Rik Ossenkoppele

PET Imaging of Tau Deposition in the Aging Human Brain

Tau pathology is a hallmark of Alzheimers disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.

Prediction of dementia in MCI patients based on core diagnostic markers for Alzheimer disease

Objectives: The current model of Alzheimer disease (AD) stipulates that brain amyloidosis biomarkers turn abnormal earliest, followed by cortical hypometabolism, and finally brain atrophy ones. The aim of this study is to provide clinical evidence of the model in patients with mild cognitive impairment (MCI). Methods: A total of 73 patients with MCI from 3 European memory clinics were included. Brain amyloidosis was assessed by CSF Aβ42 concentration, cortical metabolism by an index of temporoparietal hypometabolism on FDG-PET, and brain atrophy by automated hippocampal volume. Patients were divided into groups based on biomarker positivity: 1) Aβ42− FDG-PET− Hippo−, 2) Aβ42+ FDG-PET− Hippo−, 3) Aβ42 + FDG-PET + Hippo−, 4) Aβ42 + FDG-PET+ Hippo+, and 5) any other combination not in line with the model. Measures of validity were prevalence of group 5, increasing incidence of progression to dementia with increasing biological severity, and decreasing conversion time. Results: When patients with MCI underwent clinical follow-up, 29 progressed to dementia, while 44 remained stable. A total of 26% of patients were in group 5. Incident dementia was increasing with greater biological severity in groups 1 to 5 from 4% to 27%, 64%, and 100% (p for trend < 0.0001), and occurred increasingly earlier (p for trend = 0.024). Conclusions: The core biomarker pattern is in line with the current pathophysiologic model of AD. Fully normal and fully abnormal pattern is associated with exceptional and universal development of dementia. Cases not in line might be due to atypical neurobiology or inaccurate thresholds for biomarker (ab)normality.

The effect of physical activity on cognitive function in patients with dementia: A meta-analysis of randomized control trials.

Non-pharmacological therapies, such as physical activity interventions, are an appealing alternative or add-on to current pharmacological treatment of cognitive symptoms in patients with dementia. In this meta-analysis, we investigated the effect of physical activity interventions on cognitive function in dementia patients, by synthesizing data from 802 patients included in 18 randomized control trials that applied a physical activity intervention with cognitive function as an outcome measure. Post-intervention standardized mean difference (SMD) scores were computed for each study, and combined into pooled effect sizes using random effects meta-analysis. The primary analysis yielded a positive overall effect of physical activity interventions on cognitive function (SMD[95% confidence interval]=0.42[0.23;0.62], p<.01). Secondary analyses revealed that physical activity interventions were equally beneficial in patients with Alzheimers disease (AD, SMD=0.38[0.09;0.66], p<.01) and in patients with AD or a non-AD dementia diagnosis (SMD=0.47[0.14;0.80], p<.01). Combined (i.e. aerobic and non-aerobic) exercise interventions (SMD=0.59[0.32;0.86], p<.01) and aerobic-only exercise interventions (SMD=0.41[0.05;0.76], p<.05) had a positive effect on cognition, while this association was absent for non-aerobic exercise interventions (SMD=-0.10[-0.38;0.19], p=.51). Finally, we found that interventions offered at both high frequency (SMD=0.33[0.03;0.63], p<.05) and at low frequency (SMD=0.64[0.39;0.89], p<.01) had a positive effect on cognitive function. This meta-analysis suggests that physical activity interventions positively influence cognitive function in patients with dementia. This beneficial effect was independent of the clinical diagnosis and the frequency of the intervention, and was driven by interventions that included aerobic exercise.

Impact of molecular imaging on the diagnostic process in a memory clinic

[11C]Pittsburgh compound B ([11C]PIB) and [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose ([18F]FDG) PET measure fibrillar amyloid‐β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.

Resting metabolic connectivity in prodromal Alzheimer's disease. A European Alzheimer Disease Consortium (EADC) project

We explored resting-state metabolic connectivity in prodromal Alzheimers disease (pAD) patients and in healthy controls (CTR), through a voxel-wise interregional correlation analysis of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) by means of statistical parametric mapping. Baseline 18F-fluorodeoxyglucose-positron emission tomography of 36 patients with amnestic mild cognitive impairment who converted to Alzheimers disease (AD) dementia after an average time of 2 years (pAD) and of 105 CTR were processed. The area of hypometabolism in pAD showed less metabolic connectivity in patients than in CTR (autocorrelation and correlation with large temporal and frontal areas, respectively). pAD patients showed limited correlation even in selected nonhypometabolic areas, including the hippocampi and the dorsolateral prefrontal cortex (DLFC). On the contrary, in CTR group correlation was highlighted between hippocampi and precuneus/posterior cingulate and frontal cortex, and between dorsolateral prefrontal cortex and caudate nuclei and parietal cortex. The reduced metabolic connections both in hypometabolic and nonhypometabolic areas in pAD patients suggest that metabolic disconnection (reflecting early diaschisis) may antedate remote hypometabolism (early sign of synaptic degeneration).

Amyloid burden and metabolic function in early-onset Alzheimer's disease: parietal lobe involvement

Alzheimers disease with early onset often presents with a distinct cognitive profile, potentially reflecting a different distribution of underlying neuropathology. The purpose of this study was to examine the relationships between age and both in vivo fibrillary amyloid deposition and glucose metabolism in patients with Alzheimers disease. Dynamic [(11)C]Pittsburgh compound-B (90 min) and static [(18)F]fluorodeoxyglucose (15 min) scans were obtained in 100 patients with Alzheimers disease and 20 healthy controls. Parametric non-displaceable binding potential images of [(11)C]Pittsburgh compound-B and standardized uptake value ratio images of [(18)F]fluorodeoxyglucose were generated using cerebellar grey matter as reference tissue. Nine [(11)C]Pittsburgh compound-B-negative patients were excluded. The remaining patients were categorized into younger (n=45, age: 56 ± 4 years) and older (n=46, age: 69 ± 5 years) groups, based on the median age (62 years) at time of diagnosis. Younger patients showed more severe impairment on visuo-spatial function, attention and executive function composite scores (P<0.05), while we found a trend towards poorer memory performance for older patients (P=0.11). Differences between groups were assessed using a general linear model with repeated measures (gender adjusted) with age as between subjects factor, region (frontal, temporal, parietal and occipital and posterior cingulate cortices) as within subjects factor and [(11)C]Pittsburgh compound-B binding/[(18)F]fluorodeoxyglucose uptake as dependent variables. There was no main effect of age for [(11)C]Pittsburgh compound-B or [(18)F]fluorodeoxyglucose, suggesting that overall, the extent of amyloid deposition or glucose hypometabolism did not differ between groups. Regional distributions of [(11)C]Pittsburgh compound-B binding and [(18)F]fluorodeoxyglucose uptake (both P for interaction <0.05) differed between groups, however, largely due to increased [(11)C]Pittsburgh compound-B binding and decreased [(18)F]fluorodeoxyglucose uptake in the parietal cortex of younger patients (both P<0.05). Linear regression analyses showed negative associations between visuo-spatial functioning and parietal [(11)C]Pittsburgh compound-B binding for younger patients (standardized β: -0.37) and between visuo-spatial functioning and occipital binding for older patients (standardized β: -0.39). For [(18)F]fluorodeoxyglucose, associations were found between parietal uptake with visuo-spatial (standardized β: 0.55), attention (standardized β: 0.39) and executive functioning (standardized β: 0.37) in younger patients, and between posterior cingulate uptake and memory in older patients (standardized β: 0.41, all P<0.05). These in vivo findings suggest that clinical differences between younger and older patients with Alzheimers disease are not restricted to topographical differentiation in downstream processes but may originate from distinctive distributions of early upstream events. As such, increased amyloid burden, together with metabolic dysfunction, in the parietal lobe of younger patients with Alzheimers disease may contribute to the distinct cognitive profile in these patients.

Tau, amyloid, and hypometabolism in a patient with posterior cortical atrophy.

Determining the relative contribution of amyloid plaques and neurofibrillary tangles to brain dysfunction in Alzheimer disease is critical for therapeutic approaches, but until recently could only be assessed at autopsy. We report a patient with posterior cortical atrophy (visual variant of Alzheimer disease) who was studied using the novel tau tracer [18F]AV‐1451 in conjunction with [11C]Pittsburgh compound B (PIB; amyloid) and [18F]fluorodeoxyglucose (FDG) positron emission tomography. Whereas [11C]PIB bound throughout association neocortex, [18F]AV‐1451 was selectively retained in posterior brain regions that were affected clinically and showed markedly reduced [18F]FDG uptake. This provides preliminary in vivo evidence that tau is more closely linked to hypometabolism and symptomatology than amyloid. Ann Neurol 2014.

Metabolic Networks Underlying Cognitive Reserve in Prodromal Alzheimer Disease: A European Alzheimer Disease Consortium Project

This project aimed to investigate the metabolic basis for resilience to neurodegeneration (cognitive reserve) in highly educated patients with prodromal Alzheimer disease (AD). Methods: Sixty-four patients with amnestic mild cognitive impairment who later converted to AD dementia during follow-up, and 90 controls, underwent brain 18F-FDG PET. Both groups were divided into a poorly educated subgroup (42 controls and 36 prodromal AD patients) and a highly educated subgroup (48 controls and 28 prodromal AD patients). Brain metabolism was first compared between education-matched groups of patients and controls. Then, metabolism was compared between highly and poorly educated prodromal AD patients in both directions to identify regions of high education-related metabolic depression and compensation. The clusters of significant depression and compensation were further used as volumetric regions of interest (ROIs) in a brain interregional correlation analysis in each prodromal AD subgroup to explore metabolic connectivity. All analyses were performed by means of SPM8 (P < 0.001 uncorrected at peak level, P < 0.05 false discovery rate–corrected at cluster level; age, sex, Mini-Mental State Examination score, and center as nuisance). Results: Highly educated prodromal AD patients showed more severe hypometabolism than poorly educated prodromal AD patients in the left inferior and middle temporal gyri and the left middle occipital gyrus (ROI depression). Conversely, they showed relative hypermetabolism in the right inferior, middle, and superior frontal gyri (ROI compensation). The sites of compensation, mainly corresponding to the right dorsolateral prefrontal cortex (DLFC), showed wide metabolic correlations with several cortical areas in both hemispheres (frontotemporal cortex, parahippocampal gyrus, and precuneus) in highly educated prodromal AD patients but not in poorly educated prodromal AD patients. To provide evidence on whether these metabolic correlations represent preservation of the physiologic networks of highly educated control subjects (neural reserve) or rather the recruitment of alternative networks (neural compensation), or a combination of the two, we performed metabolic connectivity analysis of the DLFC in highly educated controls as well. The correlation sites of right DLFC partly overlapped those of highly educated prodromal AD patients but were less extended. Conclusion: The present findings suggest that highly educated prodromal AD patients can cope better with the disease thanks to neural reserve but also to the recruitment of compensatory neural networks in which the right DLFC plays a key role.

Mild cognitive impairment with suspected nonamyloid pathology (SNAP) Prediction of progression

Objectives: The aim of this study was to investigate predictors of progressive cognitive deterioration in patients with suspected non–Alzheimer disease pathology (SNAP) and mild cognitive impairment (MCI). Methods: We measured markers of amyloid pathology (CSF β-amyloid 42) and neurodegeneration (hippocampal volume on MRI and cortical metabolism on [18F]-fluorodeoxyglucose–PET) in 201 patients with MCI clinically followed for up to 6 years to detect progressive cognitive deterioration. We categorized patients with MCI as A+/A− and N+/N− based on presence/absence of amyloid pathology and neurodegeneration. SNAPs were A−N+ cases. Results: The proportion of progressors was 11% (8/41), 34% (14/41), 56% (19/34), and 71% (60/85) in A−N−, A+N−, SNAP, and A+N+, respectively; the proportion of APOE ε4 carriers was 29%, 70%, 31%, and 71%, respectively, with the SNAP group featuring a significantly different proportion than both A+N− and A+N+ groups (p ≤ 0.005). Hypometabolism in SNAP patients was comparable to A+N+ patients (p = 0.154), while hippocampal atrophy was more severe in SNAP patients (p = 0.002). Compared with A−N−, SNAP and A+N+ patients had significant risk of progressive cognitive deterioration (hazard ratio = 2.7 and 3.8, p = 0.016 and p < 0.001), while A+N− patients did not (hazard ratio = 1.13, p = 0.771). In A+N− and A+N+ groups, none of the biomarkers predicted time to progression. In the SNAP group, lower time to progression was correlated with greater hypometabolism (r = 0.42, p = 0.073). Conclusions: Our findings support the notion that patients with SNAP MCI feature a specific risk progression profile.

Differential effect of APOE genotype on amyloid load and glucose metabolism in AD dementia.

Objective: To examine the relationships between apolipoprotein E (APOE) ɛ4 dose and in vivo distributions of both fibrillary amyloid burden and glucose metabolism in the same Alzheimer disease dementia patients, selected for abnormal amyloid imaging. Methods: Twenty-two APOE ɛ4 negative, 40 heterozygous, and 22 homozygous Alzheimer disease dementia patients underwent dynamic (90 minutes) [11C]Pittsburgh compound B (PIB) and static [18F]fluorodeoxyglucose (FDG) PET scans. Parametric nondisplaceable binding potential images of [11C]PIB and standardized uptake value ratio images of [18F]FDG were generated using cerebellar gray matter as reference tissue. Frontal, parietal, temporal, posterior cingulate, and occipital cortices were selected as regions of interest. Results: Multivariate general linear models with adjustment for age, sex, and Mini-Mental State Examination showed main effects of APOE ɛ4 dose on distributions of both [11C]PIB (p for trend <0.05) and [18F]FDG (p for trend <0.01). More specifically, a univariate general linear model of individual regions showed increased [11C]PIB binding in frontal cortex of APOE ɛ4 noncarriers compared with APOE ɛ4 carriers (p < 0.05). In contrast, APOE ɛ4 carriers had reduced [18F]FDG uptake in occipital cortex (p < 0.05) and a borderline significant effect in posterior cingulate (p = 0.07) in a dose-dependent manner. Conclusion: We found a reversed APOE ɛ4 dose effect for amyloid deposition in the frontal lobe, whereas APOE ɛ4 carriership was associated with more profound metabolic impairment in posterior parts of the cortex. These findings suggest that APOE genotype has a differential effect on the distribution of amyloid plaques and glucose metabolism. This may have important implications for emerging therapies that aim to directly intervene in the disease process.