Clinical Progression Of Dementia Research Articles

Genetic and socioeconomic modulation of biomarkers

AbstractIntroductionIdentification and measurement of biomarkers has become a key component of much research in the neurodegeneration field, particularly in research linking psychosocial stressors and brain health. Socioeconomic position may influence neurodegeneration through several pathways, including behaviors and psychosocial stress levels, both of which may influence biological markers of inflammation, coagulation, and adhesion. Underserved populations, particularly from low‐to‐middle‐income countries in Latin America (LMICs), are more likely to have experienced poor, chronic stress due to discrimination, limited educational and occupational opportunities, and minimal access to social support and health care. All of these factors can modify neurodegenerative disease risk and clinical progression of dementia, in part through changes in immune function. Complicating matters, few studies have characterized inflammatory biomarker levels in LMICs, where biological and environmental exposures likely modify immune profiles. Finally, the effect of complex genetic admixture on both baseline and disease‐associated inflammatory biomarker levels remains underexplored, greatly limiting the generalizability of dementia biomarkers (beta amyloid, tau, neurofilament) that were largely developed in homogenous populations.MethodWe propose to review the existing evidence and present our ongoing study fostered in the Multi‐Partner Consortium to Expand Dementia Research in Latin America (ReDLat) cohort divided into three groups: participants with Alzheimer´s Dementia (AD), participants with Frontotemporal Dementia (FTD), and controls. We will comprehensively assess gene and protein expression measures of immune function in blood to identify single and combined measurements that provide sensitive and specific distinction between AD and FTD and all cases from controls. In addition, we will assess the modulatory effect that social determinants of health (SDOH) have on these biological biomarkers.Expected ResultsOur expected outcome is to understand how SDOH contribute to gene and protein expression measures of immune function and how they modify the gold standard biomarkers of disease and risk for AD and FTD in Latin America.ConclusionsNew opportunities for identifying novel diagnostic and therapeutic inroads may be easier to detect in Latin American populations that display a greater environmental and genomic diversity, while simultaneously elucidating potential strategies for reducing health disparities in Americans who face similar SDOH challenges.

Unraveling the potential co-contributions of cerebral small vessel vasculopathy to the pathogenesis of Alzheimer's dementia.

Emerging evidence for the potential co-contributions of small vessel vasculopathy to dementia has resulted in a more nuanced view of Alzheimer’s disease (AD) pathogenesis. Although cerebral small vessel disease, visualized on magnetic resonance imaging as hyperintense signal abnormalities, independently predicts the incidence and clinical progression of dementia, the relationships between AD pathology, white matter hyperintensity volume, genotype, and cognitive decline in AD remain unclear. The study by Morgen and colleagues, recently published in Alzheimer’s Research & Therapy, presents important new findings on the associations between apolipoprotien E ε4 genotype, white matter hyperintensities, and cognition, independent of vascular risk, in a cohort of AD patients.

The influence of multimorbidity on clinical progression of dementia in a population-based cohort

The influence of multimorbidity on clinical progression of dementia in a population-based cohort

The Influence of Multimorbidity on Clinical Progression of Dementia in a Population-Based Cohort

IntroductionCo-occurrence with other chronic diseases may influence the progression of dementia, especially in case of multiple chronic diseases. We aimed to verify whether multimorbidity influenced cognitive and daily functioning during nine years after dementia diagnosis compared with the influence in persons without dementia.MethodsIn the Kungsholmen Project, a population-based cohort study, we followed 310 persons with incident dementia longitudinally. We compared their trajectories with those of 679 persons without dementia. Progression was studied for cognition and activities of daily life (ADLs), measured by MMSE and Katz Index respectively. The effect of multimorbidity and its interaction with dementia status was studied using individual growth models.ResultsThe mean (SD) follow-up time was 4.7 (2.3) years. As expected, dementia related to both the decline in cognitive and daily functioning. Irrespective of dementia status, persons with more diseases had significantly worse baseline daily functioning. In dementia patients having more diseases also related to a significantly faster decline in daily functioning. Due to the combination of lower functioning in ADLs at baseline and faster decline, dementia patients with multimorbidity were about one to two years ahead of the decline of dementia patients without any co-morbidity. In persons without dementia, no significant decline in ADLs over time was present, nor was multimorbidity related to the decline rate. Cognitive decline measured with MMSE remained unrelated to the number of diseases present at baseline.ConclusionMultimorbidity was related to baseline daily function in both persons with and without dementia, and with accelerated decline in people with dementia but not in non-demented individuals. No relationship of multimorbidity with cognitive functioning was established. These findings imply a strong interconnection between physical and mental health, where the greatest disablement occurs when both somatic and mental disorders are present.

The Cache County Study on Memory in Aging: Factors affecting risk of Alzheimer's disease and its progression after onset

The Cache County Study on Memory in Aging is a longitudinal, population-based study of Alzheimer's disease (AD) and other dementias. Initiated in 1995 and extending to 2013, the study has followed over 5,000 elderly residents of Cache County, Utah (USA) for over twelve years. Achieving a 90% participation rate at enrolment, and spawning two ancillary projects, the study has contributed to the literature on genetic, psychosocial and environmental risk factors for AD, late-life cognitive decline, and the clinical progression of dementia after its onset. This paper describes the major study contributions to the literature on AD and dementia.

Rapid cognitive decline in Alzheimer's disease: a literature review

Background: The rate of cognitive decline in Alzheimer's disease (AD) varies considerably between individuals. Predicting rapid cognitive decline might help clinicians provide prognostic information, select subjects for trial intervention and/or reduce costs. Methods: PubMed and PsycINFO were searched for all the English written studies published until the end of 2010 on rapid cognitive decline in AD and factors associated with it. Results: More than 300 individual articles were retrieved. We selected 82 relevant studies. The main findings of these papers are that younger, more educated and more impaired patients are more likely to show rapid cognitive decline. ApoE alleles seem not to modify the velocity of clinical progression of dementia, or at most could have a very small effect. No inference can be made for all the other variables analysed. Conclusions: There are many studies on rapid cognitive decline. Results are heterogeneous and often contradictory. No reliable conclusions about factors that may be associated with rapid cognitive decline can yet be drawn.

Caregiver Coping Strategies Predict Cognitive and Functional Decline in Dementia: The Cache County Dementia Progression Study

Few longitudinal studies have studied the influence of the care environment on the clinical progression of dementia. We examined whether caregiver coping strategies predict dementia progression in a population-based sample.Longitudinal, prospective cohort study.Cache County (Utah) population.A total of 226 persons with dementia, and their caregivers, were assessed semiannually for up to 6 years.Ways of Coping Checklist-Revised, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR).Mean (SD) age of dementia onset in persons with dementia was 82.11 (5.84) years and mean caregiver age was 67.41 (13.95) years. Mean (SD) follow-up was 1.65 (1.63) years from baseline. In univariate linear mixed-effects models, increasing use of problem-focused and counting blessings by caregivers was associated with slower patient worsening on the MMSE. Problem-focused coping, seeking social support, and wishful thinking were associated with slower Clinical Dementia Rating Scale sum of boxes (CDR-sb) worsening. Considering covariates, increasing use of problem-focused coping was associated with 0.70 points per year less worsening on the MMSE and 0.55 points per year less worsening on the CDR-sb. Compared with no use, the "regular" use of this strategy was associated with 2 points per year slower worsening on the MMSE and 1.65 points per year slower worsening on the CDR-sb.Caregiver coping strategies are associated with slower dementia progression. Developing interventions that target these strategies may benefit dementia patients.

Clinical progression of dementia is worsened and accelerated by multimorbidity in a population-based study

Clinical progression of dementia is worsened and accelerated by multimorbidity in a population-based study

P3-441: Expression of mRNAs regulating local translation in synaptic terminals of MCI and early ad brain

Recent evidence suggests Alzheimer's Disease (AD) begins with subtle alterations of synaptic function producing memory deficits prior to histopathological changes. Decreased expression of presynaptic proteins before synapse loss is part of a continuum of modifications during clinical progression of dementia. However, activity–dependant expression of proteins locally translated in both pre–and post–synaptic terminals, and mRNA binding proteins regulating their translation, have not been assessed in the AD brain. Perturbation of synaptic protein synthesis could result from modifications in structure and function of the pre–synaptic terminal and/or direct effects of Ab peptides at the post–synaptic terminal. To compare expression of mRNAs locally translated at the synapse in MCI/early AD versus controls. Patients were grouped primarily according to MMSE but also adjusted for amyloid burden. Frontal cortex (Area 9) was obtained post–mortem, from 8 age–matched controls, 6 MCI/early AD and 10 moderate–to–severe AD patients. Synaptoneurosomes were prepared and mRNA extracted for Affymetrix microarray profiling and quantitative PCR. Clustering of genes and fold change data was prepared with the Bioconductor package. Gene annotation and gene ontology groupings were identified using EASE (http://david.niaid.nih.gov/david/ease.htm). We screened mRNA sequences of changed genes for 3∼ UTR regulatory motifs, such as the cytoplasmic polyadenylation element (CPE), which regulate local translation at the synapse. In MCI there is up–regulation of genes involved in synaptic transmission, transport (including vesicle–mediated transport) and cell recognition, and down–regulation of cell–cycle genes, (p<0.01). Approximately 50% of up–regulated genes code for proteins localized to the membrane. We found 50 putative CPE–containing mRNAs out of 304 up–regulated (16%) and 22 of 157 down–regulated (14%). Genes encoding the mRNA–binding proteins pumilio homolog and HuD, and some corresponding mRNAs they regulate, were also up–regulated in MCI. Synaptoneurosome samples were evaluated for in vitro translation using biotin–labeled tRNA. Immunoblots revealed biotin labeled aCAMKII in all synaptosomal preparations tested. Thus, using human synaptoneurosomes, we have enriched a group of mRNAs with regulatory sequences involved in de novo protein synthesis at the synapse. Microarray profiling reveals that some of these genes are impacted in MCI brain and may be implicated in functional impairment during AD progression.

P2-207 Clinical progression of dementia and predictive value of HMPAO-SPECT: follow-up study of 97 patients from a multidisciplinary memory clinic based in neurology

P2-207 Clinical progression of dementia and predictive value of HMPAO-SPECT: follow-up study of 97 patients from a multidisciplinary memory clinic based in neurology

Longitudinal study of cerebrospinal fluid levels of tau, A beta1-40, and A beta1-42(43) in Alzheimer's disease: a study in Japan.

To clarify the alterations of tau, amyloid beta protein (A beta) 1-40 and A beta1-42(43) in the cerebrospinal fluid (CSF) that accompany normal aging and the progression of Alzheimer's disease (AD), CSF samples of 93 AD patients, 32 longitudinal subjects among these 93 AD patients, 33 patients with non-AD dementia, 56 with other neurological diseases, and 54 normal control subjects from three independent institutes were analyzed by sensitive enzyme-linked immunosorbent assays. Although the tau levels increased with aging, a significant elevation of tau and a correlation between the tau levels and the clinical progression were observed in the AD patients. A significant decrease of the A beta1-42(43) levels and a significant increase of the ratio of A beta1-40 to A beta1-42(43) were observed in the AD patients. The longitudinal AD study showed continuous low A beta1-42(43) levels and an increase of the ratio of A beta1-40 to A beta1-42(43) before the onset of AD. These findings suggest that CSF tau may increase with the clinical progression of dementia and that the alteration of the CSF level of A beta1-42(43) and the ratio of A beta1-40 to A beta1-42(43) may start at early stages in AD. The assays of CSF tau, A beta1-40, and A beta1-42(43) provided efficient diagnostic sensitivity (71%) and specificity (83%) by using the production of tau levels and the ratio of A beta1-40 to A beta1-42(43), and an improvement in sensitivity (to 91%) was obtained in the longitudinal evaluation.

Longitudinal study of cerebral blood flow in Alzheimer's disease using single photon emission tomography

Ten patients with probable Alzheimer's disease were assessed at baseline and a mean 2 years later using a battery of neuropsychological tests, CT scans and Tc99m-HMPAO SPECT scans. The subjects had declined significantly in their functional indices. Cerebral perfusion measures declined in the parietal lobes, left hemisphere and whole brain, but the overall decline did not reach statistical significance. The decline in brain perfusion did not correlate significantly with the decline in various indices of neuropsychological function, either globally or for specific brain regions. The index of cerebral perfusion correlated significantly with global indices of neuropsychological function at baseline but not at follow-up. No single perfusion index was a significant predictor of clinical progression of dementia.