PET studies on disease progression and treatment efficacy in Alzheimer’s disease and mild cognitive impairment

Alzheimer’s disease (AD) is the most common cause of dementia. Mild cognitive impairment (MCI) is a transitional state between normal ageing and dementia. Positron emission tomography (PET) can detect the metabolic and neuro-chemical changes that occur in MCI and dementia. The aim of this thesis was to assess the use of PET as an in vivo biomarker for early disease detection, prognosis, and proof of treatment efficacy in AD and MCI. In study I, the prevalence of increased beta-amyloid deposition (assessed by 11C-PIB PET) and microglial activation (assessed by 11C-PK11195 PET) was studied in amnestic MCI (aMCI) subjects. 50% had raised amyloid deposition and 38% evidence of microglial activation. Subjects with increased PIB retention had significantly higher cortical PK11195 binding. In study II, rates at which aMCI subjects with and without increased amyloid load converted to AD were compared over one to three years of follow-up. 55% of aMCI subjects had significantly increased PIB retention at baseline and 82% of these converted to AD compared to 7% of aMCI cases with normal PIB uptake. Faster AD converters had higher PIB retention than slower converters. In study III, changes in regional cerebral Aβ deposition (assessed with 11C-PIB PET) and regional cerebral glucose metabolism (rCMRGlc) (assessed with 18F-FDG PET) were followed over three years in MCI and AD subjects. The MCI subjects demonstrated small but significant increases in 11C-PIB retention and parallel decreases in rCMRGlc. 11C-PIB retention in AD subjects remained unchanged, despite decreases in rCMRGlc and a decline in their MMSE. In study IV, the effects of passive immunisation with infusions of the anti-Aβ monoclonal antibody bapineuzumab on amyloid plaque load was assessed in AD subjects. After 78 weeks, subjects receiving bapineuzumab had reduced cortical 11C-PIB retention compared with their baseline and with placebo treated subjects. Through its detection of fibrillar Aβ, PET can detect the presence of Alzheimer pathology and provides a prognostic indicator of future progression of MCI to AD. However, PIB PET is not a marker of AD progression as the amyloid load remains relatively stable. 18F-FDG PET, a marker of synaptic activity, more closely mirrors cognitive decline as neurodegeneration progresses. Finally, PET allows the changes in glial activation in MCI to be monitored and provides a rationale for therapeutic trials of anti-inflammatory agents

An Update on Type 2 Diabetes Mellitus as a Risk Factor for Dementia

With the rapidly expanding evidence on brain structural and functional changes in type 2 diabetes mellitus (T2DM) patients, there is an increasing need to update our understanding on how T2DM associates with dementia as well as the underlying pathophysiological mechanisms. A literature search of T2DM and dementia or cognition impairments was carried out in electronic databases Medline, EMBASE, and Google Scholar. In this review, the chosen evidence was limited to human subject studies only, and data on either type 1 diabetes mellitus (T1DM) or non-classified diabetes were excluded. T2DM is a risk factor for both vascular dementia (VaD) and Alzheimer’s disease (AD), although AD pathological marker studies have not provided sufficient evidence. T2DM interacts additively or synergistically with many factors, including old age, hypertension, total cholesterol, and APOE ɛ4 carrier status for impaired cognition functions seen in patients with T2DM. In addition, comorbid T2DM can worsen the clinical presentations of patients with either AD or VaD. In summary, T2DM increases the risk for AD through different mechanisms for VaD although some mechanisms may overlap. Tau-related neurofibrillary tangles instead of amyloid-β plaques are more likely to be the pathological biomarkers for T2DM-related dementia. Degeneration of neurons in the brain, impaired regional blood supply/metabolism, and genetic predisposition are all involved in T2DM-associated dementia or cognitive impairments

Alzheimer PEThology

Scheltens, P. [Promotor]Lammertsma, A.A. [Promotor]Berckel, B.N.M. van [Copromotor]Flier, W.M. van der [Copromotor

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

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

Neural correlates of the DemTect in Alzheimer's disease and frontotemporal lobar degeneration ? A combined MRI & FDG-PET study ?

Valid screening devices are critical for an early diagnosis of dementia. The DemTect is such an internationally accepted tool. We aimed to characterize the neural networks associated with performance on the DemTect's subtests in two frequent dementia syndromes: early Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). Voxel-based group comparisons of cerebral glucose utilization (as measured by F-18-fluorodeoxyglucose positron emission tomography) and gray matter atrophy (as measured by structural magnetic resonance imaging) were performed on data from 48 subjects with AD (n = 21), FTLD (n = 14) or subjective cognitive impairment (n = 13) as a control group. We performed group comparisons and correlation analyses between multimodal imaging data and performance on the DemTect's subtests. Group comparisons showed regional patterns consistent with previous findings for AD and FTLD. Interestingly, atrophy dominated in FTLD, whereas hypometabolism in AD. Across diagnostic groups performance on the "wordlist" subtest was positively correlated with glucose metabolism in the left temporal lobe. The "number transcoding" subtest was significantly associated with glucose metabolism in both a predominantly left lateralized frontotemporal network and a parietooccipital network including parts of the basal ganglia. Moreover, this subtest was associated with gray matter density in an extensive network including frontal, temporal, parietal and occipital areas. No significant correlates were observed for the "supermarket task" subtest. Scores on the "digit span reverse" subtest correlated with glucose metabolism in the left frontal cortex, the bilateral putamen, the head of caudate nucleus and the anterior insula. Disease-specific correlation analyses could partly verify or extend the correlates shown in the analyses across diagnostic groups. Correlates of gray matter density were found in FTLD for the "number transcoding" subtest and the "digit span reverse" subtest. Correlates of glucose metabolism were found in AD for the "wordlist" subtest and in FTLD for the "digit span reverse" subtest. Our study contributes to the understanding of the neural correlates of cognitive deficits in AD and FTLD and supports an external validation of the DemTect providing preliminary conclusions about disease-specific correlates

Mild cognitive impairment: historical development and summary of research

This review article broadly traces the historical development, diagnostic criteria, clinical and neuropathological characteristics, and treatment strategies related to mild cognitive impairment (MCI), The concept of MCI is considered in the context of other terms that have been developed to characterize the elderly with varying degrees of cognitive impairment Criteria based on clinical global scale ratings, cognitive test performance, and performance on other domains of functioning are discussed. Approaches employing clinical, neuropsychological, neuroimaging, biological, and molecular genetic methodology used in the validation of MCI are considered, including results from cross-sectional, longitudinal, and postmortem investigations. Results of recent drug treatment studies of MCI and related methodological issues are also addressed

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

According to the new diagnostic criteria, the term “Alzheimer Disease” (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 β-Amyloid (Aβ42) in the cerebrospinal fluid is a valid indicator of alteration of the pathophysiological state, associated with fibrillar deposits of cerebral β-amyloid2. Comparative studies between imaging and autopsy findings have established that amyloid PET images are a valid in vivo surrogate for deposition of fibrillar β-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 β-amyloid accumulation. The first comparison was conducted between Group 1 and 2 revealing a significant accumulation of β-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 Aβ 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 "ordinary” 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 β-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 Aβ 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 Aβ 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 β-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 Aβ 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 Aβ 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 β-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 Aβ31 or CSF Aβ42 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 Aβ, 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