Associations between sex, body mass index and the individual microglial response in Alzheimer's disease.

BACKGROUND AND OBJECTIVES: 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between ß-amyloid-accumulation and microglial activation in AD. METHODS: 49 patients with AD (29 females, all Aß-positive) and 15 Aß-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and ß-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aß-PET on TSPO-PET was used to determine the Aß-plaque-dependent microglial response (slope) and the Aß-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). RESULTS: In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aß-PET z-scores were similar. The Aß-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aß-plaque-dependent microglial response was not different between sexes. The Aß-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aß-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005). CONCLUSION: While microglia response to fibrillar Aß is similar between sexes, women with AD show a stronger Aß-plaque-independent microglia response. This sex difference in Aß-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aß-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.

Tau accumulation is associated with dopamine deficiency in vivo in four-repeat tauopathies.

PURPOSE: We hypothesized that severe tau burden in brain regions involved in direct or indirect pathways of the basal ganglia correlate with more severe striatal dopamine deficiency in four-repeat (4R) tauopathies. Therefore, we correlated [18F]PI-2620 tau-positron-emission-tomography (PET) imaging with [123I]-Ioflupane single-photon-emission-computed tomography (SPECT) for dopamine transporter (DaT) availability. METHODS: Thirty-eight patients with clinically diagnosed 4R-tauopathies (21 male; 69.0 ± 8.5 years) and 15 patients with clinically diagnosed α-synucleinopathies (8 male; 66.1 ± 10.3 years) who underwent [18F]PI-2620 tau-PET and DaT-SPECT imaging with a time gap of 3 ± 5 months were evaluated. Regional Tau-PET signals and DaT availability as well as their principal components were correlated in patients with 4R-tauopathies and α-synucleinopathies. Both biomarkers and the residuals of their association were correlated with clinical severity scores in 4R-tauopathies. RESULTS: In patients with 4R-tauopathies, [18F]PI-2620 binding in basal ganglia and midbrain regions was negatively associated with striatal DaT availability (i.e. globus pallidus internus and putamen (ß = - 0.464, p = 0.006, Durbin-Watson statistics = 1.824) in a multiple regression model. Contrarily, [18F]PI-2620 binding in the dentate nucleus showed no significant regression factor with DaT availability in the striatum (ß = 0.078, p = 0.662, Durbin-Watson statistics = 1.686). Patients with α-synucleinopathies did not indicate any regional associations between [18F]PI-2620-binding and DaT availability. Higher DaT-SPECT binding relative to tau burden was associated with better clinical performance (ß = - 0.522, p = 0.011, Durbin-Watson statistics = 2.663) in patients with 4R-tauopathies. CONCLUSION: Tau burden in brain regions involved in dopaminergic pathways is associated with aggravated dopaminergic dysfunction in patients with clinically diagnosed primary tauopathies. The ability to sustain dopamine transmission despite tau accumulation may preserve motor function.

Association of Neurofilament Light Chain, [18F]PI-2620 Tau-PET, TSPO-PET, and Clinical Progression in Patients With ß-Amyloid-Negative CBS.

BACKGROUND AND OBJECTIVES: Corticobasal syndrome (CBS) with underlying 4-repeat tauopathy is a progressive neurodegenerative disease characterized by declining cognitive and motor functions. Biomarkers for assessing pathologic brain changes in CBS including tau-PET, 18 kDa translocator protein (TSPO)-PET, structural MRI, neurofilament light chain (NfL), or glial fibrillary acidic protein (GFAP) have recently been evaluated for differential diagnosis and disease staging, yet their association with disease trajectories remains unclear. Therefore, we performed a head-to-head comparison of neuroimaging (tau-PET, TSPO-PET, structural MRI) and plasma biomarkers (NfL, GFAP) as prognostic tools for longitudinal clinical trajectories in ß-amyloid (Aß)-negative CBS. METHODS: We included patients with clinically diagnosed Aß-negative CBS with clinical follow-up data who underwent baseline structural MRI and plasma-NfL analysis for assessing neurodegeneration, [18F]PI-2620-PET for assessing tau pathology, [18F]GE-180-PET for assessing microglia activation, and plasma-GFAP analysis for assessing astrocytosis. To quantify tau and microglia load, we assessed summary scores of whole-brain, cortical, and subcortical PET signal. For structural MRI analysis, we quantified subcortical and cortical gray matter volume. Plasma NfL and GFAP values were assessed using Simoa-based immunoassays. Symptom progression was determined using a battery of cognitive and motor tests (i.e., Progressive Supranuclear Palsy Rating Scale [PSPRS]). Using linear mixed models, we tested whether the assessed biomarkers at baseline were associated with faster symptom progression over time (i.e., time × biomarker interaction). RESULTS: Overall, 21 patients with Aß-negative CBS with ∼2-year clinical follow-up data were included. Patients with CBS with more widespread global tau-PET signal showed faster clinical progression (PSPRS: B/SE = 0.001/0.0005, p = 0.025), driven by cortical rather than subcortical tau-PET. By contrast, patients with higher global [18F]GE-180-PET readouts showed slower clinical progression (PSPRS: B/SE = -0.056/0.023, p = 0.019). No association was found between gray matter volume and clinical progression. Concerning fluid biomarkers, only higher plasma-NfL (PSPRS: B/SE = 0.176/0.046, p < 0.001) but not GFAP was associated with faster clinical deterioration. In a subsequent sensitivity analysis, we found that tau-PET, TSPO-PET, and plasma-NfL showed significant interaction effects with time on clinical trajectories when tested in the same model. DISCUSSION: [18F]PI-2620 tau-PET, [18F]GE-180 TSPO-PET, and plasma-NfL show prognostic potential for clinical progression in patients with Aß-negative CBS with probable 4-repeat tauopathy, which can be useful for clinical decision-making and stratifying patients in clinical trials.