alzheimer disease [Haass, C. & Selkoe, D. J. (1993) Cell 75, 1039-1042] and type II diabetes mellitus [Lorenzo, A., Razzaboni, B., Weir, G. C. & Yankner, B. A. (1994) Nature (London) 368, 756-760]. The fibrils themselves are relatively resistant to proteolysis in vitro but amyloid deposits do regress in vivo, usually with clinical benefit, if new amyloid fibril formation can be halted. Serum amyloid P component (SAP) binds to all types of amyloid fibrils and is a universal constituent of amyloid deposits, including the plaques, amorphous amyloid beta protein deposits and neurofibrillary tangles of Alzheimer disease [Coria, F., Castano, E., Prelli, F., Larrondo-Lillo, M., van Duinen, S., Shelanski, M. L. & Frangione, B. (1988) Lab. Invest. 58, 454-458; Duong, T., Pommier, E. C. & Scheibel, A. B. (1989) Acta Neuropathol. 78, 429-437]. Here we show that SAP prevents proteolysis of the amyloid fibrils of Alzheimer disease, of systemic amyloid A amyloidosis and of systemic monoclonal light chain amyloidosis and may thereby contribute to their persistence in vivo. SAP is not an enzyme inhibitor and is protective only when bound to the fibrils. Interference with binding of SAP to amyloid fibrils in vivo is thus an attractive therapeutic objective, achievement of which should promote regression of the deposits.

Como a doença de Alzheimer afeta os cuidadores informais no concelho de Abrantes

Trabalho de Projeto apresentado à Escola Superior de Educação do Instituto Politécnico de Castelo Branco para cumprimento dos requisitos necessários à obtenção do grau de Mestre em Gerontologias Social.