Radiological-pathological correlation in Alzheimer's disease : systematic review of antemortem MRI findings

Background: The standard method of ascertaining Alzheimer’s disease (AD) remains postmortem assessment of amyloid plaques and neurofibrillary degeneration. Vascular pathology, Lewy bodies, TDP-43, and hippocampal sclerosis are frequent comorbidities. There is therefore a need for biomarkers that can assess these aetiologies and provide a diagnosis in vivo. Objective: We conducted a systematic review of published radiological-pathological correlation studies to determine the relationship between antemortem magnetic resonance imaging (MRI) and neuropathological findings in AD. Methods: We explored PubMed in June-July 2015 using “Alzheimer’s disease” and combinations of radiological and pathological terms. After exclusion following screening and full-text assessment of the 552 extracted manuscripts, three others were added from their reference list. In fine, we report results based on 27 articles. Results: Independently of normal age-related brain atrophy, AD pathology is associated with whole-brain and hippocampal atrophy and ventricular expansion as observed on T1-weighted images. Moreover, cerebral amyloid angiopathy and cortical microinfarcts are also related to brain volume loss in AD. Hippocampal sclerosis and TDP-43 are respectively associated with hippocampal and medial temporal lobe atrophy. Brain volume loss correlates more strongly with tangles than with any other pathological finding. White matter hyperintensities observed on proton density, T2-weighted and FLAIR images are strongly related to vascular pathologies, but are also associated with other histological changes such as gliosis or demyelination. Discussion: Cerebral atrophy and white matter changes in the living brain reflect underlying neuropathology and may be detectable using antemortem MRI. In vivo MRI may therefore be an avenue for AD pathological staging

Braak neurofibrillary tangle staging prediction from in vivo MRI metrics

INTRODUCTION: Alzheimer’s disease (AD) diagnosis requires postmortem visualization of amyloid and tau deposits. As brain atrophy can provide assessment of consequent neurodegeneration, our objective was to predict postmortem neurofibrillary tangles (NFT) from in vivo MRI measurements. METHODS: All participants with neuroimaging and neuropathological data from the Alzheimer’s Disease Neuroimaging Initiative, the National Alzheimer’s Coordinating Center and the Rush Memory and Aging Project were selected (n=186). 232 variables were extracted from last MRI before death using FreeSurfer. Nonparametric correlation analysis and multivariable support vector machine classification were performed to provide a predictive model of Braak NFT staging. RESULTS: We demonstrated that 59 of our MRI variables, mostly temporal lobe structures, were significantly associated with Braak NFT stages (p<.005). We obtained a 62.4% correct classification rate for discrimination between transentorhinal, limbic and isocortical groups. DISCUSSION: Structural neuroimaging may therefore be considered as a potential biomarker for early detection of AD-associated neurofibrillary degeneration

Evaluation of intensive versus standard blood pressure reduction and association with cognitive decline and dementia : a systematic review and metaAnalysis

Importance: Optimal blood pressure (BP) targets for the prevention of cognitive impairment remain uncertain. Objective: To explore the association of intensive (i.e. lower than usual) BP reduction compared to guidelines on the incidence of cognitive decline and dementia in adults with hypertension. Data Sources and Study Selection: We conducted a systematic review and meta-analysis of randomized controlled trials that evaluated the association of intensive systolic BP lowering on cognitive outcomes by searching MEDLINE, Embase, CENTRAL, Web of Science, CINAHL, PsycINFO, ICTRP and ClinicalTrials.gov for data up to October 27, 2020. Data Extraction and Synthesis: Data screening and extraction were performed independently by two reviewers based on PRISMA guidelines. The risk of bias was assessed using the Cochrane risk-of-bias 2 tool. We used random-effects models using the inverse variance method for our pooled analyses. We evaluated the presence of potential heterogeneity with the I2 index. Main Outcomes and Measures: Our primary outcome was cognitive decline. Secondary outcomes included the incidence of dementia, mild cognitive impairment (MCI), cerebrovascular events, serious adverse events, and all-cause mortality. Results: From 7,755 citations, we identified sixteen publications from five trials (17,396 participants, mean age 65.7 years, 60.5% males) and two additional ongoing trials. All five trials included in quantitative analyses were considered at unclear to high risk of bias. The mean followup duration was 3.3 years (range 2.0 to 4.7 years). Intensive BP reduction was not significantly associated with global cognitive performance (SMD 0.01, 95% CI -0.04 to 0.06, I2 = 0%, four trials, 5,246 patients), incidence of dementia (RR 1.09, 95% CI 0.32 to 3.67, I2 = 27%, two trials, 9,444 patients) or incidence of MCI (RR 0.91, 95% CI 0.73 to 1.14, I2 = 74%, two trials, 10,774 patients) when compared to standard treatment. However, we found a reduction of cerebrovascular events in the intensive arm (RR 0.79, 95% CI 0.67-0.93, I2 = 0%, five trials, 17,396 patients) without an increased risk of serious adverse events or mortality. Conclusions and Relevance: We did not detect a significant association between BP reduction and lower risk of cognitive decline, dementia or MCI. The certainty of this evidence is low due to the limited sample size, the risk of bias of included trials and the observed statistical heterogeneity. Hence, current available evidence does not justify the use of lower BP targets for the prevention of cognitive decline and dementi

Caractérisation radio-histologique du vieillissement cérébral normal et pathologique

Thèse ou mémoire avec insertion d'articles.Le vieillissement cérébral entraine certaines modifications physiologiques. Lorsque ces changements neurodégénératifs surpassent ou diffèrent de ceux attendus pour l'âge, ils sont souvent accompagnés de manifestations cliniques. On parle alors d'étiologies comme la maladie d'Alzheimer (MA) et la démence vasculaire, causes les plus communes de troubles cognitifs associés au vieillissement, et dont la prévalence augmente avec le vieillissement de la population. Le seuil pathologique entrainant ces maladies est toutefois incertain. Il s'avère donc essentiel d'identifier des biomarqueurs capables de détecter précocement les individus à risque de les développer. De par sa précision, son absence de radiations, et sa disponibilité, l'imagerie par résonance magnétique (IRM) est une modalité de choix pour répondre à ce besoin. L'objectif général de cette thèse est de procéder à la caractérisation radio-histologique du vieillissement cérébral normal et pathologique afin d'en identifier les premiers signes grâce à l'IRM cérébrale in vivo. Ce travail doctoral s'articule autour de deux objectifs plus spécifiques. Le premier est dédié à l'identification de la pathologie associée à la MA à partir de l'IRM cérébrale. Le Chapitre 1 vise d'abord à établir les trouvailles à l'IRM cérébrale pré-mortem et leur corrélat histologique post-mortem dans la MA et ses principales comorbidités. Le Chapitre 2 évalue la performance d'un modèle prédictif de la dégénérescence neurofibrillaire à partir des mesures volumétriques à l'IRM cérébrale. En second, on s'intéresse aux changements cérébrovasculaires qui jouent un rôle important dans le développement des démences, dont la MA. Le Chapitre 3 examine ainsi les lésions histologiques cérébrovasculaires chez les sujets adultes normaux afin de mieux caractériser les changements attendus en fonction de l'âge. Finalement, le Chapitre 4 s'attarde à l'étude des facteurs cliniques prédicteurs du stade pathologique de la maladie cérébrale des petits vaisseaux amyloïde et non-amyloïde, deux entités communes associées au vieillissement et au développement de troubles cognitifs. En sommes, cette thèse contribue à une meilleure définition radio-histologique des lésions cérébrales associées au vieillissement avec une attention particulière portée aux formes communes de démences. Une compréhension bonifiée des mécanismes physiopathologiques à l'origine des troubles cognitifs et une identification précoce des lésions caractéristiques grâce à l'imagerie cérébrale sont des étapes nécessaires à une prise en charge optimale et au développement de thérapies ciblées visant à atténuer le fardeau associé à ces maladies dévastatrices.Brain aging is characterized by various physiological alterations. When these neurodegenerative changes exceed or differ from those normally expected for age, they are often accompanied by clinical manifestations. One talks then of conditions such as Alzheimer's disease (AD) and vascular dementia, the two most common aetiologies of age-related cognitive impairment, and whose prevalence increases as the population ages. However, the pathological threshold for developing these diseases remains uncertain. It is therefore essential to identify biomarkers capable of detecting individuals at risk of developing cognitive disorders early in the disease process. Magnetic resonance imaging (MRI), because of its accuracy, safety and relatively wide availability, seems to be an ideal modality to meet this need. Thus, the main objective of this thesis is to provide radio-histological characterization of normal and pathological brain aging in order to identify signs of decline using in vivo brain MRI. This doctoral work is articulated around two more specific objectives. The first one is dedicated to the identification of AD-related pathology from brain MRI. The article in Chapter 1 aims to establish pre-mortem brain MRI findings and their post-mortem histological correlates in AD and related comorbidities. The second article in Chapter 2 evaluates the performance of a predictive model for neurofibrillary degeneration based on brain MRI metrics. The second part of this thesis focuses on cerebrovascular changes that play an important role in the development of dementias, including AD. The third paper in Chapter 3 therefore examines cerebrovascular histological lesions in normal adults in order to better characterize the expected age-dependent changes. Finally, the fourth article in Chapter 4 examines clinical predictors of pathological amyloid and non-amyloid cerebral small vessel disease, two common entities associated with aging and cognitive decline. Altogether, the results from this thesis contribute to a better radio-histological definition of brain lesions associated with aging in pathological and non-pathological states, with a particular focus on the common forms of dementia, i.e. AD and vascular dementia. A better understanding of pathophysiological mechanisms underlying cognitive disorders and early identification of characteristic lesions are mandatory to warrant optimal management and development of targeted therapies with the ultimate goal to reduce the global burden associated with these devastating diseases

Histopathological analysis of cerebrovascular lesions associated with aging

Cerebrovascular disease (CVD) has been associated with cognitive impairment. Yet our understanding of vascular contribution to cognitive decline has been limited by heterogeneity of definitions and assessment, as well as its occurrence in cognitively healthy aging. Therefore, we aimed to establish the natural progression of CVD associated with aging. We conducted a retrospective observational study of 63 cognitively healthy participants aged 19 to 84 years selected through the histological archives of the CHU de Québec. Assessment of CVD lesions was performed independently by three observers blinded to clinical data using the Vascular Cognitive Impairment Neuropathology Guidelines (VCING). We found moderate to almost perfect interobserver agreement for most regional CVD scores. Atherosclerosis (ρ=0.758) and arteriolosclerosis (ρ=0.708) showed the greatest significant association with age, followed by perivascular haemosiderin deposits (ρ=0.432) and cerebral amyloid angiopathy (CAA; ρ=0.392). Amyloid and tau pathologies were both associated with higher CVD load, but only CAA remained significantly associated with amyloid plaques after controlling for age. Altogether, these findings support the presence of multiple CVD lesions in the brains of cognitively healthy adults, the burden of which increases with age and can be quantified in a reproducible manner using standardized histological scales such as the VCING

Molecular imaging in dementia: Past, present, and future

Molecular imaging techniques using 18F-fluorodeoxyglucose, amyloid tracers, and, more recently, tau ligands have taken dementia research by storm and undoubtedly improved our understanding of neurodegenerative diseases. The ability to image in vivo the pathological substrates of degenerative diseases and visualize their downstream impact has led to improved models of pathogenesis, better differential diagnosis of atypical conditions, as well as focused subject selection and monitoring of treatment in clinical trials aimed at delaying or preventing the symptomatic phase of Alzheimer's disease. In this article, we present the main molecular imaging techniques used in research and practice. We further summarize the key findings brought about by each technique individually and more recently, as adjuncts to each other. Specific limitations of each imaging modality are discussed, as well as recommendations to overcome them. A nonvalidated clinical algorithm is proposed for earlier and more accurate identification of complex/atypical neurodegenerative diseases

Erratum: Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders (Brain (2020) 143 DOI: 10.1093/brain/awaa018)

The authors apologize for misspelling the last name of the author Ratnavalli Ellajosyula. This has now been corrected