Evaluation of Cerebral Lateral Ventricular Enlargement Derived from Magnetic Resonance Imaging: A Candidate Biomarker of Alzheimer Disease Progression in Vivo

Alzheimer disease (AD) is the most common form of dementia and has grievous mortality rates. Measuring brain volumes from structural magnetic resonance images (MRI) may be useful for illuminating disease progression. The goal of this thesis was to (1) help refine a novel technique used to segment the lateral cerebral ventricles from MRI, (2) validate this tool, and determine group-wise differences between normal elderly controls (NEC) and subjects with mild cognitive impairment (MCI) and AD and (3) determine the number of subjects necessary to detect a 20 percent change from the natural history of ventricular enlargement with respect to genotype. Three dimensional Ti-weighted MRI and cognitive measures were acquired from 504 subjects (NEC n = 152, MCI n = 247 and AD n = 105) participating in the multi-centre Alzheimer\u27s Disease Neuroimaging Initiative. Cerebral ventricular volume was quantified at baseline and after six months. For secondary analyses, all groups were dichotomized for Apolipoprotein E genotype based on the presence of an e4 polymorphism. The AD group had greater ventricular enlargement compared to both subjects with MCI (P = 0.0004) and NEC (P \u3c 0.0001), and subjects with MCI had a greater rate of ventricular enlargement compared to NEC (P =0.0001). MCI subjects that progressed to clinical AD after six months had greater ventricular enlargement than stable MCI subjects (P = 0.0270). Ventricular enlargement was different between apolipoprotein E genotypes within the AD group (P = 0.010). The number of subjects required to demonstrate a 20% change in ventricular enlargement (AD: N=342, MCI: N=1180) was substantially lower than that required to demonstrate a 20% change in cognitive scores (MMSE) (AD: N=7056, MCI: N=7712). Therefore, ventricular enlargement represents a feasible short-term marker of disease progression in subjects with MCI and subjects with AD for multi-centre studie

Understanding the Contributions of Alzheimer’s Disease & Cardiovascular Risks to Cerebral Small Vessel Disease Manifest as White Matter Hyperintensities on Magnetic Resonance Imaging (MRI)

Introduction: Alzheimer’s Diseases (AD) & cerebral small vessel disease associated with cardiovascular risk factors (cSVD) frequently coexist, differentially affecting both imaging and clinical features associated with aging and dementia. We hypothesized that Magnetic Resonance Imaging (MRI) can be used in novel ways to identify relative contributions of AD & cardiovascular risks to cSVD and brain atrophy, generating new biomarkers & insights into mixed disease states associated with cognitive decline and dementia. Methods: Three experiments were conducted to address the overarching hypothesis. First, we visually rated the clinical MRI of 325 participants from a community-based cross-sectional sample to elucidate the relative association of age, AD (visualized as hippocampal atrophy) and cSVD (visualized as white matter hyperintensities; WMH) with global brain atrophy in experiment 1. In experiment 2, we analyzed cross-sectional MRI scans from 62 participants from the University of Kentucky Alzheimer’s Disease Center (UKADC) with available clinical data on cardiovascular risk and cerebrospinal fluid (CSF) beta-amyloid levels as a marker of AD. Voxel wise regression was used to examine the association of white matter hyperintensities with AD and/or cardiovascular risk (hypertension). Experiment 3, examined longitudinal MRI changes in WMH volumes in 377 participants from the Alzheimer’s Disease Neuroimaging Initiative 2 (ADNI 2). Subjects were categorized into three groups based on WMH volume change, including those that demonstrated regression (n=96; 25.5%), stability (n=72; 19.1%), and progression (n=209; 55.4%) of WMH volume over time. Differences in brain atrophy measures and cognitive testing among the three group were conducted. Results: In the first experiment, logistic regression analysis demonstrated that a 1-year increase in age was associated with global brain atrophy (OR = 1.04; p = .04), medial temporal lobe atrophy (MTA; a surrogate of AD) (OR = 3.7; p \u3c .001), and WMH as surrogate of cSVD (OR = 8.80; p \u3c .001). Both MTA and WMH were strongly associated with global brain atrophy in our study population, with WMH showing the strongest relationship after adjusting for age. In the second experiment, linear regression as well as mediation and moderation analyses demonstrated significant main effects of hypertension (HTN; the strongest risk factor associated with cSVD) and CSF Aβ 1-42 (a surrogate of AD) on WMH volume, but no significant HTN×CSF Aβ 1-42 interaction. Further exploration of the independence of HTN and Aβ using a voxelwise analysis approach, demonstrated unique patterns of WM alteration associated with either hypertension or CSF Aβ 1-42, confirming that both independently contribute to WMH previously classified as cSVD. Extending this work into a longitudinal model rather than focusing on purely cross-sectional associations, we demonstrated that spontaneous WMH regression is common, and that such regression is associated with a reduced rate of global brain atrophy (p = 0.012), and improvement in memory function over time (p = 0.003). Conclusion: These data demonstrate that both AD and cSVD frequently coexist in the same brain, contributing differentially to alterations in brain structure, subcortical white matter injury, and cognitive function. These effects can be disentangled using MRI, and while we currently lack therapeutic interventions to halt or reverse AD, the dynamic WMH change evident in our data clearly suggests that the ability to reverse cSVD exists today

Blood and cerebrospinal fluid biomarkers for Alzheimer’s disease: from clinical to preclinical cohorts

Dementia is a major contributor to global morbidity, mortality and costs associated with health and social care. Alzheimer’s disease (AD) is a common pathology culminating in dementia, but it has a preclinical phase of one to two decades, with early brain deposition of amyloid and tau, followed by synaptic and neuronal degeneration. Early detection during the preclinical phase of AD might enable disease-modifying therapies to be applied during a window of opportunity in which they would be more likely to work. Currently the main biomarkers of AD pathology are neuroimaging markers, which can be costly, or cerebrospinal fluid markers, which require invasive sampling. Blood biomarkers would be relatively less invasive and could be a more cost-effective means for risk stratification, early detection, monitoring progression and measuring response to treatment. The work described here used sensitive assay technology including the Simoa digital immunoassay platform, in large and well-characterised cohorts, to examine candidate blood biomarkers linked to the core AD pathologies of amyloid, tau and neurodegeneration, as specified by the National Institute on Aging and Alzheimer’s Association 2018 research framework. Firstly, experiments on samples from a cognitive clinic cohort established the stability of the blood biomarkers Aβ40, Aβ42, total tau and neurofilament light chain (NFL – a marker of neurodegeneration) to multiple freeze-thaw cycles, and the optimal blood fraction to use for quantifying each of these biomarkers in onward studies. Secondly, an unique large preclinical cohort with life course data (Insight 46, the neuroscience sub-study of 502 individuals from the MRC National Survey of Health and Development; the 1946 British birth cohort) was used to examine the cross-sectional relationships between these blood biomarkers, neuroimaging biomarkers (18F-florbetapir amyloid PET, whole brain and hippocampal volumes, white matter hyperintensity volume and cortical thickness in an AD signature region) and cognitive performance (PACC: preclinical Alzheimer’s composite and its constituents). Through a collaboration with the University of Gothenburg, a novel liquid chromatography-mass spectrometry (LC-MS) method for quantification of plasma amyloid-β species was compared with the commercial Simoa assays in Insight 46. This was the first direct method comparison study of plasma amyloid-β species for the detection of preclinical cerebral amyloid deposition. It showed that the LC-MS method, when combined with age, sex and APOE #-4 carrier status, was able to distinguish PET amyloid status with an optimal (Youden’s cut point) sensitivity of 85.7% and specificity of 72.7%. The Simoa biomarkers of plasma total tau and serum NFL were confirmed to be potentially useful prognostic markers, as lower AD signature cortical thickness was associated with higher plasma total tau and serum NFL, lower whole brain volume was associated with higher plasma total tau, and higher ventricular volume was associated with higher serum NFL. Lower PACC scores were associated with higher serum NFL and lower scores for a paired associative memory test in particular were associated with higher plasma total tau and serum NFL. Thirdly, through a collaboration with Harvard University and the University of California San Diego, a new N-terminal tau biomarker was developed in CSF and plasma that showed good accuracy in distinguishing individuals with symptomatic CSF-defined AD pathology from healthy controls. Taken together, this work has demonstrated the impact of pre-analytical factors on measurements of AD blood biomarkers, validated these biomarkers as indicators of the core pathologies of AD and helped to develop a new tau blood biomarker in AD

Updated Information on Some Cognitive Disorders

Dementia is a neurodegenerative disorder characterized by a progressive decline in cognitive and daily living activities. The present review aimed to highlight the most relevant and updated information available in the medical literature on mild cognitive impairment, Parkinson’s dementia, Alzheimer’s disease, vascular dementia, normal pressure hydrocephalus, and Wernicke-Korsakoff and to deliver some personal observations about cognitive disorders and dementia

Identification of Novel Fluid Biomarkers for Alzheimer\u27s Disease

Clinicopathological studies suggest that Alzheimer\u27s disease: AD) pathology begins to appear ~10-20 years before the resulting cognitive impairment draws medical attention. Biomarkers that can detect AD pathology in its early stages and predict dementia onset and progression would, therefore, be invaluable for patient care and efficient clinical trial design. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid: CSF) using an unbiased proteomics approach: two-dimensional difference gel electrophoresis with liquid chromatography tandem mass spectrometry). From this, we identified 47 proteins that differed in abundance between cognitively normal: Clinical Dementia Rating [CDR] 0) and mildly demented: CDR 1) subjects. To validate these findings, we measured a subset of the identified candidate biomarkers by enzyme linked immunosorbent assay: ELISA); promising candidates in this discovery cohort: N=47) were further evaluated by ELISA in a larger validation CSF cohort: N=292) that contained an additional very mildly demented: CDR 0.5) group. Levels of four novel biomarkers were significantly altered in AD, and Receiver-operating characteristic: ROC) analyses using a stepwise logistic regression model identified optimal panels containing these markers that distinguished CDR 0 from CDR\u3e0: tau, YKL-40, NCAM) and CDR 1 from CDR\u3c1: tau, chromogranin-A, carnosinase-I). Plasma levels of the most promising marker, YKL-40, were also found to be increased in CDR 0.5 and 1 groups and to correlate with CSF levels. Importantly, the CSF YKL-40/Aâ42 ratio predicted risk of developing cognitive impairment: CDR 0 to CDR\u3e0 conversion) as well as the best CSF biomarkers identified to date, tau/Aâ42 and p-tau181/Aâ42. Additionally, YKL-40 immunoreactivity was observed within astrocytes near a subset of amyloid plaques, implicating YKL-40 in the neuroinflammatory response to Aâ deposition. Utilizing an alternative, targeted proteomics approach to identify novel biomarkers, 333 CSF samples were evaluated for levels of 190 analytes using a multiplexed Luminex platform. The mean concentrations of 37 analytes were found to differ between CDR 0 and CDR\u3e0 participants. ROC and statistical machine learning algorithms identified novel biomarker panels that improved upon the ability of the current best biomarkers to discriminate very mildly demented from cognitively normal participants, and identified a novel biomarker, Calbindin, with significant prognostic potential

The relationship between brain volume and MMSE scores in older adults without dementia

Το MMSE είναι διαγνωστικό εργαλείο το οποίο χρησιμοποιείται για την έγκαιρη ανίχνευση της νόσου του Alzheimer. Η μελέτη διερεύνησε αν οι γνωστικές επιδόσεις σχετίζονταν με ογκομετρικές αλλαγές του εγκεφάλου σε γνωστικά υγιείς ηλικιωμένους. Το MMSE αξιολόγησε τη γενική γνωστική λειτουργία τους και μόνο οι ασθενείς με βαθμολογία MMSE≥24 συμπεριλήφθηκαν, ενώ η μαγνητική τομογραφία χρησιμοποιήθηκε για τον υπολογισμό των γενικών και περιφερειακών μεταβολών του όγκου. Το Geriatric Depression Scale-15 (GDS) χρησιμοποιήθηκε για τη μέτρηση της καταθλιπτικής συμπτωματολογίας. Οι υψηλότερες βαθμολογίες στο MMSE συσχετίστηκαν θετικά με τον όγκου της φαιάς ουσίας. Ενώ δεν υπήρχαν εμφανείς συσχετίσεις μεταξύ του MMSE και των περιοχών ενδιαφέροντος (ROIs). Η ηλικία συσχετίστηκε αρνητικά με τη φαιά ουσία, τη λευκή ουσία, το εγκεφαλονωτιαίο υγρό και τις βαθμολογίες του MMSE. Η ηλικία έδειξε επίσης σημαντικούς αρνητικούς συσχετισμούς με τις περιοχές ενδιαφέροντος, συμπεριλαμβανομένου του ιππόκαμπου, της αμυγδαλής, του ενδορινικού φλοιού, του προμετωπιαίου φλοιού, του πρόσθιου προσαγώγιου έλικα. Οι γυναίκες εμφάνισαν μεγαλύτερα επίπεδα κατάθλιψης από τους άνδρες. Αλλά οι άνδρες είχαν μεγαλύτερο κοιλιακό μέγεθος από τις γυναίκες. Η κατάθλιψη συσχετίστηκε επίσης αρνητικά με τον όγκο της φαιάς ουσίας και τις βαθμολογίες του MMSE. Επιπλέον, τα άτομα με υψηλότερη εκπαίδευση είχαν μεγαλύτερη κοιλιακή επέκταση από όσους είχαν λιγότερα έτη εκπαίδευσης. Οι ανωμαλίες της φαιάς ουσίας που μετρήθηκαν με το IBASPM (MatLab R2014a) σχετίζονταν με χαμηλότερη γνωστική επίδοση στον ηλικιωμένο εγκέφαλο. Αυτές οι αλλαγές θα μπορούσαν να υποδηλώνουν προκλινική άνοια και όχι υγιή γήρανση.Mini-Mental State Examination (MMSE) is a screening tool that is used for early detection of Alzheimer’s disease. The study investigated whether cognitive performance was related to volumetric brain changes in cognitively healthy older adults. The Mini Mental State Examination (MMSE) assessed their general cognitive function and only those with MMSE scoring ≥24 were included, while MRI was used to calculate gross and regional volume changes. Geriatric Depression Scale-15 (GDS) was used to measure depressive symptomatology. Higher MMSE scores were positively correlated with GM volume; whereas no significant associations were evident between MMSE and regions of interest (ROIs). Age was negatively correlated with gray matter (GM), white matter (WM), cerebrospinal fluid (CSF), and MMSE scores. Age also showed significant negative correlations with ROIs, including the hippocampus, amygdala, entorhinal cortex, prefrontal cortex, anterior cingulate gyrus. Women exhibited greater levels of depression than men. But men had greater ventricular size than women. Depression was also negatively correlated with GM volume and MMSE scores. Moreover, people with higher education had greater ventricular expansion from those with fewer years in education. Gray matter abnormalities measured by IBASPM (MatLab R2014a) were related with lower cognitive performance in the aged brain. These changes could suggest preclinical dementia and not healthy aging

Biomarkers in patients with idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a condition affecting a small percentage of the elderly population; however it is the only known treatable cause of dementia. Surgical cerebrospinal fluid (CSF) diversion is the only known treatment for the condition today. However, such a procedure is not to be offered lightly and any expected benefit has to balance the associated surgical risks. The prognosis of a favourable surgical outcome has been problematic since the conception of the syndrome. None of current prognostic tests reaches 100% sensitivity or specificity and it is felt that there might be a need for a combination of tests, rather than a single one to maximize the chances of selecting the right patients to offer a surgical CSF diversion procedure. Biomarkers are biological substances that may act as surrogate markers of response to a treatment or to characterise a disease’s progression over time. The aim of this study was to identify CSF markers of favourable surgical outcome in patients with iNPH undergoing the insertion of a ventriculoperitoneal shunt (VPS). We first describe the effects of external lumbar drainage (ELD) on the CSF biochemistry of these patients. Correlations are made with imaging data obtained from volumetric analysis and neuropsychological tests in order to obtain a complete profile of these patients. The rostrocaudal gradients of the CSF markers examined are reported showcasing the need to understand that commonly reported values from lumbar CSF do not necessarily reflect pathological changes occurring at cerebral level. Finally, we report on the individual as well as combined prognostic value of 7 CSF markers on surgical outcomes at 6 months. The pathophysiological significance of these markers is discussed individually. It is concluded that the combined power of total tau and Aβ 1-42 may be useful in predicting favourable surgical outcomes at 6 months; further studies applying the findings in a larger cohort and correlating findings with longer outcomes are warranted to enhance the clinical application. The biochemical profile of patients with iNPH appears unique and different than patients with Alzheimer’s dementia or control subjects

Development of Anatomical and Functional Magnetic Resonance Imaging Measures of Alzheimer Disease

Alzheimer disease is considered to be a progressive neurodegenerative condition, clinically characterized by cognitive dysfunction and memory impairments. Incorporating imaging biomarkers in the early diagnosis and monitoring of disease progression is increasingly important in the evaluation of novel treatments. The purpose of the work in this thesis was to develop and evaluate novel structural and functional biomarkers of disease to improve Alzheimer disease diagnosis and treatment monitoring. Our overarching hypothesis is that magnetic resonance imaging methods that sensitively measure brain structure and functional impairment have the potential to identify people with Alzheimer’s disease prior to the onset of cognitive decline. Since the hippocampus is considered to be one of the first brain structures affected by Alzheimer disease, in our first study a reliable and fully automated approach was developed to quantify medial temporal lobe atrophy using magnetic resonance imaging. This measurement of medial temporal lobe atrophy showed differences (pnovel biomarker of brain activity was developed based on a first-order textural feature of the resting state functional magnetic resonance imagining signal. The mean brain activity metric was shown to be significantly lower (pp18F labeled fluorodeoxyglucose positron emission tomography. In the final study, we examine whether combined measures of gait and cognition could predict medial temporal lobe atrophy over 18 months in a small cohort of people (N=22) with mild cognitive impairment. The results showed that measures of gait impairment can help to predict medial temporal lobe atrophy in people with mild cognitive impairment. The work in this thesis contributes to the growing evidence the specific magnetic resonance imaging measures of brain structure and function can be used to identify and monitor the progression of Alzheimer’s disease. Continued refinement of these methods, and larger longitudinal studies will be needed to establish whether the specific metrics of brain dysfunction developed in this thesis can be of clinical benefit and aid in drug development

MRI Measures of Neurodegeneration as Biomarkers of Alzheimer's Disease

Indiana University-Purdue University Indianapolis (IUPUI)Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease. Many researchers believe that an effective AD treatment will prevent the development of disease rather than treat the disease after a diagnosis. Therefore, the development of tools to detect AD-related pathology in early stages is an important goal. In this report, MRI-based markers of neurodegeneration are explored as biomarkers of AD. In the first chapter, the sensitivity of cross-sectional MRI biomarkers to neurodegenerative changes is evaluated in AD patients and in patients with a diagnosis of mild cognitive impairment (MCI), a prodromal stage of AD. The results in Chapter 1 suggest that cross-sectional MRI biomarkers effectively measure neurodegeneration in AD and MCI patients and are sensitive to atrophic changes in patients who convert from MCI to AD up to 1 year before clinical conversion. Chapter 2 investigates longitudinal MRI-based measures of neurodegeneration as biomarkers of AD. In Chapter 2a, measures of brain atrophy rate in a cohort of AD and MCI patients are evaluated; whereas in Chapter 2b, these measures are assessed in a pre-MCI stage, namely older adults with cognitive complaints (CC) but no significant deficits. The results from Chapter 2 suggest that dynamic MRI-based measures of neurodegeneration are sensitive biomarkers for measuring progressive atrophy associated with the development of AD. In the final chapter, a novel biomarker for AD, visual contrast sensitivity, was evaluated. The results demonstrated contrast sensitivity impairments in AD and MCI patients, as well as slightly in CC participants. Impaired contrast sensitivity was also shown to be significantly associated with known markers of AD, including cognitive impairments and temporal lobe atrophy on MRI-based measures. The results of Chapter 3 support contrast sensitivity as a potential novel biomarker for AD and suggest that future studies are warranted. Overall, the results of this report support MRI-based measures of neurodegeneration as effective biomarkers for AD, even in early clinical and preclinical disease stages. Future therapeutic trials may consider utilizing these measures to evaluate potential treatment efficacy and mechanism of action, as well as for sample enrichment with patients most likely to rapidly progress towards AD