Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

ObjectiveTo characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE).MethodsEleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD).ResultsAll patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls.ConclusionsMildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages

Quantification of white matter cellularity and damage in preclinical and early symptomatic Alzheimer\u27s disease

Interest in understanding the roles of white matter (WM) inflammation and damage in the pathophysiology of Alzheimer disease (AD) has been growing significantly in recent years. However, in vivo magnetic resonance imaging (MRI) techniques for imaging inflammation are still lacking. An advanced diffusion-based MRI method, neuro-inflammation imaging (NII), has been developed to clinically image and quantify WM inflammation and damage in AD. Here, we employed NII measures in conjunction with cerebrospinal fluid (CSF) biomarker classification (for β-amyloid (Aβ) and neurodegeneration) to evaluate 200 participants in an ongoing study of memory and aging. Elevated NII-derived cellular diffusivity was observed in both preclinical and early symptomatic phases of AD, while disruption of WM integrity, as detected by decreased fractional anisotropy (FA) and increased radial diffusivity (RD), was only observed in the symptomatic phase of AD. This may suggest that WM inflammation occurs earlier than WM damage following abnormal Aβ accumulation in AD. The negative correlation between NII-derived cellular diffusivity and CSF Aβ42 level (a marker of amyloidosis) may indicate that WM inflammation is associated with increasing Aβ burden. NII-derived FA also negatively correlated with CSF t-tau level (a marker of neurodegeneration), suggesting that disruption of WM integrity is associated with increasing neurodegeneration. Our findings demonstrated the capability of NII to simultaneously image and quantify WM cellularity changes and damage in preclinical and early symptomatic AD. NII may serve as a clinically feasible imaging tool to study the individual and composite roles of WM inflammation and damage in AD. Keywords: Inflammation, White matter damage, Diffusion basis spectrum imaging, Neuro-inflammation imaging, Cerebrospinal fluid, Preclinical Alzheimer disease, Early symptomatic Alzheimer disease, Magnetic resonance imagin

Applicability of in vivo staging of regional amyloid burden in a cognitively normal cohort with subjective memory complaints: the INSIGHT-preAD study.

BACKGROUND:Current methods of amyloid PET interpretation based on the binary classification of global amyloid signal fail to identify early phases of amyloid deposition. A recent analysis of 18F-florbetapir PET data from the Alzheimer's disease Neuroimaging Initiative cohort suggested a hierarchical four-stage model of regional amyloid deposition that resembles neuropathologic estimates and can be used to stage an individual's amyloid burden in vivo. Here, we evaluated the validity of this in vivo amyloid staging model in an independent cohort of older people with subjective memory complaints (SMC). We further examined its potential association with subtle cognitive impairments in this population at elevated risk for Alzheimer's disease (AD). METHODS:The monocentric INSIGHT-preAD cohort includes 318 cognitively intact older individuals with SMC. All individuals underwent 18F-florbetapir PET scanning and extensive neuropsychological testing. We projected the regional amyloid uptake signal into the previously proposed hierarchical staging model of in vivo amyloid progression. We determined the adherence to this model across all cases and tested the association between increasing in vivo amyloid stage and cognitive performance using ANCOVA models. RESULTS:In total, 156 participants (49%) showed evidence of regional amyloid deposition, and all but 2 of these (99%) adhered to the hierarchical regional pattern implied by the in vivo amyloid progression model. According to a conventional binary classification based on global signal (SUVRCereb = 1.10), individuals in stages III and IV were classified as amyloid-positive (except one in stage III), but 99% of individuals in stage I and even 28% of individuals in stage II were classified as amyloid-negative. Neither in vivo amyloid stage nor conventional binary amyloid status was significantly associated with cognitive performance in this preclinical cohort. CONCLUSIONS:The proposed hierarchical staging scheme of PET-evidenced amyloid deposition generalizes well to data from an independent cohort of older people at elevated risk for AD. Future studies will determine the prognostic value of the staging approach for predicting longitudinal cognitive decline in older individuals at increased risk for AD

Unconventional markers of Alzheimer Disease

Although typically conceptualized as a cortical disease, recent neuropathological and neuroimaging investigations on Alzheimer Disease suggest that other brain structures play an important role in the pathogenesis and progression of this devastating condition. In this thesis, we explored novel markers of Alzheimer Disease beyond the classical cortical pathology measures of amyloid, tau, and neurodegeneration. We focused on the role of white matter abnormalities, assessed with magnetic resonance imaging but also with amyloid positron emission tomography, in predicting early pathologic changes and disease progression, as well as on the added value of cognition to amyloid, tau, and neurodegeneration biomarkers. Overall, we found that these unconventional markers provide useful information to detect the earliest pathological changes of the disease, providing a better understanding of the mechanisms that lead to amyloid deposition and cognitive decline

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