Phenotypic heterogeneity and preclinical change in familial Alzheimer's disease

This thesis investigates relationships between clinical, neuroimaging and neuropathological features in autosomal dominant familial Alzheimer’s disease (FAD), with the aim of studying phenotypic heterogeneity and preclinical change. Chapters 1 and 2 introduce the background to the problem to be addressed in this thesis with an emphasis on current understanding of clinical and imaging changes in AD, and specifically in FAD. The FAD phenotype can be highly variable and, although it shares many clinical features with sporadic AD, it also possesses important differences. The clinical spectrum of FAD is first investigated, through analysis of all symptomatic cases studied at our research centre over the past twenty-five years (Chapter 3). Associations between phenotypic and pathological heterogeneity are then explored, with a study investigating genetic determinants of white matter hyperintensities and cerebral amyloid angiopathy (CAA) in FAD (Chapter 4). CAA is a common but variable feature of AD that appears to be an important factor in amyloid-modifying therapy and the term ‘ARIA’ has been coined to describe amyloid-related imaging abnormalities, thought to relate to vascular amyloid, that have been observed in a variety of amyloid-modifying therapy trials. Spontaneous changes of ARIA in FAD and the genetic risk factors that may provoke them are then described (Chapter 5). The recent launch of preclinical treatment trials for FAD necessitates better understanding of the trajectory of biomarker changes early in the disease. Observations from amyloid imaging studies, of presymptomatic amyloid deposition in the thalamus and striatum, motivated the final study, which examines changes in volume and diffusivity of these subcortical structures and their connecting white matter tracts in symptomatic and presymptomatic FAD mutation carriers (Chapter 6). Together, these studies demonstrate that exploring phenotypic heterogeneity and preclinical imaging changes can illuminate aspects of the underlying disease process, informing our understanding of FAD and potential effects of treatment

Brain imaging evidence of early involvement of subcortical regions in familial and sporadic Alzheimer's disease

Recent brain imaging studies have found changes in subcortical regions in presymptomatic autosomal dominant Alzheimer's disease (ADAD). These regions are also affected in sporadic Alzheimer's disease (sAD), but whether such changes are seen in early-stage disease is still uncertain. In this review, we discuss imaging studies published in the past 12 years that have found evidence of subcortical involvement in early-stage ADAD and/or sAD. Several papers have reported amyloid deposition in the striatum of presymptomatic ADAD mutation carriers, prior to amyloid deposition elsewhere. Altered caudate volume has also been implicated in early-stage ADAD, but findings have been variable. Less is known about subcortical involvement in sAD: the thalamus and striatum have been found to be atrophied in symptomatic patients, but their involvement in the preclinical phase remains unclear, in part due to the difficulties of studying this stage in sporadic disease. Longitudinal imaging studies comparing ADAD mutation carriers with individuals at high-risk for sAD may be needed to elucidate the significance of subcortical involvement in different AD clinical stages

Pengaruh Pendidikan Kesehatan Terhadap Perubahan Pengetahuan, Sikap dan Perilaku Tentang Kebiasaan Berperilaku Hidup Bersih dan Sehat Siswa SDN 1 Mandong

School age children are past the age of children who are very different from adults. Obtained within this period many health issues that determine the quality of the child's future . At the elementary school students faced health problems associated with living clean and healthy behavior that have not been implemented well . From the observations and interviews of 7 students , 5 students in the habit of littering them is not in place , there are often students do not participate in sports at school , students snack foods outside of school , many students did not wash their hands before taking food . The research objective was to determine the effect of health education on changes in knowledge , attitudes and behaviors about clean living habits and unhealthy behavior SDN 1 Mandong students . This type of research is a quantitative research design one group pre test and post test design . Sampling technique with a total sampling with a sample of 52 respondents . Research instrument in the form of knowledge and attitude questionnaires and observation sheets for behavior . Research data obtained by giving the test twice before and after the health education given health education . Analysis of research data using paired t test and Wilcoxon rank test test . Results reveal the knowledge , attitudes and behaviors of students increased after receiving health education . Knowledge of data analysis results obtained by paired sample test = 9.543 p = 0.001 , analysis of data obtained attitude test for paired samples = 11.122 with p = 0.001 and behavior change with the value of Wilcoxon rank test = 3.411 with p = 0.001 . Studies conclusion was no effect of health education on changes in knowledge , attitudes and behaviors of good hygiene practices and healthy school SDN 1 Mandong

Spontaneous ARIA (Amyloid-Related Imaging Abnormalities) and Cerebral Amyloid Angiopathy Related Inflammation in Presenilin 1-Associated Familial Alzheimer's Disease

Amyloid-related imaging abnormalities (ARIA), thought to reflect immune responses to vascular amyloid, have been detected in several amyloid-modifying therapy trials for Alzheimer's disease (AD). We report a case of ARIA developing spontaneously during the course of Presenilin 1 (PSEN1)-associated familial AD (FAD), in an APOE4 homozygous patient. Severe cerebral amyloid angiopathy with associated inflammation was subsequently found at autopsy. Recognition that ARIA may arise spontaneously during FAD and of the potential risk factors for its development are important observations given the recent launch of amyloid-modifying therapy trials for FAD

Variability in the type and layer distribution of cortical A beta pathology in familial Alzheimer's disease

Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD

Hubungan Antara Stres, Pola Makan Dan Kebiasaan Merokok Dengan Terjadinya Kekambuhan Pada Penderita Hipertensi Di Puskesmas Bendosari Sukoharjo

Hipertensi merupakan penyebab kematian utama melalui proses terjadinya stroke, kematian jaringan otot jantung dan kegagalan fungsi ginjal. Berbagai faktor resiko hipertensi meliputi genetik, ras, usia, jenis kelamin, merokok, obesitas, serta stress psikologis dan faktor yang menyebabkan kambuhnya hipertensi antara lain pola makan, merokok dan stres. Penelitian ini bertujuan untuk mengetahui hubungan antara stres, pola makan dan kebiasaan merokok dengan terjadinya kekambuhan pada penderita hipertensi di Puskesmas Bendosari Sukoharjo. Penelitian ini merupakan penelitian deskriptif analitik dengan pendekatan studi cross sectional. Populasi penelitian adalah pasien hipertensi di Puskesmas Bendosari Sukoharjo pada tahun 2011, sedangkan sampel penelitian sebanyak 70 pasien menggunakan metode insidental sampling. Instrumen penelitian berupa kuesioner dan dokumentasi. Teknik pengujian hipotesis adalah uji Chi Square. Berdasarkan analisis dan pembahasan maka penelitian ini menyimpulkan bahwa: (1) ada hubungan antara stres dengan kekambuhan pasien hipertensi di Puskesmas Bendosari Sukoharjo, (2) ada hubungan antara pola makan dengan kekambuhan pasien hipertensi di Puskesmas Bendosari Sukoharjo, dan (3) ada hubungan antara kebiasaan merokok dengan kekambuhan pasien hipertensi di Puskesmas Bendosari Sukoharjo

Clinical Association of White Matter Hyperintensities Localization in a Mexican Family with Spastic Paraparesis Carrying the PSEN1 A431E Mutation

Presenilin 1 gene (PSEN1) mutations are the most common cause of familial Alzheimer’s disease (FAD). One of the most abundant FAD mutations, PSEN1 A431E, has been reported to be associated with spastic paraparesis in about half of its carriers, but the determining mechanisms of this phenotype are still unknown. In our study we characterized three A431E mutation carriers, one symptomatic and two asymptomatic, from a Mexican family with a history of spastic paraparesis in all of its affected members. At cognitive assessment and MRI, the symptomatic subject showed an atypical non-amnestic mild cognitive impairment with visuospatial deficits, olfactory dysfunction and significant parieto-occipital brain atrophy. Furthermore, we found several periventricular white matter hyperintensities whose progression pattern and localization correlated with their motor impairment, cognitive profile, and non-motor symptoms. Together, our data suggests that in this family the A431E mutation leads to a divergent neurological disorder in which cognitive deterioration was clinically exceeded by motor impairment and that it involves early glial and vascular pathological changes

Disease duration in autosomal dominant familial Alzheimer disease

OBJECTIVE: To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. METHODS: Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival was assessed with respect to age at onset, year of birth, APOE ε4 status, cognitive presentation, and sex using multilevel mixed-effects Weibull survival models. The contribution of mutation and family to variance in age at onset and duration was also assessed. RESULTS: Estimated mean survival was 11.6 (10.4–12.9) years and was similar for APP and PSEN1 mutations. Sixty-seven percent of the variance in age at onset was explained by mutation and 72% by mutation and family together. In contrast, only 6% of the variance in disease duration was explained by mutation specificity and 18% by family membership. Irrespective of gene, survival appeared longer for successive generations and in individuals with atypical presentations. Older age at onset was associated with longer duration within PSEN1 and shorter duration within APP mutation carriers. No differences in survival time were found between sexes or between mutations located before or beyond codon 200 within PSEN1. CONCLUSIONS: Survival is influenced by mutation to a much lesser extent than age at onset. Survival time has increased over time and is longer in atypical presentations. These insights may inform the interpretation of disease-modifying therapy trials in ADAD

The age-dependent associations of white matter hyperintensities and neurofilament light in early- and late-stage Alzheimer's disease

Neurofilament light (NFL) is an emerging marker of axonal degeneration. This study investigated the relationship between white matter hyperintensities (WMHs) and plasma NFL in a large elderly cohort with, and without, cognitive impairment. We used the Alzheimer's Disease Neuroimaging Initiative and included 163 controls, 103 participants with a significant memory concern, 279 with early mild cognitive impairment (EMCI), 152 with late mild cognitive impairment (LMCI), and 130 with Alzheimer's disease, with 3T MRI and plasma NFL data. Multiple linear regression models examined the relationship between WMHs and NFL, with and without age adjustment. We used smoking status, history of hypertension, history of diabetes, and BMI as additional covariates to examine the effect of vascular risk. We found increases of between 20% and 41% in WMH volume per 1SD increase in NFL in significant memory concern, early mild cognitive impairment, late mild cognitive impairment, and Alzheimer's disease groups (p < 0.02). Marked attenuation of the positive associations between WMHs and NFL were seen after age adjustment, suggesting that a significant proportion of the association between NFL and WMHs is age-related. No effect of vascular risk was observed. These results are supportive of a link between WMH and axonal degeneration in early to late disease stages, in an age-dependent, but vascular risk-independent manner