Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

A Modest Increase in 11C-PK11195-Positron Emission Tomography TSPO Binding in Depression Is Not Associated With Serum C-Reactive Protein or Body Mass Index.

BACKGROUND: Immune mechanisms have been implicated in the pathogenesis of depression. Translocator protein (TSPO)-targeted positron emission tomography (PET) has been used to assess neuroinflammation in major depressive disorder. We aimed to 1) test the hypothesis of significant case-control differences in TSPO binding in the anterior cingulate cortex, prefrontal cortex, and insula regions; and 2) explore the relationship between cerebral TSPO binding and peripheral blood C-reactive protein (CRP) concentration. METHODS: A total of 51 depressed subjects with Hamilton Depression Rating Scale score >13 (median 17; interquartile range, 16-22) and 25 healthy control subjects underwent dynamic brain 11C-PK11195 PET and peripheral blood immune marker characterization. Depressed subjects were divided into high CRP (>3 mg/L; n = 20) and low CRP (<3 mg/L; n = 31). RESULTS: Across the three regions, TSPO binding was significantly increased in depressed versus control subjects (η2p = .09; F1,71 = 6.97, p = .01), which was not influenced by body mass index. The case-control difference was greatest in the anterior cingulate cortex (d = 0.49; t74 = 2.00, p = .03) and not significant in the prefrontal cortex or insula (d = 0.27 and d = 0.36, respectively). Following CRP stratification, significantly higher TSPO binding was observed in low-CRP depression compared with controls (d = 0.53; t54 = 1.96, p = .03). These effect sizes are comparable to prior major depressive disorder case-control TSPO PET data. No significant correlations were observed between TSPO and CRP measures. CONCLUSIONS: Consistent with previous findings, there is a modest increase in TSPO binding in depressed patients compared with healthy control subjects. The lack of a significant correlation between brain TSPO binding and blood CRP concentration or body mass index poses questions about the interactions between central and peripheral immune responses in the pathogenesis of depression.

Magnetic resonance spectroscopy evidence for declining gliosis in MS patients treated with ocrelizumab versus interferon beta-1a.

BACKGROUND: Magnetic resonance spectroscopy quantitatively monitors biomarkers of neuron-myelin coupling (N-acetylaspartate (NAA)), and inflammation (total creatine (tCr), total choline (tCho), myo-inositol (mI)) in the brain. OBJECTIVE: This study aims to investigate how ocrelizumab and interferon beta-1a differentially affects imaging biomarkers of neuronal-myelin coupling and inflammation in patients with relapsing multiple sclerosis (MS). METHODS: Forty patients with relapsing MS randomized to either treatment were scanned at 3T at baseline and weeks 24, 48, and 96 follow-up. Twenty-four healthy controls were scanned at weeks 0, 48, and 96. NAA, tCr, tCho, mI, and NAA/tCr were measured in a single large supra-ventricular voxel. RESULTS: There was a time × treatment interaction in NAA/tCr (p = 0.04), primarily driven by opposing tCr trends between treatment groups after 48 weeks of treatment. Patients treated with ocrelizumab showed a possible decline in mI after week 48 week, and stable tCr and tCho levels. Conversely, the interferon beta-1a treated group showed possible increases in mI, tCr, and tCho over 96 weeks. CONCLUSIONS: Results from this exploratory study suggest that over 2 years, ocrelizumab reduces gliosis compared with interferon beta-1a, demonstrated by declining ml, and stable tCr and tCho. Ocrelizumab may improve the physiologic milieu by decreasing neurotoxic factors that are generated by inflammatory processes.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Dynamic 11C-PiB PET Shows Cerebrospinal Fluid Flow Alterations in Alzheimer Disease and Multiple Sclerosis.

Cerebrospinal fluid (CSF) plays an important role in solute clearance and maintenance of brain homeostasis. 11C-Pittsburgh compound B (PiB) PET was recently proposed as a tool for detection of CSF clearance alterations in Alzheimer disease. The current study investigates the magnitude of 11C-PiB PET signal in the lateral ventricles of an independent group of Alzheimer and mild cognitive impairment subjects. We have also evaluated multiple sclerosis as a model of disease with CSF clearance alterations without amyloid-ß tissue accumulation. Methods: A set of 11 Alzheimer and 12 mild cognitive impairment subjects and a set of 20 multiple sclerosis subjects with matched controls underwent MRI and dynamic 11C-PiB PET. Lateral ventricle regions of interest were generated manually from MRI data. PET data were analyzed using cerebellum or a supervised reference region for the Alzheimer and multiple sclerosis data sets, respectively. The magnitude of 11C-PiB signal in the lateral ventricles was calculated as area under the curve from 35 to 80 min and SUV ratio (SUVR) from 50 to 70 min. Compartmental modeling analysis was performed on a separate data set containing 11 Alzheimer and matched control subjects; this analysis included an arterial input function, to further understand the kinetics of the lateral ventricular 11C-PiB signal. Results: ANOVA revealed significant group differences in lateral ventricular SUVR across the Alzheimer, mild cognitive impairment, and healthy control groups (P = 0.004). Pairwise comparisons revealed significantly lower lateral ventricular SUVR in Alzheimer subjects than in healthy controls (P < 0.001) or mild cognitive impairment subjects (P = 0.029). Lateral ventricular SUVR was significantly lower in multiple sclerosis subjects than in healthy controls (P = 0.008). Compartmental modeling analysis revealed significantly lower uptake rates of 11C-PiB signal from blood (P = 0.005) and brain tissue (P = 0.004) to the lateral ventricles and significantly lower 11C-PiB signal clearance out of the lateral ventricles (P = 0.002) in Alzheimer subjects than in healthy controls. Conclusion: These results indicate that dynamic 11C-PiB PET can be used to observe pathologic changes in CSF dynamics. We have replicated previous work demonstrating CSF clearance deficits in Alzheimer disease associated with amyloid-ß deposits and have extended the observations to include ventricular CSF clearance deficits in mild cognitive impairment and multiple sclerosis.