Synaptic loss in the primary tauopathies of Progressive Supranuclear Palsy and Corticobasal Degeneration

In this thesis I address the debilitating symptom of cognitive dysfunction in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD). Both PSP and CBD are associated with an accumulation of 4-repeat tau in cortical and subcortical areas. As well as movement disorders, they impair cognitive function, even where there is minimal atrophy. Neurophysiological studies have also identified electrophysiological changes associated with cognitive dysfunction, in areas without atrophy. I propose that synaptic loss prior to cell loss contributes to these effects of disease. Chapter two summarises my cohort and principal methods. I quantify synaptic density in vivo with dynamic [11C]UCB-J PET, and molecular pathology with [18F]AV1451 PET. Brain structural changes are quantified by MRI. Disease severity and cognition are assessed with the PSP rating scale, and neuropsychological tests. Patients with CBD are negative on amyloid-imaging ([11C]PiB PET) to exclude those with Alzheimer’s pathology. In chapter three, [11C]UCB-J PET reveals widespread loss of synapses in PSP and CBD including areas with minimal atrophy. The loss of synapses correlated with cognition and disease severity. In chapter four, I test whether presynaptic changes (from [11C]UCB-J PET) are correlated with postsynaptic abnormalities (i.e. changes to postsynaptic dendritic microstructural integrity quantified by MRI using the Neurite Orientation and Dispersion Index, NODDI). In accordance with in vitro and animal models, I confirm that loss of dendritic complexity is tightly coupled with presynaptic density, over and above the effects of atrophy. In chapter five, I test the relationship between the molecular pathology in primary tauopathies (tau burden) and synaptic loss, using [18F]AV-1451 and [11C]UCB-J PET. The use of the “tau” ligand [18F]AV-1451 has become controversial in PSP. With due consideration to the caveats, I report that brain regions with a higher synaptic density have higher [18F]AV-1451 binding, consistent with the hypothesis of connectivity-based progression of tauopathy. I further show that accrual of pathology in any given area is associated with loss of synapses, consistent with synaptic injury from tauopathy. I conclude my thesis in chapter 6, by discussing and highlighting the importance of synaptic density in primary tauopathies. The findings are relevant to other neurodegenerative disorders, and support early interventional studies targeting synaptic maintenance and restoration.Association of British Neurologists - Patrick Berthoud Charitable Trus

Secondary prevention of Alzheimer's dementia: neuroimaging contributions

BACKGROUND: In Alzheimer's disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations. MAIN BODY: Amyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation. CONCLUSION: We propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI

Secondary prevention of Alzheimer's dementia: neuroimaging contributions

BACKGROUND: In Alzheimer's disease (AD), pathological changes may arise up to 20 years before the onset of dementia. This pre-dementia window provides a unique opportunity for secondary prevention. However, exposing non-demented subjects to putative therapies requires reliable biomarkers for subject selection, stratification, and monitoring of treatment. Neuroimaging allows the detection of early pathological changes, and longitudinal imaging can assess the effect of interventions on markers of molecular pathology and rates of neurodegeneration. This is of particular importance in pre-dementia AD trials, where clinical outcomes have a limited ability to detect treatment effects within the typical time frame of a clinical trial. We review available evidence for the use of neuroimaging in clinical trials in pre-dementia AD. We appraise currently available imaging markers for subject selection, stratification, outcome measures, and safety in the context of such populations. MAIN BODY: Amyloid positron emission tomography (PET) is a validated in-vivo marker of fibrillar amyloid plaques. It is appropriate for inclusion in trials targeting the amyloid pathway, as well as to monitor treatment target engagement. Amyloid PET, however, has limited ability to stage the disease and does not perform well as a prognostic marker within the time frame of a pre-dementia AD trial. Structural magnetic resonance imaging (MRI), providing markers of neurodegeneration, can improve the identification of subjects at risk of imminent decline and hence play a role in subject inclusion. Atrophy rates (either hippocampal or whole brain), which can be reliably derived from structural MRI, are useful in tracking disease progression and have the potential to serve as outcome measures. MRI can also be used to assess comorbid vascular pathology and define homogeneous groups for inclusion or for subject stratification. Finally, MRI also plays an important role in trial safety monitoring, particularly the identification of amyloid-related imaging abnormalities (ARIA). Tau PET to measure neurofibrillary tangle burden is currently under development. Evidence to support the use of advanced MRI markers such as resting-state functional MRI, arterial spin labelling, and diffusion tensor imaging in pre-dementia AD is preliminary and requires further validation. CONCLUSION: We propose a strategy for longitudinal imaging to track early signs of AD including quantitative amyloid PET and yearly multiparametric MRI

Diffusion imaging markers of cerebral small vessel disease

Diffusion magnetic resonance imaging (MRI) is widely used as a research tool to assess (subtle) alterations of the cerebral white matter. Measures derived from diffusion MRI appear to be valuable markers for cerebral small vessel disease (SVD). However, SVD is frequently co-occurring with Alzheimer’s disease (AD), and disturbed white matter integrity and altered diffusion measures are considered key findings in both conditions. Yet, the contribution of SVD and AD to diffusion alterations is unclear, which hampers the interpretation of research studies in patients with mixed disease, e.g. memory clinic patients. Study 1 of this thesis aimed to clarify the effect of SVD and AD on diffusion measures by including multiple (memory clinic) samples covering the entire spectrum of SVD, mixed disease, and AD. We calculated diffusion measures from diffusion tensor imaging (DTI) and free water imaging. Within each sample of the disease spectrum, we applied simple regression analyses and multivariable random forest analyses between AD biomarkers (amyloid-beta, tau), conventional MRI markers of SVD, and global diffusion measures. Furthermore, we investigated regional associations between tau on positron emission tomography (PET) and diffusion measures in voxel-wise analyses. Our main findings are that conventional MRI markers of SVD were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analyses across all memory clinic samples. Regional analyses between tau PET and diffusion measures were not significant. We conclude that SVD rather than AD determines diffusion alterations in memory clinic patients. Our findings validate diffusion measures as markers for SVD. Study 2 applied diffusion MRI markers to study gait impairment in SVD. Gait impairment is a commonly reported clinical deficit in SVD patients, but the underlying mechanisms are still debated. The proposed mechanisms include SVD-related white matter alterations resulting in impaired supraspinal locomotor control, cognitive deficits (e.g. planning and execution of movements), and factors independent of SVD, such as age-related instability (e.g. joint wear, sarcopenia) and comorbidities (e.g. neurodegenerative pathology). A reason for the lack of knowledge on gait impairment in SVD is that studies in elderly, sporadic SVD patients are typically confounded by effects of normal-aging and age-related comorbidities. Therefore, Study 2 of this thesis aimed to study the effect of pure SVD on gait performance in a relatively young sample of genetically defined SVD patients without age-related confounding. We performed comprehensive gait assessment using an electronic walkway to obtain multiple spatio-temporal gait parameters standardized based on data from healthy controls. Importantly, we tested the association between diffusion MRI markers of SVD-related white matter alterations and gait performance, since (strategic) white matter alterations are discussed as a major cause of gait decline in the elderly. Furthermore, we assessed the relation between cognitive deficits and gait performance. Our main finding is that, despite severe white matter alterations in pure SVD patients, gait performance was relatively preserved. Cognitive deficits in our study participants were not related to gait impairment. Thus, our results query isolated white matter alterations, in the absence of comorbidities, as a main factor of gait impairment in SVD and suggest that their combination with age-related comorbidities and/or normal-aging may play a crucial role in gait decline. In conclusion, diffusion measures are valid MRI markers of SVD-related white matter alterations. They have significant value both in future research on altered white matter and potentially also in the diagnostic work-up of memory clinic patients, to differentiate between vascular and neurodegenerative disease. Researchers may select target populations for clinical trials based on diffusion measures, e.g. to identify patients with a low SVD burden as targets for prevention and early intervention in SVD. Clinicians and researchers should always consider SVD as the origin of diffusion alterations in patients with mixed pathology. The field of application of diffusion measures is wide and may provide new insights into effects of subtle white matter alterations on clinical deficits, as shown in Study 2 on gait impairment in pure SVD. Future studies should investigate measures from advanced diffusion models and diffusion-based brain network analysis, to further elucidate the mechanisms of clinical deficits in SVD patients

Bundle-specific associations between white matter microstructure and Aβ and tau pathology in preclinical Alzheimer\u27s disease

Beta-amyloid (Aβ) and tau proteins, the pathological hallmarks of Alzheimer\u27s disease (AD), are believed to spread through connected regions of the brain. Combining diffusion imaging and positron emission tomography, we investigated associations between white matter microstructure specifically in bundles connecting regions where Aβ or tau accumulates and pathology. We focused on free-water-corrected diffusion measures in the anterior cingulum, posterior cingulum, and uncinate fasciculus in cognitively normal older adults at risk of sporadic AD and presymptomatic mutation carriers of autosomal dominant AD. In Aβ-positive or tau-positive groups, lower tissue fractional anisotropy and higher mean diffusivity related to greater Aβ and tau burden in both cohorts. Associations were found in the posterior cingulum and uncinate fasciculus in preclinical sporadic AD, and in the anterior and posterior cingulum in presymptomatic mutation carriers. These results suggest that microstructural alterations accompany pathological accumulation as early as the preclinical stage of both sporadic and autosomal dominant AD

Diffusion imaging markers of cerebral small vessel disease

Diffusion magnetic resonance imaging (MRI) is widely used as a research tool to assess (subtle) alterations of the cerebral white matter. Measures derived from diffusion MRI appear to be valuable markers for cerebral small vessel disease (SVD). However, SVD is frequently co-occurring with Alzheimer’s disease (AD), and disturbed white matter integrity and altered diffusion measures are considered key findings in both conditions. Yet, the contribution of SVD and AD to diffusion alterations is unclear, which hampers the interpretation of research studies in patients with mixed disease, e.g. memory clinic patients. Study 1 of this thesis aimed to clarify the effect of SVD and AD on diffusion measures by including multiple (memory clinic) samples covering the entire spectrum of SVD, mixed disease, and AD. We calculated diffusion measures from diffusion tensor imaging (DTI) and free water imaging. Within each sample of the disease spectrum, we applied simple regression analyses and multivariable random forest analyses between AD biomarkers (amyloid-beta, tau), conventional MRI markers of SVD, and global diffusion measures. Furthermore, we investigated regional associations between tau on positron emission tomography (PET) and diffusion measures in voxel-wise analyses. Our main findings are that conventional MRI markers of SVD were strongly associated with diffusion measures and showed a higher contribution than AD biomarkers in multivariable analyses across all memory clinic samples. Regional analyses between tau PET and diffusion measures were not significant. We conclude that SVD rather than AD determines diffusion alterations in memory clinic patients. Our findings validate diffusion measures as markers for SVD. Study 2 applied diffusion MRI markers to study gait impairment in SVD. Gait impairment is a commonly reported clinical deficit in SVD patients, but the underlying mechanisms are still debated. The proposed mechanisms include SVD-related white matter alterations resulting in impaired supraspinal locomotor control, cognitive deficits (e.g. planning and execution of movements), and factors independent of SVD, such as age-related instability (e.g. joint wear, sarcopenia) and comorbidities (e.g. neurodegenerative pathology). A reason for the lack of knowledge on gait impairment in SVD is that studies in elderly, sporadic SVD patients are typically confounded by effects of normal-aging and age-related comorbidities. Therefore, Study 2 of this thesis aimed to study the effect of pure SVD on gait performance in a relatively young sample of genetically defined SVD patients without age-related confounding. We performed comprehensive gait assessment using an electronic walkway to obtain multiple spatio-temporal gait parameters standardized based on data from healthy controls. Importantly, we tested the association between diffusion MRI markers of SVD-related white matter alterations and gait performance, since (strategic) white matter alterations are discussed as a major cause of gait decline in the elderly. Furthermore, we assessed the relation between cognitive deficits and gait performance. Our main finding is that, despite severe white matter alterations in pure SVD patients, gait performance was relatively preserved. Cognitive deficits in our study participants were not related to gait impairment. Thus, our results query isolated white matter alterations, in the absence of comorbidities, as a main factor of gait impairment in SVD and suggest that their combination with age-related comorbidities and/or normal-aging may play a crucial role in gait decline. In conclusion, diffusion measures are valid MRI markers of SVD-related white matter alterations. They have significant value both in future research on altered white matter and potentially also in the diagnostic work-up of memory clinic patients, to differentiate between vascular and neurodegenerative disease. Researchers may select target populations for clinical trials based on diffusion measures, e.g. to identify patients with a low SVD burden as targets for prevention and early intervention in SVD. Clinicians and researchers should always consider SVD as the origin of diffusion alterations in patients with mixed pathology. The field of application of diffusion measures is wide and may provide new insights into effects of subtle white matter alterations on clinical deficits, as shown in Study 2 on gait impairment in pure SVD. Future studies should investigate measures from advanced diffusion models and diffusion-based brain network analysis, to further elucidate the mechanisms of clinical deficits in SVD patients

The preservation of right cingulum fibers in subjective cognitive decline of preclinical phase of Alzheimer’s disease

IntroductionSubjective cognitive decline (SCD) with a positive amyloid burden has been recognized as the earliest clinical symptom of the preclinical phase of Alzheimers disease (AD), providing invaluable opportunities to improve our understanding of the natural history of AD and determine strategies for early therapeutic interventions.MethodsThe microstructure of white matter in patients showing SCD in the preclinical phase of AD (SCD of pre-AD) was evaluated using diffusion images, and voxel-wise fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities were assessed and compared among participant groups. Significant clusters in the tracts were extracted to determine their associations with alterations in the cognitive domains.ResultsWe found that individuals with SCD of pre-AD may have subclinical episodic memory impairment associated with the global amyloid burden. Meanwhile, we found significantly reduced FA and λ1 in the right cingulum (cingulate and hippocampus) in AD dementia, while significantly increased FA and decreased MD as well as λ23 in the SCD of pre-AD group in comparison with the HC group.DiscussionIn conclusion, increased white matter microstructural integrity in the right cingulum (cingulate and hippocampus) may indicate compensation for short-term episodic memory in individuals with SCD of pre-AD in comparison with individuals with AD and healthy elderly individuals

Assessment Of The Interplay Between Regional β-Amyloid Burden And White Matter Hyperintensities On Cognition And Default Mode Network In Clinically Normal Older Participants

Objective: Alzheimer’s disease (AD) and subcortical vascular dementia are considered the most common pathologic contributors to dementia in the aging population. Both frequently coexist in over 80% of community dwelling adults with dementia. The neuropathological development of AD arguably begins with β-amyloid (Aβ) deposition in the brain. This series of studies aims to test the hypothesis that early focal regional amyloid deposition in the brain is associated with cognitive performance in specific cognitive domain scores in preclinical AD (pAD) (study1). Since mixed dementia is widely recognized as the norm rather than the exception, the second study aimed to explore the relation between regional and global Aβ and WMH with core cognitive function (executive function (EF) and memory) scores in cognitively normal (CN) older adults (study2). Finally, the relationship between WMH and Aβ is strongly determined by the spatial distribution of the two pathologies, so the third study aimed to quantify Aβ in Default mode network (DMN) regions to examine whether cerebral small vessels disease (SVD) disruption of connectivity affects Aβ deposition in disconnected DMN regions (study3). Method: Global and regional Standard Uptake Value ratios (SUVr) from Aβ-PET, WMH volumes from MRI FLAIR images, and cognitive test scores were analyzed across a sample of CN participants. Linear regression models adjusted for age, sex and education used to assess the relationships between regional SUVr and cognitive test scores across 99 CN from Sanders Brown Center on Aging (study1). Moderation, and mediation modeling were used to define the interplay between global, regional Aβ and WMHs measures in relation to EF and memory composite scores outcomes at baseline and after approximately 2 years across a sample of 714 CN from the Alzheimer’s Disease Neuroimaging Initiative ADNI (study2). The association of WMH volume in anatomically defined white matter tracts of atlas-based fiber tract with Aβ SUVr specifically in connected cortical regions within DMN was tested across sample of 74 CN from ADNI3. Results: EF performance was associated with increased regional SUVr in the precuneus and posterior cingulate regions only (p \u3c 0.05). The moderation regression analysis showed additive effects of Aβ and WMH over baseline memory and EF scores (p =0.401 and 0.061 respectively) and synergistic effects over follow-up EF (p \u3c 0.05). Through mediation analysis, the data from study 2 showed that WMH affects, mediated by global and regional amyloid burden, are responsible for baseline cognitive performance deficits in memory and EF. Finally, the regression analysis from study 3 demonstrated that increased WMH volumes in superior longitudinal fasciculus (SLF) was associated with increased regional SUVr in inferior parietal lobule (IPL) (p \u3c 0.05). Conclusion: While the prevailing view in the field suggests that memory performance is the earliest clinical hallmark of AD, the present data demonstrate that changes in EF, mediated by Aβ deposition in the precuneus and posterior cingulate may precede memory decline in pAD. After adding the second key driver of cognitive decline in CN, the finding suggested that WMH dependent changes in baseline cognitive performance are related to direct effect of WMH and an indirect effect through both global and regional Aβ burden. Further studies are needed to show the longitudinal influences of WMH on Aβ distributions in participants with mixed dementia