Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes.

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.This study was supported by the National Institute for Health Research (NIHR, RG64473), Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia, and the Alzheimer's Society. Elijah Mak was in the receipt of the Gates Cambridge studentship

Structural neuroimaging in preclinical dementia: From microstructural deficits and grey matter atrophy to macroscale connectomic changes.

The last decade has witnessed a proliferation of neuroimaging studies characterising brain changes associated with Alzheimer's disease (AD), where both widespread atrophy and 'signature' brain regions have been implicated. In parallel, a prolonged latency period has been established in AD, with abnormal cerebral changes beginning many years before symptom onset. This raises the possibility of early therapeutic intervention, even before symptoms, when treatments could have the greatest effect on disease-course modification. Two important prerequisites of this endeavour are (1) accurate characterisation or risk stratification and (2) monitoring of progression using neuroimaging outcomes as a surrogate biomarker in those without symptoms but who will develop AD, here referred to as preclinical AD. Structural neuroimaging modalities have been used to identify brain changes related to risk factors for AD, such as familial genetic mutations, risk genes (for example apolipoprotein epsilon-4 allele), and/or family history. In this review, we summarise structural imaging findings in preclinical AD. Overall, the literature suggests early vulnerability in characteristic regions, such as the medial temporal lobe structures and the precuneus, as well as white matter tracts in the fornix, cingulum and corpus callosum. We conclude that while structural markers are promising, more research and validation studies are needed before future secondary prevention trials can adopt structural imaging biomarkers as either stratification or surrogate biomarkers.This study was supported by the National Institute for Health Research (NIHR, RG64473), Cambridge Biomedical Research Centre and Biomedical Research Unit in Dementia, and the Alzheimer's Society. Elijah Mak was in the receipt of the Gates Cambridge studentship

Executive Functioning and Risk for Alzheimer\u27s Disease in The Cognitively Intact: Family History Predicts Wisconsin Card Sorting Test Performance

Alzheimer’s disease (AD) research typically focuses on memory. However, executive functioning (EF) deficits are also common among AD patients; these deficits are associated with decreased functioning in activities of daily living, an important criterion in diagnosing AD. A classic test of EF ability, the Wisconsin Card Sort Test (WCST), has demonstrated sensitivity to differentiating individuals with AD from healthy controls, discriminating AD groups based on disease severity, and distinguishing AD from other types of dementia. Such sensitivity to AD raises the possibility that the WCST is also sensitive to very early, preclinical differences between those who have heightened risk for AD and those with lower risks. Method: The current study, therefore, examined WCST performance in healthy, cognitively intact older adults with a first-degree (i.e., sibling or parent) family history (FH) of AD (n _ 18) and those with no such FH of AD (n _ 24). Results: Results revealed significant group differences for Categories Achieved, Percent Conceptual Level Responses, Total Errors, Perseverative Errors, and Non-Perseverative Errors, with the FH_ group consistently exhibiting poorer performance. Moreover, hierarchical regression analyses indicated that after accounting for age, sex, and education, FH significantly predicted all 5 of these variables. Conclusions: These results speak to the potential role of EF in bolstering the current understanding of early cognitive markers of future decline. Furthering what is known about the relationship between AD and nonmemory specific domains of cognition such as executive functioning may allow for better prediction of cognitive decline and potential progression to AD

Tau pathology in Alzheimer's disease and other dementias : translational approach from in vitro autoradiography to in vivo PET imaging

Tauopathies, including Alzheimer's disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), are complex neurodegenerative disorders characterized by the pathological accumulation of tau proteins in the brain. These often overlapping disorders, with intricate pathologies and growing prevalence, lack definitive treatments, highlighting the necessity for advanced research. Positron emission tomography (PET) imaging aids in the diagnosis and monitoring of diseases, by providing in vivo insights into pathological features. This thesis focused on deciphering the binding properties and brain regional distribution of PET tracers for accurate disease differentiation. Spanning four studies, we aimed to bridge in vitro and in vivo PET data to investigate tau pathology and its association with dementia-related markers such as reactive astrogliosis, peripheral inflammation, and dopaminergic dysfunction. The 2nd generation tau PET tracers, 3H-MK6240 and 3H-PI2620, demonstrated high affinity and specificity in AD post-mortem brain tissues, especially in early-onset AD, compared to controls. 3H-PI2620, 3H-MK6240, and 3HRO948 displayed similar binding patterns in AD tissue, with multiple binding sites and equivalent high affinities (Papers I and II). 3H-PI2620 showed specificity in CBD and PSP tissues, in contrast to 3H-MK6240. However, differentiating CBD from PSP brains with 3H-PI2620 remained challenging in multiple brain regions, potentially due to complex tracer-target interactions (Papers II and III). Reactive astrogliosis PET tracers 3H-Deprenyl and 3H-BU99008 bound primarily to stable distinct high-affinity binding sites in AD, CBD and PSP, but also to transient binding sites, differing by brain region and condition. This pattern implied that these tracers may interact with similar or diverse subtypes or populations of astrocytes, expressing varying ratios of transient sites, which may vary depending on the brain location and the disease (Paper III). Using 3H-FEPE2I, we delineated a reduction in dopamine transporter (DAT) levels within the putamen across CBD, PSP and Parkinson's Disease (PD) brains. Concomitantly, elevated 3H-Raclopride binding reflected higher dopamine D2 receptor (D2R) levels in PSP and PD. Nonetheless, our observations underscored the heterogeneity inherent to these neurodegenerative pathologies, emphasizing the criticality of individual variability in neuropathological manifestations (Paper III). Lastly, we investigated late middle-aged cognitively unimpaired Hispanic individuals, in dichotomous groups of in vivo amyloid-β (Aβ) PET (18F-Florbetaben) and plasma neurofilament light (NfL) biomarkers. Our findings suggest that elevated plasma inflammation and tau burden as measured by 18FMK6240, can be detected at early preclinical stages of AD, offering potential for early diagnosis (Paper IV). This thesis underscored the importance of PET imaging in advancing our understanding of tauopathies. The innovative use of multiple PET tracers provided crucial insights into their potential use in clinics to distinguish pathological features of AD, CBD and PSP. The findings emphasized the need for more studies applying a multifaceted approach to studying and managing these complex neurodegenerative disorders, combining advanced imaging techniques with a broad spectrum of biological markers

Central adiposity and brain vulnerability in mid-life : evidence for early risk

This set of projects focused on visceral fat, measured using proximal and direct methods. Specifically, I was interested in the effects of visceral fat on brain structure and integrity in middle age. Study 1 looked at waist to hip ratio (WHR) as a proximal measure of visceral fat and used statistical mediation to directly examine a possible mechanism behind the relationship between visceral fat and cognitive decline. Reductions in executive function seen in middle-aged adults with high visceral fat were found to occur in the context of lowered serum brain derived neurotrophic factor (BDNF) a key neurotrophin involved in synaptic plasticity as well as neuronal regeneration. Study 2 utilized Dual Energy X Ray Absorptiometry (DXA) to directly estimate visceral fat mass and volume as well as thickness of the cortical mantle in middle age. High-resolution Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) images were used. High visceral fat was found to predict increased thickness in the posterior cingulate cortex independently of age and cardiovascular risk in a cognitively intact middle-aged sample. Study 3 examined changes in concentrations of crucial cerebral metabolites in the posterior cingulate cortex among individuals with high visceral fat. Results indicated that visceral fat predicted reduced concentrations of N Acetyl Asparate, a marker of neuronal viability and increased concentrations of myo-inositol, a glial marker that is implicated in a number of disease states including prodromal Alzheimer’s Disease and Multiple Sclerosis. Collectively, the 3 studies highlight important evidence for early brain vulnerability even in cognitively intact middle- aged adults with high levels of cognitive reserve. An important next step would be to examine modifiable mediators of these relationships, such as inflammation and BDNF so that targeted interventions may be developed.Psycholog

Early detection of Alzheimer’s disease - Twin study on episodic memory and imaging biomarkers of neuroinflammation and β-amyloid

The disease process of Alzheimer’s disease (AD) causes damage to the brain for several years leading to the development of mild cognitive impairment (MCI) and finally to dementia which interferes with independent living. The early detection of AD disease process is key for the prevention and treatment of disease. The aim of this thesis was to improve the assessment of episodic memory (EM) and cognitive performance with a telephone interview and neuroimaging of early AD. The study population belonged to the older Finnish Twin Cohort study. 2631 twins (856 pairs) participated in the telephone interview (TELE, TICS) during 1999–2007 and 1817 twins (559 pairs) participated in the interview (TELE, TICS, TICS-m) during 2013– 2017. Cognitively discordant twin pairs were asked to participate in more detailed examinations. 11 twin pairs participated in [11C]PBR28 positron emission tomography (PET) imaging measuring neuroinflammation during 2014–2017 and 45 twin pairs participated in [11C]PiB PET imaging measuring β-amyloid (Aβ) deposits during 2005–2017. Twins who had co-twins with dementia (n=101) performed poorer than average in a word list learning test. When using the telephone interview TICS-m, the education‐adjusted classification resulted in a higher proportion of apolipoprotein (APOE) ε4 allele carriers among those identified as having MCI. Twins with poorer EM performance (n=10) had higher cortical [11C]PBR28 uptake compared to their better-performing co-twins. In addition, higher cortical [11C]PiB uptake was associated with poorer EM performance. The results from the telephone interview studies indicate that poorer word list learning performance may be an early marker of dementia risk and that the use of education‐adjustment may increase the accuracy of MCI classification. The twin pair setting controlling for genetic and environmental effects indicated that brain Aβ load and neuroinflammation have a negative association with EM performance.Alzheimerin taudin varhainen havaitseminen – Kaksostutkimus episodisesta muistista ja neuroinflammaation ja β-amyloidin kuvantamisbiomarkkereista Alzheimerin taudin (AT) prosessi vaurioittaa aivoja vuosien ajan ja johtaa lievään kognitiiviseen heikentymiseen (MCI) ja lopulta itsenäistä selviytymistä häiritsevään dementiaan. AT:n dementiaan johtavan prosessin varhainen havaitseminen on avainasemassa ehkäisyn ja hoidon kannalta. Tämän väitöskirjatutkimuksen tavoitteena oli kehittää puhelinhaastattelun käyttöä episodisen muistin (EM) ja muiden tiedonkäsittely- eli kognitiivisten toimintojen arvioimisessa sekä AT:n varhaista kuvantamista. Tutkimusjoukko kuului vanhempaan suomalaisen kaksoskohorttitutkimukseen. 2631 kaksosta (856 paria) osallistui puhelinhaastatteluun (TELE, TICS) 1999–2007 aikana ja 1817 kaksosta (559 paria) osallistui haastatteluun (TELE, TICS, TICS-m) 2013–2017 aikana. Kognitiivisesti diskordantit kaksosparit kutsuttiin tarkempiin jatkotutkimuksiin. 11 kaksosparia osallistui neuroinflammaatiota mittaavaan [11C]PBR28-merkkiaineen positroniemissiotomografia (PET) - kuvaukseen 2014–2017 aikana ja 45 kaksosparia osallistui aivojen β-amyloidikertymää mittaavaan [11C]PiB-merkkiaineen PET-kuvaukseen 2005–2017 aikana. Sellaisten kognitiivisesti normaalien ikääntyneiden kaksosten (n=101), joiden sisaruksella oli dementia, havaittiin suoriutuvan keskimääräistä heikommin sanalistan oppimista mittaavassa testissä. Käytettäessä TICS-m-puhelinhaastattelua koulutuskorjauksen käyttäminen johti siihen, että MCI:tä sairastavien joukossa oli suurempi osuus apolipoproteiini E:n (APOE) ε4-alleelin kantajia. Kaksosilla (n=10), jotka suoriutuivat heikommin EM-testeissä, oli suurempi aivokuoren [11C]PBR28-kertymä verrattuna paremmin suoriutuviin sisaruksiinsa. Myös suurempi aivokuoren [11C]PiB-kertymä oli yhteydessä heikompaan EM-suoritukseen. Puhelinhaastattelujen tulokset viittaavat siihen, että sanalistan oppiminen voi olla dementiariskistä kertova varhainen merkki ja että koulutuskorjauksen käyttö voi lisätä MCI-luokittelun tarkkuutta. Kaksosasetelma, joka kontrolloi geneettisten ja ympäristötekijöiden vaikutusta, osoitti, että aivojen β-amyloidikertymä ja neuroinflammaatio ovat negatiivisessa yhteydessä EM:n toiminnan kanssa

Early detection of Alzheimer’s disease in experimental and natural animal models using novel biologics

According to the World Alzheimer report published in 2020, 50 million people are currently living with dementia and this number is predicted to rise to 150 million in 2050. Alzheimer’s disease (AD) is the most common form of dementia (60% - 70% of cases). Early and accurate diagnosis of AD is a major goal in order to reduce the impact of dementia and also represents an urgent unmet medical need globally. Canine Cognitive Dysfunction (CCD) in aged dogs is a progressive neurodegenerative disorder exhibiting gradual decline of cognitive function and memory loss similar to human AD. In parallel with progressive amyloid beta (Aβ) neuropathology, aged dogs display progressive decline in measures of learning and memory. Of importance, for both AD in human and CCD in dogs, the abnormal accumulation of amyloid beta plaques (Aβp) in the brain is one of the major pathological lesions associated with this devastating disorder. Aβ is subdivided into three major assemblies, including monomers, oligomers, and fibrils of which Aβ soluble oligomers (Aβo) are the most neurotoxic to neurons. Aβo is believed to trigger the pathophysiology of AD and is normally detected two decades before clinical onset of the disease. Similarly, aged dogs affected with CCD display cognitive decline which occurs prior to accumulation of Aβp in the canine brain, suggesting that earlier assembly states of Aβ (e.g., oligomers) may be the neurotoxic species in dogs, as described for human AD. This thesis particularly focused on the early detection of Aβo with the aim of developing a cost-effective diagnostic test for AD before neuropathological and clinical deficits have ensued. Also, to provide an insight to develop the dog as a natural translational model of AD. Accumulating evidence described in my thesis suggested that retinal changes and pathophysiological processes could provide valuable insights into early diagnosis of AD. This thesis provides a strong basis to further validate dogs as a natural AD model where all the AD neuropathological hallmarks have been observed in the brain and retina. Finally, such a model will certainly facilitate the development and clinical applications of an easily accessible, inexpensive, and non-invasive retinal imaging of preclinical AD diagnostic platform to predict and diagnose early stages of AD and monitor disease therapies

Neural Correlates of Unimanual and Bimanual Eye-Hand Coordination across Healthy and Dementia-Risk Populations

Eye-hand coordination is essential to our functional independence and relies on communication between widespread brain regions for successful unimanual and bimanual motor control. Eye-hand coordination performance has been shown to differ between the sexes, as well as between healthy aging individuals and those with dementia risk. The studies included within this dissertation were designed to characterize the structural and functional neural correlates of skilled movements across various populations in order to gain a better understanding of previously reported behavioural performance differences. The first two studies investigated changes in structural and functional integrity, respectively, of brain networks that may underlie known visuomotor behavioural deficits in older adults with an increased genetic (APOE e4) risk for Alzheimer’s disease. Alzheimer’s disease is thought to be a disconnection syndrome with characteristic patterns of disruption to structural and functional connectivity in the brain. A visuomotor task requiring the integration of different cognitive and motor domains via communication across multiple brain regions presents one way to test the integrity of these brain networks. The anatomical, diffusion-weighted, and resting state functional connectivity imaging data revealed that in older adult APOE e4 carriers, visuomotor deficits were predicted by i) lower grey matter volume and thickness of medial temporal lobe regions, ii) lower white matter integrity in several major tracts, and iii) decreased functional connectivity within the default mode and dorsal attention networks, in advance of any cognitive deficits. Historically, sex differences in unimanual and bimanual eye-hand coordination have also been observed, and a better understanding of the neural correlates of these differences could inform clinical practices on how to better tailor bimanual movement-based rehabilitation to the individual. The third study investigated the sex differences in functional connectivity of bimanual control, demonstrating connectivity differences between men and women despite equivalent behavioural performance. Taken together, these data provide novel insight into the neural correlates underlying one of our most fundamental human behaviours, eye-hand coordination, and their potential clinical implications

Neural Correlates of Unimanual and Bimanual Eye-Hand Coordination across Healthy and Dementia-Risk Populations

Eye-hand coordination is essential to our functional independence and relies on communication between widespread brain regions for successful unimanual and bimanual motor control. Eye-hand coordination performance has been shown to differ between the sexes, as well as between healthy aging individuals and those with dementia risk. The studies included within this dissertation were designed to characterize the structural and functional neural correlates of skilled movements across various populations in order to gain a better understanding of previously reported behavioural performance differences. The first two studies investigated changes in structural and functional integrity, respectively, of brain networks that may underlie known visuomotor behavioural deficits in older adults with an increased genetic (APOE e4) risk for Alzheimers disease. Alzheimers disease is thought to be a disconnection syndrome with characteristic patterns of disruption to structural and functional connectivity in the brain. A visuomotor task requiring the integration of different cognitive and motor domains via communication across multiple brain regions presents one way to test the integrity of these brain networks. The anatomical, diffusion-weighted, and resting state functional connectivity imaging data revealed that in older adult APOE e4 carriers, visuomotor deficits were predicted by i) lower grey matter volume and thickness of medial temporal lobe regions, ii) lower white matter integrity in several major tracts, and iii) decreased functional connectivity within the default mode and dorsal attention networks, in advance of any cognitive deficits. Historically, sex differences in unimanual and bimanual eye-hand coordination have also been observed, and a better understanding of the neural correlates of these differences could inform clinical practices on how to better tailor bimanual movement-based rehabilitation to the individual. The third study investigated the sex differences in functional connectivity of bimanual control, demonstrating connectivity differences between men and women despite equivalent behavioural performance. Taken together, these data provide novel insight into the neural correlates underlying one of our most fundamental human behaviours, eye-hand coordination, and their potential clinical implications

Early Medial Temporal Atrophy Scale (EMTA)

186 p.[ES]La atrofia del lóbulo temporal medial puede ser medida a través del uso de escalas de atrofia visual tales como la escala de atrofia del lóbulo temporal medial (MTA). La escala MTA ha sido diseñada y validada para el estudio de pacientes con Enfermedad de Alzheimer moderada (EA). Sin embargo, la MTA no ha sido diseñada para medir los cambios de atrofia de bajo grado que ocurren en la etapa precoz y media del proceso de envejecimiento. El objetivo de este estudio fue desarrollar y validar una nueva MTA; La “Goiz” (en Euskera) GMTA o “Early” (en ingles) EMTA, una nueva escala diseñada para la valoración de la atrofia precoz del lóbulo temporal medial que tiene la capacidad de medir los cambios de atrofia de bajo grado.[EN]Medial temporal lobe atrophy can be measured through visual rating scales such us the medial temporal lobe atrophy scale (MTA). MTA has been designed and validated for the study of patients with mild to moderate Alzheimer disease (AD). However, MTA has not been designed to measure the low-grade atrophy changes that occur at the early and middle aging process. The aim of this study was develop and validate a new MTA; the early (“Goiz” in Basque language) medial temporal lobe atrophy scale (EMTA) that has the capability to measure the low-grade atrophy changes