Cerebral blood flow, amyloid burden, and cognition in cognitively normal individuals.

PURPOSE: The role of cerebral blood flow (CBF) in the early stages of Alzheimer's disease is complex and largely unknown. We investigated cross-sectional and longitudinal associations between CBF, amyloid burden, and cognition, in cognitively normal individuals with subjective cognitive decline (SCD). METHODS: We included 187 cognitively normal individuals with SCD from the SCIENCe project (65 ± 8 years, 39% F, MMSE 29 ± 1). Each underwent a dynamic (0-70 min) [18F]florbetapir PET and T1-weighted MRI scan, enabling calculation of mean binding potential (BPND; specific amyloid binding) and R1 (measure of relative (r)CBF). Eighty-three individuals underwent a second [18F]florbetapir PET (2.6 ± 0.7 years). Participants annually underwent neuropsychological assessment (follow-up time 3.8 ± 3.1 years; number of observations n = 774). RESULTS: A low baseline R1 was associated with steeper decline on tests addressing memory, attention, and global cognition (range betas 0.01 to 0.27, p < 0.05). High BPND was associated with steeper decline on tests covering all domains (range betas - 0.004 to - 0.70, p < 0.05). When both predictors were simultaneously added to the model, associations remained essentially unchanged. Additionally, we found longitudinal associations between R1 and BPND. High baseline BPND predicted decline over time in R1 (all regions, range betasBP×time - 0.09 to - 0.14, p < 0.05). Vice versa, low baseline R1 predicted increase in BPND in frontal, temporal, and composite ROIs over time (range betasR1×time - 0.03 to - 0.08, p < 0.05). CONCLUSION: Our results suggest that amyloid accumulation and decrease in rCBF are two parallel disease processes without a fixed order, both providing unique predictive information for cognitive decline and each process enhancing the other longitudinally.

Tau pathology as determinant of changes in atrophy and cerebral blood flow: a multi-modal longitudinal imaging study.

PURPOSE: Tau pathology is associated with concurrent atrophy and decreased cerebral blood flow (CBF) in Alzheimer's disease (AD), but less is known about their temporal relationships. Our aim was therefore to investigate the association of concurrent and longitudinal tau PET with longitudinal changes in atrophy and relative CBF. METHODS: We included 61 individuals from the Amsterdam Dementia Cohort (mean age 65.1 ± 7.5 years, 44% female, 57% amyloid-ß positive [Aß +], 26 cognitively impaired [CI]) who underwent dynamic [18F]flortaucipir PET and structural MRI at baseline and 25 ± 5 months follow-up. In addition, we included 86 individuals (68 CI) who only underwent baseline dynamic [18F]flortaucipir PET and MRI scans to increase power in our statistical models. We obtained [18F]flortaucipir PET binding potential (BPND) and R1 values reflecting tau load and relative CBF, respectively, and computed cortical thickness from the structural MRI scans using FreeSurfer. We assessed the regional associations between i) baseline and ii) annual change in tau PET BPND in Braak I, III/IV, and V/VI regions and cortical thickness or R1 in cortical gray matter regions (spanning the whole brain) over time using linear mixed models with random intercepts adjusted for age, sex, time between baseline and follow-up assessments, and baseline BPND in case of analyses with annual change as determinant. All analyses were performed in Aß- cognitively normal (CN) individuals and Aß+ (CN and CI) individuals separately. RESULTS: In Aß+ individuals, greater baseline Braak III/IV and V/VI tau PET binding was associated with faster cortical thinning in primarily frontotemporal regions. Annual changes in tau PET were not associated with cortical thinning over time in either Aß+ or Aß- individuals. Baseline tau PET was not associated with longitudinal changes in relative CBF, but increases in Braak III/IV tau PET over time were associated with increases in parietal relative CBF over time in Aß + individuals. CONCLUSION: We showed that higher tau load was related to accelerated cortical thinning, but not to decreases in relative CBF. Moreover, tau PET load at baseline was a stronger predictor of cortical thinning than change of tau PET signal.

Differential associations between neocortical tau pathology and blood flow with cognitive deficits in early-onset vs late-onset Alzheimer's disease.

PURPOSE: Early-onset Alzheimer's disease (EOAD) and late-onset Alzheimer's disease (LOAD) differ in neuropathological burden and type of cognitive deficits. Assessing tau pathology and relative cerebral blood flow (rCBF) measured with [18F]flortaucipir PET in relation to cognition may help explain these differences between EOAD and LOAD. METHODS: Seventy-nine amyloid-positive individuals with a clinical diagnosis of AD (EOAD: n = 35, age-at-PET = 59 ± 5, MMSE = 23 ± 4; LOAD: n = 44, age-at-PET = 71 ± 5, MMSE = 23 ± 4) underwent a 130-min dynamic [18F]flortaucipir PET scan and extensive neuropsychological assessment. We extracted binding potentials (BPND) and R1 (proxy of rCBF) from parametric images using receptor parametric mapping, in medial and lateral temporal, parietal, occipital, and frontal regions-of-interest and used nine neuropsychological tests covering memory, attention, language, and executive functioning. We first examined differences between EOAD and LOAD in BPND or R1 using ANOVA (region-of-interest analysis) and voxel-wise contrasts. Next, we performed linear regression models to test for potential interaction effects between age-at-onset and BPND/R1 on cognition. RESULTS: Both region-of-interest and voxel-wise contrasts showed higher [18F]flortaucipir BPND values across all neocortical regions in EOAD. By contrast, LOAD patients had lower R1 values (indicative of more reduced rCBF) in medial temporal regions. For both tau and flow in lateral temporal, and occipitoparietal regions, associations with cognitive impairment were stronger in EOAD than in LOAD (EOAD BPND - 0.76 ≤ stß ≤ - 0.48 vs LOAD - 0.18 ≤ stß ≤ - 0.02; EOAD R1 0.37 ≤ stß ≤ 0.84 vs LOAD - 0.25 ≤ stß ≤ 0.16). CONCLUSIONS: Compared to LOAD, the degree of lateral temporal and occipitoparietal tau pathology and relative cerebral blood-flow is more strongly associated with cognition in EOAD.

Classification of negative and positive 18F-florbetapir brain PET studies in subjective cognitive decline patients using a convolutional neural network.

PURPOSE: Visual reading of 18F-florbetapir positron emission tomography (PET) scans is used in the diagnostic process of patients with cognitive disorders for assessment of amyloid-ß (Aß) depositions. However, this can be time-consuming, and difficult in case of borderline amyloid pathology. Computer-aided pattern recognition can be helpful in this process but needs to be validated. The aim of this work was to develop, train, validate and test a convolutional neural network (CNN) for discriminating between Aß negative and positive 18F-florbetapir PET scans in patients with subjective cognitive decline (SCD). METHODS: 18F-florbetapir PET images were acquired and visually assessed. The SCD cohort consisted of 133 patients from the SCIENCe cohort and 22 patients from the ADNI database. From the SCIENCe cohort, standardized uptake value ratio (SUVR) images were computed. From the ADNI database, SUVR images were extracted. 2D CNNs (axial, coronal and sagittal) were built to capture features of the scans. The SCIENCe scans were randomly divided into training and validation set (5-fold cross-validation), and the ADNI scans were used as test set. Performance was evaluated based on average accuracy, sensitivity and specificity from the cross-validation. Next, the best performing CNN was evaluated on the test set. RESULTS: The sagittal 2D-CNN classified the SCIENCe scans with the highest average accuracy of 99% ± 2 (SD), sensitivity of 97% ± 7 and specificity of 100%. The ADNI scans were classified with a 95% accuracy, 100% sensitivity and 92.3% specificity. CONCLUSION: The 2D-CNN algorithm can classify Aß negative and positive 18F-florbetapir PET scans with high performance in SCD patients.

Correction to: Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer's disease.

The authors regret to inform readers that the following error was detected in the original article. The values for entorhinal, limbic and neortical SUVr were switched between SCD Aß + and Aß- in Table 1 and have now been corrected. Unnecessary symbols in Table 2 have been removed.

Regional [18F]flortaucipir PET is more closely associated with disease severity than CSF p-tau in Alzheimer's disease.

PURPOSE: In vivo Alzheimer's disease (AD) biomarkers for tau pathology are cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and [18F]flortaucipir positron emission tomography (PET). Our aim was to assess associations between CSF p-tau with [18F]flortaucipir PET and the associations of both tau biomarkers with cognition and atrophy. METHODS: We included 78 amyloid positive cognitively impaired patients (clinical diagnoses mild cognitive impairment (MCI, n = 8) and AD dementia (n = 45) and 25 cognitively normal subjects with subjective cognitive decline (SCD) (40% amyloid-positive)). Dynamic 130 min [18F]flortaucipir PET scans were acquired to generate binding potential (BPND) images using receptor parametric mapping and standardized uptake values ratios of 80-100 min (SUVr80-100min) post injection. We obtained regional BPND and SUVr from entorhinal, limbic, and neocortical regions-of-interest (ROIs), closely aligning to the neuropathological tau staging schemes. Cognition was assessed using MMSE and composite scores of four cognitive domains, and atrophy was measured using gray matter volume covering the major brain lobes. First, we used linear regressions to investigate associations between CSF p-tau (independent variable) and tau PET (dependent variable). Second, we used linear regressions to investigate associations between CSF p-tau, tau PET (separate independent variables, model 1), and cognition (dependent variable). We then assessed the independent effects of CSF p-tau and tau PET on cognition by simultaneously adding the other tau biomarker as a predictor (model 2). Finally, we performed the same procedure for model 1 and 2, but replaced cognition with atrophy. Models were adjusted for age, sex, time lag between assessments, education (cognition only), and total intracranial volume (atrophy only). RESULTS: Higher [18F]flortaucipir BPND was associated with higher CSF p-tau (range of standardized betas (sß) across ROIs, 0.43-0.46; all p < 0.01). [18F]flortaucipir BPND was more strongly associated with cognition and atrophy than CSF p-tau. When [18F]flortaucipir BPND and CSF p-tau were entered simultaneously, [18F]flortaucipir BPND (range sß = - 0.20 to - 0.57, all p < 0.05) was strongly associated with multiple cognitive domains and atrophy regions. SUVr showed comparable results to BPND. CONCLUSION: Regional [18F]flortaucipir BPND correlated stronger with cognition and neurodegeneration than CSF p-tau, suggesting that tau PET more accurately reflects disease severity in AD.

Tau pathology and relative cerebral blood flow are independently associated with cognition in Alzheimer's disease.

PURPOSE: We aimed to investigate associations between tau pathology and relative cerebral blood flow (rCBF), and their relationship with cognition in Alzheimer's disease (AD), by using a single dynamic [18F]flortaucipir positron emission tomography (PET) scan. METHODS: Seventy-one subjects with AD (66 ± 8 years, mini-mental state examination (MMSE) 23 ± 4) underwent a dynamic 130-min [18F]flortaucipir PET scan. Cognitive assessment consisted of composite scores of four cognitive domains. For tau pathology and rCBF, receptor parametric mapping (cerebellar gray matter reference region) was used to create uncorrected and partial volume-corrected parametric images of non-displaceable binding potential (BPND) and R1, respectively. (Voxel-wise) linear regressions were used to investigate associations between BPND and/or R1 and cognition. RESULTS: Higher [18F]flortaucipir BPND was associated with lower R1 in the lateral temporal, parietal and occipital regions. Higher medial temporal BPND was associated with worse memory, and higher lateral temporal BPND with worse executive functioning and language. Higher parietal BPND was associated with worse executive functioning, language and attention, and higher occipital BPND with lower cognitive scores across all domains. Higher frontal BPND was associated with worse executive function and attention. For [18F]flortaucipir R1, lower values in the lateral temporal and parietal ROIs were associated with worse executive functioning, language and attention, and lower occipital R1 with lower language and attention scores. When [18F]flortaucipir BPND and R1 were modelled simultaneously, associations between lower R1 in the lateral temporal ROI  and worse attention remained, as well as for lower parietal R1 and worse executive functioning and attention. CONCLUSION: Tau pathology was associated with locally reduced rCBF. Tau pathology and low rCBF were both independently associated with worse cognitive performance. For tau pathology, these associations spanned widespread neocortex, while for rCBF, independent associations were restricted to lateral temporal and parietal regions and the executive functioning and attention domains. These findings indicate that each biomarker may independently contribute to cognitive impairment in AD.

Plasma Amyloid as Prescreener for the Earliest Alzheimer Pathological Changes.

OBJECTIVE: We investigated the association of plasma amyloid beta (Abeta)40, Abeta42, and total tau (tTau) with the presence of Alzheimer pathological changes in cognitively normal individuals with subjective cognitive decline (SCD). METHODS: We included 248 subjects with SCD (61 ± 9 years, 42% female, Mini-Mental State Examination = 28 ± 2) from the SCIENCe project and Amsterdam Dementia Cohort. Subjects were dichotomized as amyloid abnormal by cerebrospinal fluid (CSF) and positron emission tomography (PET). Baseline plasma Abeta40, Abeta42, and tTau were measured using Simoa technology. Associations between plasma levels and amyloid status were assessed using logistic regression analyses and receiver operating characteristic analyses. Association of plasma levels with risk of clinical progression to mild cognitive impairment (MCI) or dementia was assessed using Cox proportional hazard models. RESULTS: Fifty-seven (23%) subjects were CSF-amyloid abnormal. Plasma Abeta42/Abeta40 ratio and plasma Abeta42 alone, but not tTau, identified abnormal CSF-amyloid status (plasma ratio: area under the curve [AUC] = 77%, 95% confidence interval [CI] = 69-84%; plasma Abeta42: AUC = 66%, 95% CI: 58-74%). Combining plasma ratio with age and apolipoprotein E resulted in AUC = 83% (95% CI = 77-89%). The Youden cutoff of the plasma ratio gave a sensitivity of 76% and specificity of 75%, and applying this as a prescreener would reduce the number of lumbar punctures by 51%. Using PET as outcome, a comparable reduction in number of PET scans would be achieved when applying the plasma ratio as prescreener. In addition, low plasma ratio was associated with clinical progression to MCI or dementia (hazard ratio = 2.0, 95% CI = 1.4-2.3). INTERPRETATION: Plasma Abeta42/Abeta40 ratio has potential as a prescreener to identify Alzheimer pathological changes in cognitively normal individuals with SCD. Ann Neurol 2018;84:656-666.

Smaller medial temporal lobe volumes in individuals with subjective cognitive decline and biomarker evidence of Alzheimer's disease-Data from three memory clinic studies.

INTRODUCTION: Previous studies showed associations of brain volume differences and biomarker evidence for Alzheimer's disease (AD) in subjective cognitive decline (SCD). The consistency of this finding across SCD studies has not been investigated. METHODS: We studied gray matter volume differences between SCD subjects with and without cerebrospinal fluid biomarker evidence for AD across three European memory clinic samples (German Center for Neurodegenerative Diseases Longitudinal Cognitive Impairment and Dementia study, Amsterdam, Barcelona). Analysis of covariance models with samples and cerebrospinal fluid biomarkers as between-subject factors were calculated. RESULTS: A significant main effect for AD biomarker (Aß42- > Aß42+) in the left medial temporal lobe (MTL) was found, with the absence of main effects for sample or interaction effects between AD biomarker and sample. This indicates consistent lower left MTL volume across three samples in SCD subjects with abnormal Aß42 levels. DISCUSSION: Our results support the model that in the presence of AD pathology, SCD corresponds to the late preclinical stage (stage 2 of AD) with smaller MTL volumes.

Subjective cognitive decline and rates of incident Alzheimer's disease and non-Alzheimer's disease dementia.

INTRODUCTION: In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS: Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS: In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION: SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.

A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline.

OBJECTIVES: Grey matter network disruptions in Alzheimer's disease (AD) are associated with worse cognitive impairment cross-sectionally. Our aim was to investigate whether indications of a more random network organization are associated with longitudinal decline in specific cognitive functions in individuals with subjective cognitive decline (SCD). EXPERIMENTAL DESIGN: We included 231 individuals with SCD who had annually repeated neuropsychological assessment (3 ± 1 years; n = 646 neuropsychological investigations) available from the Amsterdam Dementia Cohort (54% male, age: 63 ± 9, MMSE: 28 ± 2). Single-subject grey matter networks were extracted from baseline 3D-T1 MRI scans and we computed basic network (size, degree, connectivity density) and higher-order (path length, clustering, betweenness centrality, normalized path length [lambda] and normalized clustering [gamma]) parameters at whole brain and/or regional levels. We tested associations of network parameters with baseline and annual cognition (memory, attention, executive functioning, language composite scores, and global cognition [all domains with MMSE]) using linear mixed models, adjusted for age, sex, education, scanner and total gray matter volume. PRINCIPAL OBSERVATIONS: Lower network size was associated with steeper decline in language (ß ± SE = 0.12 ± 0.05, p < 0.05FDR). Higher-order network parameters showed no cross-sectional associations. Lower gamma and lambda values were associated with steeper decline in global cognition (gamma: ß ± SE = 0.06 ± 0.02); lambda: ß ± SE = 0.06 ± 0.02), language (gamma: ß ± SE = 0.11 ± 0.04; lambda: ß ± SE = 0.12 ± 0.05; all p < 0.05FDR). Lower path length values in precuneus and fronto-temporo-occipital cortices were associated with a steeper decline in global cognition. CONCLUSIONS: A more randomly organized grey matter network was associated with a steeper decline of cognitive functioning, possibly indicating the start of cognitive impairment.

A neuroimaging approach to capture cognitive reserve: Application to Alzheimer's disease.

Cognitive reserve (CR) explains interindividual differences in the ability to maintain cognitive function in the presence of neuropathology. We developed a neuroimaging approach including a measure of brain atrophy and cognition to capture this construct. In a group of 511 Alzheimer's disease (AD) biomarker-positive subjects in different stages across the disease spectrum, we performed 3T magnetic resonance imaging and predicted gray matter (GM) volume in each voxel based on cognitive performance (i.e. a global cognitive composite score), adjusted for age, sex, disease stage, premorbid brain size (i.e. intracranial volume) and scanner type. We used standardized individual differences between predicted and observed GM volume (i.e. W-scores) as an operational measure of CR. To validate this method, we showed that education correlated with mean W-scores in whole-brain (r = -0.090, P < 0.05) and temporoparietal (r = -0.122, P < 0.01) masks, indicating that higher education was associated with more CR (i.e. greater atrophy than predicted from cognitive performance). In a voxel-wise analysis, this effect was most prominent in the right inferior and middle temporal and right superior lateral occipital cortex (P < 0.05, corrected for multiple comparisons). Furthermore, survival analyses among subjects in the pre-dementia stage revealed that the W-scores predicted conversion to more advanced disease stages (whole-brain: hazard ratio [HR] = 0.464, P < 0.05; temporoparietal: HR = 0.397, P < 0.001). Our neuroimaging approach captures CR with high anatomical detail and at an individual level. This standardized method is applicable to various brain diseases or CR proxies and can flexibly incorporate different neuroimaging modalities and cognitive parameters, making it a promising tool for scientific and clinical purposes. Hum Brain Mapp 38:4703-4715, 2017. © 2017 Wiley Periodicals, Inc.

Arterial spin labeling-based Z-maps have high specificity and positive predictive value for neurodegenerative dementia compared to FDG-PET.

OBJECTIVE: Cerebral perfusion analysis based on arterial spin labeling (ASL) MRI has been proposed as an alternative to FDG-PET in patients with neurodegenerative disease. Z-maps show normal distribution values relating an image to a database of controls. They are routinely used for FDG-PET to demonstrate disease-specific patterns of hypometabolism at the individual level. This study aimed to compare the performance of Z-maps based on ASL to FDG-PET. METHODS: Data were combined from two separate sites, each cohort consisting of patients with Alzheimer's disease (n = 18 + 7), frontotemporal dementia (n = 12 + 8) and controls (n = 9 + 29). Subjects underwent pseudocontinuous ASL and FDG-PET. Z-maps were created for each subject and modality. Four experienced physicians visually assessed the 166 Z-maps in random order, blinded to modality and diagnosis. RESULTS: Discrimination of patients versus controls using ASL-based Z-maps yielded high specificity (84%) and positive predictive value (80%), but significantly lower sensitivity compared to FDG-PET-based Z-maps (53% vs. 96%, p < 0.001). Among true-positive cases, correct diagnoses were made in 76% (ASL) and 84% (FDG-PET) (p = 0.168). CONCLUSION: ASL-based Z-maps can be used for visual assessment of neurodegenerative dementia with high specificity and positive predictive value, but with inferior sensitivity compared to FDG-PET. KEY POINTS: • ASL-based Z-maps yielded high specificity and positive predictive value in neurodegenerative dementia. • ASL-based Z-maps had significantly lower sensitivity compared to FDG-PET-based Z-maps. • FDG-PET might be reserved for ASL-negative cases where clinical suspicion persists. • Findings were similar at two study sites.

Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer's disease.

INTRODUCTION: We examined the association between decreased cerebral blood flow (CBF) and cognitive impairment in Alzheimer's disease (AD), mild cognitive impairment (MCI), and subjective cognitive decline (SCD). METHODS: We included 161 AD, 95 MCI, and 143 SCD patients from the Amsterdam Dementia Cohort. We used 3-T pseudo-continuous arterial spin labeling to estimate whole-brain and regional partial volume-corrected CBF. Neuropsychological tests covered global cognition and five cognitive domains. Associations were investigated using linear regression analyses. RESULTS: In the whole sample, reduced overall and regional CBF was associated with impairment in all cognitive domains. We found significant interactions between diagnosis and CBF for language and between diagnosis and parietal CBF for global cognition and executive functioning. Stratification showed that decreased CBF was associated with worse performance in AD patients but not in MCI or SCD. DISCUSSION: Our results suggest that CBF may have potential as a functional marker of disease severity.

Application of Machine Learning to Arterial Spin Labeling in Mild Cognitive Impairment and Alzheimer Disease.

Purpose To investigate whether multivariate pattern recognition analysis of arterial spin labeling (ASL) perfusion maps can be used for classification and single-subject prediction of patients with Alzheimer disease (AD) and mild cognitive impairment (MCI) and subjects with subjective cognitive decline (SCD) after using the W score method to remove confounding effects of sex and age. Materials and Methods Pseudocontinuous 3.0-T ASL images were acquired in 100 patients with probable AD; 60 patients with MCI, of whom 12 remained stable, 12 were converted to a diagnosis of AD, and 36 had no follow-up; 100 subjects with SCD; and 26 healthy control subjects. The AD, MCI, and SCD groups were divided into a sex- and age-matched training set (n = 130) and an independent prediction set (n = 130). Standardized perfusion scores adjusted for age and sex (W scores) were computed per voxel for each participant. Training of a support vector machine classifier was performed with diagnostic status and perfusion maps. Discrimination maps were extracted and used for single-subject classification in the prediction set. Prediction performance was assessed with receiver operating characteristic (ROC) analysis to generate an area under the ROC curve (AUC) and sensitivity and specificity distribution. Results Single-subject diagnosis in the prediction set by using the discrimination maps yielded excellent performance for AD versus SCD (AUC, 0.96; P < .01), good performance for AD versus MCI (AUC, 0.89; P < .01), and poor performance for MCI versus SCD (AUC, 0.63; P = .06). Application of the AD versus SCD discrimination map for prediction of MCI subgroups resulted in good performance for patients with MCI diagnosis converted to AD versus subjects with SCD (AUC, 0.84; P < .01) and fair performance for patients with MCI diagnosis converted to AD versus those with stable MCI (AUC, 0.71; P > .05). Conclusion With automated methods, age- and sex-adjusted ASL perfusion maps can be used to classify and predict diagnosis of AD, conversion of MCI to AD, stable MCI, and SCD with good to excellent accuracy and AUC values. © RSNA, 2016.

Cerebral perfusion and glucose metabolism in Alzheimer's disease and frontotemporal dementia: two sides of the same coin?

OBJECTIVES: Alzheimer's disease (AD) and frontotemporal (FTD) dementia can be differentiated using [(18)F]-2-deoxy-2-fluoro-D-glucose (FDG)-PET. Since cerebral blood flow (CBF) is related to glucose metabolism, our aim was to investigate the extent of overlap of abnormalities between AD and FTD. METHODS: Normalized FDG-PET and arterial spin labelling (ASL-MRI)-derived CBF was measured in 18 AD patients (age, 64 ± 8), 12 FTD patients (age, 61 ± 8), and 10 controls (age, 56 ± 10). Voxel-wise comparisons, region-of-interest (ROI), correlation, and ROC curve analyses were performed. RESULTS: Voxel-wise comparisons showed decreased CBF and FDG uptake in AD compared with controls and FTD in both precuneus and inferior parietal lobule (IPL). Compared with controls and AD, FTD patients showed both hypometabolism and hypoperfusion in medial prefrontal cortex (mPFC). ASL and FDG were related in precuneus (r = 0.62, p < 0.001), IPL (r = 0.61, p < 0.001), and mPFC across groups (r = 0.74, p < 001). ROC analyses indicated comparable performance of perfusion and metabolism in the precuneus (AUC, 0.72 and 0.74), IPL (0.85 and 0.94) for AD relative to FTD, and in the mPFC in FTD relative to AD (both 0.68). CONCLUSIONS: Similar patterns of hypoperfusion and hypometabolism were observed in regions typically associated with AD and FTD, suggesting that ASL-MRI provides information comparable to FDG-PET. KEY POINTS: • Similar patterns of hypoperfusion and hypometabolism were observed in patients with dementia. • For both imaging modalities, parietal abnormalities were found in Alzheimer's disease. • For both imaging modalities, prefrontal abnormalities were found in frontotemporal dementia.

Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis.

IMPORTANCE: Amyloid-ß positron emission tomography (PET) imaging allows in vivo detection of fibrillar plaques, a core neuropathological feature of Alzheimer disease (AD). Its diagnostic utility is still unclear because amyloid plaques also occur in patients with non-AD dementia. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid positivity on PET in a wide variety of dementia syndromes. DATA SOURCES: The MEDLINE and Web of Science databases were searched from January 2004 to April 2015 for amyloid PET studies. STUDY SELECTION: Case reports and studies on neurological or psychiatric diseases other than dementia were excluded. Corresponding authors of eligible cohorts were invited to provide individual participant data. DATA EXTRACTION AND SYNTHESIS: Data were provided for 1359 participants with clinically diagnosed AD and 538 participants with non-AD dementia. The reference groups were 1849 healthy control participants (based on amyloid PET) and an independent sample of 1369 AD participants (based on autopsy). MAIN OUTCOMES AND MEASURES: Estimated prevalence of positive amyloid PET scans according to diagnosis, age, and apolipoprotein E (APOE) ε4 status, using the generalized estimating equations method. RESULTS: The likelihood of amyloid positivity was associated with age and APOE ε4 status. In AD dementia, the prevalence of amyloid positivity decreased from age 50 to 90 years in APOE ε4 noncarriers (86% [95% CI, 73%-94%] at 50 years to 68% [95% CI, 57%-77%] at 90 years; n = 377) and to a lesser degree in APOE ε4 carriers (97% [95% CI, 92%-99%] at 50 years to 90% [95% CI, 83%-94%] at 90 years; n = 593; P < .01). Similar associations of age and APOE ε4 with amyloid positivity were observed in participants with AD dementia at autopsy. In most non-AD dementias, amyloid positivity increased with both age (from 60 to 80 years) and APOE ε4 carriership (dementia with Lewy bodies: carriers [n = 16], 63% [95% CI, 48%-80%] at 60 years to 83% [95% CI, 67%-92%] at 80 years; noncarriers [n = 18], 29% [95% CI, 15%-50%] at 60 years to 54% [95% CI, 30%-77%] at 80 years; frontotemporal dementia: carriers [n = 48], 19% [95% CI, 12%-28%] at 60 years to 43% [95% CI, 35%-50%] at 80 years; noncarriers [n = 160], 5% [95% CI, 3%-8%] at 60 years to 14% [95% CI, 11%-18%] at 80 years; vascular dementia: carriers [n = 30], 25% [95% CI, 9%-52%] at 60 years to 64% [95% CI, 49%-77%] at 80 years; noncarriers [n = 77], 7% [95% CI, 3%-18%] at 60 years to 29% [95% CI, 17%-43%] at 80 years. CONCLUSIONS AND RELEVANCE: Among participants with dementia, the prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid imaging for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.

Precision estimates of relative and absolute cerebral blood flow in Alzheimer's disease and cognitively normal individuals.

Alzheimer's disease is characterized by regional reductions in cerebral blood flow (CBF). Although the gold standard for measuring CBF is [15O]H2O PET, proxies of relative CBF, derived from the early distribution phase of amyloid and tau tracers, have gained attention. The present study assessed precision of [15O]H2O derived relative and absolute CBF, and compared precision of these measures with that of (relative) CBF proxies. Dynamic [15O]H2O, [18F]florbetapir and [18F]flortaucipir PET test-retest (TrT) datasets with eleven, nine and fourteen subjects, respectively, were included. Analyses were performed using an arterial input model and/or a simplified reference tissue model, depending on the data available. Relative CBF values (i.e. K1/K1' and/or R1) were obtained using cerebellar cortex as reference tissue and TrT repeatability (i.e. precision) was calculated and compared between tracers, parameters and clinical groups. Relative CBF had significantly better TrT repeatability than absolute CBF derived from [15O]H2O (r = -0.53), while best TrT repeatability was observed for [18F]florbetapir and [18F]flortaucipir R1 (r = -0.23, r = -0.33). Furthermore, only R1 showed, better TrT repeatability for cognitively normal individuals. High precision of CBF proxies could be due to a compensatory effect of the extraction fraction, although changes in extraction fraction could also bias these proxies, but not the gold standard.

The Effects of a Digital, Transdiagnostic, Clinically and Peer-Moderated Treatment Platform for Young People With Emerging Mental Health Complaints: Repeated Measures Within-Subjects Study.

BACKGROUND: To address the growing prevalence of youth mental health problems, early intervention is crucial to minimize individual, societal, and economic impacts. Indicative prevention aims to target emerging mental health complaints before the onset of a full-blown disorder. When intervening at this early stage, individuals are more responsive to treatment, resulting in cost-effective outcomes. The Moderated Online Social Therapy platform, which was successfully implemented and proven effective in Australia, is a digital, peer- and clinically moderated treatment platform designed for young people. The Netherlands was the first country outside Australia to implement this platform, under the name Engage Young People Early (ENYOY). It has the potential to reduce the likelihood of young people developing serious mental health disorders. OBJECTIVE: This study aims to investigate the effects on young people using the ENYOY-platform in relation to psychological distress, psychosocial functioning, and positive health parameters. METHODS: Dutch-speaking young people with emerging mental health complaints (N=131) participated in the ENYOY-platform for 6 months in a repeated measures within-subjects study. Psychological distress, psychosocial functioning, and positive health parameters were assessed at baseline and 3, 6, and 12 months. Repeated measures ANOVA was conducted and adjusted for age, sex, therapy, and community activity. The Reliable Change Index and Clinically Significant Index were computed to compare the baseline with the 6- and 12-month measurements. The missing data rate was 22.54% and the dropout rate 62.6% (82/131). RESULTS: The primary analysis (77/131, 58.8%) showed that psychological distress decreased and psychosocial functioning improved over time with large effect sizes (P<.001 in both cases; ηp2=0.239 and 0.318, respectively) independent of age (P=.76 for psychological distress and P=.48 for psychosocial functioning), sex (P=.24 and P=.88, respectively), therapy activity (P=.49 and P=.80, respectively), or community activity (P=.59 and P=.48, respectively). Similarly, secondary analyses (51/131, 38.9%) showed significant effects of time on the quality of life, well-being, and meaningfulness positive health parameters (P<.05; ηp2=0.062, 0.140, and 0.121, respectively). Improvements in all outcome measures were found between baseline and 3 and 6 months (P≤.001-.01; d=0.23-0.62) and sustained at follow-up (P=.18-.97; d=0.01-0.16). The Reliable Change Index indicated psychological distress improvements in 38% (39/102) of cases, no change in 54.9% (56/102) of cases, and worsening in 5.9% (6/102) of cases. Regarding psychosocial functioning, the percentages were 50% (51/102), 43.1% (44/102), and 6.9% (7/102), respectively. The Clinically Significant Index demonstrated clinically significant changes in 75.5% (77/102) of cases for distress and 89.2% (91/102) for functioning. CONCLUSIONS: This trial demonstrated that the ENYOY-platform holds promise as a transdiagnostic intervention for addressing emerging mental health complaints among young people in the Netherlands and laid the groundwork for further clinical research. It would be of great relevance to expand the population on and service delivery of the platform. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12888-021-03315-x.

Altered brain metabolism in frontotemporal dementia and psychiatric disorders: involvement of the anterior cingulate cortex.

BACKGROUND: Behavioural symptoms and frontotemporal hypometabolism overlap between behavioural variant of frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD), hampering diagnostic distinction. Voxel-wise comparisons of brain metabolism might identify specific frontotemporal-(hypo)metabolic regions between bvFTD and PPD. We investigated brain metabolism in bvFTD and PPD and its relationship with behavioural symptoms, social cognition, severity of depressive symptoms and cognitive functioning. RESULTS: Compared to controls, bvFTD showed decreased metabolism in the dorsal anterior cingulate cortex (dACC) (p < 0.001), orbitofrontal cortex (OFC), temporal pole, dorsolateral prefrontal cortex (dlPFC) and caudate, whereas PPD showed no hypometabolism. Compared to PPD, bvFTD showed decreased metabolism in the dACC (p < 0.001, p < 0.05FWE), insula, Broca's area, caudate, thalamus, OFC and temporal cortex (p < 0.001), whereas PPD showed decreased metabolism in the motor cortex (p < 0.001). Across bvFTD and PPD, decreased metabolism in the temporal cortex (p < 0.001, p < 0.05FWE), dACC and frontal cortex was associated with worse social cognition. Decreased metabolism in the dlPFC was associated with compulsiveness (p < 0.001). Across bvFTD, PPD and controls, decreased metabolism in the PFC and motor cortex was associated with executive dysfunctioning (p < 0.001). CONCLUSIONS: Our findings indicate subtle but distinct metabolic patterns in bvFTD and PPD, most strongly in the dACC. The degree of frontotemporal and cingulate hypometabolism was related to impaired social cognition, compulsiveness and executive dysfunctioning. Our findings suggest that the dACC might be an important region to differentiate between bvFTD and PPD but needs further validation.