An insight into the brain of patients with type-2 diabetes mellitus and impaired glucose tolerance using multi-modal magnetic resonance image processing

The purpose of this thesis was to investigate brain anatomy and physiology of subjects with impaired glucose tolerance (IGT - 12 subjects), type-2 diabetes (T2DM - 17 subjects) and normoglycemia (16 subjects) using multi-modal magnetic resonance imaging (MRI) at 3T. Perfusion imaging using quantitative STAR labeling of arterial regions (QUASAR) arterial spin labeling (ASL) was the core dataset. Optimization of the post-processing methodology for this sequence was performed and the outcome was used for hemodynamic analysis of the cohort. Typical perfusion-related parameters, along with novel hemodynamic features were quantified. High-resolution structural, angiographic and carotid flow scans were also acquired and processed. Functional acquisitions were repeated following a vasodilating stimulus. Differences between the groups were examined using statistical analysis and a machine-learning framework. Hemodynamic parameters differing between the groups emerged from both baseline and post-stimulus scans for T2DM and mainly from the post-stimulus scan for IGT. It was demonstrated that quantification of not-typically determined hemodynamic features could lead to optimal group-separation. Such features captured the pattern of delayed delivery of the blood to the arterial and tissue compartments of the hyperglycemic groups. Alterations in gray and white matter, cerebral vasculature and carotid blood flow were detected for the T2DM group. The IGT cohort was structurally similar to the healthy cohort but demonstrated functional similarities to T2DM. When combining all extracted MRI metrics, features driving optimal separation between different glycemic conditions emerged mainly from the QUASAR scan. The only highly discriminant non-QUASAR feature, when comparing T2DM to healthy subjects, emerged from the cerebral angiogram. In this thesis, it was demonstrated that MRI-derived features could lead to potentially optimal differentiation between normoglycemia and hyperglycemia. More importantly, it was shown that an impaired cerebral hemodynamic pattern exists in both IGT and T2DM and that the IGT group exhibits functional alterations similar to the T2DM group

Regional hyperperfusion in cognitively normal APOE ε4 allele carriers in mid-life: analysis of ASL pilot data from the PREVENT-Dementia cohort

Background: Regional cerebral hypoperfusion is characteristic of Alzheimer’s disease (AD). Previous studies report conflicting findings in cognitively normal individuals at high risk of AD. Understanding early preclinical perfusion alterations may improve understanding of AD pathogenesis and lead to new biomarkers and treatment targets. Methods: 3T arterial spin labelling MRI scans from 162 participants in the PREVENT-Dementia cohort were analysed (cognitively normal participants aged 40–59, stratified by future dementia risk). Cerebral perfusion was compared vertex-wise according to APOE ε4 status and family history (FH). Correlations between individual perfusion, age and cognitive scores (COGNITO battery) were explored. Results: Regional hyperperfusion was found in APOE ε4+group (left cingulate and lateral frontal and parietal regions p<0.01, threshold-free cluster enhancement, TFCE) and in FH +group (left temporal and parietal regions p<0.01, TFCE). Perfusion did not correlate with cognitive test scores. Conclusions: Regional cerebral hyperperfusion in individuals at increased risk of AD in mid-life may be a very early marker of functional brain change related to AD. Increased perfusion may reflect a functional ‘compensation’ mechanism, offsetting the effects of early neural damage or may itself be risk factor for accelerating spread of degenerative pathology

Higher midlife CAIDE score is associated with increased brain atrophy in a cohort of cognitively healthy middle-aged individuals

Abstract: Background: Structural brain changes associated with Alzheimer’s disease (AD) can occur decades before the onset of symptoms. The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score has been suggested to be associated with accelerated brain atrophy in middle-aged subjects but the regional specificity of atrophic areas remains to be elucidated. Methods: 3T T1-weighted magnetic resonance imaging scans of 160 cognitively healthy middle-aged participants (mean age = 52) in the PREVENT-Dementia cohort, from baseline and from follow-up after 2 years, were examined. Images were preprocessed using Computational Anatomy Toolbox 12. Voxel-based morphometry was performed in FSL 6.0.1 to identify areas of grey matter (GM) volume differences both cross-sectionally and longitudinally between subjects with high and low baseline CAIDE score (CAIDE score was dichotomized at cohort-median). A GM percentage of change map was created for each subject for evaluation of atrophy over 2 years. Analyses were adjusted for age, gender, education and total intracranial volume. Results: Compared to subjects with CAIDE score ≤ 6 (low risk), subjects with CAIDE score > 6 (high risk) showed lower GM volume in the temporal, occipital, and fusiform cortex and lingual gyrus at baseline, and greater percentage of GM loss over 2 years in the supramarginal gyrus, angular gyrus, precuneus, lateral occipital cortex, superior parietal lobule and cingulate gyrus (corrected P < 0.05). Conclusion: This study demonstrated accelerated GM atrophy concentrated in several AD signature cortical regions in healthy middle-aged subjects with high CAIDE scores

Comprehensive allostatic load risk index is associated with increased frontal and left parietal white matter hyperintensities in mid-life cognitively healthy adults

To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.</p

Evidence of cerebral hemodynamic dysregulation in middle-aged APOE ε4 carriers: The PREVENT-Dementia study.

Accumulating evidence suggests vascular dysregulation in preclinical Alzheimer's disease. In this study, cerebral hemodynamics and their coupling with cognition in middle-aged apolipoprotein ε4 carriers (APOEε4+) were investigated. Longitudinal 3 T T1-weighted and arterial spin labelling MRI data from 158 participants (40-59 years old) in the PREVENT-Dementia study were analysed (125 two-year follow-up). Cognition was evaluated using the COGNITO battery. Cerebral blood flow (CBF) and cerebrovascular resistance index (CVRi) were quantified for the flow territories of the anterior, middle and posterior cerebral arteries. CBF was corrected for underlying atrophy and individual hematocrit. Hemodynamic measures were the dependent variables in linear regression models, with age, sex, years of education and APOEε4 carriership as predictors. Further analyses were conducted with cognitive outcomes as dependent variables, using the same model as before with additional APOEε4 × hemodynamics interactions. At baseline, APOEε4+ showed increased CBF and decreased CVRi compared to non-carriers in the anterior and middle cerebral arteries, suggestive of potential vasodilation. Hemodynamic changes were similar between groups. Interaction analysis revealed positive associations between CBF changes and performance changes in delayed recall (for APOEε4 non-carriers) and verbal fluency (for APOEε4 carriers) cognitive tests. These observations are consistent with neurovascular dysregulation in middle-aged APOEε4+

Differential association of cerebral blood flow and anisocytosis in APOE ε4 carriers at midlife

Cerebral hemodynamic alterations have been observed in apolipoprotein ε4 (APOE4) carriers at midlife, however the physiological underpinnings of this observation are poorly understood. Our goal was to investigate cerebral blood flow (CBF) and its spatial coefficient of variation (CoV) in relation to APOE4 and a measure of erythrocyte anisocytosis (red blood cell distribution width – RDW) in a middle-aged cohort. Data from 563 participants in the PREVENT-Dementia study scanned with 3 T MRI cross-sectionally were analysed. Voxel-wise and region-of-interest analyses within nine vascular regions were run to detect areas of altered perfusion. Within the vascular regions, interaction terms between APOE4 and RDW in predicting CBF were examined. Areas of hyperperfusion in APOE4 carriers were detected mainly in frontotemporal regions. The APOE4 allele differentially moderated the association between RDW and CBF, an association which was more prominent in the distal vascular territories (p – [0.01, 0.05]). The CoV was not different between the considered groups. We provide novel evidence that in midlife, RDW and CBF are differentially associated in APOE4 carriers and non-carriers. This association is consistent with a differential hemodynamic response to hematological alterations in APOE4 carriers

Αυτο-ιασώμενα ολοκληρωμένα κυκλώματα/συστήματα σε νανομετρικές τεχνολογίες ημιαγωγών

The evolution of CMOS technology over the years has allowed the presence of billions of transistors in an integrated circuit. As the size of the transistors escalates, important reliability issues, both at the transistor level and at the circuits and systems level, have emerged, due to aging phenomena such as bias-temperature instability (BTI), hot-carrier injection (HCI), dielectric breakdown and electromigration or due to ever-changing environmental conditions. One approach to cope with reliability issues is the self-healing concept. That is, developing circuits and systems that will "sense" their aging status as well as changes that the environment sets and react appropriately to continue operating reliably under any conditions. The present thesis focuses on the analysis of the mechanisms that influence the reliable operation of VLSI circuits and systems and the development of innovative methods that can offer them self-healing so that they function reliably and uninterrupted throughout their life. The target of this dissertation is to develop embedded techniques in the field of SRAM memories for early, on-line, excess aging prediction and oncoming failure diagnosis, aiming to maintain, by proper actions, the reliable operation and prolong the lifetime of the integrated circuit/system where the SRAM belongs. These techniques will allow the sensing of the SRAM status and thus, the prediction of upcoming failures on its sub-circuits. Next, our goal is to present SRAM operation adjusting techniques or repairing options for the self-healing of the corresponding sub-circuits in order to maintain the memory’s reliable operation. Two new self-healing methods are proposed for the SRAM Memory Cells and Sense Amplifiers (SAs) and one new method for the SRAM Decoders. Firstly, a scheme that addresses individually the SRAM SAs and the SRAM Memory Cells for aging monitoring on their transistors is presented and corresponding self-healing options are suggested in order to maintain the reliability of the SRAM. The monitoring scheme is based on the use of a small Differential Ring Oscillator (DRO) and the duty cycle of the DRO signal is used for the discrimination of aged memory cells or SAs. Next, a unified approach of the above scheme is presented for the aging monitoring of both memory cells and SAs. An alteration of this technique is also proposed with the use of a reconfigurable DRO (rDRO) for the needs of the self-healing on SRAM SAs. Finally, an aging monitoring technique for the SRAM Decoders, along with an adjusting technique to succeed self-healing are presented. The monitoring scheme suggests the addition of a simple, low cost embedded circuit in order to early diagnose the Decoder’s aging and properly react to ensure reliability and prolong the lifetime of the SRAM. The simulations performed on the above schemes validate their ability for early (before thepresence of failures) self-healing of overaged cells, SAs and Decoders respectively, while offering low cost in silicon area as well as the ability to avoid aging of the circuits implemented when the SRAM is operating in normal mode.Η εξέλιξη της CMOS τεχνολογίας κατά τη διάρκεια των ετών επέτρεψε την παρουσία δισεκατομμυρίων τρανζίστορ σε ένα ολοκληρωμένο κύκλωμα. Καθώς το μέγεθος των τρανζίστορ κλιμακώνεται, προέκυψαν σημαντικά ζητήματα αξιοπιστίας, τόσο σε επίπεδο τρανζίστορ όσο και σε επίπεδο κυκλωμάτων και συστημάτων, λόγω των φαινομένων γήρανσης όπως αστάθεια πόλωσηςθερμοκρασίας (BTI), έγχυση θερμών φορέων (HCI), κατάρρευση διηλεκτρικού καιηλεκτρομετανάστευση ή λόγω των συνεχώς μεταβαλλόμενων περιβαλλοντικών συνθηκών. Μιαπροσέγγιση για την αντιμετώπιση προβλημάτων αξιοπιστίας είναι η έννοια της αυτο-ίασης. Δηλαδή,αναπτύσσοντας κυκλώματα και συστήματα που θα "αισθάνονται" τη γήρανσή τους καθώς και τιςαλλαγές που το περιβάλλον θέτει και θα αντιδρούν κατάλληλα για να συνεχίσουν να λειτουργούναξιόπιστα υπό οποιεσδήποτε συνθήκες. Η παρούσα διατριβή επικεντρώνεται στην ανάλυση των μηχανισμών που επηρεάζουν την αξιόπιστη λειτουργία των κυκλωμάτων και συστημάτων VLSI και στην ανάπτυξη καινοτόμων μεθόδων που μπορούν να προσφέρουν αυτο-ίαση έτσι ώστε να λειτουργούν αξιόπιστα και αδιάκοπα καθ 'όλη τη διάρκεια της ζωής τους. Σκοπός της παρούσας διατριβής είναι να αναπτύξει ενσωματωμένες τεχνικές στον τομέα των μνημών SRAM για πρόβλεψη γήρανσης και άμεσης διάγνωσης βλαβών με σκοπό την διατήρηση, με κατάλληλες ενέργειες, της αξιόπιστης λειτουργίας και παράτασης της διάρκειας ζωής του ολοκληρωμένου κυκλώματος/συστήματος όπου ανήκει η SRAM. Αυτές οι τεχνικές θα επιτρέψουν την ανίχνευση της κατάστασης της SRAM και, συνεπώς, την πρόβλεψη των επερχόμενων βλαβών στα υποκυκλώματά της. Στη συνέχεια, στόχος είναι να παρουσιαστούν τεχνικές ρύθμισης της λειτουργίας SRAM ή δυνατότητες επισκευής για την αυτό-ίαση των αντίστοιχων υποκυκλωμάτων, προκειμένου να διατηρηθεί η αξιόπιστη λειτουργία της μνήμης. Δύο νέες μέθοδοι αυτο-ίασης προτείνονται για τα κελιά μνήμης και τους αισθητήρες σήματος SRAM και μία νέα μέθοδο για τους αποκωδικοποιητές SRAM. Αρχικά, παρουσιάζεται ένα σχήμα που απευθύνεται ξεχωριστά στους αισθητήρες σήματος και τα κελιά μνήμης SRAM για ανίχνευση γήρανσης στα τρανζίστορ τους και προτείνονται οι αντίστοιχες επιλογές αυτο-ίασης προκειμένου να διατηρηθεί η αξιοπιστία της SRAM. Το σχήμα ανίχνευσης βασίζεται στη χρήση ενός μικρού κυκλικού διαφορικού ταλαντωτή (DRO) και ο κύκλος λειτουργίας του σήματος DRO χρησιμοποιείται για τη διάκριση των γερασμένων στοιχείων. Στη συνέχεια, παρουσιάζεται μια ενοποιημένη προσέγγιση του παραπάνω σχεδίου για την ανίχνευση γήρανσης τόσο των κελιών μνήμης όσο και των αισθητήρων σήματος. Μια τροποποίηση αυτής της τεχνικής προτείνεται επίσης με τη χρήση ενός επαναρυθμιζόμενου ταλαντωτή (rDRO) για τις ανάγκες της αυτο-ίασης στους αισθητήρες σήματος SRAM. Τέλος, παρουσιάζεται μια τεχνική ανίχνευσης γήρανσης για τους αποκωδικοποιητές SRAM, μαζί με μια τεχνική προσαρμογής για την επιτυχή αυτο-ίαση. Το σχήμα παρουσιάζει την προσθήκη ενός απλού, χαμηλού κόστους ενσωματωμένου κυκλώματος προκειμένου να εντοπιστεί έγκαιρα η γήρανση του αποκωδικοποιητή και να αντιδράσει σωστά για να εξασφαλιστεί η αξιοπιστία και να παραταθεί η διάρκεια ζωής της SRAM. Οι προσομοιώσεις που πραγματοποιήθηκαν στα παραπάνω σχήματα επιβεβαιώνουν την ικανότητά τους να παρέχουν αυρο-ίασης σε γερασμένα κελιά μνήμης, αισθητήρες σήματος και αποκωδικοποιητές αντίστοιχα, ενώ ταυτόχρονα προσφέρουν χαμηλό κόστος στην επιφάνεια πυριτίου καθώς και την ικανότητα αποφυγής της γήρανσης των κυκλωμάτων όταν η SRAM βρίσκεται σε κανονική λειτουργία

Fractal dimension of the brain in neurodegenerative disease and dementia: A systematic review.

Sensitive and specific antemortem biomarkers of neurodegenerative disease and dementia are crucial to the pursuit of effective treatments, required both to reliably identify disease and to track its progression. Atrophy is the structural magnetic resonance imaging (MRI) hallmark of neurodegeneration. However in most cases it likely indicates a relatively advanced stage of disease less susceptible to treatment as some disease processes begin decades prior to clinical onset. Among emerging metrics that characterise brain shape rather than volume, fractal dimension (FD) quantifies shape complexity. FD has been applied in diverse fields of science to measure subtle changes in elaborate structures. We review its application thus far to structural MRI of the brain in neurodegenerative disease and dementia. We identified studies involving subjects who met criteria for mild cognitive impairment, Alzheimer's Disease, Vascular Dementia, Lewy Body Dementia, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, Parkinson's Disease, Huntington's Disease, Multiple Systems Atrophy, Spinocerebellar Ataxia and Multiple Sclerosis. The early literature suggests that neurodegenerative disease processes are usually associated with a decline in FD of the brain. The literature includes examples of disease-related change in FD occurring independently of atrophy, which if substantiated would represent a valuable advantage over other structural imaging metrics. However, it is likely to be non-specific and to exhibit complex spatial and temporal patterns. A more harmonious methodological approach across a larger number of studies as well as careful attention to technical factors associated with image processing and FD measurement will help to better elucidate the metric's utility.Alzheimer's Society UK Cambridge NIHR Biomedical centre Cambridge Centre for Parkinson’s Plus Alzheimer’s Research U

Volumetric alterations in the hippocampal subfields of subjects at increased risk of dementia.

The hippocampus is one of the first regions to demonstrate atrophy during the prodromal stage of Alzheimer's disease. Volumetric analysis of its individual subfields could provide biomarkers with higher sensitivity than whole hippocampal volume during an earlier disease stage. We quantified the hippocampal subfields volume in a large cohort comprising healthy participants (aged 40-59) with dementia family history (FH) and controls (without FH), examined at 2 time points across 2 years. Subfield volumes were quantified using both a T1-weighted and a high-resolution T2 hippocampal magnetic resonance imaging acquisition with Freesurfer. The participants were stratified based on dementia FH, APOE genotype, and CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score. Whole hippocampal volume did not differ between the groups. The volume of the molecular layer was lower in participants with an APOE ε4 genotype, but there were no differences between subjects with and without dementia FH or with an increasing CAIDE score. The molecular layer may be the first hippocampal region to demonstrate volumetric alterations in subjects at risk of dementia

Fluid-attenuated inversion recovery magnetic resonance imaging textural features as sensitive markers of white matter damage in midlife adults.

White matter hyperintensities are common radiological findings in ageing and a typical manifestation of cerebral small vessel disease. White matter hyperintensity burden is evaluated by quantifying their volume; however, subtle changes in the white matter may not be captured by white matter hyperintensity volumetry. In this cross-sectional study, we investigated whether magnetic resonance imaging texture of both white matter hyperintensities and normal appearing white matter was associated with reaction time, white matter hyperintensity volume and dementia risk in a midlife cognitively normal population. Data from 183 cognitively healthy midlife adults from the PREVENT-Dementia study (mean age 51.9 ± 5.4; 70% females) were analysed. White matter hyperintensities were segmented from 3 Tesla fluid-attenuated inversion recovery scans using a semi-automated approach. The fluid-attenuated inversion recovery images were bias field corrected and textural features (intensity mean and standard deviation, contrast, energy, entropy, homogeneity) were calculated in white matter hyperintensities and normal appearing white matter based on generated textural maps. Textural features were analysed for associations with white matter hyperintensity volume, reaction time and the Cardiovascular Risk Factors, Aging and Dementia risk score using linear regression models adjusting for age and sex. The extent of normal appearing white matter surrounding white matter hyperintensities demonstrating similar textural associations to white matter hyperintensities was further investigated by defining layers surrounding white matter hyperintensities at increments of 0.86 mm thickness. Lower mean intensity within white matter hyperintensities was a significant predictor of longer reaction time (t = -3.77, P < 0.01). White matter hyperintensity volume was predicted by textural features within white matter hyperintensities and normal appearing white matter, albeit in opposite directions. A white matter area extending 2.5 - 3.5 mm further from the white matter hyperintensities demonstrated similar associations. White matter hyperintensity volume was not related to reaction time, although interaction analysis revealed that participants with high white matter hyperintensity burden and less homogeneous white matter hyperintensity texture demonstrated slower reaction time. Higher Cardiovascular Risk Factors, Aging, and Dementia score was associated with a heterogeneous normal appearing white matter intensity pattern. Overall, greater homogeneity within white matter hyperintensities and a more heterogeneous normal appearing white matter intensity profile were connected to a higher white matter hyperintensity burden, while heterogeneous intensity was related to prolonged reaction time (white matter hyperintensities of larger volume) and dementia risk (normal appearing white matter). Our results suggest that the quantified textural measures extracted from widely used clinical scans, might capture underlying microstructural damage and might be more sensitive to early pathological changes compared to white matter hyperintensity volumetry.This work was funded by a grant for the PREVENT-Dementia program from the UK Alzheimer's Society (grant numbers 178 and 264), and the PREVENT-Dementia study is also supported by the US Alzheimer's Association (grant number TriBEKa-17–519007) and philanthropic donations. AL is supported by the Lee Kuan Yew Fitzwilliam PhD Scholarship and the Tan Kah Kee Postgraduate Scholarship. LS is supported by the Cambridge National Institute for Health Research Biomedical Research Center and Alzheimer's Research UK (ARUK-SRF2017B-1). HSM is supported by an National Institute for Health Research Senior Investigator award. JOB and HSM receive infrastructural support from the Cambridge National Institute for Health Research Biomedical Research Center