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The blood–brain barrier (BBB) protects the brain but is also an important obstacle for the effective delivery of therapeutics in Alzheimer’s disease and other neurodegenerative disorders. Transcranial magnetic resonance-guided focused ultrasound (MRgFUS) has been shown to reversibly disrupt the BBB. However, treatment of diffuse regions across the brain along with the effect on Alzheimer’s disease relevant pathology need to be better characterized. This study is an open-labelled single-arm trial (NCT03739905) to investigate the feasibility of modulating BBB permeability in the default mode network and the impact on cognition, amyloid and tau pathology as well as BBB integrity. Nine participants [mean age 70.2 ± 7.2 years, mean Mini-Mental State Examination (MMSE) 21.9] underwent three biweekly procedures with follow-up visits up to 6 months. The BBB permeability of the bilateral hippocampi, anterior cingulate cortex and precuneus was transiently increased without grade 3 or higher adverse events. Participants did not experience worsening trajectory of cognitive decline (ADAS-cog11, MMSE). Whole brain vertex-based analysis of the 18F-florbetaben PET imaging demonstrated clusters of modest SUVR reduction in the right parahippocampal and inferior temporal lobe. However, CSF and blood biomarkers did not demonstrate any amelioration of Alzheimer’s disease pathology (P-tau181, amyloid-β42/40 ratio), nor did it show persistent BBB dysfunction (plasma PDGFRbeta and CSF-to-plasma albumin ratio). This study provides neuroimaging and fluid biomarker data to characterize the safety profile of MRgFUS BBB modulation in neurodegeneration as a potential strategy for enhanced therapeutic delivery.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aβ-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aβ-PET signal in WM regions. Here, we investigated the relative contributions of diffusion MRI-based microstructural alterations, including free water and tissue-specific properties, to Aβ-PET in WM and to cognition. We included a unique cohort of 115 participants covering the spectrum of low-to-severe white matter hyperintensity (WMH) burden and cognitively normal to dementia. We applied a bi-tensor diffusion-MRI model that differentiates between (i) the extracellular WM compartment (represented via free water), and (ii) the fiber-specific compartment (via free water-adjusted fractional anisotropy [FA]). We observed that, in regions of WMH, a decrease in Aβ-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aβ-PET related more closely to higher cortical Aβ (together with lower free water-adjusted FA). In relation to cognitive impairment, we observed a closer relationship with higher free water than with either free water-adjusted FA or WM PET. Our findings support free water and Aβ-PET as markers of WM abnormalities in patients with mixed dementia, and contribute to a better understanding of processes giving rise to the WM PET signal.

GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of the lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy in patients with PD. However, recombinant GCase has limited penetration through the blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt the BBB for drug delivery.This open-label phase I study investigated the safety and feasibility of MRgFUS putaminal delivery of intravenous GCase at escalating doses (15 to 30 to 60 IU/kg) every 2 weeks in four patients with PD with GBA1 mutations.BBB permeability was achieved and restored in all patients as quantified by dynamic contrast-enhanced magnetic resonance imaging after treatment. There were no serious adverse events. Two patients developed transient dyskinesia after treatment. Blinded Movement Disorder Society-Unified Parkinson's Disease Rating Scale motor scores off medication decreased by 12% at 6 months from baseline (from 26 ± 9 to 22 ± 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography imaging in the treated putamen reduced from 1.66 ± 0.14 to 1.27 ± 0.08.Results from this study demonstrate the safety and feasibility of MRgFUS GCase delivery in PD and support further investigation of this approach. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

INTRODUCTIONIt remains unclear to which extent vascular burden promotes neurodegeneration and cognitive dysfunction in a cohort spanning low-to-severe small vessel disease (SVD) and amyloid-beta pathology.METHODSIn 120 subjects, we investigated 1) whether vascular burden, quantified as total or lobar white matter hyperintensity (WMH) volumes, is associated with different cognitive domains; and 2) whether the total WMH effect on cognition is mediated by amyloid (18F-AV45-PET), glucose metabolism (18F-FDG-PET), and/or cortical atrophy.RESULTSIncreased total WMH volume was associated with poorer performance in all cognitive domains tested, with the strongest effects observed for semantic fluency. These relationships were mediated mainly through cortical atrophy, particularly in the temporal lobe, and to a lesser extent through amyloid and metabolism. WMH volumes differentially impacted cognition depending on lobar location and amyloid status.DISCUSSIONOur study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive impairment through temporal lobe atrophy.

Abnormal mitochondrial metabolism has been described in the Alzheimer's disease (AD) brain. However, the relationship between AD pathophysiology and key mitochondrial processes remains elusive. The purpose of this study was to investigate whether mitochondrial complex I dysfunction is associated with amyloid aggregation or glucose metabolism and brain atrophy in patients with mild AD using positron emission tomography (PET).Amyloid- and tau-positive symptomatic AD patients with clinical dementia rating 0.5 or 1 (N = 30; mean age ± standard deviation: 71.8 ± 7.6 years) underwent magnetic resonance imaging and PET scans with [[In symptomatic cases, although mitochondrial complex I reduction is linked to a wide range of downstream neurodegenerative processes such as hypometabolism, atrophy, and cognitive decline, a link to amyloid was not observable. The data presented here support [

Microglial activation and tau accumulation propagate together in patients with Alzheimer's disease, suggesting an interaction that determines disease progression. Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer's disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([C-11]PBR28), amyloid-beta (A beta) ([F-18]AZD4694) and tau ([F-18]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 (TREM2) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [C-11]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of A beta, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A beta and activated microglia sets the pace for tau spread across Braak stages.

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer’s disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer’s disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer’s disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer’s disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Activated microglia express the translocator protein (TSPO) on the outer mitochondrial membrane. 18F-PBR111 is a second-generation positron emission tomography (PET) ligand that specifically binds the TSPO, allowing in-vivo visualization and quantification of neuroinflammation. The aim of this study is to evaluate if the test-retest variability of 18F-PBR111 in healthy controls is acceptable to detect a psychosis-associated neuroinflammatory signal in schizophrenia. Methods: Dynamic 90-min 18F-PBR111 scans were obtained in 17 healthy male controls (HC) and 11 male schizophrenia patients during a psychotic episode (SP). Prior genotyping for the rs6917 polymorphism distinguished high- (HAB) and mixed-affinity binders (MAB). Total volume of distribution (VT) was determined from two-tissue compartment modeling with vascular trapping and a metabolite-corrected plasma input function. A subgroup of HCs (n = 12; 4 HAB and 8 MAB) was scanned twice to assess absolute test-retest variability and intraclass correlation coefficients (ICC) of the regional VT values. Differences in TSPO binding between HC and SP were assessed using mixed model analysis adjusting for age, genotype and age*cohort. The effect of using different scan durations (VT-60min versus VT-90min) was determined based on Pearsons r. Data was presented as mean ± SD. Results: Mean absolute variability in VT ranged from 16 ± 14% (19 ± 20% HAB; 15 ± 11% MAB) in the cortical gray matter to 22 ± 15% (23 ± 15% HAB; 22 ± 16% MAB) in the hippocampus. ICCs were consistently between 0.64 0.82 for all tested regions. TSPO binding in SP compared to HC depended on age (cohort*age: P < 0.05) and was increased by +14 ± 4% over the regions. There was a significant effect of genotype on TSPO binding, and VT of HABs was 30 ± 8% (HC: 17 ± 5%, SP: 55 ± 13%) higher than MABs. Across all clinical groups, VT-60min and VT-90min were strongly correlated (r > 0.7, P < 0.0001). Conclusion: 18F-PBR111 can be used for monitoring of TSPO binding, as shown by medium test-retest variability and reliability of VT in HCs. Microglial activation is present in SPs depending on age and needs to be adjusted for genotype.

Objective To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers. Method Second-generation radioligand [18F]-PBR111 TSPO PET-CT was used for longitudinal dynamic imaging in 14 male psychosis patients and 17 male age-matched healthy control subjects. Patients were first scanned during an acute psychotic episode followed by a second scan after treatment. Prior genotyping of subjects for the rs6917 polymorphism distinguished high- and mixed-affinity binders. The main outcome was regional volume of distribution (VT), representing TSPO binding. Plasma concentrations of CRP, cytokines and kynurenines were measured at each timepoint. Results We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in VT existed between cohorts during the psychotic state, but not at follow-up. Patients’ relative change in VT over time correlated with age (cortical grey matter Pearson’s r.574). PANSS positive subscale scores correlated with regional VT during psychosis (cortical grey matter r.767). Plasma CRP and quinolinic acid were independently associated with lower VT. Conclusions We identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18F-FDG SUVR. CSF measures included Aβ1–42, Aβ1–40, T-tau, P-tau181, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p, Highlights • FDG-PET and MRI HV are the strongest predictors of cognitive decline and conversion to AD. • Combination of visuospatial construction testing with FDG-PET or MRI HV present high predicting power of conversion. • CSF and amyloid-PET seem less suitable markers of disease progression. • Increased AV45-PET predicts short-term cognitive decline if SUVR is referenced to WM instead of CB.

Introduction Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18F-florbetapir (eAV45), the 18F-AV45 delivery rate (R1), and 18F-FDG against 15O-H2O PET and assess how they change with disease severity. Methods This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed. Results FDG standardized uptake value ratio, eAV45 (0–2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H2O PET (regional Pearson r = 0.54–0.82, 0.70–0.94, and 0.65–0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36–0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG. Discussion R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD.

Background Treatment targeting the immune system is a promising new approach in schizophrenia. In search for tools for stratification and treatment monitoring, much effort has been invested in the use of positron emission tomography (PET) and radioligands binding to a glial marker, the 18 kDa translocator protein (TSPO). We previously demonstrated lower TSPO in psychosis patients in an individual participant data (IPD) meta-analysis of studies using second generation TSPO radioligands (Plavén-Sigray et al., 2018). Subsequently, a summary-statistics meta-analysis, including one newly published study, showed no difference (Marques et al., 2019). Here, the aim was to repeat the IPD analysis including this new sample, and an additional unpublished dataset in first episode psychosis patients. The primary objective was to re-evaluate the hypotheses of 1) higher or 2) lower or 3) no difference in radioligand binding between patients and healthy control subjects. Secondary objectives were to assess the effects of antipsychotic medication on TSPO binding, as well as relationships between TSPO binding and disease duration and symptom measures. Methods Individual participant data were obtained from PET studies that 1) used a second generation TSPO radioligand, 2) reported distribution volume (VT) values in brain in patients with psychosis as compared to healthy controls, and 3) reported TSPO affinity type of all participants. The outcome measure was VT in frontal cortex (FC), temporal cortex (TC) and hippocampus (HIP). Bayes factors (BF) were applied to examine the relative support for higher, lower, or no-change of TSPO levels in patients compared to healthy controls. Results Individual participant data from seven studies were included, amounting to 99 patients with first-episode psychosis or schizophrenia and 109 healthy control subjects. In all regions investigated, BF showed moderate to strong support (BF > 5) for lower VT in patients as compared to no difference, and strong support (BF > 10) for lower VT compared to higher VT in patients. Mean patient-control differences in standardized VT values were -0.41 for FC (95%CI -0.67 to -0.15, p = 0.0022), -0.38 for TC (95%CI -0.64 to -0.12, p = 0.0048) and -0.53 for HIP (95% CI -0.79 to -0.27, p = 0.0001). The mean change in standardized VT due to medication was 0.10 for FC (CI95% -0.10 to 0.30, p = 0.615), -0.08 for TC (CI95% -0.32 to 0.48, p = 0.666) and 0.08 for HIP (CI95% -0.46 to 0.30, p = 0.682). No association was observed between VT and disease duration or symptom levels (all p > 0.526). Discussion In this updated IPD meta-analysis including two new datasets, we found moderate to strong support for lower TSPO in psychosis patients compared to control subjects. In vitro data has shown a lack of correspondence between TSPO and pro-inflammatory activation, also recently confirmed in a post-mortem study in schizophrenia. Hence, based on the present results no firm conclusions can be made regarding the pro- versus anti-inflammatory status of glial cells in psychosis patients. Additional work is needed to understand the biological relevance of the observed lower TSPO in patients.

To determine whether state-associated changes in microglial activity, measured with translocator-protein positron emission tomography (TSPO PET), can be identified in psychosis patients through longitudinal evaluation of their regional tracer uptake over the clinical course from acute psychosis to post-treatment follow-up, and comparison to healthy controls. We also evaluated the relation between tracer uptake, clinical symptoms and peripheral immunological markers.Second-generation radioligand [We found a significant three-way interaction between time of scan, age and cohort (cortical grey matter F6.50, p.020). Age-dependent differences in VWe identified a differential age-dependent pattern of TSPO binding from psychosis to follow-up in our cohort of male psychosis patients. We recommend future TSPO PET studies in psychosis patients to differentiate between clinical states and consider potential age-related effects.

Increased brain uptake of [18F]-AV45 visualized by PET is a key biomarker for Alzheimers disease (AD). The standardized uptake value ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (VT) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min [18F]-AV45 (291 ± 67 MBq) and 1-min [15O]-H2O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD dementia, 15 amnestic mild cognitive impairment (aMCI) and 10 cognitively healthy controls (HC). [18F]-AV45 VT was determined from two-tissue compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min p.i., using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as reference. Additionally, whole cerebellum, pons, centrum semiovale and a composite region were examined as alternative references. Blood flow was quantified by [15O]-H2O SUV. Data are presented as mean ± standard error of the mean (SEM). Results: There was rapid metabolization of [18F]-AV45 with only 35% of unchanged parent remaining at 10 minutes. Compared to VT, differences in cortical Aβ-load between aMCI and AD were overestimated by SUVRWM (+4 ± 2%) and underestimated by SUVRCB (-10 ± 2%). VT correlated better with SUVRWM (Pearsons r: from 0.63 for posterior cingulate to 0.89 for precuneus, p < 0.0001) than with SUVRCB (Pearsons r: from 0.51 for temporal lobe (p = 0.002) to 0.82 for precuneus (p < 0.0001)) in all tested regions. Correlation results for the alternative references were in-between those for CB and WM. [15O]-H2O data showed that blood flow was decreased in AD compared to aMCI in cortical regions (-5 ± 1%) and in the reference regions (CB: -9 ± 8%, WM: -8 ± 8%). Conclusion: Increased brain uptake of [18F]-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-beta (A beta) increases when the CSF A beta(1-42)/A beta(1-40) ratio is used as compared to CSF A beta(1-42) levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [F-18] Florbetapir ([F-18]AV45) PET scan, [F-18] FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A beta(1-42), A beta(1-40), T-tau, P-tau(181)). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [F-18]AV45 PET measures when the CSF A beta(1-42)/A beta(1-40) was applied compared to A beta(1-42) alone. CSF biomarkers were stronger associated to [F-18]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusion: The concordance between CSF A beta and [F-18]AV45 PET increases when the CSF A beta(1-42)/A beta(1-40) ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Increased brain uptake of