Structural and metabolic correlates of neuropsychological profiles in multiple system atrophy and Parkinson's disease.

BACKGROUND: Despite increased recognition of cognitive impairment in Multiple System Atrophy (MSA), its neuroanatomical correlates are not well defined. We aimed to explore cognitive profiles in MSA with predominant parkinsonism (MSA-P) and Parkinson's disease (PD) and their relationship to frontostriatal structural and metabolic changes. METHODS: Detailed clinical and neuropsychological evaluation was performed together with diffusion tensor imaging (DTI) and [18F]-fluoro-deoxyglucose positron emission tomography ([18F]-FDG-PET) in patients with MSA-P (n = 11) and PD (n = 11). We compared clinical and neuropsychological data to healthy controls (n = 9) and correlated neuropsychological data with imaging findings in MSA-P and PD. RESULTS: Patients with MSA-P showed deficits in executive function (Trail Making Test B-A) and scored higher in measures of depression and anxiety compared to those with PD and healthy controls. Widespread frontostriatal white matter tract reduction in fractional anisotropy was seen in MSA-P and PD compared to an imaging control group. Stroop Test interference performance correlated with [18F]-FDG uptake in the bilateral dorsolateral prefrontal cortex (DLPFC) and with white matter integrity between the striatum and left inferior frontal gyrus (IFG) in PD. Trail Making Test performance correlated with corticostriatal white matter integrity along tracts from the bilateral IFG in MSA-P and from the right DLPFC in both groups. CONCLUSION: Executive dysfunction was more prominent in patients with MSA-P compared to PD. DLPFC metabolism and frontostriatal white matter integrity seem to be a driver of executive function in PD, whereas alterations in corticostriatal white matter integrity may contribute more to executive dysfunction in MSA-P.

Amyloid-ß and APOE genotype predict memory decline in cognitively unimpaired older individuals independently of Alzheimer's disease polygenic risk score.

BACKGROUND: What combination of risk factors for Alzheimer's disease (AD) are most predictive of cognitive decline in cognitively unimpaired individuals remains largely unclear. We studied associations between APOE genotype, AD-Polygenic Risk Scores (AD-PRS), amyloid-ß pathology and decline in cognitive functioning over time in a large sample of cognitively unimpaired older individuals. METHODS: We included 276 cognitively unimpaired older individuals (75 ± 10 years, 63% female) from the EMIF-AD PreclinAD cohort. An AD-PRS was calculated including 83 genome-wide significant variants. The APOE gene was not included in the PRS and was analyzed separately. Baseline amyloid-ß status was assessed by visual read of [18F]flutemetamol-PET standardized uptake value images. At baseline and follow-up (2.0 ± 0.4 years), the cognitive domains of memory, attention, executive function, and language were measured. We used generalized estimating equations corrected for age, sex and center to examine associations between APOE genotype and AD-PRS with amyloid-ß status. Linear mixed models corrected for age, sex, center and education were used to examine associations between APOE genotype, AD-PRS and amyloid-ß status, and their interaction on changes in cognitive functioning over time. RESULTS: Fifty-two participants (19%) had abnormal amyloid-ß, and 84 participants (31%) carried at least one APOE ε4 allele. APOE genotype and AD-PRS were both associated with abnormal amyloid-ß status. Increasingly more risk-full APOE genotype, a high AD-PRS and an abnormal amyloid-ß status were associated with steeper decline in memory functioning in separate models (all p ≤ 0.02). A model including 4-way interaction term (APOE×AD-PRS×amyloid-ß×time) was not significant. When modelled together, both APOE genotype and AD-PRS predicted steeper decline in memory functioning (APOE ß(SE)=-0.05(0.02); AD-PRS ß(SE)=-0.04(0.01)). Additionally, when modelled together, both amyloid-ß status and AD-PRS predicted a steeper decline in memory functioning (amyloid-ß ß(SE)=-0.07(0.04); AD-PRS ß(SE)=-0.04(0.01)). Modelling both APOE genotype and amyloid-ß status, we observed an interaction, in which APOE genotype was related to steeper decline in memory and language functioning in amyloid-ß abnormal individuals only (ß(SE)=-0.13(0.06); ß(SE)=-0.22(0.07), respectively). CONCLUSION: Our results suggest that APOE genotype is related to steeper decline in memory and language functioning in individuals with abnormal amyloid-ß only. Furthermore, independent of amyloid-ß status other genetic risk variants contribute to memory decline in initially cognitively unimpaired older individuals.

Modifiable and non-modifiable risk factors of dementia on midlife cerebral small vessel disease in cognitively healthy middle-aged adults: the PREVENT-Dementia study.

BACKGROUND: Considerable overlap exists between the risk factors of dementia and cerebral small vessel disease (SVD). However, studies remain limited to older cohorts wherein pathologies of both dementia (e.g. amyloid) and SVD (e.g. white matter hyperintensities) already co-exist. In younger asymptomatic adults, we investigated differential associations and interactions of modifiable and non-modifiable inherited risk factors of (future) late-life dementia to (present-day) mid-life SVD. METHODS: Cognitively healthy middle-aged adults (aged 40-59; mean 51.2 years) underwent 3T MRI (n = 630) as part of the PREVENT-Dementia study. To assess SVD, we quantified white matter hyperintensities, enlarged perivascular spaces, microbleeds, lacunes, and computed composite scores of SVD burden and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy (CAA). Non-modifiable (inherited) risk factors were APOE4 status and parental family history of dementia. Modifiable risk factors were derived from the 2020 Lancet Commission on dementia prevention (early/midlife: education, hypertension, obesity, alcohol, hearing impairment, head injuries). Confirmatory factor analysis (CFA) was used to evaluate the latent variables of SVD and risk factors. Structural equation modelling (SEM) of the full structural assessed associations of SVD with risk factors and APOE4*risk interaction. RESULTS: In SEM, the latent variable of global SVD related to the latent variable of modifiable midlife risk SVD (ß = 0.80, p = .009) but not non-modifiable inherited risk factors of APOE4 or family history of dementia. Interaction analysis demonstrated that the effect of modifiable risk on SVD was amplified in APOE4 non-carriers (ß = - 0.31, p = .009), rather than carriers. These associations and interaction effects were observed in relation to the SVD subtype of hypertensive arteriopathy, rather than CAA. Sensitivity analyses using separate general linear models validated SEM results. CONCLUSIONS: Established modifiable risk factors of future (late-life) dementia related to present-day (mid-life) SVD, suggesting that early lifestyle modifications could potentially reduce rates of vascular cognitive impairment attributed to SVD, a major 'silent' contributor to global dementia cases. This association was amplified in APOE4 non-carriers, suggesting that lifestyle modifications could be effective even in those with genetic predisposition to dementia.

Evaluation of in vivo staging of amyloid deposition in cognitively unimpaired elderly aged 78-94.

Amyloid-beta (Aß) deposition is common in cognitively unimpaired (CU) elderly >85 years. This study investigated amyloid distribution and evaluated three published in vivo amyloid-PET staging schemes from a cognitively unimpaired (CU) cohort aged 84.9 ± 4.3 years (n = 75). SUV-based principal component analysis (PCA) was applied to 18F-flutemetamol PET data to determine an unbiased regional covariance pattern of tracer uptake across grey matter regions. PET staging schemes were applied to the data and compared to the PCA output. Concentration of p-tau181 was measured in blood plasma. The PCA revealed three distinct components accounting for 91.2% of total SUV variance. PC1 driven by the large common variance of uptake in neocortical and striatal regions was significantly positively correlated with global SUVRs, APOE4 status and p-tau181 concentration. PC2 represented mainly non-specific uptake in typical amyloid-PET reference regions, and PC3 the occipital lobe. Application of the staging schemes demonstrated that the majority of the CU cohort (up to 93%) were classified as having pathological amount and distribution of Aß. Good correspondence existed between binary (+/-) classification and later amyloid stages, however, substantial differences existed between schemes for low stages with 8-17% of individuals being unstageable, i.e., not following the sequential progression of Aß deposition. In spite of the difference in staging outcomes there was broad spatial overlap between earlier stages and PC1, most prominently in default mode network regions. This study critically evaluated the utility of in vivo amyloid staging from a single PET scan in CU elderly and found that early amyloid stages could not be consistently classified. The majority of the cohort had pathological Aß, thus, it remains an open topic what constitutes abnormal brain Aß in the oldest-old and what is the best method to determine that.

CAIDE dementia risk score relates to severity and progression of cerebral small vessel disease in healthy midlife adults: the PREVENT-Dementia study.

BACKGROUND: Markers of cerebrovascular disease are common in dementia, and may be present before dementia onset. However, their clinical relevance in midlife adults at risk of future dementia remains unclear. We investigated whether the Cardiovascular Risk Factors, Ageing and Dementia (CAIDE) risk score was associated with markers of cerebral small vessel disease (SVD), and if it predicted future progression of SVD. We also determined its relationship to systemic inflammation, which has been additionally implicated in dementia and SVD. METHODS: Cognitively healthy midlife participants were assessed at baseline (n=185) and 2-year follow-up (n=158). To assess SVD, we quantified white matter hyperintensities (WMH), enlarged perivascular spaces (EPVS), microbleeds and lacunes. We derived composite scores of SVD burden, and subtypes of hypertensive arteriopathy and cerebral amyloid angiopathy. Inflammation was quantified using serum C-reactive protein (CRP) and fibrinogen. RESULTS: At baseline, higher CAIDE scores were associated with all markers of SVD and inflammation. Longitudinally, CAIDE scores predicted greater total (p<0.001), periventricular (p<0.001) and deep (p=0.012) WMH progression, and increased CRP (p=0.017). Assessment of individual CAIDE components suggested that markers were driven by different risk factors (WMH/EPVS: age/hypertension, lacunes/deep microbleeds: hypertension/obesity). Interaction analyses demonstrated that higher CAIDE scores amplified the effect of age on SVD, and the effect of WMH on poorer memory. CONCLUSION: Higher CAIDE scores, indicating greater risk of dementia, predicts future progression of both WMH and systemic inflammation. Findings highlight the CAIDE score's potential as both a prognostic and predictive marker in the context of cerebrovascular disease, identifying at-risk individuals who might benefit most from managing modifiable risk.

Astrocyte Biomarkers in Alzheimer Disease: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis to determine whether fluid and imaging astrocyte biomarkers are altered in Alzheimer's disease (AD). METHODS: PubMed and Web of Science databases were searched for articles reporting fluid or imaging astrocyte biomarkers in AD. Pooled effect sizes were determined with mean differences (SMD) using the Hedge's G method with random-effects to determine biomarker performance. Adapted questions from QUADAS-2 were applied for quality assessment. A protocol for this study has been previously registered in PROSPERO (registration number: CRD42020192304). RESULTS: The initial search identified 1,425 articles. After exclusion criteria were applied, 33 articles (a total of 3,204 individuals) measuring levels of GFAP, S100B, YKL-40 and AQP4 in the blood and cerebrospinal fluid (CSF), as well as MAO-B, indexed by positron emission tomography 11C-deuterium-L-deprenyl ([11C]-DED), were included. GFAP (SMD = 0.94; 95% CI = 0.71-1.18) and YKL-40 (SMD = 0.76; CI 95% = 0.63-0.89) levels in the CSF, S100B levels in the blood (SMD = 2.91; CI 95% = 1.01-4.8) were found significantly increased in AD patients. CONCLUSIONS: Despite significant progress, applications of astrocyte biomarkers in AD remain in their early days. The meta-analysis demonstrated that astrocyte biomarkers are consistently altered in AD and supports further investigation for their inclusion in the AD clinical research framework for observational and interventional studies.

Imaging tau burden in dementia with Lewy bodies using [18F]-AV1451 positron emission tomography.

Alzheimer's disease (AD) pathology is frequently observed as a comorbidity in people with dementia with Lewy bodies (DLB). Here, we evaluated the in vivo distribution of tau burden and its influence on the clinical phenotype of DLB. Tau deposition was quantified using [18F]-AV1451 positron emission tomography in people with DLB (n = 10), AD (n = 27), and healthy controls (n = 14). A subset of patients with Lewy body diseases (n = 4) also underwent [11C]-PK11195 positron emission tomography to estimate microglial activation. [18F]-AV1451 BPND was lower in DLB than AD across widespread regions. The medial temporal lobe [18F]-AV1451 BPND distinguished people with DLB from AD (AUC = 0.87), and negatively correlated with Addenbrooke's Cognitive Examination-Revised and Mini-Mental State Examination. There was a high degree of colocalization between [18F]-AV1451 and [11C]-PK11195 binding (p < 0.001). Our findings of minimal tau burden in DLB confirm previous studies. Nevertheless, the associations of [18F]-AV1451 binding with cognitive impairment suggest that tau may interact synergistically with other pathologic processes to aggravate disease severity in DLB.

Proximity to dementia onset and multi-modal neuroimaging changes: The prevent-dementia study.

BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.

11C-UCB-J synaptic PET and multimodal imaging in dementia with Lewy bodies.

OBJECTIVE: Dementia with Lewy bodies (DLB) is a common cause of dementia, but atrophy is mild compared to Alzheimer's disease. We propose that DLB is associated instead with severe synaptic loss, and we test this hypothesis in vivo using positron emission tomography (PET) imaging of 11C-UCB-J, a ligand for presynaptic vesicle protein 2A (SV2A), a vesicle membrane protein ubiquitously expressed in synapses. METHODS: We performed 11C-UCB-J PET in two DLB patients (an amyloid-negative male and an amyloid-positive female in their 70s) and 10 similarly aged healthy controls. The DLB subjects also underwent PET imaging of amyloid (11C-PiB) and tau (18F-AV-1451). 11C-UCB-J binding was quantified using non-displaceable binding potential (BPND) determined from dynamic imaging. Changes in 11C-UCB-J binding were correlated with MRI regional brain volume, 11C-PiB uptake and 18F-AV-1451 binding. RESULTS: Compared to controls, both patients had decreased 11C-UCB-J binding, especially in parietal and occipital regions (FDR-corrected p < 0.05). There were no significant correlations across regions between 11C-UCB-J binding and grey matter, tau (18F-AV1451) or amyloid (11C-PiB) in either patient. CONCLUSIONS: Quantitative imaging of in vivo synaptic density in DLB is a promising approach to understanding the mechanisms of DLB, over and above changes in grey matter volume and concurrent amyloid/tau deposition. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s41824-020-00093-9.

Gray matter changes related to microglial activation in Alzheimer's disease.

Neuroinflammation is increasingly recognized as playing a key pathogenetic role in Alzheimer's disease (AD). We examined the relationship between in vivo neuroinflammation and gray matter (GM) changes. Twenty-eight subjects with clinically probable AD (n = 14) and amyloid-positive mild cognitive impairment (n = 14) (age 71.9 ± 8.4 years, 46% female) and 24 healthy controls underwent structural 3T brain MRI. AD/mild cognitive impairment participants exhibited GM atrophy and cortical thinning in AD-related temporoparietal regions (false discovery rate-corrected p < 0.05). Patients also showed increased microglial activation in temporal cortices. Higher 11C-PK11195 binding in these regions was associated with reduced volume and cortical thickness in parietal, occipital, and cingulate areas (false discovery rate p < 0.05). Hippocampal GM atrophy and parahippocampal cortical thinning were related to worse cognition (p < 0.05), but these effects were not mediated by microglial activation. This study demonstrates an association between in vivo microglial activation and markers of GM damage in AD, positioning neuroinflammation as a potential target for immunotherapeutic strategies.

Correction to: Relevance of biomarkers across different neurodegenerative diseases.

An amendment to this paper has been published and can be accessed via the original article.

Relevance of biomarkers across different neurodegenerative diseases.

BACKGROUND: The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. PURPOSE OF REVIEW: Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care.

Imaging biomarkers in neurodegeneration: current and future practices.

There is an increasing role for biological markers (biomarkers) in the understanding and diagnosis of neurodegenerative disorders. The application of imaging biomarkers specifically for the in vivo investigation of neurodegenerative disorders has increased substantially over the past decades and continues to provide further benefits both to the diagnosis and understanding of these diseases. This review forms part of a series of articles which stem from the University College London/University of Gothenburg course "Biomarkers in neurodegenerative diseases". In this review, we focus on neuroimaging, specifically positron emission tomography (PET) and magnetic resonance imaging (MRI), giving an overview of the current established practices clinically and in research as well as new techniques being developed. We will also discuss the use of machine learning (ML) techniques within these fields to provide additional insights to early diagnosis and multimodal analysis.

Prognostic value of Alzheimer's biomarkers in mild cognitive impairment: the effect of age at onset.

OBJECTIVE: The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer's biomarkers in a large sample of patients with mild cognitive impairment (MCI). METHODS: We measured Aß42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers. RESULTS: In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease. DISCUSSION: FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.

Astrocyte Biomarkers in Alzheimer's Disease.

Astrocytic contributions to Alzheimer's disease (AD) progression were, until recently, largely overlooked. Astrocytes are integral to normal brain function and astrocyte reactivity is an early feature of AD, potentially providing a promising target for preclinical diagnosis and treatment. Several in vivo AD biomarkers already exist, but presently there is a paucity of specific and sensitive in vivo astrocyte biomarkers that can accurately measure preclinical AD. Measuring monoamine oxidase-B with neuroimaging and glial fibrillary acidic protein from bodily fluids are biomarkers that are currently available. Developing novel, more specific, and sensitive astrocyte biomarkers will make it possible to pharmaceutically target chemical pathways that preserve beneficial astrocytic functions in response to AD pathology. This review discusses astrocyte biomarkers in the context of AD.

Longitudinal association between astrocyte function and glucose metabolism in autosomal dominant Alzheimer's disease.

PURPOSE: The spatial resolution of 18F-fluorodeoxyglucose PET does not allow the specific cellular origin of its signal to be determined, but it is commonly accepted that transport and trapping of 18F-fluorodeoxyglucose reflects neuronal glucose metabolism. The main frameworks for the diagnosis of Alzheimer's disease suggest that hypometabolism measured with 18F-fluorodeoxyglucose PET is a biomarker of neuronal injury and neurodegeneration. There is preclinical evidence to suggest that astrocytes contribute, at least partially, to the in vivo 18F-fluorodeoxyglucose PET signal. However, due to a paucity of PET tracers for imaging astrocytic processes, the relationship between astrocyte function and glucose metabolism in human brain is not fully understood. The aim of this study was to investigate the longitudinal association between astrocyte function and glucose metabolism in Alzheimer's disease. METHODS: The current investigation combined longitudinal PET data from patients with autosomal dominant Alzheimer's disease, including data on astrocyte function (11C-deuterium-L-deprenyl binding) and glucose metabolism (18F-fluorodeoxyglucose uptake). Research participants included 7 presymptomatic and 4 symptomatic mutation carriers (age 44.9 ± 9.8 years and 58.0 ± 3.7 years, respectively) and 16 noncarriers (age 51.1 ± 14.2 years). Eight carriers and eight noncarriers underwent longitudinal follow-up PET imaging at an average of 2.8 ± 0.2 and 3.0 ± 0.5 years from baseline, respectively. RESULTS: Longitudinal decline in astrocyte function as measured using 11C-deuterium-L-deprenyl PET was significantly associated with progressive hypometabolism (18F-fluorodeoxyglucose uptake) in mutation carriers; no significant association was observed in noncarriers. CONCLUSION: The emerging data shift the accepted wisdom that decreases in cerebral metabolism measured with 18F-fluorodeoxyglucose solely reflect neuronal injury, and places astrocytes more centrally in the development of Alzheimer's disease.

Dual-phase [18F]florbetapir in frontotemporal dementia.

PURPOSE: The PET tracer [18F]florbetapir is a specific fibrillar amyloid-beta (Aß) biomarker. During the late scan phase (> 40 min), it provides pathological information about Aß status. Early scan phase (0-10 min) can provide FDG-'like' information. The current investigation tested the feasibility of using florbetapir as a dual-phase biomarker in behavioural variant frontotemporal dementia (bvFTD). METHODS: Eight bvFTD patients underwent [18F]florbetapir and [18]FDG-PET scans. Additionally, ten healthy controls and ten AD patients underwent florbetapir-PET only. PET data were acquired dynamically for 60-min post-injection. The bvFTD PET data were used to define an optimal time window, representing blood flow-related pseudo-metabolism ('pseudo-FDG'), of florbetapir data that maximally correlated with the corresponding real FDG SUVR (40-60 min) in a composite neocortical FTD region. RESULTS: A 2 to 5-min time window post-injection of the florbetapir-PET data provided the largest correlation (Pearson's r = 0.79, p = 0.02) to the FDG data. The pseudo-FDG images demonstrated strong internal consistency with actual FDG data and were also visually consistent with the bvFTD patients' hypometabolic profiles. The ability to identify bvFTD from blind visual rating of pseudo-FDG images was consistent with previous reports using FDG data (sensitivity = 75%, specificity = 85%). CONCLUSIONS: This investigation demonstrates that early phase florbetapir uptake shows a reduction of frontal lobe perfusion in bvFTD, similar to metabolic findings with FDG. Thus, dynamic florbetapir scans can serve as a dual-phase biomarker in dementia patients to distinguish FTD from AD and cognitively normal elderly, removing the need for a separate FDG-PET scan in challenging dementia cases.

Resilience to cognitive impairment in the oldest-old: design of the EMIF-AD 90+ study.

BACKGROUND: The oldest-old (subjects aged 90 years and older) population represents the fastest growing segment of society and shows a high dementia prevalence rate of up to 40%. Only a few studies have investigated protective factors for cognitive impairment in the oldest-old. The EMIF-AD 90+ Study aims to identify factors associated with resilience to cognitive impairment in the oldest-old. In this paper we reviewed previous studies on cognitive resilience in the oldest-old and described the design of the EMIF-AD 90+ Study. METHODS: The EMIF-AD 90+ Study aimed to enroll 80 cognitively normal subjects and 40 subjects with cognitive impairment aged 90 years or older. Cognitive impairment was operationalized as amnestic mild cognitive impairment (aMCI), or possible or probable Alzheimer's Disease (AD). The study was part of the European Medical Information Framework for AD (EMIF-AD) and was conducted at the Amsterdam University Medical Centers (UMC) and at the University of Manchester. We will test whether cognitive resilience is associated with cognitive reserve, vascular comorbidities, mood, sleep, sensory system capacity, physical performance and capacity, genetic risk factors, hallmarks of ageing, and markers of neurodegeneration. Markers of neurodegeneration included an amyloid positron emission tomography, amyloid ß and tau in cerebrospinal fluid/blood and neurophysiological measures. DISCUSSION: The EMIF-AD 90+ Study will extend our knowledge on resilience to cognitive impairment in the oldest-old by extensive phenotyping of the subjects and the measurement of a wide range of potential protective factors, hallmarks of aging and markers of neurodegeneration. TRIAL REGISTRATION: Nederlands Trial Register NTR5867 . Registered 20 May 2016.

The EMIF-AD PreclinAD study: study design and baseline cohort overview.

BACKGROUND: Amyloid pathology is the pathological hallmark in Alzheimer's disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. METHODS: From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [18F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. RESULTS: We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. CONCLUSIONS: A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.

Comparison of Early-Phase 11C-Deuterium-l-Deprenyl and 11C-Pittsburgh Compound B PET for Assessing Brain Perfusion in Alzheimer Disease.

UNLABELLED: The PET tracer (11)C-deuterium-L-deprenyl ((11)C-DED) has been used to visualize activated astrocytes in vivo in patients with Alzheimer disease (AD). In this multitracer PET study, early-phase (11)C-DED and (11)C-Pittsburgh compound B ((11)C-PiB) (eDED and ePiB, respectively) were compared as surrogate markers of brain perfusion, and the extent to which (11)C-DED binding is influenced by brain perfusion was investigated. METHODS: (11)C-DED, (11)C-PiB, and (18)F-FDG dynamic PET scans were obtained in age-matched groups comprising AD patients (n = 8), patients with mild cognitive impairment (n = 17), and healthy controls (n = 16). A modified reference Patlak model was used to quantify (11)C-DED binding. A simplified reference tissue model was applied to both (11)C-DED and (11)C-PiB to measure brain perfusion relative to the cerebellar gray matter (R1) and binding potentials. (11)C-PiB retention and (18)F-FDG uptake were also quantified as target-to-pons SUV ratios in 12 regions of interest (ROIs). RESULTS: The strongest within-subject correlations with the corresponding R1 values (R1,DED and R1,PiB, respectively) and with (18)F-FDG uptake were obtained when the eDED and ePiB PET data were measured 1-4 min after injection. The optimum eDED/ePiB intervals also showed strong, significant ROI-based intersubject Pearson correlations with R1,DED/R1,PiB and with (18)F-FDG uptake, whereas (11)C-DED binding was largely independent of brain perfusion, as measured by eDED. Corresponding voxelwise correlations confirmed the ROI-based results. Temporoparietal eDED or ePiB brain perfusion measurements were highly discriminative between patient and control groups, with discriminative ability statistically comparable to that of temporoparietal (18)F-FDG glucose metabolism. Hypometabolism extended over wider regions than hypoperfusion in patient groups compared with controls. CONCLUSION: The 1- to 4-min early-frame intervals of (11)C-DED or (11)C-PiB are suitable surrogate measures for brain perfusion. (11)C-DED binding is independent of brain perfusion, and thus (11)C-DED PET can provide information on both functional (brain perfusion) and pathologic (astrocytosis) aspects from a single PET scan. In comparison with glucose metabolism, early-phase (11)C-DED and (11)C-PiB perfusion appear to provide complementary rather than redundant information.