Julien Lagarde

Early and protective microglial activation in Alzheimer's disease: a prospective study using 18F-DPA-714 PET imaging.

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimers disease, the impact of the microglia response in Alzheimers disease remains a matter of debate. We aimed to study microglial activation in early Alzheimers disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimers disease and 32 controls, from the IMABio3 study, who had both (11)C-Pittsburgh compound B and (18)F-DPA-714 positron emission tomography imaging. Patients with Alzheimers disease were classified as prodromal Alzheimers disease (n = 38) and Alzheimers disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimers disease were dichotomized into slow decliners (n = 10) or fast decliners (n = 20) after 2 years of follow-up. All patients with Alzheimers disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimers disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimers disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimers disease and amyloidosis controls.

Distinct tau PET imaging patterns in typical and atypical Alzheimer’s disease

This scientific commentary refers to ‘Tau PET patterns mirror clinical and neuroanatomical variability in Alzheimer’s disease’, by Ossenkoppele et al. (doi:10.1093/brain/aww027). Specific protein inclusions define most neurodegenerative diseases at the pathological level. Alzheimer’s disease is characterized by abnormal extracellular amyloid-β deposits associated with intraneuronal tau aggregation in the cell body (neurofibrillary tangles), in the dendrites (neuropil threads) or in the axons of the senile plaque corona. In typical Alzheimer’s disease, the progression of cognitive deficits is consistent with the extension of tau pathology from the medial temporal regions (entorhinal cortex, parahippocampal gyrus and hippocampal formation) through the neocortical associative areas, resulting in early progressive impairment of episodic memory followed by aphasia, apraxia and agnosia. Aside from this common presentation, some patients with a diagnosis confirmed at post-mortem present with atypical clinical symptoms such as primary progressive aphasia, usually of the logopenic type, visuo-spatial deficits (posterior cortical atrophy), or predominant dysexecutive (frontal) syndrome (Alladi et al. , 2007). In addition, age of onset influences the clinical presentation. In early onset Alzheimer’s disease, temporo-parietal cortical damage is predominant with relative sparing of episodic memory, whereas greater medial temporal lobe atrophy and severe amnesia have been observed in late onset Alzheimer’s disease (Hamelin et al. , 2015). In this issue of Brain , Ossenkoppele et al. (2016) study the heterogeneity of tau deposition in patients with clinical variants of Alzheimer’s disease by using molecular PET imaging to examine the underlying biological mechanisms in vivo . Recent advances in Alzheimer’s disease biomarkers provide information about the pathophysiological process associated with the disease, and make it possible to go beyond the clinical diagnosis. Biomarkers are classified into two major categories: (i) biomarkers of amyloid-β accumulation, namely high tracer retention on amyloid PET imaging and low CSF amyloid-β; and (ii) biomarkers of neuronal degeneration …

Cholinergic Changes in Aging and Alzheimer Disease: An [18f]-f-a-85380 Exploratory Pet Study.

The central cholinergic system undergoes changes during the physiological process of aging and the pathologic process of Alzheimer disease (AD). We aimed to analyze the impairment of cholinergic pathways by positron emission tomography using the [18F]-F-A-85380 (FA85) tracer, which has a high affinity for nicotinic acetylcholine receptors (nAChRs). Aging was assessed by comparing young (n=10) and elderly (n=4) healthy subjects, and the pathologic process of AD was assessed by comparing elderly controls and age-matched AD patients (n=8). We measured an index of the nAChR density in the cortex and the hippocampus and the total number of FA85-binding sites by taking into account the volume changes. In AD, the nAChR density was preserved in both the cortex and hippocampus. The total estimated number of FA85-binding sites was decreased in the hippocampus despite the lack of a significant loss of volume, whereas the difference in the cortex did not withstand the adjustment for multiple comparisons despite a significant loss of volume. In contrast, in aging, the estimated number of FA85-binding sites was decreased in both the cortex and hippocampus with significant hippocampal atrophy. These findings suggest a preferential impairment of cholinergic pathways in the cortex during aging, whereas in AD, this damage predominated in the hippocampus with a potential compensatory cholinergic effect in the cortex.

Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimers disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimers disease. First, in a large cohort of patients with Alzheimers disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimers disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimers disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimers disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimers disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimers disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.

Neutrophil hyperactivation correlates with Alzheimer's disease progression: Neutrophil Hyperactivation in Alzheimer's Disease

Recent studies have underlined the effect of systemic inflammation on the pathophysiology of Alzheimers disease (AD). Neutrophils are key components of early innate immunity and contribute to uncontrolled systemic inflammation if not tightly regulated. The aim of our study was to fully characterize human circulating neutrophils at different disease stages in AD.

Progressive Supranuclear Palsy Syndrome and Semantic Dementia in Neuropathologically Proven Lewy Body Disease: A Report of Two Cases

The impact of neuropathological lesions on the clinical symptoms and progression of Lewy body disease (LBD) remains unclear. To address this issue, we describe two illustrative cases of autopsy-proven LBD that presented atypical phenotypes of progressive supranuclear palsy syndrome and semantic dementia. Postmortem examination revealed diffuse LBD with massive brainstem involvement in case 1, whereas Lewy bodies predominated in the amygdala and neocortex in case 2. Alzheimers disease pathology was present in both cases, and TDP-43 inclusions were noted in case 2. These cases illustrate two contrasted clinical presentations and highlight the heterogeneity within the underlying proteinopathies of neurodegenerative diseases.

Executive and social-cognitive determinants of environmental dependency syndrome in behavioral frontotemporal dementia

Objective: Environmental dependency syndrome (EDS), including utilization (UB) and imitation (IB) behaviors, is often reported in behavioral variant frontotemporal dementia (bvFTD). These behaviors are commonly attributed to executive dysfunction. However, inconsistent associations between EDS and poor executive performance has led to an alternative “social hypothesis,” instead implicating patients’ misinterpretation of the examiner’s intention. We investigated the possible explanatory cognitive mechanisms of EDS in bvFTD by relating UB and IB to performance on tests of executive functioning and theory of mind (ToM). Method: This study analyzed retrospective data of 32 bvFTD patients. Data included scores of UB and IB, various executive measures, and ToM assessment using the faux pas test, from which we extracted a mental attribution score. Results: Of the patients, 15.6% and 40.6% exhibited UB and IB, respectively. We conducted an automatic linear modeling analysis with executive and mental attribution measures as predictor variables, and UB and IB sequentially considered as target variables. ToM mental attribution score, visual abstraction and flexibility measures from the Wisconsin Card Sorting Test, and motor sequence performance significantly (corrected ps < .05) predicted IB. No executive or ToM measures significantly predicted UB. Conclusions: These findings reveal a complex interaction between executive dysfunction and mental attribution deficits influencing the prevalence of EDS in bvFTD. Further investigation is required to improve our understanding of the mechanisms underlying these behaviors.

TAU PET IMAGING IN PATIENTS WITH PROGRESSIVE AMNESIA NOT DUE TO AD

(Table 1) scanned with F-AV-1451 PET was evaluated. All tau PET SUVR images were qualitatively interpreted using 4 rating scales. Three rating scales visually assessed F-AV-1451 uptake in 7 cortical regions (medial, inferior and lateral temporal, medial and lateral parietal, frontal and occipital) either by presence/ absence of uptake or on a severity scale, from 0 to 2 and 0 to 3. The fourth rating scale looked at F-AV-1451 uptake in 3 regions corresponding to the Braak stages (Braak I/II, III/IVand V/VI). The results of the visual interpretation were compared to the average global F-AV-1451 SUVR as well as amyloid status and clinical diagnosis. The rating scale providing best correlations with global tau quantification was chosen for further analysis. A second reader independently interpreted the 60 scans and inter-rater agreement was assessed. Results: Final scores of all visual rating scales were significantly and strongly associated with quantification of global F-AV-1451 uptake (Table 2). The strongest correlation was found with the scale allowing differentiation between mild, moderate and intense uptake across 7 regions (correlation coefficient 1⁄4 0.92). As expected, mean visual rating scores within each diagnostic category were lower for amyloid negative subjects than for amyloid positive subjects. Moreover, we found an increasing trend directly correlated with diagnosis, with controls having the lowest, MCI an intermediate, and AD the highest values (Figure 1 and Table 3). Two-way ANOVA model confirmed that both clinical diagnosis (p<0.001) and PIB status (p<0.001) independently contributed to the visual score. Interrater agreement was excellent (linear weighted Kappa 0.833; correlation coefficient 0.946; R 0.915 – Figure 2). Conclusions: Our data show that visual rating scales strongly correlate with tau SUVR quantification, particularly when allowing differentiation between mild, moderate and intense uptake. This is a reliable, easily reproducible and promising alternative approach to tau measurement in clinical settings.

PROGRESSION OF CORTICAL MICROGLIAL ACTIVATION IN ALZHEIMER’S DISEASE: A TWO-YEAR LONGITUDINAL PET STUDY USING [ 18 F]DPA-714

Lorraine Hamelin, Julien Lagarde, Guillaume Doroth ee, MarieClaude Potier, H el ene Corne, Ludovic Fillon, Fabien Caill e, Philippe Gervais, Michel Bottlaender, Marie Sarazin, Neurology of Memory and Language, Universit e Paris Descartes, Sorbonne Paris Cit e, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France; INSERM-UPMC UMRS 938, Centre de Recherche Saint-Antoine, Paris, France; Brain and Spine Institute (ICM), UPMC/Inserm UMR-S 975, CNRS UMR 7225, Paris, France; Sorbonne Universit es, Universit e Pierre et Marie Curie (UPMC), Paris, France; CATI Project, Paris, France; CEA, Orsay, France; NeuroSpin, Institut d’Imagerie Biom edicale, Direction des Sciences du Vivant, Commissariat a l’Energie Atomique, Gif sur Yvette, France; Neurologie de la M emoire et du Langage, Universit e Paris Descartes, Sorbonne Paris Cit e, INSERM UMR S894, Centre Hospitalier Sainte Anne, Paris, France. Contact e-mail: J.LAGARDE@ ch-sainte-anne.fr

Sudden proximal paraparesis secondary to statin myositis

Myotoxicity due to statin medication is a well-known entity. Statin myopathies usually evolve either subacutely or chronically.1 They are classically diffuse, affecting all four limbs mainly proximally; focal myositis is rare in this setting.2 ,3 We report an atypical case of statin myopathy predominantly involving the quadriceps muscles with an unexpectedly abrupt onset. A 75-year-old man presented with sudden onset of bilateral proximal lower limb weakness. On trying to stand up after finishing dinner, he had fallen backwards without losing consciousness. He had great difficulty getting up again and lay on the floor for several hours before being able to call for help. He had never previously experienced muscle pain or weakness and had not performed any unusual exercise in the preceding days or hours. He had a history of hypertension, diabetes mellitus, myocardial infarction and coronary bypass surgery. He took atenolol, metformin, aspirin and rosuvastatin. He did not …