256 research outputs found

    The Spatial Evolution of Tau Pathology in Alzheimerā€™s Disease: Influence of Functional Connectivity and Education

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    Alzheimerā€™s disease is neuropathologically characterized by extracellular accumulation of amyloid beta plaques and intracellular aggregation of misfolded tau proteins, which eventually lead to neurodegeneration and cognitive impairment. With the recent advances in neuroimaging, these two proteinopathies can now be studied in vivo using positron emission tomography (PET). Combining this imaging technique with functional magnetic resonance imaging has consistently revealed a spatial overlap between amyloid beta accumulates and functional connectivity networks (Buckner et al., 2009; Grothe et al., 2016), indicating functional connectivity as mechanistic pathway in the distribution of neuropathologies. While the infiltration of these neuronal networks by amyloid beta deposits seems uniform across individuals with Alzheimerā€™s disease, there nevertheless exists inter-individual differences in the clinical expression of the disease despite similar pathological burden (Stern, 2012). This observation has fuelled the concept of existing resilience mechanisms, which are supported by lifetime and ā€“style factors and, which magnitude varies between individuals, contributing to the clinical heterogeneity seen in Alzheimerā€™s disease. Even though the spreading and resilience mechanisms in the phase of amyloid beta accumulation are now better understood, no information on tau pathology in vivo were available in this regard until recently. Given the recent introduction of tau PET compounds, this thesis therefore aimed to address two questions: 1) whether functional connectivity contributes to the distribution of tau pathology across brain networks, and 2) whether the consequence of tau pathology on cognitive and neuronal function is mitigated by a resilience proxy, namely education. Using [18F]-AV-1451 PET imaging to quantify tau pathology in a group of Alzheimerā€™s disease patients, we observed that tau pathology arises synchronously in independent components of the brain, which in turn moderately overlap with known functional connectivity networks. This suggest that functional connectivity may act as contributing factor in the stereotypical distribution of tau pathology. Moreover, the results of this thesis demonstrate that the consequence of regional tau pathology on cognition differs depending on the level of education. Despite equal clinical presentation, higher educated patients can tolerate more tau pathology, already in regions related to advanced disease stage, than lower educated patients. Furthermore, tau pathology is less paralleled by neuronal dysfunction at higher levels of education. Thus, higher educated individuals show a relative preservation of neuronal function despite the aggregation of misfolded tau proteins. This maintenance of neuronal function may in turn explain the relative preservation of cognitive function albeit progressive tau pathology aggregation. Taken together, the results of this thesis provide novel insights into the spreading mechanisms and the role of resilience factors towards tau pathology aggregation, which may not only be relevant for Alzheimerā€™s disease, but other neurodegenerative diseases, in particular,tauopathies. Better understanding of the spreading mechanisms in these diseases will permit a more precise prediction of disease progression and will thus be valuable for disease monitoring. Concomitantly, the development of sensitive biomarkers for disease monitoring is crucial for the evaluation of anti-tau-based therapies. Regarding the development of pharmacological strategies, the current results also indicate that proxy measures of resilience, such as education, need to be considered when allocating patients to treatment groups. Biased allocation may otherwise lead to a misinterpretation of observed effects that are not due to the drug but the group characteristics. Aside from this, sensitive tools for the early identification of at-risk individuals with high resilience need to be established to allow for a timely intervention. Current hypothesis is that an early intervention has the highest chance of success in modifying the disease course. However, as demonstrated by this work, individuals with high resilience remain undiagnosed until late in the disease course. Further research into resilience mechanisms may thus support the development of sensitive diagnostic tools and additionally offer potential targets that can be harnessed for novel treatment strategies. Hopefully, one day supporting the development of effective disease-modifying treatments

    Integrating cerebrospinal fluid and [18F]-fluorodeoxyglucose positron emission tomography to diagnose Alzheimer's disease and research its pathophysiological substrates

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    Revealing the complex interactions and assessing potential integration between biomarkers is essential, especially in the early stages of AD, when biomarker alterations may serve to stage patients throughout the disease spectrum, improve phenotyping, and indicate the likelihood of progression to dementia. In this research, the integration of [18F]-FDG-PET and CSF biomarkers, two of the most used biomarkers in centers focused on neurocognitive disorders, enabled us to collect evidence on their analytical and diagnostic performance when used in a step-wise fashion. As part of the ongoing endeavor to create a common diagnostic chart for the precise and cost-effective use of biomarkers in neurocognitive diseases with neurodegenerative origin, these data gain further significance. Additionally, by combining semiquantitative [18F]-FDG-PET and CSF data, we were able to identify precise topographic correlations between metabolic values and CSF proteins that indicated distinct underlying disease processes. These findings add to the knowledge regarding the distribution of hypometabolism linked to neuronal loss, which is distinct from metabolic changes reflecting synaptic or axonal injury, and provide an indirect insight of the pathological processes taking place at various times in different parts of the brain. These results will be expanded into bigger cohorts in future research, which will also integrate additional newly discovered synaptopathy-expressing proteins for diagnostic and prognostic purposes

    Cerebral and CSF amyloid load, and recovery of semantic material in Alzheimer disease patients

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    According to the new diagnostic criteria, the term ā€œAlzheimer Diseaseā€ (AD) refers to a set of neuropathological changes that can be evaluated in vivo, rather than to a specific clinical symptomatology1. It is now widely accepted that Ī²-Amyloid (AĪ²42) in the cerebrospinal fluid is a valid indicator of alteration of the pathophysiological state, associated with fibrillar deposits of cerebral Ī²-amyloid2. Comparative studies between imaging and autopsy findings have established that amyloid PET images are a valid in vivo surrogate for deposition of fibrillar Ī²-amyloid3-10. We analyzed the values of cerebral spinal cord (CSF) biomarkers in 40 patients with clinical diagnosis of AD. Two groups emerged: the first with both clinical and liquor biomarkers consistent with AD; the second was clinically in line with AD, but it was missing its pathognomic CSF biomarkers. At this point we asked ourselves about the nosological entity of the second group. All patients underwent flutemetamol-PET and the second group was dichotomically divided into two more groups based on the PET report. Schematically: Group 1: CSF + / PET +; Group 2: CSF- / PET +; Group 3: CSF- / PET-. Our study then correlated the PET images through statistical software (spm12) in order to highlight any differences in cerebral Ī²-amyloid accumulation. The first comparison was conducted between Group 1 and 2 revealing a significant accumulation of Ī²-amyloid in the regions of the posterior cingulate gyrus. The posterior cingulate gyrus is involved in maintaining spatio-temporal orientation and memory functions, thanks to the connections with the parahippocampal cortex11. Involvement of the posterior cingulate gyrus is classic in patients with a typical clinical presentation of AD11. This result is also in agreement with the typical cerebral distribution of AĪ² in AD (Braak and Braak stages)12 and highlights instead the possibility of non-typical deposits in the second group, for which a different etiopathogenetic mechanism from "ordinaryā€ AD is hypothesized13. In support of this assumption, the results of the second comparison conducted between Group 2 versus Group 1, which showed a pattern of regional accumulation of cerebral Ī²-amyloid in the regions of the frontal lobe, are explanatory. On the basis of this evidence, we hypothesized that the CSF- / PET + condition represents a clinical variant of the AD pathology defined in the literature as "frontal variant of the AD"13. Several studies have found that in the frontal variant of AD, the neuro-fibrillary tangle load (NFT) is about 10 times higher in the frontal cortex13 than in the typical AD group. On the other hand, patients with typical AD showed a greater accumulation of NFT in the entorhinal cortex, cingulate gyrus and temporal cortex13. Both evidences are consistent with the results of our study. Starting from the analysis of the neuropsychological tests carried out in AP patients behavioral and language alterations to the onset of illness have emerged, in addition to the memory impairment which is a pathognomonic sign of the typical AD. The typical AD refers to a pattern characterized by an early episodic memory loss followed by various combinations of deficits including attentional-executive deficit, language and visuospatial capacity deficits, which reflect the spread of the disease from the medial temporal lobe to other neocortical areas14-17. In contrast to this typical profile, the focal cortical variants of AD18 present an atypical symptomatological picture (executive dysfunctions19-20, deficits in design skills, behavioral abnormalities, impulsiveness, inattention to detail, inability to plan and language deficit21) . Despite the serious alterations to the tests that investigate the functioning of the frontal lobe, the performance of neuropsychological tests were similar to the typical AD group. This suggests that severe frontal deficiency is the main neuropsychological feature on top of an otherwise typical AD profile13. Several studies suggest that the deposition of fibrillar AĪ² explains at most, a small part of the clinical-anatomical heterogeneity of AD13. In fact, in the frontal AD variant an increase in tangles of tau fibrils but not of amyloid plaques has been observed22-23. It is now widely accepted that in AD the neurofibrillary lesions begin to accumulate in the limbic and temporo-parietal regions and only then would they progress to the frontal and occipital cortex. Thus the frontal lobes would be affected by neurodegenerative lesions typical of AD in a subsequent temporal sequence12. It is therefore possible that in the AD variants there is a focal deficit that is indicative of a selective, early and prominent vulnerability of some regions of the brain that are normally involved in pato This result is also in agreement with the cerebral distribution typical of AĪ² in AD (Braak and Braak stages)12 and highlights instead the possibility of non-typical deposits in the second group, for which a different etiopathogenetic mechanism is hypothesized from that "typical" of AD13. In support of this hypothesis, the results of the second comparison conducted between Group 2 versus Group 1, which showed a pattern of regional accumulation of cerebral Ī²-amyloid in the regions of the frontal lobe (Fig.2), are explanatory. On the basis of this evidence, we hypothesized that the CSF-/PET + condition represents a clinical variant of the AD pathology defined in the literature as "frontal variant of the AD"13. Several studies have found that in the frontal variant of AD, the neuro-fibrillary tangle load (NFT) is about 10 times higher in the frontal cortex13 than in the typical AD group. On the other hand, patients with typical AD showed a greater accumulation of NFT in the entorhinal cortex, cingulate gyrus and temporal cortex13. Both evidences are consistent with the results of our study. Starting from the analysis of the neuropsychological tests carried out in AP patients, behavioral and language alterations to the onset of illness have emerged, in addition to the memory impairment which is a pathognomonic sign of the typical AD. Typical AD refers to a pattern characterized by an early episodic memory loss followed by various combinations of deficits including attentional-executive deficit, language and visuospatial capacity deficits, which reflect the spread of the disease from the medial temporal lobe to other neocortical areas14-17. In contrast to this typical profile, the focal cortical variants of AD18 present an atypical symptomatological picture (including executive dysfunctions19-20, deficits in planing skills, behavioral abnormalities, impulsiveness, inattention to detail, inability to plan and language deficit21) . Despite the serious alterations emerged at the tests investigating the functioning of the frontal lobe, the performance of neuropsychological tests were similar to the typical AD group. This suggests that severe frontal deficiency is the main neuropsychological feature on top of an otherwise typical AD profile13. Several studies suggest that the deposition of fibrillar AĪ² explains at most a small part of the clinical-anatomical heterogeneity of AD13. Indeed, an increase in tau fibril tangles but not in amyloid plaques was observed in the frontal variant of AD.22-23. It is now widely accepted that in AD the neurofibrillary lesions begin to accumulate in the limbic and temporo-parietal regions and only afterwards they would progress towards the frontal and occipital cortex. Thus the frontal lobes would be affected by neurodegenerative lesions typical of AD in a subsequent temporal sequence12. It is therefore possible that in the AD variants there is a focal deficit that is indicative of a selective, early and prominent vulnerability of some brain regions which generally, as mentioned, will normally be involved in the AD pathology in a subsequent time sequence. This vulnerability would be caused by the primary deposition of tau at the frontal level24-28. On the other hand, the frontal variant of AD is characterized by a pathological process that does not seem to remain limited to the frontal lobes for a long time18. Aggregation of AĪ² would be driven by the total flux of neuronal activity while tau aggregation would depend on trans-neuronal diffusion, generating neurodegeneration models that coincide with specific functional networks that eventually lead to specific clinical phenotypes (AD variants)13. A better understanding of the factors that drive the heterogeneity of these clinical phenotypes can provide important insights into the mechanisms of the disease and have direct implications on the diagnosis and management of patients with emerging disease-specific therapies18. Finally, in our study, the third and fourth comparisons were conducted between Group 1 and Group 3 and between Group 2 and Group 3 respectively. Both groups showed a significant pattern of accumulation of cerebral Ī²-amyloid widespread almost in all brain areas. This result is not surprising, in light of the fact that Group 3 probably configures the SNAP Group (suspected non-Alzheimer's pathophysiology), or a syndrome defined by normal levels of amyloid biomarkers (CSF- / PET-) but neurodegeneration patterns evident at MRI or FDG-PET29 imaging study. In fact, from 10% to 30% of clinically diagnosed ADs do not show neuropathological alterations of AD during an autopsy30 and a similar proportion has AĪ²31 or CSF AĪ²42 levels normal31-40. Thus the multi-domain anamnestic phenotype of dementia is not specific. it may be the product of other diseases as well as AD31. To date, SNAP remains a not yet well-defined nosological entity. The clinical diagnosis of AD is often "incorrect" but there are significant differences with regard to clinical progress, genetic susceptibility and progression of the pathology, which have crucial implications for a precise and correct diagnosis, for clinical management and effectiveness of clinical trials on drugs29. SNAP is a very frequent condition in clinically normal subjects > 65 years and appears to be age-related. A study found that the frequency of SNAP was 0% in the age group between 50-60 years while it reached 24% around the age of 8929. However, the literature does not agree. The main controversy in the literature is whether SNAP is an indipendent pathological entity or can evolve into AD41. Some researchers believe that SNAP should be included as an integral part of the AD spectrum; if so, the pathogenetic explanation of the amyloid-centric models of AD and the concept of preclinical AD42 are wrong and should therefore be reviewed. On the contrary, if SNAP is a different entity from AD, the amyloid-centric models of AD and preclinical AD42 are completely consistent with current knowledge. In both cases, multiple studies have shown that the pathogenesis of SNAP is linked to the deposition of tau fibrils, which justify cerebral neurodegeneration; it would then be AĪ², even in small quantities, to act as the biological driver of taupathy, and cause the "spread" of tau in a widespread manner throughout the brain43,44. Therefore a better understanding of the factors that guide the clinical and etiopathogenetic heterogeneity of AD studied thanks to methods such as flutemetamol-PET can provide direct implications on correct diagnosis and prognostic precision in clinical practice. Furthermore, understanding the different nosological entities in study allows a better stratification of the patients in the future trials and the management of emerging specific therapies for this disease

    Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing

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    The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner ā€” a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes

    Role of Cerebrovascular Abnormality in Neurodegenerative Disease and Subcortical Ischemic Disease: CT Perfusion and PET Imaging

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    Clinical studies indicate that about 30% ~ 50% of patients have cognitive impairment after the first or recurrent stroke. Ischemic injury, particularly subcortical lesions, caused by stroke has been demonstrated to further exacerbate cognitive impairment of Alzheimerā€™s disease (AD) and vascular dementia. However, the mechanisms whereby cerebrovascular abnormalities contribute to neurodegeneration at early stage of disease and eventually to cognitive decline remain unclear. CT perfusion and positron emission tomography (PET) were used to investigate early mechanisms in a rat comorbid model of cerebral ischemia (CI) and Ī²-amyloid (AĪ², a pathological hallmark of AD) toxicity, and in patients with small subcortical ischemic lesions. Chapter 2 investigates the early hemodynamic disturbances within the first month after transient CI insult in the presence of AĪ² toxicity in the comorbid rat model. CT perfusion revealed significantly lower cerebral blood flow (CBF) and blood volume (CBV) at acute phase due to the transient ischemia, and increased CBF and CBV in the ipsilateral striatum of CI+AĪ² and CI groups at the first week post ischemia. These results suggest that CI is the primary driving factor of cerebrovascular abnormalities at early stage, and prolonged hyperperfusion and hypervolemia may imply reperfusion-related injury and downstream inflammation. Chapter 3 further addresses these questions with CT Perfusion-PET imaging. Chapter 3 describes the temporal profiles of blood-brain barrier (BBB) disruption and neuroinflammation over 3 months after CI with and without concurrent AĪ² toxicity in the comorbid rat model. CT perfusion showed significantly higher BBB permeability surface product (BBB-PS) in the ipsilateral striatum of CI+AĪ² group at day 7, month 2 and 3, as compared to CI and sham group. PET imaging revealed the highest level of neuroinflammation as reflected by the significantly increased 18F-FEPPA uptake due to microglial activation in the striatal lesion of CI+AĪ² group at day 7 and 14. The temporal features of these cererbrovascular and cellular changes may serve as early imaging biomarkers for development of cognitive impairment in high-risk patients post ischemic insult. Chapter 4 investigates the temporal changes in BBB-PS and cerebral perfusion using CT perfusion over the first 3 months after small lacunar/subcortical stroke in patients. This longitudinal investigation suggests the chronic BBB leakage detected by CT perfusion may contribute to cognitive impairment and associated pathology in lacunar/subcortical stroke. Overall, the imaging results presented in this thesis have demonstrated that BBB-PS, CBF, CBV and activated microglia can be used as imaging biomarkers for delineating the early pathogenic pattern and underlying contribution of cerebral ischemia to the disease development in the animal comorbid model and subcortical stroke patients

    The activity of amyloid beta binding alcohol dehydrogenase in Alzheimer's disease

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    The mitochondria are a vibrant hub for many problems that occur in Alzheimerā€™s disease. The enzyme amyloid-Ɵ binding alcohol dehydrogenase (ABAD) and Cyclophilin D (CypD) are two key mitochondrial proteins that have essential functions in Alzheimerā€™s disease. ABAD is crucial in the generation of energy via the Ɵ-oxidation of fatty acids, and CypD has been linked to Alzheimerā€™s disease through the initiation of necrosis. Changes in glucose metabolism have been observed in the brains of Alzheimerā€™s disease sufferers. This suggests that neurons require an alternative energy source that can bypass glycolysis in order to produce energy. The oxidation of fatty acids is crucial at this point as the products of this catabolism can feed into the second stage of the respiratory cycle. In Alzheimerā€™s disease, Amyloid-Ɵ (AƟ) has been found to bind to ABAD distorting the catalytic site changing its activity. The first objective of this thesis was to investigate a potential previously reported interaction between ABAD and CypD. To explore this further, FRET analysis and immunoprecipitation studies were conducted. Though no strong interactions were observed from the immunoprecipitation studies, live cell FRET analysis did reveal a small/weak interaction between CypD and ABAD. Additional studies also showed a decrease in ABAD activity in the presence of CypD, suggesting that there could be functional consequences from this interaction between CypD and ABAD.I also explored the effect of changing cellular energy sources on the activity of ABAD. ABAD activity was found to increase under conditions of reduced glucose in both HEK 293 and SK-N-SH cells expressing ABAD. In addition, Alois Alzheimer initially reported changes in lipids. These reported changes in lipids were explored under conditions where there was increased expression of ABAD and in the presence of AƟ. On the whole, the changes suggested that there was a shift in the metabolism of fatty acids when ABAD was expressed further implying a change in energy sources in the Alzheimerā€™s disease brain

    Topological Biomarker of Alzheimerā€™s Disease

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    For years, it has been assumed that the cerebral accumulation of pathologic protein forms is the main trigger of Alzheimerā€™s disease (AD) pathology; however, recent studies revealed strong evidences that the alternations in synaptic activity precede and affect the homeostasis of amyloid-beta and tau, both of which aggregate during AD. Given that the neuropathological changes, characteristic for AD, start decades before the onset of the first symptoms, when alternations become irreversible, it is crucial to find a biomarker that can detect the preclinical signs of disease, presumably synaptic dysfunction of specific cerebral areas. Here is presented a novel, a high potential neuroimaging biomarker that can detect the postsynaptic dysfunction of specific neural substrate located in medial prefrontal cortex (mPFC) during sensory gating processing of a simple auditory stimulus. The magnetoencephalography-based localization of mPFC gating activation has the potential not only to detect symptomatic AD but also to become a predictor of cognitive decline related to the pathophysiological processes of AD, both at the individual level. The strengths of proposed biomarker lie in the simplicity of using a binary value, i.e., activated or not activated a neural generator along with its potential to follow the evolution of the pathophysiological process of disease from preclinical phase. The novel biomarker does not require estimation of uniform cutoff levels and standardization processes, the main problems of so far proposed biomarkers. Ability to individually detect AD pathology during putative preclinical and clinical stages, absolute noninvasiveness, and large effect size give this biomarker a high translation capacity and clinical potential
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