Blood-brain barrier opening of the default mode network in Alzheimer's disease with magnetic resonance-guided focused ultrasound.

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 (NCT04118764) 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-ß42/40 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.

Investigating the impact of hypertension with and without diabetes on Alzheimer's disease risk: A clinico-pathological study.

INTRODUCTION: Hypertension and diabetes are common cardiovascular risk factors that increase Alzheimer's disease (AD) risk. However, it is unclear whether AD risk differs in hypertensive individuals with and without diabetes. METHODS: Cognitively normal individuals (N = 11,074) from the National Alzheimer's Coordinating Center (NACC) were categorized as having (1) hypertension with diabetes (HTN+/DM+), (2) hypertension without diabetes (HTN+/DM-), or (3) neither (HTN-/DM-). AD risk in HTN+/DM+ and HTN+/DM- was compared to HTN-/DM-. This risk was then investigated in those with AD neuropathology (ADNP), cerebral amyloid angiopathy (CAA), cerebrovascular neuropathology (CVNP), arteriolosclerosis, and atherosclerosis. Finally, AD risk in HTN-/DM+ was compared to HTN-/DM-. RESULTS: Seven percent (N = 830) of individuals developed AD. HTN+/DM+ (hazard ratio [HR] = 1.31 [1.19-1.44]) and HTN+/DM- (HR = 1.24 [1.17-1.32]) increased AD risk compared to HTN-/DM-. AD risk was greater in HTN+/DM+ with ADNP (HR = 2.10 [1.16-3.79]) and CAA (HR = 1.52 [1.09-2.12]), and in HTN+/DM- with CVNP (HR = 1.54 [1.17-2.03]). HTN-/DM+ also increased AD risk (HR = 1.88 [1.30-2.72]) compared to HTN-/DM-. DISCUSSION: HTN+/DM+ and HTN+/DM- increased AD risk compared to HTN-/DM-, but pathological differences between groups suggest targeted therapies may be warranted based on cardiovascular risk profiles. HIGHLIGHTS: AD risk was studied in hypertensive (HTN+) individuals with/without diabetes (DM+/-). HTN+/DM+ and HTN+/DM- both had an increased risk of AD compared to HTN-/DM-. Post mortem analysis identified neuropathological differences between HTN+/DM+ and HTN+/DM-. In HTN+/DM+, AD risk was greater in those with AD neuropathology and CAA. In HTN+/DM-, AD risk was greater in those with cerebrovascular neuropathology.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Perivascular spaces, plasma GFAP, and speeded executive function in neurodegenerative diseases.

INTRODUCTION: We investigated the effect of perivascular spaces (PVS) volume on speeded executive function (sEF), as mediated by white matter hyperintensities (WMH) volume and plasma glial fibrillary acidic protein (GFAP) in neurodegenerative diseases. METHODS: A mediation analysis was performed to assess the relationship between neuroimaging markers and plasma biomarkers on sEF in 333 participants clinically diagnosed with Alzheimer's disease/mild cognitive impairment, frontotemporal dementia, or cerebrovascular disease from the Ontario Neurodegenerative Disease Research Initiative. RESULTS: PVS was significantly associated with sEF (c = -0.125 ± 0.054, 95% bootstrap confidence interval [CI] [-0.2309, -0.0189], p = 0.021). This effect was mediated by both GFAP and WMH. DISCUSSION: In this unique clinical cohort of neurodegenerative diseases, we demonstrated that the effect of PVS on sEF was mediated by the presence of elevated plasma GFAP and white matter disease. These findings highlight the potential utility of imaging and plasma biomarkers in the current landscape of therapeutics targeting dementia. HIGHLIGHTS: Perivascular spaces (PVS) and white matter hyperintensities (WMH) are imaging markers of small vessel disease. Plasma glial fibrillary protein acidic protein (GFAP) is a biomarker of astroglial injury. PVS, WMH, and GFAP are relevant in executive dysfunction from neurodegeneration. PVS's effect on executive function was mediated by GFAP and white matter disease.

TSPO PET brain inflammation imaging: A transdiagnostic systematic review and meta-analysis of 156 case-control studies.

INTRODUCTION: The 18-kDa translocator protein (TSPO) is increasingly recognized as a molecular target for PET imaging of inflammatory responses in various central nervous system (CNS) disorders. However, the reported sensitivity and specificity of TSPO PET to identify brain inflammatory processes appears to vary greatly across disorders, disease stages, and applied quantification methods. To advance TSPO PET as a potential biomarker to evaluate brain inflammation and anti-inflammatory therapies, a better understanding of its applicability across disorders is needed. We conducted a transdiagnostic systematic review and meta-analysis of all in vivo human TSPO PET imaging case-control studies in the CNS. Specifically, we investigated the direction, strength, and heterogeneity associated with the TSPO PET signal across disorders in pre-specified brain regions, and explored the demographic and methodological sources of heterogeneity. METHODS: We searched for English peer-reviewed articles that reported in vivo human case-control TSPO PET differences. We extracted the demographic details, TSPO PET outcomes, and technical variables of the PET procedure. A random-effects meta-analysis was applied to estimate case-control standardized mean differences (SMD) of the TSPO PET signal in the lobar/whole-brain cortical grey matter (cGM), thalamus, and cortico-limbic circuitry between different illness categories. Heterogeneity was evaluated with the I2 statistic and explored using subgroup and meta-regression analyses for radioligand generation, PET quantification method, age, sex, and publication year. Significance was set at the False Discovery Rate (FDR)-corrected P < 0.05. RESULTS: 156 individual case-control studies were included in the systematic review, incorporating data for 2381 healthy controls and 2626 patients. 139 studies documented meta-analysable data and were grouped into 11 illness categories. Across all the illness categories, we observed a significantly higher TSPO PET signal in cases compared to controls for the cGM (n = 121 studies, SMD = 0.358, PFDR < 0.001, I2 = 68%), with a significant difference between the illness categories (P = 0.004). cGM increases were only significant for Alzheimer's disease (SMD = 0.693, PFDR < 0.001, I2 = 64%) and other neurodegenerative disorders (SMD = 0.929, PFDR < 0.001, I2 = 73%). Cortico-limbic increases (n = 97 studies, SMD = 0.541, P < 0.001, I2 = 67%) were most prominent for Alzheimer's disease, mild cognitive impairment, other neurodegenerative disorders, mood disorders and multiple sclerosis. Thalamic involvement (n = 79 studies, SMD = 0.393, P < 0.001, I2 = 71%) was observed for Alzheimer's disease, other neurodegenerative disorders, multiple sclerosis, and chronic pain and functional disorders (all PFDR < 0.05). Main outcomes for systemic immunological disorders, viral infections, substance use disorders, schizophrenia and traumatic brain injury were not significant. We identified multiple sources of between-study variance to the TSPO PET signal including a strong transdiagnostic effect of the quantification method (explaining 25% of between-study variance; VT-based SMD = 0.000 versus reference tissue-based studies SMD = 0.630; F = 20.49, df = 1;103, P < 0.001), patient age (9% of variance), and radioligand generation (5% of variance). CONCLUSION: This study is the first overarching transdiagnostic meta-analysis of case-control TSPO PET findings in humans across several brain regions. We observed robust increases in the TSPO signal for specific types of disorders, which were widespread or focal depending on illness category. We also found a large and transdiagnostic horizontal (positive) shift of the effect estimates of reference tissue-based compared to VT-based studies. Our results can support future studies to optimize experimental design and power calculations, by taking into account the type of disorder, brain region-of-interest, radioligand, and quantification method.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance-Guided Focused Ultrasound in Parkinson's Disease: A Phase I Study.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Mitochondrial complex I abnormalities underlie neurodegeneration and cognitive decline in Alzheimer's disease.

BACKGROUND AND PURPOSE: 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). METHODS: 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 [18 F]2-tert-butyl-4-chloro-5-2H-pyridazin-3-one (BCPP-EF), [11 C]Pittsburgh Compound-B (PiB) and [18 F]fluorodeoxyglucose (FDG) to assess brain atrophy, mitochondrial complex I dysfunction, amyloid deposition, and glucose metabolism, respectively. Local cortical associations among these biomarkers and gray matter volume were evaluated with voxel-based regressions models. RESULTS: [18 F]BCPP-EF standardized uptake value ratio (SUVR) was positively correlated with [18 F]FDG SUVR in the widespread brain area, while its associations with gray matter volume were restricted to the parahippocampal gyrus. Reductions in [18 F]BCPP-EF SUVR were associated with domain-specific cognitive performance. We did not observe regional associations between mitochondrial dysfunction and amyloid burden. CONCLUSIONS: 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 [18 F]BCPP-EF as an excellent imaging tool to investigate mitochondrial dysfunction in AD.

State-associated changes in longitudinal [18F]-PBR111 TSPO PET imaging of psychosis patients: Evidence for the accelerated ageing hypothesis?

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.

18F-FDG PET, the early phases and the delivery rate of 18F-AV45 PET as proxies of cerebral blood flow in Alzheimer's disease: Validation against 15O-H2O PET.

INTRODUCTION: Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-ß 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.

Microglial Positron Emission Tomography Imaging In Vivo : Positron Emission Tomography Radioligands: Utility in Research and Clinical Practice.

Microglia, the resident immune cells of the central nervous system (CNS) play a key role in regulating and maintaining homeostasis in the brain. However, the CNS is also vulnerable to infections and inflammatory processes. In response to CNS perturbations, microglia become reactive, notably with expression of the translocator protein (TSPO), primarily on their outer mitochondrial membrane. Despite TSPO being commonly used as a marker for microglia, it is also present in other cell types such as astrocytes. Positron emission tomography (PET) ligands that target the TSPO enable the noninvasive detection and quantification of glial reactivity. While some limitations were raised, TSPO PET remains an attractive biomarker of CNS infection and inflammation. This book chapter delves into the development and application of microglial PET imaging with a focus on the TSPO PET. First, we provide an overview of the evolution of TSPO PET radioligands from first-generation to second-generation ligands and their applications in studying neuroinflammation (or CNS inflammation). Subsequently, we discuss the limitations and challenges associated with TSPO PET. Then we go on to explore non-TSPO targets for microglial PET imaging. Finally, we conclude with future directions for research and clinical practice in this field.

Tau follows principal axes of functional and structural brain organization in Alzheimer's disease.

Alzheimer's disease (AD) is a brain network disorder where pathological proteins accumulate through networks and drive cognitive decline. Yet, the role of network connectivity in facilitating this accumulation remains unclear. Using in-vivo multimodal imaging, we show that the distribution of tau and reactive microglia in humans follows spatial patterns of connectivity variation, the so-called gradients of brain organization. Notably, less distinct connectivity patterns ("gradient contraction") are associated with cognitive decline in regions with greater tau, suggesting an interaction between reduced network differentiation and tau on cognition. Furthermore, by modeling tau in subject-specific gradient space, we demonstrate that tau accumulation in the frontoparietal and temporo-occipital cortices is associated with greater baseline tau within their functionally and structurally connected hubs, respectively. Our work unveils a role for both functional and structural brain organization in pathology accumulation in AD, and supports subject-specific gradient space as a promising tool to map disease progression.

Amyloid-PET of the white matter: Relationship to free water, fiber integrity, and cognition in patients with dementia and small vessel disease.

White matter (WM) injury is frequently observed along with dementia. Positron emission tomography with amyloid-ligands (Aß-PET) recently gained interest for detecting WM injury. Yet, little is understood about the origin of the altered Aß-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 Aß-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 Aß-PET related most closely to higher free water and higher WMH volume. In contrast, in normal-appearing WM, an increase in Aß-PET related more closely to higher cortical Aß (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 Aß-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.

Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-ß 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-ß 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-ß levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-ß42/40 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.

Microglial activation and tau propagate jointly across Braak stages.

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 ([11C]PBR28), amyloid-ß (Aß) ([18F]AZD4694) and tau ([18F]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 [11C]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 Aß, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aß and activated microglia sets the pace for tau spread across Braak stages.

Association of short-term cognitive decline and MCI-to-AD dementia conversion with CSF, MRI, amyloid- and 18F-FDG-PET imaging.

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-ß (Aß) 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 Aß1-42, Aß1-40, 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: ß = +0.43 [p < 0.001] and + 0.37 [p = 0.005], resp.) at baseline. In addition, faster cognitive decline was significantly associated with higher baseline Aß burden only if SUVR was referenced to the subcortical white matter (e.g., Δstory recall: ß = -0.28 [p = 0.020]). Patients with MCI converted to AD dementia at an annual rate of 31%, which could be best predicted by combining neuropsychological testing (visuospatial construction skills) with either MRI-based HV or 18F-FDG-PET. Combining all three markers resulted in 96% specificity and 92% sensitivity. Neither amyloid-PET nor CSF biomarkers could discriminate short-term converters from non-converters.

18F-PBR111 PET Imaging in Healthy Controls and Schizophrenia: Test-Retest Reproducibility and Quantification of Neuroinflammation.

Activated microglia express the translocator protein (TSPO) on the outer mitochondrial membrane. 18F-PBR111 is a second-generation PET ligand that specifically binds the TSPO, allowing in vivo visualization and quantification of neuroinflammation. The aim of this study was to evaluate whether 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 (HCs) and 11 male schizophrenia patients (SPs) during a psychotic episode. Prior genotyping for the rs6917 polymorphism distinguished high-affinity binders (HABs) and mixed-affinity binders (MABs). Total volume of distribution (VT) was determined from 2-tissue-compartment modeling with vascular trapping and a metabolite-corrected plasma input function. A subgroup of HCs (n = 12; 4 HABs and 8 MABs) was scanned twice to assess absolute test-retest variability and intraclass correlation coefficients 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-60 min versus VT-90 min) was determined based on Pearson r. Data were 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. Intraclass correlation coefficients were consistently between 0.64 and 0.82 for all tested regions. TSPO binding in SP compared with 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 31% ± 8% (HC: 17% ± 5%, SP: 61% ± 14%) higher than MABs. Across all clinical groups, VT-60 min and VT-90 min 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.

A simulation study on the impact of the blood flow-dependent component in [18F]AV45 SUVR in Alzheimer's disease.

BACKGROUND: Increased brain uptake on [18F]AV45 PET is a biomarker for Alzheimer's disease (AD). The standardised uptake value ratio (SUVR) is widely used for quantification but is subject to variability. Here we evaluate how SUVR of a cortical target region is affected by blood flow changes in the target and two frequently used reference regions. METHODS: Regional baseline time-activity curves (TACs) were simulated based on metabolite-corrected plasma input functions and pharmacokinetic parameters obtained from our previously acquired data in healthy control (HC; n = 10), amnestic mild cognitive impairment (aMCI; n = 15) and AD cohorts (n = 9). Blood flow changes were simulated by altering the regional tracer delivery rate K1 (and clearance rate k2) between -40% and +40% from its regional baseline value in the target region and/or cerebellar grey (CB) or subcortical white matter (WM) reference regions. The corresponding change in SUVR was calculated at 50-60 min post-injection. RESULTS: A -40% blood flow reduction in the target resulted in an increased SUVRtarget (e.g. SUVRprecuneus: +10.0±5% in HC, +2.5±2% in AD), irrespective of the used reference region. A -40% blood flow reduction in the WM reference region increased SUVRWM (+11.5±4% in HC, +13.5±3% in AD) while a blood flow reduction in CB decreased SUVRCB (-9.5±6% in HC, -5.5±2% in AD), irrespective of the used target region. A -40% flow reduction in both the precuneus and reference WM (i.e., global flow change) induced an increased SUVR (+22.5±8% in HC, +16.0±4% in AD). When considering reference CB instead, SUVR was decreased by less than -5% (both in HC and AD). CONCLUSION: Blood flow changes introduce alterations in [18F]AV45 PET SUVR. Flow reductions in the CB and WM reference regions resulted in a decreased and increased SUVR of the target, respectively. SUVR was more affected by global blood flow changes when considering WM instead of CB normalization.

Validation of the Semiquantitative Static SUVR Method for 18F-AV45 PET by Pharmacokinetic Modeling with an Arterial Input Function.

Increased brain uptake of 18F-AV45 visualized by PET is a key biomarker for Alzheimer disease (AD). The SUV 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, 15 amnestic mild cognitive impairment (aMCI), and 10 cognitively healthy controls (HCs). 18F-AV45 VT was determined from 2-tissue-compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min after injection, using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as the 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 ± SEM. Results: There was rapid metabolization of 18F-AV45, with only 35% of unchanged parent remaining at 10 min. Compared with VT, differences in cortical Aß load between aMCI and AD were overestimated by SUVRWM (+4% ± 2%) and underestimated by SUVRCB (-10% ± 2%). VT correlated better with SUVRWM (Pearson r: from 0.63 for posterior cingulate to 0.89 for precuneus, P < 0.0001) than with SUVRCB (Pearson 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 with 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 Aß load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.