Dissertations / Theses on the topic 'Dementia, vascular'

Dementia is a devastating disorder that commonly affects people over the age of 65. Alzheimer's disease and vascular dementia are the most common forms of dementias. A number of studies have implicated cardiovascular risks as important factors in the development of dementia. These risks include high-risk behaviors such as smoking and risks related at least partially to health behaviors such as diet and exercise. This study examines a group of cardiovascular risk factors, as defined by the Framingham study, to ascertain if they are predictors of dementia. A retrospective chart review of 481consecutive patients seen in a geriatric medicine clinic produced a sample of 177 individuals diagnosed with dementia and 304 individuals without a dementia diagnosis. Relative risk ratio (RRR) results indicate that a history of hypertension (RRR= 1.80, p = .009) and a history of hypercholesterolemia (RRR = 1.85, p = .016) are significant predictors of Alzheimer's disease. A history of tobacco use (RRR = 2.18, p = .01) is a significant predictor of vascular dementia. Stepwise regression analyses indicate that hypercholesterolemia is an independent predictor of dementia (b = -.113, p = .009) and hypercholesterolemia (b = -.104, p = .018) and hypertension (b = -.094, p = .031) clustered together have an additive risk factor effect. These results are discussed in terms of the importance of specific health behaviors in the development and possible prevention of dementia.

Alzheimer’s Dementia (AD) is among the most common diseases in the Geriatric population, and its prevalence is expected to quadruple by 2047.Vascular Dementia (VaD) is the second most frequent cause of dementia, with studies indicating VaD accounts for 10-20% of dementia cases across the globe. A diagnostic model differentiating AD and VaD would be clinically and scientifically valuable, considering the treatment approaches for these conditions are different. Although there are differences between AD and VaD on their neuropsychological profiles, a diagnostic model that successfully differentiates AD and VaD on neuropsychological testing has not been developed, despite previous attempts. Our study addresses this gap in the literature by examining two diagnostic models used to predict the conversion of AD from mild cognitive impairment, and a third model was proposed to differentiate AD from VaD. We conducted ROC Analyses using the variables LM II Standard Score, Animals Total, and CDRS Sum based on a previous diagnostic model. The sensitivity and specificity for the diagnosis of mild VaD were calculated for all possible scores of each test measure. The Animals Total cutoff score of 7 achieved excellent sensitivity and specificity, receiving 96% and 92%, respectively. In this sample, patients who could name at least seven animals under 60 seconds were highly likely to be diagnosed with VaD. LM II Scaled Score also achieved statistical significance (p <0.001) and a cutoff score of 4 received 96% sensitivity and 77% specificity. Patients who achieved an LM II Scaled Score of 4 or higher were highly likely to be diagnosed with VaD.

INTRODUCCIÓ: El deteriorament cognitiu d’origen vascular, i més concretament la demència vascular (DV), s’associa al compromís persistent del flux sanguini cerebral i representa la segona causa més freqüent de demència al món, després de la malaltia d’Alzheimer. La DV és una malaltia caracteritzada per múltiples i discretes lesions isquèmiques, lesions difuses a la substància blanca (leucoaraiosi) i hemorràgies cerebrals, entre d’altres. S’han dedicat gran quantitat d’esforços en la recerca dels mecanismes fisiopatològics subjacents a aquesta patologia però encara no es coneixen amb precisió. Les tècniques de neuroimatge, com la imatge per ressonància (MRI), van suposar un gran avenç en el diagnòstic d’aquesta patologia. Per aquest motiu, en aquest treball de tesi doctoral s’ha proposat l’estudi longitudinal de canvis estructurals i funcionals vasculars al llarg del temps en animals d’experimentació, en el curs dels símptomes de la malaltia, i sota la influència de diversos factors de risc, mitjançant diferents tècniques de MRI per trobar nous biomarcadors no invasius per la DV, i per avançar en l’estudi de la seva fisiopatologia, així com en el diagnòstic precoç i la monitorització de l’efectivitat de noves teràpies. MATERIAL I MÈTODES: Es van utilitzar un total de 174 ratolins de dues soques, ratolins ApoE-/-, que tenen predisposició a desenvolupar aterosclerosi amb l’edat, i els ratolins control C57Bl6 de tres edats diferents, des de l’adult jove (6 mesos) fins a la vellesa (18 mesos) incloent una edat intermitja (12 mesos). Es va realitzar un seguiment longitudinal amb tècniques de MRI per estudiar diferents característiques de les lesions vasculars, que es van correlacionar proves de comportament. La validació de les tècniques de MRI es va realitzar mitjançant tincions d’immunohistoquímica per MBP i la clarificació de talls gruixuts de cervell (2 mm) per quantificació de la microvasculatura. RESULTATS: Es van detectar alteracions relacionades amb aterosclerosi i hipoperfusió en longitud i tortuositat de les principals artèries que irriguen el cervell mitjançant angiografia TOF. També en relació a la irrigació del cervell, es van trobar canvis en el flux sanguini cerebral mitjançant perfusió ASL, associats a les tres condicions estudiades (envelliment, aterosclerosi i hipoperfusió). Així mateix, les tres condicions experimentals van provocar alteracions en les fibres de mielina, detectades amb l’anàlisi dels diferents components dels tensors de difusió (DTI). Aquests canvis es van trobar a estructures relacionades amb les alteracions en les proves de conducta, com ara en ansietat, 11 memòria de reconeixement, debilitat muscular i pertorbacions en la marxa. D’altra banda, l’índex Q va mostrar menys sensibilitat que l’anàlisi histopatològic per a l’estudi de la densitat microvascular. Tot i això, va servir per detectar canvis en la densitat microvascular associats a l’edat. Els canvis en el gruix de l’escorça cerebral (atròfia cortical) mesurats per MRI va resultar ser un bon biomarcador de la mort neuronal produïda per l’envelliment i la hipoperfusió. CONCLUSIONS: Els resultats d’aquest estudi confirmen la utilitat de la MRI com a eina per avaluar els canvis estructurals i funcionals de la neuropatologia de l’envelliment, l’aterosclerosi i la hipoperfusió en recerca traslacional.

This study examined differences in scoring patterns among those diagnosed with Alzheimer's dementia and vascular dementia on the clock-drawing test. Archival clock drawing data was retrieved on 279 patients presenting at a county hospital-based memory clinic. Analysis of drawings was based on frequency of qualitative errors, as well as an overall quantitative score. Mean comparisons found those patients with Alzheimer's dementia to perform worse on both quantitative and qualitative scoring measures. However, Pearson's chi-squared test revealed a significantly higher rate of spacing errors among subjects with vascular dementia. Such lends support to my hypothesis that impaired executive functioning in vascular dementia patients would lead to poor qualitative performance. Logistic regression found significant predictive ability for the qualitative criteria in diagnosis (χ2 = 25.49, p < .001), particularly the rate of omission (z = 8.96, p = .003) and addition errors (z = 7.58, p = .006). Such findings hold important implications for the use of qualitative criteria in cognitive screening assessments.

Thesis (M.A.)--Central Connecticut State University, 2001.
Thesis advisor: C. Charles Mate-Kole. " ... in partial fulfillment of the requirements for the degree of Master of Arts in Psychology." Includes bibliographical references (leaves 36-44). Also available via the World Wide Web.

Identification of modifiable risk factors for Alzheimer’s disease (AD) is crucial in order to diminish suffering from this devastating disease. The aim of this thesis was to investigate if different aspects of glucose metabolism, insulin, fatty-acid composition or other vascular risk factors predict the future development of AD and dementia. This thesis is based on the Uppsala Longitudinal Study of Adult Men (ULSAM) cohort, which started in 1970. A total of 2322 men at age 50 were examined with focus on vascular risk factors. The cohort was re-examined at ages 60, 71, 77, 82 and 88. Incident diagnoses of AD, vascular dementia, other dementias and cognitive impairment were assessed in 2005–2010. The risk of AD was increased in subjects with lower early insulin response measured with both an intravenous glucose tolerance test at 50 years and an oral glucose tolerance test at 71 years of age. The presence of vascular risk factors such as hypertension, obesity, hypercholesterolemia and smoking increased the risk of future vascular dementia but not of AD. Furthermore, saturated fatty acids at midlife were inversely associated with risk of AD. No evidence of a protective effect of omega-3 fatty acids against dementia was found. The susceptibility allele, APOE ε4, was the strongest individual risk factor. APOE ε4 carriers with vascular risk factors had the greatest risk of developing dementia. Low insulin response was a risk factor for AD mainly in APOE ε4 non-carriers. Disturbances in insulin and glucose metabolism, vascular risk factors and fatty acids are linked differentially to the pathogenesis of AD and vascular dementia. These observations should be considered when future clinical approaches are planned to prevent and postpone the onset of dementia.
ULSAM

The aim of this thesis was to study the biomarker homocysteine and other novel potential vascular risk factors for dementia. In an out-patient based study of a cohort of 926 consecutive subjects referred to our Memory Unit during 1996―2000, serum-folate was lower and total plasma homocysteine (tHcy) and serum methyl malonate were higher in subjects being prescribed with B12. In the subgroup diagnosed with dementia and with a positive family history of dementia, tHcy was higher than in the subgroup diagnosed as non-demented. It is necessary to supplement subjects with vitamin B12 deficiency with B12, but our results indicate that it is not sufficient with B12 alone because this gives rise to intracellular folate deficiency. We also found indications of a genetic component in dementia because tHcy was higher in the group with a positive family history of dementia. These findings prompted further studies of homocysteine metabolism. The frequency of mutations in the gene for folate receptor-α (FOLR-1), and the fibrinolytic pattern in dementia and non-dementia were studied in the two cohorts DGM (n=300) and AS (n=389). The DGM cohort is a consecutive series of subjects attending our Memory Care Unit for investigation of suspected cognitive problems or dementia between 2003 - 2007. The AS (= active seniors) cohort comprises retired, apparently healthy subjects from central Sweden, actively participating in study circles. A rare haplotype in the FOLR-1, with mutations in two nearby loci, was discovered, possibly associated with lower serum-folate and higher tHcy concentrations and was more frequent in the DGM group. The transport of folate to the CSF was studied in the DGM-cohort. Dementia with a vascular component was associated with a lower CSF to serum folate ratio indicative of reduced transport of folate to the CSF and further to the brain. The vascular endothelial derived fibrinolytic markers tPA, tPA/PAI-1-complex, and vWF were not only higher in vascular dementia (VaD) but also in Alzheimer’s Disease (AD) when compared to the AS group. The impaired fibrinolytic activity in both vascular dementia and in AD is a novel finding, signifying a vascular component in the development of dementia. In conclusion we found that both hereditary and nutritional background factors were linked to dementia and furthermore that a dysregulated fibrinolysis was linked to both VaD and AD.

Introdução: Estudos prévios analisaram a associação entre fatores de risco cardiovascular (FRCV) associados ao diagnóstico de demência vascular (DV) provável ou possível. No entanto, não foram encontrados estudos que analisassem a associação entre FRCV e a ocorrência de DV definitiva. Dessa maneira, ainda permanece obscura a associação entre os FRCV e a ocorrência de DV definitiva, ou seja, aquela diagnosticada por meio do exame neuropatológico, no qual se apresenta como padrão ouro. Objetivo: Avaliar a associação entre os FRCV e a ocorrência de DV definitiva, pura e mista. Método: Por meio de um estudo transversal foram analisados 707 casos pertencentes à casuística do Banco de Encéfalos Humanos do Grupo de Estudos em Envelhecimento (BEHGEEC) da FMUSP, que respeitaram os critérios de inclusão. A existência de fatores de risco cardiovascular em vida (Hipertensão Arterial, Diabetes Mellitus, Dislipidemia, Tabagismo, Etilismo, Obesidade e Sedentarismo), reportada por um informante com convivido minimamente semanal durante a autópsia, foi associada ao diagnóstico neuropatológico de demência vascular emitido por um neuropatologista. Modelos de regressão logística (sem e com ajuste para sexo, idade e raça) foram construídos para testar a associação entre os FRCV e o diagnóstico de DV, DV pura e DV mista. Foi testada a capacidade preditiva dos fatores que se mostraram preditores de DV por meio da Curva ROC. Resultados: O sedentarismo foi um preditor independente de DV (OR 1,943; IC95% 1,198 3,151; p= 0,007) e DV pura (OR 3,148; IC95% 1,428 6,941;p= 0,004). A HAS foi um preditor independente de DV mista (OR 2,240; IC95% 1,216 4,126; p= 0.01). O sedentarismo não apresentou boa capacidade preditiva para a DV e DV Pura (AUC = 0,380 e 0,337, respectivamente), assim como a HAS para a DV Mista (AUC = 0,459). Conclusões: Dentre os FRCV o sedentarismo e a HAS foram os que se associaram a um aumento no risco de DV.
Introduction: Previous studies have analyzed the association between cardiovascular risk factors (CVRF) associated with the diagnosis (probable or possible) of vascular dementia (VaD). However, there are no studies that have analyzed the association between CVRF and the occurrence of definitive VaD. The association between CVRF and the occurrence of definite VaD, neuropathologically defined and considered as gold-standard, remains obscure. Objectives: To evaluate the association between CVRF and the occurrence of definitive VaD, pure and mixed. Methods: This is a cross-sectional study which evaluated 707 cases belonging to the Bain Bank of the Brazilian Aging Brain Study Group (BBBABSG) of FMUSP, respecting the inclusion criteria. The history of existence of cardiovascular risk factors in life (hypertension, diabetes mellitus, dyslipidemia, smoking, alcoholism, obesity, and sedentarism) reported by a knowledgeable next-of-kin, with at least weekly contact with the deceased, was associated with the neuropathological diagnosis of vascular dementia reported by a neuropathologist after the autopsy exam. Logistic regression models (with and without adjustment for sex, age and race) were tested to show the association between CVRF and the diagnosis of VaD, pure Vad and mixed VaD. It was also tested the predictive capacity of the factors that proved to be predictors of VaD through the ROC Curve. Results: Sedentary lifestyle was an independent predictor of VaD (OR 1,943, CI 95% 1,198 - 3,151, p = 0.007) and of Pure VaD (OR 3,148, 95% CI, 1.428 - 6.941, p = 0.004). Hypertension was an independent predictor of Mixed VaD (OR 2,240, 95% CI 1,216 - 4,126, p = 0.01). Sedentary lifestyle did not present good predictive capacity for VaD and Pure VaD (AUC = 0.380 and 0.337, respectively), as Hypertension for Mixed DV did not either (AUC = 0.459). Conclusions: Among the CVRF, sedentarism and hypertension were those associated with an increase VaD risk.

Vascular dementia (VaD), the second most common cause of dementia, causes substantial distress to patients and represents a significant burden to their families and communities. Currently, there is no effective treatment to reverse the brain damage associated with VaD. In general the drugs available for the management of cognitive problems in VaD are expensive and outcomes are uncertain. It is, therefore, important to seek out alternative approaches, which may prove effective, cheaper and safer. Chinese herbal medicine (CHM) has been used for the treatment of dementia-like disorders for centuries. Data from many preclinical studies and some clinical studies have suggested the potential effectiveness of CHM for the treatment of VaD. Based on the literature review conducted as part of this thesis, however, most of the studies were published in Chinese literature and failed to demonstrate methodological rigour or to report sufficient methodological detail. Randomised controlled trials (RCTs) using scientific methods of diagnosis and outcome measures are urgently needed. Wei Nao Kang (WNK) is a three-herb formula developed by Xi Yuan Hospital, China Academy of Chinese Medical Sciences. Preclinical experiments of WNK have demonstrated significant improvement in learning and memory function in VaD animal models in rats and mice. Human case studies have also signalled the potential value of WNK in VaD. Although the results of these studies were encouraging, strong scientific evidence from a well-designed RCT is still required. A rigorous clinical trial methodology, including scientific diagnostic criteria and outcome measures, was designed and applied to the evaluation of WNK for VaD. The trial was successfully conducted over a two-year period. Cognitive functions, as evidenced by the ADAS-cog, were significantly improved in the study group taking WNK herbal medication compared with the placebo group. The ADAS-cog was simultaneously validated as a measure of cognitive function in VaD. Blinding was verified and no major adverse effects were found related to WNK treatment. However, neither group demonstrated long-lasting effect on a 16 weeks follow-up after completion of treatment. WNK demonstrated a significant effect on quality of life (measured by SF-36) and some effect on activities of daily living (measured by ADCS-ADL) in VaD patients. The SF-36 was validated as a measure of general health status and the ADCS-ADL as a measure of activities of daily living in patients with VaD. Both scales were proven sensitive to the presence of VaD, and provided useful supplementary outcome measures for VaD. A cerebral perfusion study was conducted to identify changes in cerebral blood flow and its relationship with clinical symptoms. The study showed that WNK had marked increases in blood flow in the inferior frontal and anterior temporal regions, both of which are closely related to cognitive function in human brains. This study has provided scientific evidence in support of the clinical effect of WNK on VaD. In addition, it validated several outcome measures in assessing improvements in cognitive functions, activities of daily living and quality of life in VaD patients. One of the highlights of this study is the application of SPECT scans as an outcome measure. This provided an excellent objective parameter for assessing the effects of WNK. To the best of our knowledge, SPECT scanning has never been used in VaD trials of herbal medicines.

Thesis (Ph.D.)--University of Western Sydney, 2008.
A thesis presented to the University of Western Sydney, College of Health and Science, Centre for Complementary Medicine, in fulfilment of the requirements for the degree of Doctor of Philosophy. Includes bibliographies.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is one of the most common forms of hereditary vascular dementia (VaD). Characterised by early-onset strokes and cognitive impairment in the absence of vascular risk factors, CADASIL is an ideal model to understand the pathophysiology of VaD. Pathogenic mutations in the NOTCH3 gene, which encodes a single-pass transmembrane cell surface receptor expressed predominantly in vascular smooth muscle cells (VSMC), cause severe vascular alterations including VSMC degeneration, hyalinosis, deposition of CADASIL-specific granular osmiophilic material (GOM) and white matter (WM) changes. While these changes have been well-described, their causative mechanism or difference between sporadic VaD is poorly understood. The aim of the project was to quantitatively characterise various aspects of cerebral pathology of CADASIL in order to reveal the pathological basis of CADASIL phenotypes, especially of cognitive dysfunction. Firstly, we assessed vascular and perivascular changes in CADASIL brain areas and found significant vessel wall thickening and perivascular space enlargement, even compared to sporadic VaD. Secondly, by using immunogold electron microscopy, NOTCH3 extracellular domain (N3ECD) was located within GOM in the wall of cerebral arteries/arterioles/capillaries, establishing at least one component of GOM and its wide-spread existence in the vasculature. This study also suggested the possible existence of intracellular N3ECD accumulation and involvement of inflammatory response in the pathogenesis of CADASIL. Finally, we provide neuronal density data from the hippocampal formation in CADASIL brains to identify the neural substrates of VaD in CADASIL. Overall, the number of neurons in CA1, CA2 and entorhinal cortex was relatively spared in CADASIL while pyramidal neuronal subpopulation, as shown by SMI32 immunoreactivity, was slightly decreased. In addition, SMI32 staining revealed extensive chronic damage to WM tracts, especially those in the frontal-parietal area. These data suggest that vascular dysfunction and inflammation result in frontal disconnection, which could underlie cognitive impairment in CADASIL patients.

Quantitative magnetic resonance imaging (MRI) was used to assess global and regional cerebral volumes in patients with a clinical diagnosis of subcortical vascular dementia (VD) and Alzheimer’s disease (AD). Whole brain volume, cerebrospinal fluid volume, volumes of the temporal, frontal and parietal lobes, the cerebellum and the amygdala-hippocampus complex were determined using a personal computer-based software. Seventeen patients with VD, 22 patients with AD and 13 healthy controls were included. Analysis of covariance using age as covariate demonstrated significant mean differences between controls and dementia groups with respect to all morphological parameters. However, apart from the volume of the cerebellum no significant volumetric differences were found between VD and AD. These results indicate that MRI-based volumetry allows differentiation between AD or VD from normal controls and that measurement of cerebellar volume may be of use to separate vascular and degenerative dementia. However, since the distribution of cerebral atrophy in both dementia groups is very similar, it is suggested that the atrophic changes are not specific to the underlying cause but rather reflect the selective vulnerability of neuronal structures
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

Quantitative magnetic resonance imaging (MRI) was used to assess global and regional cerebral volumes in patients with a clinical diagnosis of subcortical vascular dementia (VD) and Alzheimer’s disease (AD). Whole brain volume, cerebrospinal fluid volume, volumes of the temporal, frontal and parietal lobes, the cerebellum and the amygdala-hippocampus complex were determined using a personal computer-based software. Seventeen patients with VD, 22 patients with AD and 13 healthy controls were included. Analysis of covariance using age as covariate demonstrated significant mean differences between controls and dementia groups with respect to all morphological parameters. However, apart from the volume of the cerebellum no significant volumetric differences were found between VD and AD. These results indicate that MRI-based volumetry allows differentiation between AD or VD from normal controls and that measurement of cerebellar volume may be of use to separate vascular and degenerative dementia. However, since the distribution of cerebral atrophy in both dementia groups is very similar, it is suggested that the atrophic changes are not specific to the underlying cause but rather reflect the selective vulnerability of neuronal structures.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

In spite of impressive recent progress, the aetiopathogenesis of Alzheimer’s disease (AD) remains incompletely understood. The distinctive neuropathological features of AD, in particular the plaques and tangles, have been the particular focus of most aetiological theories. It is well accepted that AD is a multifactorial disease, with alterations to a variety of brain structures and cell types, including neurons, glia and the brain vasculature. Studies of risk factors have revealed a diversity of genetic variables that interact with health, diet and lifestyle-related factors in the causation of AD. These factors influence the structure, aggregation and function of a set of proteins that are increasingly the focus of research. The work in this thesis has focused on the pathophysiological aspects of some of these proteins in a number of cellular compartments and brain. Several assays have been established and techniques utilized in the completion of this work, including; differential detergent fractionation of brain tissue, 1D and 2D PAGE, western blotting with chemiluminescence detection, ELISA assays of Abeta 1-40 and 1-42, quantitative ECNI GCMS of o- and m-tyrosine as well as metabolites of the kynurenine pathway, quantitative MALDI-TOF assay of hemorphins and LCMSMS based proteomics, to identify proteins with altered expression levels in AD relative to control brain tissue. A variety of regional differences have been observed in the biochemistry of the AD cortex which are probably the outcome of local response variations to AD pathology. One of the most consistent threads throughout this work has been an apparent resilience of the occipital lobe relative to the other brain regions, as reflected in lower overall levels of oxidative stress and increased levels of proteins associated with metabolic processes, neuronal remodeling and stress reduction.

Age-related neurologic disease is a significant and growing burden on our society. Although the largest share of research effort has typically been devoted to the common neurodegenerative illnesses (such as Alzheimer’s disease, or AD), the reality is that nearly all cases of neurodegenerative disease possess elements of mixed pathology. Vascular contributions to cognitive impairment and dementia (VCID) is a complex form of dementia, combining aspects of vascular disease and other forms of dementia, such as Alzheimer’s disease. This pathology is heterogeneous and can include cerebral amyloid angiopathy (CAA), hemorrhages, white matter infarcts, and changes to the neurovascular unit. Given the heterogeneous nature of VCID, we hypothesized that we could further elucidate mechanisms that drive dementia in VCID by examining pathology in mouse models and use this data to guide the study of human autopsy cases. Using a mouse model of VCID, we identified NHE1, a sodium hydrogen exchanger that was upregulated in these mice, as a possible candidate for a factor involved in cerebrovascular disease in humans. We saw a significant age effect of NHE1 in cases with Down syndrome (DS), leading us to further examine cerebrovascular pathology in individuals with DS. People with DS are at a high risk of developing cognitive impairment and dementia after the age of 50. In fact, virtually all adults with DS develop the neuropathology for an AD (beta-amyloid (Aß) senile plaques and tau neurofibrillary tangles) diagnosis by the age of 40 due to a triplication of chromosome 21. We found that these individuals develop CAA and microhemorrhages as a function of age, and that these rates are as severe as sporadic AD, despite an age difference of ~30 years. We also found that individuals with DS have different microglial morphologies than controls or individuals with AD. This data indicates that people with DS develop significant cerebrovascular and AD pathology, indicative of VCID. Overall, we found that mixed pathologies, specifically VCID, is an important contributor to the development of dementia and should be studied further to better understand how this pathology drives cognitive impairment. Further, it is clear that mouse models map imperfectly onto complex human diseases, and that significant work remains to be done towards achieving an adequate model of VCID.

La « fragilité » fait référence à un état de forte vulnérabilité qui résulte d’une réduction des réserves adaptatives de multiples systèmes biologiques et physiologiques sous l’action conjuguée de l’âge, de maladies et du contexte de la vie. Ce syndrome accroit la vulnérabilité de l’individu ainsi que son risque de dépendance, de chutes, d’hospitalisations, d’entrée en institution et de mortalité. La définition la plus utilisée, celle de Fried et collaborateurs, est basée sur la prise en compte d’éléments exclusivement physiques mais la possibilité d’inclure à cette définition d’autres composantes non-physiques, parmi lesquelles la cognition, est actuellement débattue. Cette thèse aborde donc la question d’un point de vue épidémiologique du possible lien entre l’altération des performances cognitives et la fragilité grâce aux données de deux études en population, une cohorte française et une cohorte mexicaine. Les résultats présentés dans cette thèse nous permettent d’affirmer l’existence d’une association entre la fragilité et un déficit cognitif. Qu’il s’agisse de la cohorte de Coyoacan ou des 3 Cités, les deux premières études de cette thèse ont montré une force d’association majorée sur l’incidence d’incapacité, d’hospitalisation ou de décès lorsqu’on considère la fragilité et le déficit cognitif de manière combinée, un résultat plaidant en faveur de l’intégration de la mesure de la cognition dans la définition de la fragilité. Concernant le risque de survenue de démence en revanche, la troisième étude ne montre pas d’effet majoré lorsque ces deux conditions étaient présentes puisque seuls les participants ayant un déficit cognitif étaient à risque de démence, indépendamment de leur statut de fragilité. Enfin, si la fragilité ne constituait pas un risque en soi de démence tous types confondus, la dernière étude de cette thèse a montré une forte association entre l’état de fragilité et le risque de démence vasculaire. Les résultats de cette thèse, ajoutés aux données de la littérature décrivant la présence d’atteintes vasculaires et cérébro-vasculaires dans le syndrome de fragilité, nous ont conduits à formuler l’hypothèse selon laquelle la fragilité pourrait être un état prodromique de démence vasculaire
“Frailty” is a clinical syndrome characterized by physiological loss of reserves and resilience and represents the summatory action of age, disease and living environment. This geriatric syndrome increases the vulnerability of elderly persons and their risk of disability, falls, hospitalization, institutionalization, and mortality. The definition most widely used, the one proposed by Fried and collaborators, only includes physical elements. Nonetheless, the inclusion of other non-physical components, in particular cognitive function is currently debated. Therefore, the aim of this thesis was the study, from an epidemiological point of view, of the association between cognitive function and frailty using the data of two population-based studies, a French cohort and a Mexican one. The results are in favor of the existence of an association between frailty and cognitive impairment. In the first two studies presented in this thesis, an increased risk of incident disability, hospitalization, and death was found. Therefore, including cognitive function in the phenotype of frailty may be relevant since both processes seem to contribute to the development of negative health-related outcomes. However, regarding the risk of dementia, the results of the third study show that only elderly subjects with cognitive impairment have an increased risk of developing dementia irrespective of their frailty status. Nevertheless, if frailty per se may not be a risk factor of dementia, all types confounded, the last study evidences a strong association between frailty and the incidence of vascular dementia. Such results along with previous studies reporting the existence of vascular and cerebrovascular damage in frail elderly lead us to postulate that frailty could be a prodromal state of vascular dementia

This research involves an examination of the relationship between education and age on a wide array of neuropsychological test measures among patients diagnosed with Alzheimer's and vascular dementia. The purpose of this study was to investigate the role of education as an attenuating factor to neurocognitive decline in dementia. Although numerous studies have been published regarding the relationship between educational attainment and AD, few have included other subtypes of dementia in their investigation. To further expand the generalizability of previous findings, the sample in this study included both AD and VaD. While previous research has demonstrated a relationship between education and age-related neurocognitive decline in AD, most studies have utilized the MMSE or brief screening instrument to assess cognitive functioning. The present research included VaD and examined a variety of cognitive domains such as measures of global functioning, verbal intelligence, verbal memory, visual memory, attention/concentration, language, visuospatial skills, speed-of-processing, and abstract reasoning/executive functioning. Two standard multiple regression analyses were conducted, the first including age and education as the independent variables to assess the effects on one over and above that of the other. The second analysis included age, education, and their interaction term in order to determine if education attenuates age-related neurocognitive decline in the diagnostic groups. Raw neuropsychological test measure scores were included in all analyses as dependent measures. Results revealed that age minimally predicted performance in both groups, whereas education better predicted neurocognitive test performance in the AD group than in the VaD group. Furthermore, findings suggest that among individuals with AD, the rate of neurocognitive impairment in encoding verbal information and visuoconstructional ability is buffered by higher levels of education attainment. None of the interaction terms were significant for the VaD group. The current findings question the extent and generalizability of the presumed protective effects of higher education on age-related neurocognitive decline.

Idiopathic normal pressure hydrocephalus (INPH) is a dementia treatable by insertion of a cerebrospinal fluid shunt. It has been suggested that INPH has similar pathophysiological mechanisms as cerebrovascular disease, but the vascular risk factor (VRF) profile of INPH patients has not been assessed using a modern epidemiological approach. The cognitive symptoms of INPH resemble the symptoms of depression, but the prevalence of depression among INPH patients is unknown. In addition, few studies investigate the impact of shunting on the quality of life (QoL), and no study has investigated the impact of comorbidity on QoL in INPH patients. The objective of this dissertation was to present the VRF profile of INPH and to investigate the hypothesis that INPH may be a subgroup of vascular dementia. Additional objectives were to assess the prevalence of depression in INPH patients and to investigate the impact of shunting and comorbidities on QoL in INPH. In the first cohort, the prevalence of possible INPH was assessed through clinical and radiological examinations in patients with a transient ischemic attack (TIA), consecutively admitted to the same hospital during 2006-2008. In the second cohort, VRFs, vascular disease and QoL were analysed in INPH patients consecutively shunted 2008-2010 in five out of six neurosurgical centres in Sweden. Patients remaining after inclusion (n=176, within the age-span 60-85 years and not having dementia) were compared to population-based age- and gender-matched controls (n=368, same inclusion criteria as for the INPH patients). Assessed VRFs were: hypertension, diabetes, obesity, hyperlipidemia, psychosocial factors (stress and depression), smoking, alcohol intake, physical activity and, dietary pattern. Cardiovascular, cerebrovascular and peripheral vascular disease as well as QoL were also assessed. Parameters were assessed through questionnaires, clinical examinations, measurements, ECG and, blood samples. In the first cohort, 4% of the TIA patients had clinically and radiologically verified INPH. In the second cohort, VRFs were overrepresented among the INPH patients compared with the controls. The VRFs independently associated with INPH were: hyperlipidemia (Odds ratio (OR): 2.4, 95%CI: 1.4-4.0), diabetes (OR: 2.2, 95%CI: 1.2-3.9), obesity (OR: 5.4, 95%CI: 2.5-11.8) and, psychosocial factors (OR: 5.3, 95%CI: 3.2-8.9). When adding the VRFs that were overrepresented in INPH, although not independently (physical inactivity and hypertension), these six VRFs accounted for 24% of the INPH cases in the elderly population (population attributable risk %: 24). Depression was overrepresented in shunted INPH patients compared to the controls (46% vs. 13%, p<0.001) and the main predictor for low QoL was a coexisting depression (p<0.001). In conclusion, the results of the INPH-CRasH study are consistent with a vascular pathophysiological component of INPH and indicate that INPH may be subgroup of vascular dementia. In clinical care and research, a complete risk factor analysis as well as screening for depression and a measurement for quality of life should be included in the work-up of INPH patients. The effect of targeted interventions against modifiable VRFs and anti-depressant treatment in INPH patients should be evaluated.
Idiopatisk normaltryckshydrocefalus (INPH, från engelskans ”idiopathic normal pressure hydrocephalus”) är en neurokirurgiskt behandlingsbar demens. Behandlingen är att operera in en shunt som dränerar cerebrospinalvätska från ventriklarna. Det har föreslagits att INPH skulle kunna orsakas av liknande patofysiologiska mekanismer som vid cerebrovaskulär sjukdom, men den vaskulära riskfaktorprofilen hos INPH-patienter har aldrig undersökts i en modern epidemiologisk studie. De kognitiva symtomen vid INPH påminner om symtomen vid depression, men prevalensen av depression hos INPH-patienter är okänd. Få studier undersöker hur shuntning påverkar livskvalitet och ingen studie har undersökt hur komorbiditet påverkar livskvaliteten vid INPH. Syftet med den här avhandlingen var att undersöka den vaskulära riskfaktorprofilen hos INPH-patienter samt att utforska hypotesen att INPH skulle kunna vara en undergrupp till vaskulär demens. Ytterligare ett syfte med avhandlingen var att undersöka hur många INPH-patienter som har depression samt undersöka hur shunting och komorbiditet påverkar livskvalitet vid INPH. I den första kohorten undersöktes kliniska och radiologiska fynd som tydde på INPH hos de patienter som blivit diagnostiserade med en TIA (från engelskans: transient ischemic attack) 2006-2008 på Norrlands Universitetssjukhus i Umeå. I den andra kohorten undersöktes konsekutivt shuntade INPH-patienter 2008-2010 från fem av sex neurokirurgiska kliniker i Sverige. De patienter som inkluderades i studien (n=176, ålder: 60-85 år, ej dementa) jämfördes med köns- och åldersmatchade kontroller från normalpopulationen (n=368, samma inklusionskriterier som för INPH-patienterna). De riskfaktorer som undersöktes var: hypertension, hyperlipidemi, diabetes, fetma, psykosociala faktorer (stress och depression), rökning, alkohol, fysisk aktivitet och diet. Även kardiovaskulära och cerebrovaskulära sjukdomar undersöktes, liksom perifer vaskulär sjukdom samt livskvalitet. Datainsamling skedde genom frågeformulär, kliniska undersökningar, mätningar, EKG och blodprov. I den första kohorten hade 4% av TIA-patienterna kliniskt och radiologiskt verifierad INPH. I den andra kohorten var vaskulära riskfaktorer överrepresenterade hos INPH-patienterna jämfört med iv normalpopulationen. Hyperlipidemi (OR: 2.4, 95%CI: 1.4-4.0), diabetes (OR: 2.2, 95%CI: 1.2-3.9), fetma (OR: 5.4, 95%CI: 2.5-11.8) och psykosociala faktorer (OR: 5.3, 95%CI: 3.2-8.9) var associerade med INPH oberoende av kön, ålder och de andra riskfaktorerna. Hypertension och fysisk inaktivitet var också associerade med INPH, dock inte oberoende av övriga riskfaktorer. Sammanlagd PAR% (från engelskans: population attributable risk %) för de här sex riskfaktorerna var 24%. INPH-patienterna hade depression i högre utsträckning än kontrollerna (46% vs. 13%, p<0.001), och depression var den viktigaste prediktorn för låg livskvalitet. Resultaten tyder på att vaskulär sjukdom och vaskulära riskfaktorer är involverade i den patofysiologiska mekanismen vid INPH. INPH kan vara en undergrupp till vaskulär demens. En fullständig riskfaktoranalys och screening för depression bör ingå i den preoperativa utvärderingen såväl som i forskning på INPH-patienter, och ett mått på livskvalitet bör införas. Effekten av riktade insatser mot såväl vaskulära riskfaktorer som depression vid INPH bör utvärderas.

The purpose of the current study was to explore the relationship between cognitive status and depression in a sample of geriatric patients. Participants included 282 geriatric patients ranging in age from 65 to 96 years who were classified according to diagnosis as: DAT, VaD, MCI, and Norm. All were referred for neurocognitive testing from the Geriatric Assessment Program (GAP) at the University of North Texas Health Science Center (UNTHSC) in Fort Worth, Texas. This study sought to identify factor structures for two versions of the GDS using a geriatric sample of cognitively impaired and intact patients. It then compared these factors to each other to determine whether the GDS-15 is truly a shorter version of the GDS-30. These were then compared to a previously determined factor structure. This study explored whether the four-factors of the GDS-30 are able to differentiate cognitive diagnostic groups. Further, this study sought to identify whether the severity of cognitive decline impacted GDS factor score for each of the cognitively impaired groups. Results revealed a two-factor model of the GDS - 15 and a four-factor model with the GDS - 30. The GDS-15 factors did not differ from the first two factors of the GDS-30. Comparison between the GDS-30 factor structure and that reported by Hall and Davis (in press) revealed no significant differences despite the inclusion of a normal, non-demented group in the current study. Comparisons of subscale scores revealed that DAT patients tended to score lower than the other groups on all but the cognitive impairment subscale. Severity level analyses indicated that as severity of deficits increases, awareness of deficits decreases. This study found that although the GDS-30 is a good screening tool for depression in geriatric patients, it is not particularly useful in differentiating cognitive status group. Also, the GDS-15 was not found to be a good substitute for the GDS-30.

Diabetes is a disease with a deleterious pathology that currently impacts 4.5 million individuals within the United States. This study examined the ability of a specific neuropsychological battery to identify and classify dementia type, investigated the impact of diabetes on cognition and analyzed the ability of the memory measures of the 7 Minute Screen (7MS) and the Rey-Osterrieth Recall to correctly categorize dementia type when not used in combination with a full battery. The battery in addition to exhaustive patient history, medical chart review and pertinent tests were used in initial diagnosis. Results indicated the battery was sufficient in the identification and classification of dementia type. Within the sample, diabetes did not appear to significantly impact overall battery results whereby only two measures were minimally affected by diabetes. Finally, the memory measures of the 7MS and the Rey-Osterrieth Recall were sufficient to predict membership into the Alzheimer's (AD) and vascular dementia (VD) groups with 86.4% accuracy. The classification percentage dropped to 68.3% with addition of the mild cognitive impairment category. The full battery correctly classified AD and VD dementia 87.5% and appeared to be the most robust.

INTRODUÇÃO: Os quadros demenciais comprometem gradualmente todos os domínios cognitivos e comportamentais. Deterioração progressiva nas funções de linguagem também é observada, e pode ser uma medida importante no diagnóstico precoce de demência. É escasso o conhecimento sobre o padrão de linguagem na Demência Vascular (DV). Os poucos estudos existentes têm analisado aspectos lingüísticos isolados e produzido resultados conflitantes. A Bateria Arizona para Desordens da Comunicação em Demência (ABCD) foi desenvolvida para identificar e avaliar alterações de comunicação funcional associadas à demência, relacionando-as com habilidades de memória episódica e construção visoespacial. A inexistência de estudos utilizando a ABCD em pacientes com DV e, a necessidade de ampliar a experiência brasileira quanto ao uso desta bateria em pacientes com Doença de Alzheimer, foram os aspectos que motivaram a realização deste estudo. OBJETIVOS: Descrever as habilidades lingüísticas de pacientes com DV em fase leve e compará-las às habilidades linguísticas de pacientes com DA e idosos cognitivamente normais. MÉTODOS: Foram avaliados 23 pacientes com DV leve - GDV (médias de idade: 71,7 (6,9) e escolaridade: 9,1(5)), 20 pacientes com DA leve - GDA (médias de idade: 77,3 (3,9) e escolaridade: 6,7(4,3)) e 31 sujeitos controles - GC (médias de idade: 72,7 (6,9) e escolaridade: 9,0(4,4)) utilizando-se a ABCD e outros testes para avaliação de funções cognitivas de suporte da linguagem. RESULTADOS: Houve diferenças estatisticamente significativas entre o GDV e o GC em todas as medidas da ABCD, com exceção do subteste de Questões Comparativas do construto de Compreensão Linguística. A acurácia da ABCD foi superior a 80%, em todos os construtos e no escore total da ABCD, para discriminação entre GDV e GC. A comparação entre o GDV e o GDA mostrou diferenças estatisticamente significativas nas medidas de dois construtos da ABCD. Memória Episódica, Expressão Linguística (subteste de Nomeação por Confrontação). Conclusão: As habilidades linguísticas dos pacientes com DV leve mostraram-se prejudicadas em todos os subtestes de Expressão e Compreensão linguística da ABCD, com exceção do subteste de Questões Comparativas. Diferenças linguísticas entre os pacientes com DV leve e os pacientes com DA leve foram observadas somente no subteste de Nomeação por Confrontação da ABCD
INTRODUCTION: Dementia gradually affects all cognitive and behavioral domains. A progressive deterioration in language is also observed, and may be used as an important measure in the differential diagnosis. Little is known about the language pattern in Vascular Dementia (VaD). The few existing studies have addressed specific aspects of language and produced conflicting results. The Arizona Battery of Communication Disorders in Dementia (ABCD) was designed to identify and evaluate functional communication disorders and other abilities as episodic memory and visuospatial construction in dementia. The lack of studies using the ABCD in patients with VaD, and the need to expand the Brazilian experience in the use of this battery in patients with Alzheimer\'s Disease (AD), were the aspects that motivated this study. OBJECTIVES: To describe the linguistic abilities in mild VaD patients compared to AD patients and cognitively normal elderly. METHODS: We evaluated 23 mild VaD patients - VaDG (mean age: 71,7(6,9) and schooling: 9,1(5)), 20 mild AD patients - ADG (mean age: 77,3(3,9) and schooling: 6,7(4,3)) and 31 controls - CG (mean age: 72,7(6,9) and schooling: 9,0(4,4)) using the ABCD and tests to evaluate cognitive functions supporting language. RESULTS: There were statistically differences significant between VaDG and CG in all ABCD measures, except for the subtest Comparative Question from Linguistic Comprehension Construct. The accuracy of the ABCD was above 80% to discriminate VaDG and CG in all constructs. Comparison between VaDG and ADG showed statistically differences significant in two constructs of ABCD: in the Episodic Memory Construct, and in the Linguistic Expression Construct (Confrontation Naming subtest). CONCLUSIONS: Linguistic abilities of mild VaD patients were impaired in all measures of the Linguistic Expression and Linguistic Comprehension Constructs, except for the Comparative Questions subtest. Linguistic differences between mild VaD patients and mild AD patients were observed only in the Confrontation Naming subtest of ABCD

The relationship between cerebrovascular disease (CVD) risk factors and cognitive impairment or dementia has been widely studied with significant variability in findings between groups. We hypothesized that chronic small vessel injury in the form of arteriolar sclerosis, measured quantitatively using MRI to measure total white matter hyperintensity (WMH) volumes, would identify specific association of CVD risk factors and patterns of cognitive decline, associated with mild cognitive impairment of the cerebrovascular type, that represent the core features of vascular cognitive impairment in our cohort. A Cross-sectional analysis of clinical and quantitative MRI data on 114 subjects with normal cognitive function (n=52) and mild cognitive impairment (MCI; n=62) was performed. Quantitative total WMH volumes were examined in relation to potentially causative CVD risk factors and resultant test scores across cognitive domains using linear regression models adjusted for age, gender, and education. Among CVD risk factors analyzed, age (p< 0.001), education (p= 0.003), hypertension (p= 0.012), and hyperlipidemia (p= 0.008) demonstrated the strongest associations with WMH volumes. Conversely, diabetes, smoking, history of heart attacks, atrial fibrillation, and history of stroke that have shown associations with CVD pathology on imaging in other studies were not statistically associated with increased WMH in this cohort. WMH volumes were associated with decrease performance on the Trial Making Test type A & B and long delayed free recall on the California Verbal Learning Test. Our findings suggest similarities and yet differences in comparison to other studies. Hypertension and hyperlipidemia appear to represent common shared risks across geographically disparate groups. Our findings, like others, suggest CVD pathology impact processing speed and executive function and provide further evidence for CVD effects on short-term memory in those at risk for cognitive decline and the future development of dementia in our cohort.

La démence est caractérisée par une détérioration progressive des capacités mentales qui compromettent l’autonomie des patients. Le vieillissement en est le facteur de risque majeur. La population mondiale vieillissante, l’absence de traitement, ainsi que l’augmentation des individus touchés estimé à 50 millions, permettent d’estimer un coût de santé publique triplé à 4 trillions de dollars d’ici à 2050. Les études récentes tendent à montrer un rôle crucial de la dysfonction vasculaire dans les pathologies de démence. En effet une large étude neuropathologique basée sur l’autopsie des patients a permis de mettre en évidence que 80% des patients diagnostiqués de Maladie d’Alzheimer (MA) présentaient une pathologie vasculaire. Néanmoins, les mécanismes cellulaires et moléculaires entrainants ces dysfonctions vasculaires et altérant l’intégrité de la barrière hémato-encéphalique (BHE) dans le cas de la démence en général restent encore aujourd’hui méconnus. Au niveau moléculaire, la voie Wnt est impliqué dans le maintien de l’intégrité de la BHE. Le laboratoire a récemment identifié une E3-ubiquitine-ligase, PDZRN3 qui agit comme un médiateur de la signalisation Wnt non-canonique dans les cellules endothéliales en réprimant la voie Wnt canonique. Cette ubiquitine-ligase est impliquée dans la perméabilité vasculaire, faisant de cette dernière une cible pour réguler l’intégrité de cette barrière. Nous avons alors posé l’hypothèse suivante : La BHE ést déstabilisée dans la mise en place des démences dont la MA ; en maintenant l’intégrité de la BHE en réprimant la signalisation Wnt, permettrait de ralentir la sévérité de la MA et des altérations cognitives associées. Nous avons généré une lignée murine délétée pour Pdzrn3 dans l’endothélium de façon inductible (iECKO) et les avons soumises à une hypoperfusion cérébrale graduelle par la pose de constricteurs sur les artères carotides communes. Alors que les performances des souris contrôles sont impactées par l’hypoperfusion, celles des souris iECKO sont maintenues. Nos résultats montrent que les souris iECKO présentent une réduction significative des lésions cérébrales (micro-infarcts) ainsi qu’une réduction significative de la perte neuronale dans la zone CA1 de l’hippocampe jouant un rôle clé dans les processus mnésiques de reconnaisance spatiale. À l’inverse les souris surexprimant Pdzrn3 dans l’endothélium (iECOE) présentent le phénotype opposé à celui des souris iECKO, avec une détérioration mnésique plus importante que les contrôles associés à des fuites de la BHE, des lésions cérébrales, une perte neuronale hippocampale et une inflammation exacerbée. Nous avons aussi voulu étudier l’impact de la délétion dans les CE de Pdzrn3 dans le cadre de la MA. Nous avons généré et validé un modèle murin triple mutant en croisant les souris APP/PS1, modèle de MA, avec nos souris iECKO pour générer une souche APP/PS1 ; iECKO. Étonnamment, nos résultats montrent une réduction significative des dépôts amyloïdes à 6 mois dans les souris APP/PS1 ; Pdzrn3 iECKO comparés à leurs contrôles APP/PS1. À 8 mois les souris APP/PS1 apparaissent comme ayant une fonction cognitive sévèrement touchée dans un test mnésique de reconnaissance spatiale alors que les souris APP/PS1 ; Pdzrn3 iECKO ont une performance comparable à celle des contrôles de même âge non déments
Dementia is characterized by a progressive deterioration of mental capacity that inevitably compromises independent living. Advancing age is the main risk factor, and due to the aging of the world population and lack of effective treatments, the number of affected individuals, estimated at 50 million worldwide, is anticipated to triple by 2050 at a cost approaching 4 trillion dollars. Recent studies tend to show a crucial role of vascular dysfunction in dementia pathologies. Indeed, a large autopsy-based neuropathological study has revealed that 80% of patients diagnosed with Alzheimer’s disease (AD) exhibit vascular pathology. However, the cellular and molecular mechanisms underlying vascular dysfunction and alteration of the blood brain barrier (BBB) integrity associated with dementia and AD remain to be elucidated. Body of evidences point out the Wnt pathway role in the maintenance of BBB integrity. The laboratory recently identified an E3-ubiquitin-ligase, PDZRN3 acting like Wnt non-canonical pathway modulator in endothelial cells repressing canonical Wnt pathway. This ubiquitin-ligase is involved in vascular permeability, making it a promising modulatory target to act upon alterations of the BBB integrity. We then hypothesized that: BBB is destabilized in the early onset of dementia & AD, keeping EC in a differentiated “barrier” state through Wnt signaling modulation should modulates early onset of dementia. We have generated Pdzrn3 inducible EC knockout (iECKO) mice and submitted them to gradual cerebral hypoperfusion by implanting ameroïd constrictors on both common carotid arteries. While memory performance of wild-type littermates is impaired under hypoperfusion, that of iECKO mice is preserved. Importantly, our data show that iECKO mice exhibit a significant decrease in the number of brain lesions (microinfarctions) as well as reduced neuronal loss in the CA1 hippocampal region known to play a crucial role in spatial recognition memory. Conversely, endothelial PDZRN3 overexpression (iECOE) produces phenotypes opposite to those of Pdzrn3-deleted mice (iECKO) with a clear deterioration of memory function associated with increased BBB leakage, brain lesions, hippocampal neuronal loss and inflammation compared to controls. We also wanted to investigate the impact of endothelial deletion of Pdzrn3 in AD. To this end, we have generated and validated a dedicated triple transgenic mouse model by crossing APP/PS1, AD mouse model with with Pdzrn3 iECKO mice to generate APP/PS1;Pdzrn3 iECKO colonies. Strikingly, our findings point to a significant decrease of Aβ-deposits at 6 months in APP/PS1;Pdzrn3 iECKO compared to APP/PS1 littermate control mice. At 8 months, APP/PS1 littermate controls appears severely impaired in a spatial recognition memory paradigm whereas APP/PS1;Pdzrn3 iECKO performed as well as non-demented age-matched Pdzrn3 iECKO and littermate controls

A hipoperfusão cerebral crônica (HCC) é um importante fator de risco para o declínio cognitivo e outras disfunções cerebrais, tais como Doença de Alzheimer e Demência Vascular. O objetivo deste estudo foi investigar o efeito neuroprotetor do Resveratrol (RSV), avaliando parâmetros comportamentais, bioquímicos e morfológicos, em um modelo experimental de Demência Vascular. Ratos Wistar adultos foram submetidos ao modelo modificado da HCC através da oclusão permanente de 2 vasos (2VO) e tratamento diário, iniciado uma hora após oclusão permanente dos vasos, com injeções intraperitoneais (20 mg/kg) de RSV durante 7 dias. Os testes comportamentais foram realizados entre o 35° e 45° dias após a cirurgia - 2VO, através da tarefa do labirinto aquático de Morris, na qual os animais foram avaliados quanto ao desempenho da memória espacial. Ao final dos testes comportamentais, um grupo dos animais foi perfundido transcardiacamente para análise histológica, outro grupo foi submetido à eutanásia em 3 tempos (3, 14 e 45 dias após a lesão isquêmica) para avaliação da expressão de NGF (fator de crescimento do nervo). Os resultados demonstraram que o tratamento com RSV atenuou significativamente a morte das células piramidais na região CA1 do hipocampo e preveniu o déficit da memória espacial. O aumento da expressão de NGF foi evidenciado no 3° dia após indução da HCC em todos os animais isquêmicos e no 45° dia após indução da HCC nos animais tratados com RSV. Com base nesses dados, hipotetizamos que o aumento, em longo prazo, na expressão de NGF no hipocampo após a HCC pode caracterizar uma das vias envolvidas nos mecanismos neuroprotetores do RSV.
Chronic cerebral hypoperfusion (CCH) is an important risk factor for cognitive decline and other brain dysfunctions, such as Alzheimer’s Disease and Vascular Dementia. The aim of the present study was to investigate the neuroprotective effect of Resveratrol (RSV) on behavioral, biochemical and morphological parameters in an experimental model of Vascular Dementia. Adult Wistar rats were submitted to the CCH modified model by means of permanent 2-vessel occlusion (2VO) and daily treatment, initiated one hour after permanent vessel occlusion, with intraperitoneal injections (20 mg/kg) of RSV for 7 days. Behavioral testing was performed between the 35th and the 45th day after 2VO surgery in the Morris Water Maze task, allowing for the evaluation of spatial memory function. At the end of the behavioral assessment, half of the animals were transcardially perfused for histological analysis and the remaining were euthanized in 3 times (3. 14 and 45 days after ischemic injury) for NGF expression evaluation (neural growth factor). Results demonstrate that the treatment with RSV significantly attenuated pyramidal cell death in CA1 hippocampal field and prevented spatial memory impairment. The increase of NGF expression was evidenced on the 3rd day after CCH induction in all ischemic animals and on the 45th day after CCH induction in animals treated with RSV. On the basis of these data, we hypothesize that the long term increase in NGF expression in the hippocampus after CCH may characterize one pathway involved in the neuroprotective mechanisms of RSV.

A doença de Alzheimer (DA) e a demência vascular (DV), especialmente a sua forma subcortical, são responsáveis pela maioria dos quadros de demência em idosos, nem sempre facilmente diferenciadas do ponto de vista clínico. O objetivo do estudo foi comparar o desempenho de pacientes com DA e com DV em uma bateria breve de testes cognitivos (Mini-exame do estado mental e bateria Neuropsi para confirmar o diagnóstico de demência; CLOX 1 e 2, fluência verbal categoria animal e fonêmica, EXIT 25 e teste de memória tardia da bateria breve de rastreio cognitivo), e verificar seu valor no diagnóstico diferencial entre elas. O desempenho do grupo DV foi inferior ao DA nos testes: CLOX 2, fluência verbal animal e fonêmica. O grupo DA obteve desempenho inferior a DV no subitem evocação do teste de memória tardia.
Alzheimer’s disease (AD) and vascular dementia (VaD), especially its subcortical form, are responsible for the majority of dementia cases in the elderly and are not always easily differentiated from a clinical point of view. The aim of this study was to compare the performance of mild VaD and AD patients in a series of brief cognitive tests (Mini-mental State Examination and Neuropsi battery, in order to confirm the diagnosis of dementia; CLOX 1 and 2, category and letter fluency, a delayed recall test of 10 simple figures and the EXIT 25), and to evaluate the potential use of these tests for the differential diagnosis between them. The performance of the VaD group was significantly impaired, in relation to the AD group, in the tests CLOX 2, category verbal fluency and letter verbal fluency, while the AD patients performed significantly worst in the delayed recall test.

Stroke is the fifth leading cause of death in the United States and a major cause of long-term disability in industrialized countries. The core region of an ischemic stroke dies within minutes due to activation of necrotic pathways. Outside of this core region is the penumbral zone, where some perfusion is maintained via collateral arteries. Delayed cell death occurs in this area due to the triggering of apoptotic mechanisms, which expands the ischemic injury over time. The cellular and molecular events that produce the expansion of the ischemic core continue to be poorly understood. The increases in the amyloid precursor protein and pathogenic secretases lead to the increase in amyloid-β (Aβ) production. The relatively small amount of research in this area has hampered development of stroke therapy designed to prevent neuronal and glial cell degeneration in the penumbra. Currently, there is a significant lack of therapeutic options for acute ischemic stroke, and no drug has been approved for treating patients at delayed time points (≥ 4.5 hr post-stroke). Afobazole, an anxiolytic currently used clinically in Russia, has been shown to reduce neuronal and glial cell injury in vitro following ischemia, both of which have been shown to play important roles following an ischemic stroke. Treatment with afobazole decreased microglial activation in response to ATP and Aβ, as indicated by reduced membrane ruffling and cell migration. Prolonged exposure of microglia to ischemia or Aβ conditions resulted in glial cell death that was associated with increased expression of the pro-apoptotic protein, Bax, the death protease, caspase-3 and a reduced expression in Bcl-2. Co-application of afobazole decreased the number of cells expressing both Bax and caspase-3, while increasing the cells expressing Bcl-2 resulting in a concomitant enhancement in cell survival. While afobazole inhibited activation of microglia cells by Aβ25-35, it preserved normal functional responses in these cells following exposure to the amyloid peptide. Intracellular calcium increases induced by ATP were depressed in microglia after 24 hr exposure to Aβ25-35. However, co-incubation with afobazole returned these responses to near control levels. Therefore, stimulation of sigma-1 and sigma-2 receptors by afobazole prevents Aβ25-35 activation of microglia and inhibits Aβ25-35-associated cytotoxicity. Examining the molecular mechanisms involved in the increased neuronal survival demonstrates that ischemia or Aβ results in an increased expression of the pro-apoptotic protein Bax and the death protease caspase-3, while at the same time decreasing expression of the anti-apoptotic protein, Bcl-2. However, unlike observations made with microglia, afobazole was unable to modulate this ischemia-induced expression, but was able to modulate Aβ-induced expression of apoptotic proteins while still rescuing neurons from death. Additional experiments were carried out to understand this disparity between the failures of afobazole to prevent the up-regulation of pro-apoptotic genes while retaining the ability to mitigate neuronal death. Although the neurons were still alive they were in a senescent state and were unresponsive to depolarization by high K+. However, these findings are still positive due to the ability of afobazole to delay neuron death, thus minimalizing the toxic environment of the penumbra. These comorbidities of ischemia and Aβ toxicity may lead to potentiated responses and increase the risk for various vascular dementias. It was of particular interest to study how the convergence of ischemia, acidosis and Aβ influence cellular activity and survival within core and penumbral regions. Application of Aβ increased the [Ca2+]i overload produced by concurrent ischemia + acidosis application in isolated cortical neurons. We found that the acid-sensing ion channels 1a (ASIC1a) are involved in the potentiation of [Ca2+]i overload induced by Aβ. Furthermore, afobazole (100 uM) abolished Aβ potentiation of ischemia + acidosis evoked [Ca2+]i overload, which may represent a therapeutic strategy for mitigating injury produced by Aβ and stroke.

INTRODUÇÃO: Estudos prévios, com técnicas de imagem, documentam de forma consistente a existência de alterações da substância branca cerebral relacionadas com o envelhecimento (ASBRE). Tais alterações poderão ter um papel importante no declínio funcional do idoso, reflectindo‐se sobretudo no desempenho motor e cognitivo, com repercussão evidente na prática clínica. Apesar disso, a caracterização em definitivo dos fenótipos clínicos e da evolução das ASBRE continua por esclarecer, possivelmente pelas dificuldades metodológicas de que se reveste o seu estudo, incluindo: a adequação das baterias neuropsicológicas, a utilização de amostras de doentes com diferentes graus de severidade e de envolvimento regional, as limitações das diferentes escalas e a sensibilidade dos diferentes métodos de imagem. A Ressonância Magnética (RM) de difusão tem revelado grande sensibilidade para as alterações isquémicas, admitindo‐se que poderá permitir uma melhor caracterização das ASBRE e deste modo possibilitar uma correlação mais precisa com as variáveis cognitivas e motoras, permitindo avaliar ainda a substância branca aparentemente normal (SBAN). OBJECTIVOS: Descrever a evolução imagiológica das ASBRE no intervalo de um ano e analisar a sua expressão clínica e impacto funcional; identificar factores preditivos de progressão das ASBRE e de declínio funcional associado. Descrever a expressão clínica e perfil evolutivo dos doentes com ASBRE com envolvimento preferencial da região parieto‐occipital; comparar este grupo de doentes com os doentes com ASBRE, sem envolvimento preferencial desta região. Medir os coeficientes de difusão aparente (CDA), utilizando regiões de interesse (RDI), em diferentes localizações da substância branca, incluindo substância branca lesada e SBAN, descrever sua evolução temporal no intervalo de um ano e determinar suas correlações clínicas e imagiológicas. MÉTODOS: Utilizando uma amostra de conveniência, foram estudados 30 doentes, com mais de 65 anos, sem incapacidade funcional ou com incapacidade mínima, avaliada pela escala de actividades instrumentais da vida diária (IADL), apresentando ASBRE em TC. Foi utilizado um protocolo exaustivo de avaliação clínica (com particular destaque para as funções motoras e cognitivas) e imagiológica, em dois momentos de avaliação separados por um ano de intervalo (t0 e t1). As ASBRE foram avaliadas com escalas visuais, escala ARWMC e escala de Fazekas, e os doentes foram estudados em função do grau de severidade (ligeiro versus moderado a grave na escala de Fazekas) e de um envolvimento preferencial posterior (definido como 2 ou mais pontos na escala ARWMC na região parieto‐occipital por comparação com a região frontal). Os CDA foram avaliados mediante estudo de RDI, na substância branca frontal lesada (SBFL) e SBAN frontal, parieto‐occipital e dos pedúnculos cerebelosos. Para verificar diferenças na ordem de distribuição das variáveis foi usado o teste de Mann‐Whitney e para comparação de proporções, o teste exacto de Fisher. Na comparação entre a avaliação em t0 e t1 foi usado o teste Wilcoxon Signed Ranks na comparação da distribuição da ordem das variáveis e o teste McNemar na análise de frequências. Na análise correlacional foram utilizados os testes de T para variáveis emparelhadas e as correlações entre estas foram efectuadas com o coeficiente de correlação de Spearman ou de Pearson. O trabalho foi aprovado pela Comissão de Ética do hospital onde foi realizado e todos os doentes incluídos assinaram um consentimento informado. RESULTADOS: A idade média da população estudada foi 72,5 anos (17 doentes eram do sexo masculino). No final de um ano, 1 doente tinha falecido e 3 doentes não completaram a avaliação imagiológica. Registou‐se uma progressão significativa das ASBRE segundo a escala ARWMC (t0: 8,37 / t1: 9,65 ; p<0,001). Na análise funcional, motora e cognitiva, não houve um agravamento significativo. Avaliando os doentes em t0 e t1 segundo o grau de severidade das ASBRE, o grupo com atingimento moderado a grave (ASBRE2) comparado com o grupo com atingimento ligeiro (ASBRE1) apresentava: maior extensão de lesão da substância branca (ARWMC t0: 11,9 / 4,8 ; p<0.001 ; t1: 14,0 / 5,9 ; p<0,001); tendência a pior desempenho funcional (IADL t0: 90,7 / 99,2 ; p=0,023; t1: 86,4 / 96,7 ; p=n.s.) e motor (SPPB t0: 9,8 / 10,3 ; p=n.s. ; t1: 9,5 / 10,5 ; p=0,058); tendência a maior compromisso do humor (Escala Cornell t0: 6,7 / 3,5 ; p=0,037; t1: 6,2 / 4,5 ; p=n.s.). Analisando a evolução, de t0 para t1, de cada um dos grupos (ASBRE2 e ASBRE1) registou‐se: aumento da extensão da lesão da substância branca em ambos (ASBRE2: 12,0 / 14,0;z=‐2,687 ; p=0,007; ASBR1: 4,8 / 5,9 ; z=‐2,724 ; p=0,006); variação não significativa funcional e motora; tendência ao agravamento em ambos na prova de Cancelamento de dígitos (ASBRE2: 17,5 / 17,4 ; p=n.s. ; ASBRE1: 19,9 / 16,9 ; z=‐2,096 ; p=0,036);tendência à melhoria em ambos no MMS (ASBRE2: 25,7 / 27,5 ; z=‐2,155 ; p=0,031; ASBRE1: 27,5 / 28,2 ; p=n.s). Avaliando os doentes em t0 e t1 em função do padrão de distribuição das ASBRE, os doentes com um envolvimento preferencial posterior (ASBREP) comparados com os restantes (ASBREnP), apresentavam: maior extensão da lesão (ARWMC t0: 10,8 / 6,9 ; p=0,025; t1: 12,9 / 7,6 ; p=0,011); diferenças não significativas no desempenho motor; tendência a melhor desempenho na prova dos Labirintos (t0: 8,1 / 11,8 ; p=0,06; t1: 8,7 / 9,5 ; p=n.s.) e Cancelamento de dígitos (t0: 20,9 / 17,4 ; p=0,045; t1: 18,5 / 16,3 ; p=n.s.); tendência a maior compromisso depressivo na GDS (t0: 5,0 / 3,68 ; p=n.s. ; t1: 5,7 / 3,3 p=0,033). Analisando o perfil evolutivo de t0 para t1, registou‐se: aumento da extensão da lesão nos dois grupos (ASBREP: 10,8 / 12,9 ; z=‐2,555 ; P=0,011; ASBREnP: 6,4 / 7,6 ; z=‐2,877 ; p=0,04); variação em sentidos diferentes com melhoria funcional no grupo ASBREP (91,0 / 95,5 ; z=‐0,926 ; p=0,036) e agravamento no grupo ASBREnP (96,7 / 89,8 ; z=‐2,032 ; p=0,042); variação sem sentidos diferentes, com agravamento significativo no grupo ASBREnP no item estação de pé do SPPB (ASBREP 3,8/3,9 p=n.s.; ASBREnP 3,9/3,6; z=‐2,236 ; p=0,025); tendência à melhoria nos dois grupos no MMS (ASBREP: 27,2 / 28,2 ; p=n.s.; ASBREnP: 26,3 / 27,7 ; z=‐2,413 ; p=0,016) e tendência em sentidos diferentes no Trail Making, com eventual melhoria no grupo ASBREP (113,9 / 91,6 ; p=n.s.) e agravamento no grupo ASBREnP (113,7 / 152,0 ; z=‐2,155 ; p=0,031). Na análise da imagem, utilizando a escala ARWMC e o estudo dos CDA, na avaliação transversal na inclusão, a comparação entre as pontuações médias da escala ARWML nas diferentes regiões mostrava diferenças significativas (F=39,54 , p<0,0001). A análise comparativa post‐hoc de Bonferroni mostrou valores significativamente mais altos para as regiões frontais e parieto‐occipitais (p<0,0001). Os valores médios dos CDA eram significativamente diferentes entre regiões (F=44,56; p<0,0001), sendo mais altos na SBFL (p<0,0001). Não existia diferença significativa entre os valores registados na SBAN nas regiões frontais e parieto‐occipitais. As pontuações regionais da escala ARWMC e os valores médios dos CDA correlacionavam‐se todos de forma positiva. A pontuação da escala ARWMC na região frontal correlacionava‐se significativamente com os valores do CDA da SBFL (r=0,467 ; p=0,012). Existia tendência para uma correlação positiva entre as pontuações da escala ARWMC na região frontal e os valores médios dos CDA na SBAN frontal (r=0,276 ; p=0,155). As pontuações da escala ARWMC e os CDA correlacionavam‐se de forma positiva com a idade e com a tensão arterial (TA). Foram encontradas correlações significativas entre: idade e SBAN frontal (r=0,440 ; p=0,019); TA diastólica e SBFL (r=0,386 ; p=0,034); TA sistólica e SBAN Parieto‐occipital (r=0,407 ; P=0,032). Na avaliação motora e cognitiva, dado elevado número de variáveis, foi efectuada uma análise de factor principal. Registou‐se uma tendência global negativa na correlação entre as pontuações da escala visual na região frontal, os valores dos CDA, e o desempenho motor e cognitivo. Na análise evolutiva, (n=19), registou‐se variação significativa dos CDA, com aumento na SBFL (Direita: z=‐2,875 ; p=0,004 ; Esquerda: z=‐2,113 ; p=0,035) e diminuição na SBAN dos pedúnculos cerebelosos (Direita: z=‐2,094 ; p=0,036 ; Esquerda: z=‐1,989 ; p=0,047). Foi observada uma correlação negativa entre a variação do CDA na SBAN dos pedúnculos cerebelosos e na SBFL contralateral (SBAN pedúnculo cerebeloso Esquerdo / SBFL Direita: r=‐0,133 ; p=n.s.; SBAN pedúnculo cerebeloso Direito / SBFL Esquerda: r=‐0,561 ; p=0,012). Os valores dos CDA à direita correlacionavam‐se de forma positiva com a velocidade da marcha (r=0,562 ; p=0,012). CONCLUSÕES: A progressão das ASBRE pode ser observada com uma escala visual detalhada no intervalo de um ano. Contudo, o eventual agravamento da incapacidade funcional, motora e cognitiva, não parece ser apreciável em igual intervalo de tempo. A maior severidade das ASBRE associa‐se a uma tendência para um maior compromisso funcional, motor e possivelmente do humor. A questão da progressão em escalas simplificadas, de um estádio ligeiro para um estádio moderado a grave, não é elucidada pelos resultados do presente trabalho. Os doentes com um envolvimento preferencial da região parieto‐occipital poderão constituir um subgrupo distinto que, apesar de ter maior extensão de lesão, parece ter um melhor desempenho motor e cognitivo. O perfil evolutivo destes doentes parece igualmente ser distinto, não se observando a tendência ao agravamento funcional, motor e cognitivo (sobretudo em provas de função executiva) que se encontra nos restantes doentes. A análise transversal na inclusão, utilizando uma escala visual e o estudo dos CDA, sugere que a severidade das ASBRE se correlaciona com o compromisso motor e cognitivo, bem como com a idade e com a TA. Uma maior vulnerabilidade da substância branca frontal à lesão vascular parece ter um papel importante no compromisso motor e na disfunção executiva, (essencialmente à custa do compromisso da atenção), possivelmente associada à desconexão dos circuitos fronto‐subcorticais. A análise dos CDA sugere que isso é válido igualmente para a SBAN e sublinha que, as imagens de RM convencional poderão não traduzir a verdadeira extensão da lesão e consequentemente do compromisso motor e cognitivo. A relação entre a progressão da doença vascular em lesões frontais constituídas e a redução do CDA no pedúnculo cerebeloso contralateral poderá estar associada a um pior desempenho motor. A disrupção dos circuitos fronto‐cerebelosos, determinando hipometabolismo e diminuição da perfusão no cerebelo, poderá ser responsável pela diminuição do CDA no cerebelo. ABSTRACT INTRODUCTION: Previous studies, with new imaging techniques, have consistently documented the presence of age‐related white matter lesions (ARWML), emphasizing their role in agerelated functional decline, mainly related to motor and cognitive impairment, and inherent consequences in clinical practice. However clinical significance of ARWML remains to be elucidated, probably on account of methodological difficulties such as: specific neuropsychological batteries, utilization of samples with different degrees of severity and regional involvement, utilization of different imaging scales and different sensitivity of imaging techniques. Recently, Diffusion Weighted Magnetic Ressonance imaging (DWI) has shown a higher sensitivity to ischemic lesions, suggesting it might be superior for characterization of ARWML, allowing more precise correlation with motor and cognitive variables, and evaluating also normal appearing white matter (NAWM). OBJECTIVES: To describe imagiologic evolution of ARWML within one year interval and to analyse its clinical and functional significance. To identify predictors of ARWML progression and associated functional impairment. To describe clinical characteristics and evolution profile of patients with predominantly posterior lesions; to compare this group of patients with patients without predominantly posterior lesions. To study average Apparent Diffusion Coeficcients (ADC) in different white matter regions using regions of interest (ROI); to analyse their evolution profile and to determine their clinical and imagiologic correlations. METHODS: A sample of 30 patients older than 65 years, without functional impairment or with minimal impairment, according to the Instrumental Activities of Daily Lliving scale, with ARWML on CT scan, were studied in a cross‐sectional design. An extensive clinical(with detailed motor and cognitive evaluation) and imagiologic protocol was applied in two one‐year interval separate moments (t0 and t1). ARWML were studied using visual scales, ARWMC and Fazekas’s scale, and patients were studied according to degree of severity (Fazekas scale mild versus moderate / severe) and preferential involvement of the posterior region (defined as 2 or more points in the ARWMC scale in the parietooccipital region compared with frontal region). Evaluation of ADC was performed using ROI in frontal lesioned white matter (FLWM) and NAWM (frontal, parieto‐occipital and cerebellar regions). To study differences in the distribution of variables the Mann‐Whitney test was used and to compare proportions the exact Fisher Test was used. To compare temporal evolution profile between t0 and t1, the Wilcoxon Signed ranks Test was used to analyse the distribution of variables and the Mc Nemar Test to analyse frequencies. Correlation analysis was performed using Spearman or Pearson tests. The study was approved by the local Ethics Committee and all patients signed an informed consent. RESULTS: Mean age was 72.5 years (17 patients were male). By the end of the study, one patient was dead and 3 patients did not undergo brain imaging. There was a higher extent of ARWML evaluated with the ARWMC scale (t0: 8.37 / t1: 9.65 ; p<0.001). Functional, motor and cognitive performance did not progress significantly. Evaluating patients in t0 and t1 according to the degree of severity (Fazekas scale), the moderate / severe group of patients (WML2), compared with the mild group (WML1), showed: higher extent of lesion (ARWMC scale t0: 11.9 / 4.8 ; p<0.001 ; t1: 14.0 / 5.9 ; p<0.001); tendency to worse functional (IADL t0: 90.7 / 99.2 ; p=0.023; t1: 86.4 / 96.7 ; p=n.s.) and motor (SPPB t0: 9.8 / 10.3 ; p=n.s. ; t1: 9.5 / 10.5 ; p=0.058) performance; tendency to higher depressive scores (Cornell Scale t0: 6.7 / 3.5 ; p=0.037; t1: 6.2 / 4.5; p=n.s.). Analysing the evolution profile from t0 to t1 of each group (WML2 and WML1), there was a higher extent of lesion (ARWMC scale) in both (WML2: 12.0 / 14.0; z=‐2.687 ; p=0.007; WML1: 4.8 / 5.9 ; z=‐2.724 ; p=0.006); non‐significant variation in functional and motor performances; tendency to worse performance on the Digit Cancelling (WML2: 17.5 / 17.4 ; p=n.s. ; WML1: 19.9 / 16.9 ; z=‐2.096 ; p=0,036) and to better performance on the MMS (WML2: 25.7 / 27.5 ; z=‐2.155 ; p=0.031; WML1: 27.5/ 28.2 ; p=n.s). Evaluating patients in t0 and t1 according to the regional distribution of ARWML, patients with predominantly posterior lesions (WMLP) compared with the rest of the group (WMLnP), showed: higher extent of lesion (ARWMC scale t0: 10.8 / 6.9 ; p=0.025; t1:12.9 / 7.6 ; p=0.011); non significant differences on motor evaluation; tendency to a better performance on Maze (t0: 8.1 / 11.8 ; p=0.06; t1: 8.7 / 9.5 ; p=n.s.) and Digit cancelling (t0: 20.9 / 17.4 ; p=0.045; t1: 18.5 / 16.3 ; p=n.s.) tests;tendency to higher scores on GDS (t0: 5.0 / 3.68 ; p=n.s. ; t1: 5.7 / 3.3 p=0.033). Analysing the evolution profile from t0 to t1 of each group (WMLP and WMLnP), there was: higher extent of lesion (ARWMC scale) in both groups (WMLP: 10.8 / 12.9 ;z=‐2,555 ; P=0,011; WMLnP: 6.4 / 7.6 ; z=‐2.877; p=0.04); variation in different directions with better functional performance in the group WMLP (91.0 / 95.5 ;z=‐0.926 ; p=0.036) and worse in WMLnP (96.7 / 89.8 ; z=‐2.032 ; p=0.042); variation in different directions with worse motor performance in one SPPB item (total stands) in the group WMLnP (WMLP 3.8/3.9 p=n.s.; ASBREnP 3.9/3.6; z=‐2.236 ; p=0.025);tendency to improvement in both groups in MMS (WMLP: 27.2 / 28.2 ; p=n.s.; WMLnP:26.3 / 27.7 ; z=‐2.413 ; p=0.016); tendency to a variation in different directions in the Trail Making Test, with possible improvement in the group WMLP (113.9 / 91.6 ;p=n.s.) and worsening in the group WMLnP (113.7 / 152.0 ; z=‐2.155 ; p=0.031). Imaging analysis in the inclusion, using the ARWMC scale and ADC evaluation, showed significant differences in different regions (F=39.54, p<0.0001). Comparative post‐hoc Bonferroni analysis showed significantly higher scores in the frontal and parieto‐occipital regions (p<0.0001. ADC values were significantly different between regions (F=44.56; p<0.0001), being higher in FLWM (p<0‐0001). There was no significant difference between ADC in NAWM in frontal and parieto‐occipital regions. ARWMC scores and ADC values correlated positively. Significant correlations were found between frontal ARWMC score and FLWM ADC values (r=0.467 ; p=0.012). ARWMC scores and ADC values correlated positively with age and blood pressure. Significant correlations were: age and frontal NAWM (r=0.440 ; p=0.019); Diastolic blood pressure and FLWM (r=0.386 ; p=0.034); sistolic blood pressure and parietooccipital NAWM (r=0.407 ; P=0.032). Due to the higher number of motor and cognitive variables a preliminary study was done, using principal component analysis. A global tendency to a negative correlation was found between ARWMC scores, ADC values and motor and cognitive performances. Evolutive analysis of ADC (n=19), showed a significant variation, with higher values in t1 in FLWM (Right: z=‐2.875 ; p=0.004 ; Left: z=‐2.113 ; p=0.035) and lower values in t1 in cerebellar NAWM (Right: z=‐2.094 ; p=0.036 ; Left: z=‐1.989 ; p=0.047). A negative correlation was found between ADC variation in cerebellar NAWM and contralateral FLWM (Left cerebellar NAWM / Right FLWM: r=‐0.133 ; p=n.s.; Right cerebellar NAWM/ Left FLWM: r=‐0.561 ; p=0.012). ADC values on the right correlated positively with walking speed (r=0,562 ; p=0,012). CONCLUSIONS: Progression of ARWML can be documented with a detailed visual scale in a one year interval. However, functional, motor and cognitive impairment, do not seem to progress significantly within the same period. A higher severity of ARWML is associated with a tendency to a worse functional and motor performance (and possibly to higher scores in depression scales). The issue of progression in a simplified visual scale from a mild to a moderate / severe degree of ARWML is not further elucidated. Patients with predominantly posterior lesions may be a subset of ARWML patients, with a different profile, that despite higher extent of lesion, seem to fair better than the rest of the group, namely with better performance on motor and cognitive tests. Evolution profile of this subset of patients also seems to be different, without a clearcut tendency to worsening functional, motor and cognitive (particularly for executive function tests) performance that is observed in the rest of the group. Imaging analysis, with a visual scale and ADC evaluation, suggests that severity of ARWML correlates negatively with cognitive and motor performance and positively with age and blood pressure. A higher vulnerability of frontal white matter to vascular disease seems to play an important role in motor and cognitive dysfunction, mainly determined by impairment of attention skills associated with frontal‐subcortical disconnection. DWI results, suggest that this may also be true for NAWM, underlining that conventional MR images may not represent the true extent of cognitive decline. The relation between vascular disease progression inside frontal lesions and ADC reduction in contralateral cerebellar peduncles, may be associated with a worse motor performance. Disruption of fronto‐cerebellar cicuits, with associated regional hypometabolism, may be responsible for the reduction of cerebellar ADC.

Introduction: The Test of Premorbid Functioning (TOPF) is a relatively new reading test designed to estimate premorbid intelligence in people with a diagnosed or suspected dementia. A discrepancy between premorbid and current functioning is indicative of cognitive decline. Previous studies have reported mixed results on the validity of reading tests in people with dementia, and the TOPF has yet to be investigated as to how well it holds in dementia. Objectives: To assess the robustness of the TOPF against the Spot-the-Word (version 2; STW-2) and a demographic regression equation in estimating premorbid ability in people with Alzheimer’s disease (AD), vascular dementia (VD) and mixed dementias (AVD). Design: A cross-sectional study with two groups of participants assessed on three measures of premorbid ability. Methods: Thirty patients with an ICD-10 diagnosis of probable AD, VD or ADV were recruited from two NHS Older Adult Community Mental Health teams and their scores on the TOPF, STW-2 and a demographic equation were compared with thirty healthy matched controls. Results: Significant between-group differences were found for both the TOPF and STW-2, with an average difference of 5-7 IQ points and a medium effect size. The results suggest that both reading tests systematically under-estimated premorbid IQ in the dementia group. The demographic equation provided a significantly higher estimation of IQ than both of the reading tests for people with a dementia. When the dementia group was arbitrarily split into a “less impaired” and “more impaired” group, based on the median ACE-III score of 65, there was still a medium effect size between the healthy controls and the dementia groups on the TOPF and STW-2. Conclusion: The findings of this study suggest that the TOPF underestimates premorbid IQ in people with a dementia. Clinicians should exercise caution when interpreting the results of reading tests by considering and reporting the confidence intervals for obtained-minus-predicted IQ discrepancies and with clear reference to the clinical history and other cognitive test results. These findings are discussed with respect to the literature on the validity of reading tests and recommendations for future research are provided. Limitations of the study included a modest sample size and the use of a demographic equation which has not been normed against the current WAIS-IV. Practitioner points: 1) The TOPF and STW-2 provide similar estimates of premorbid IQ in people with a dementia. 2) Both reading tests systematically underestimated premorbid ability in people with a dementia, by between 5 and 7 IQ points. 3) When using reading tests to determine an obtained-minus-predicted discrepancy score, confidence intervals should be considered and reported in the analysis and there should be clear reference to the clinical history and other cognitive test results. 4) This study was based on a modest sample size and utilised a demographic equation which has not been normed against the current WAIS-IV.

La dépression (caractérisée ou subsyndromique) est fréquente tout au long de la vie et les démences sont des pathologies fréquentes du sujet âgé. Une association longitudinale entre la dépression ou les symptômes dépressifs et la démence a été rapportée. Cependant, le sens de cette association demeure incertain et ses mécanismes pathogéniques selon l’âge de l’apparition des manifestations dépressives sont largement méconnus. Les facteurs de risque vasculaires sont associés à la démence et une comorbidité vasculaire est également retrouvée chez le sujet âgé dépressif. L’hypothèse qu’un ou des facteurs de risque cardiovasculaires constitue(nt) l’ultime dénominateur commun des troubles de l’humeur et de démences devrait être vérifié. L’objectif de cette thèse était d’étudier les liens entre la pression artérielle, la dépression et la démence. Dans un échantillon de 9294 sujets âgés de 65 ans et plus (Etude 3C), non institutionnalisés, suivis pendant 4 ans, nous avons retrouvé une association entre les symptômes dépressifs sévères à l’inclusion et le risque de démence (en particulier vasculaire) incidente. A l’opposé, les antécédents dépressifs n’augmentaient pas le risque de démence. Nos analyses transversales indiquaient une pression artérielle plus basse chez les sujets dépressifs comparés aux sujets non dépressifs. Pour terminer, l’association entre les symptômes dépressifs sévères et la démence n’était pas médiée par l’hypertension artérielle. Nos résultats indiquent que les symptômes dépressifs semblent constituer une expression non cognitive de la phase prodromale de la démence plutôt que d’en être un facteur de risque. L’explication d’une pression artérielle plus basse chez les sujets dépressifs comparés aux sujets non dépressifs n’est pas univoque. Une pression artérielle basse pourrait conduire à une hypoperfusion cérébrale, corrélée aux lésions de la substance blanche dans les régions les plus sensibles aux modifications du flux sanguin cérébral et dont l’altération est associée aux manifestations dépressives et cognitives. Ce travail offre de nouvelles perspectives de définition des groupes de population à haut risque de démence, et des perspectives de recherche sur les mécanismes biologiques liant la pression artérielle et la dépression. D’un point de vu méthodologique, il met l’accent sur la nécessité des méthodes d’évaluation fiables et précises des cas pathologiques (dépressifs et déments), lesquels influencent réciproquement l’évaluation de chacun
Depression is highly common throughout the life course and dementia is common in late life. Depression has been linked with dementia, yet the direction and pathological mechanisms of this association (whether depression is a prodromal feature or consequence of, or a risk factor for dementia) remains unclear. Vascular risk factors are associated to the risk of incident cognitive impairment and dementia and comorbid vascular disease is a feature of depression in latelife. Therefore, the hypothesis that vascular risk factors are the ultim denominator of psychological perturbations and dementia is to be verified. The aim of this work was to study the links between blood pressure, depression and dementia. In a cohort of 9294 community-dwelling elderly individuals aged 65 years and over, participating to the longitudinal population-based 3 City Study, followed up for 4 years, we found an association between baseline depressive symptoms’ severity and the incident dementia risk (particularly of vascular type). Conversely, we found no association between history of depression and incident dementia. Moreover, our cross sectional analyses exhibited an inverse association between systolic and diastolic blood pressure values and depression. Overall, however, the association between depressive symptoms and dementia was not mediated by hypertension. These results indicate that depression is rather a prodromal symptom of vascular dementia than a risk factor for it. The explanation for the inverse association found between blood pressure values and depression is not straightforward. Low blood pressure may lead to cerebral hypoperfusion found to be associated with white matter lesions in cerebral regions vulnerable to alterations of cerebral blood flow, and associated with cognitive impairment and depression. This work offers the opportunity for the definition of group of populations at high risk to develop dementia, vascular one in particular. It also gives the perspective of research on the biological mechanisms linking blood pressure and depression. From a methodological point of view, it emphasizes the need for instruments assessing precisely and thoroughly these two conditions which influence the assessment of each other

Denna avhandling fokuserar på det meningsskapande och begripliggörande som fortgår vid tilltagande demenssjukdom, i det sociala samspelet, och de utmaningar för demens-omsorgen som detta innebär. Studien är aktörsorienterad och adresserar frågan om hur personer med åldersrelaterade progressiva demenssjukdomar i den vardagliga kommuni-kationen söker förstå sina situationer, omgivningen och sina liv – alltsammans inom ra-men för det dagliga samspelet på ett demensboende. Av särskilt intresse är hur dessa per-soner hanterar problem som har att göra med att handla tillsammans med andra i en gemensamt delad värld och hitta sin roll i det pågående samspelet, och hur de etablerar och upprätthåller en identitet i detta samspel. Detta trots svåra minnesproblem, desorien-tering i tid och rum, olika sätt att förstå den pågående situationen samt svårigheter att be-rätta om sina liv på ett sätt som både stämmer överens med biografiska data och har en tillfredsställande temporal organisering. Avhandlingen adresserar också frågan om hur omsorgspersonalen kan hantera det komplexa samspelet mellan de boende i den dagliga omsorgen, med avseende på att upprätthålla och respektera dessa personers värdighet. Studien ansluter till en växande tradition av att studera interaktion vid demens som meningsbaserad och situerad i en kontext snarare än enbart som beteende som orsakas av kognitiva svårigheter. Metodologiskt är studien etnografisk och bygger på observationer fördelade över en tidsperiod av sex månader. Materialet, som består av ca 150 h videoma-terial och kompletterande fältanteckningar, möjliggör att samspelet studeras både i detalj och i relation till det större sammanhang som det ingår i. Studien visar på kvarvarande kompetenser och bidrar med ny kunskap om strategier som personerna med demens använder sig av i ett aktivt, kreativt och på många sätt ratio-nellt meningsskapande i det sociala samspelet med andra människor. Detta diskuteras i termer av resurser för demensomsorgen i relation till den stora utmaning som det innebär att lappa ihop och upprätthålla en begriplig och socialt delad värld, samt upprätthålla kon-tinuitet med personernas livshistorier på ett sätt som möjliggör en önskad identitet.
This thesis focuses on the identity work and the meaning- or sense-making that continue in the face of evolving dementia diseases, in social interaction, and the challenges for care this involves. The study adopts an actor-oriented approach and addresses the question of how persons with age-related progressive dementia diseases in everyday communication make sense of their situations, their surroundings, and their lives – all within the context of daily life in residential care. Of particular interest is how these persons handle issues of joint action in a shared world and how they establish and maintain an identity in the inte-raction. This is in spite of severe memory problems, disorientation in time and space, dif-fering understandings of the current situation, and difficulties in telling “accurate” and temporally ordered stories about their lives. The thesis also addresses the question of how caregivers may handle the complex interplay between residents in daily care, in maintain-ing and respecting these persons’ dignity. The study follows a growing tradition of studying interaction in dementia as mean-ing-based and situated in a context rather than merely as behavior caused by cognitive impairment. Methodologically, this is an ethnographic study based on observations made within a period of six months. The data consist of around 150 hours of video recordings and complementary field notes. This extensive material has made it possible to study the social interaction both in detail and situated in a larger context. The findings point to remaining competences and strategies that persons with demen-tia use actively and creatively in the ongoing interaction – and, given the premises, often in a rational way. This is discussed in terms of resources for dementia care, in relation to the great challenge of patching up and putting together a comprehensive socially shared world as well as maintaining continuity with the persons’ previous life histories in a way that preserves a positive self-identity.

A literatura científica vem debatendo sobre a existência de uma associação entre diabetes mellitus (DM) e demência, doença de Alzheimer (DA) e demência vascular (DV). O DM é um conhecido fator de risco para a doença cerebrovascular (DCV) e DV, porém não há consenso até o momento do real papel do DM no desenvolvimento das alterações neuropatológicas da DA. Objetivos: verificar a associação entre DM e demência, DM e alterações neuropatológicas da DA e DV. Métodos: os dados foram coletados do Banco de Encéfalos Humanos do Grupo de Estudos em Envelhecimento Cerebral da FMUSP estudados de 2004 a 2015. A amostra foi dividida em dois grupos: não diabéticos e diabéticos. Os diagnósticos de DM e de demência foram estabelecidos post-mortem mediante entrevista com informante. O diagnóstico de demência exigiu escore >= 1 na Escala de Avaliação Clínica da Demência (CDR) e Questionário sobre Declínio Cognitivo no Idoso (IQCODE) >= 3,42. O diagnóstico etiológico da demência foi determinado por exame neuropatológico por imuno-histoquímica. A proporção de casos de demência, de DA e de DV de não diabéticos e diabéticos foi determinada, assim como a relação entre DM e placas neuríticas (PN) e emaranhados neurofibrilares (ENF), e neuropatologia vascular. As análises estatísticas empregadas foram o teste de Mann-Whitney e regressão linear múltipla para variáveis quantitativas, teste de ?2, teste exato de Fisher e regressão logística múltipla para variáveis categóricas. Resultados: amostra total foi de 1.037 indivíduos, sendo 758 não diabéticos (73,1%) e 279 diabéticos (26,9%). Demência foi constatada em 28,7% em diabéticos. O DM não se associou à frequência mais elevada de demência (OR: 1,22; IC 95%: 0,81-1,82; p=0,34). O DM não está associado com ENF (p=0,81), PN (p=0,31), grupo infarto (p=0,94), angiopatia amiloide (p=0,42) e arteriolosclerose hialina (p=0,07). Após o ajuste para variáveis demográficas e para os fatores de risco vascular, o diagnóstico de DM não se associou ao diagnóstico neuropatológico de DA e vascular. Conclusão: o DM não está associado à demência e às alterações neuropatológicas da DA e de DV
The scientific literature has been debating the existence of an association between diabetes mellitus (DM) and dementia, Alzheimer\'s disease (AD) and vascular dementia (VaD). DM is a known risk factor for cerebrovascular disease (CVD) and VaD, but there is still no consensus on the real role of DM in the development of AD neuropathology. Objectives: to investigate the association among DM and dementia, neuropathology (NP) of AD and VaD. Methods: Data were collected from the cases included in the Brain Bank of the Brazilian Aging Brain Study Group between 2004 and 2015. Cases were divided into 2 groups: no diabetics and diabetics. Clinical diagnosis of dementia was determined by the scores >= 1.0 in the Clinical Dementia Rating (CDR) and >= 3.42 in the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Etiological diagnoses of dementia were determined by neuropathological examination, using immunohistochemistry. The proportion of dementia cases, AD and VaD of no diabetics and diabetics were investigated as well as the relationship among DM and neuritic plaques (NPq) and neurofibrillary tangles (NFT). Mann-Whitney test and multiple linear regression for quantitative variables, and chi-square test and multiple logistic regression for categorical variables were the statistical analyses applied. Results: Total sample included 1037 subjects, divided in 758 (73.1%) no diabetics and 279 diabetics (26.9%). Dementia was present in 27.8% of diabetics. DM did not increase the frequency for dementia (OR: 1.22; IC 95%: 0.81-1.82; p=0.34). DM was not associated with NFT (p=0.81), NPq (p=0.31), infarct group (0.94), cerebral amyloid angiopathy (0.42) and hyaline arteriolosclerosis (p=0.07). After adjustment for demographic variables and vascular risk factors, DM was not associated with DA and vascular NP. Conclusion: DM is not associated with dementia, AD and vascular neuropathology