Plasma biomarker profiles in autosomal dominant Alzheimer's disease.

Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.

Age, sex and APOE-ε4 modify the balance between soluble and fibrillar ß-amyloid in non-demented individuals: topographical patterns across two independent cohorts.

Amyloid (Aß) pathology is the earliest detectable pathophysiological event along the Alzheimer's continuum, which can be measured both in the cerebrospinal fluid (CSF) and by Positron Emission Tomography (PET). Yet, these biomarkers identify two distinct Aß pools, reflecting the clearance of soluble Aß as opposed to the presence of Aß fibrils in the brain. An open question is whether risk factors known to increase Alzheimer's' disease (AD) prevalence may promote an imbalance between soluble and deposited Aß. Unveiling such interactions shall aid our understanding of the biological pathways underlying Aß deposition and foster the design of effective prevention strategies. We assessed the impact of three major AD risk factors, such as age, APOE-ε4 and female sex, on the association between CSF and PET Aß, in two independent samples of non-demented individuals (ALFA: n = 320, ADNI: n = 682). We tested our hypotheses both in candidate regions of interest and in the whole brain using voxel-wise non-parametric permutations. All of the assessed risk factors induced a higher Aß deposition for any given level of CSF Aß42/40, although in distinct cerebral topologies. While age and sex mapped onto neocortical areas, the effect of APOE-ε4 was prominent in the medial temporal lobe, which represents a target of early tau deposition. Further, we found that the effects of age and APOE-ε4 was stronger in women than in men. Our data indicate that specific AD risk factors affect the spatial patterns of cerebral Aß aggregation, with APOE-ε4 possibly facilitating a co-localization between Aß and tau along the disease continuum.

Longitudinal pathways of cerebrospinal fluid and positron emission tomography biomarkers of amyloid-ß positivity.

Mismatch between CSF and PET amyloid-ß biomarkers occurs in up to ≈20% of preclinical/prodromal Alzheimer's disease individuals. Factors underlying mismatching results remain unclear. In this study we hypothesized that CSF/PET discordance provides unique biological/clinical information. To test this hypothesis, we investigated non-demented and demented participants with CSF amyloid-ß42 and [18F]Florbetapir PET assessments at baseline (n = 867) and at 2-year follow-up (n = 289). Longitudinal trajectories of amyloid-ß positivity were tracked simultaneously for CSF and PET biomarkers. In the longitudinal cohort (n = 289), we found that participants with normal CSF/PET amyloid-ß biomarkers progressed more frequently toward CSF/PET discordance than to full CSF/PET positivity (χ2(1) = 5.40; p < 0.05). Progression to CSF+/PET+ status was ten times more frequent in cases with discordant biomarkers, as compared to csf-/pet- cases (χ2(1) = 18.86; p < 0.001). Compared to the CSF+/pet- group, the csf-/PET+ group had lower APOE-ε4ε4 prevalence (χ2(6) = 197; p < 0.001; n = 867) and slower rate of brain amyloid-ß accumulation (F(3,600) = 12.76; p < 0.001; n = 608). These results demonstrate that biomarker discordance is a typical stage in the natural history of amyloid-ß accumulation, with CSF or PET becoming abnormal first and not concurrently. Therefore, biomarker discordance allows for identification of individuals with elevated risk of progression toward fully abnormal amyloid-ß biomarkers, with subsequent risk of neurodegeneration and cognitive decline. Our results also suggest that there are two alternative pathways ("CSF-first" vs. "PET-first") toward established amyloid-ß pathology, characterized by different genetic profiles and rates of amyloid-ß accumulation. In conclusion, CSF and PET amyloid-ß biomarkers provide distinct information, with potential implications for their use as biomarkers in clinical trials.

Association of cortical microstructure with amyloid-ß and tau: impact on cognitive decline, neurodegeneration, and clinical progression in older adults.

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-ß and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11C-Pittsburgh compound-B-PET, 18F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-ß, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-ß, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-ß, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-ß and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-ß, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials.

Clinical impact of 18F-FDG-PET among memory clinic patients with uncertain diagnosis.

PURPOSE: To assess the clinical impact and incremental diagnostic value of 18F-fluorodeoxyglucose (FDG-PET) among memory clinic patients with uncertain diagnosis. METHODS: The study population consisted of 277 patients who, despite extensive baseline cognitive assessment, MRI, and CSF analyses, had an uncertain diagnosis of mild cognitive impairment (MCI) (n = 177) or dementia (n = 100). After baseline diagnosis, each patient underwent an FDG-PET, followed by a post-FDG-PET diagnosis formulation. We evaluated (i) the change in diagnosis (baseline vs. post-FDG-PET), (ii) the change in diagnostic accuracy when comparing each baseline and post-FDG-PET diagnosis to a long-term follow-up (3.6 ± 1.8 years) diagnosis used as reference, and (iii) comparative FDG-PET performance testing in MCI and dementia conditions. RESULTS: FDG-PET led to a change in diagnosis in 86 of 277 (31%) patients, in particular in 57 of 177 (32%) MCI and in 29 of 100 (29%) dementia patients. Diagnostic change was greater than two-fold in the sub-sample of cases with dementia "of unclear etiology" (change in diagnosis in 20 of 32 (63%) patients). In the dementia group, after results of FDG-PET, diagnostic accuracy improved from 77 to 90% in Alzheimer's disease (AD) and from 85 to 94% in frontotemporal lobar degeneration (FTLD) patients (p < 0.01). FDG-PET performed better in dementia than in MCI (positive likelihood ratios >5 and < 5, respectively). CONCLUSION: Within a selected clinical population, FDG-PET has a significant clinical impact, both in early and differential diagnosis of uncertain dementia. FDG-PET provides significant incremental value to detect AD and FTLD over a clinical diagnosis of uncertain dementia.

Tau PET imaging in neurodegenerative tauopathies-still a challenge.

The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.g., [18F]THK5317, [18F]THK5351, [18F]AV1451, and [11C]PBB3) and second-generation compounds [namely [18F]MK-6240, [18F]RO-948 (previously referred to as [18F]RO69558948), [18F]PI-2620, [18F]GTP1, [18F]PM-PBB3, and [18F]JNJ64349311 ([18F]JNJ311) and its derivative [18F]JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-ß and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.

Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer's disease.

Neuroinflammation, as defined by the activation of microglia and astrocytes, has emerged in the last years as a key element of the pathogenesis of neurodegenerative diseases based on genetic findings and preclinical and human studies. This has raised the need for new methodologies to assess and follow glial activation in patients, prompting the development of PET ligands for molecular imaging of glial cells and novel structural MRI and DTI tools leading to a multimodal approach. The present review describes the recent advancements in microglia and astrocyte biology in the context of health, ageing, and Alzheimer's disease, the most common dementia worldwide. The review further delves in molecular imaging discussing the challenges associated with past and present targets, including conflicting findings, and finally, presenting novel methodologies currently explored to improve our in vivo knowledge of the neuroinflammatory patterns in Alzheimer's disease. With glial cell activation as a potential therapeutic target in neurodegenerative diseases, the translational research between cell biologists, chemists, physicists, radiologists, and neurologists should be strengthened.

Longitudinal association between astrocyte function and glucose metabolism in autosomal dominant Alzheimer's disease.

PURPOSE: The spatial resolution of 18F-fluorodeoxyglucose PET does not allow the specific cellular origin of its signal to be determined, but it is commonly accepted that transport and trapping of 18F-fluorodeoxyglucose reflects neuronal glucose metabolism. The main frameworks for the diagnosis of Alzheimer's disease suggest that hypometabolism measured with 18F-fluorodeoxyglucose PET is a biomarker of neuronal injury and neurodegeneration. There is preclinical evidence to suggest that astrocytes contribute, at least partially, to the in vivo 18F-fluorodeoxyglucose PET signal. However, due to a paucity of PET tracers for imaging astrocytic processes, the relationship between astrocyte function and glucose metabolism in human brain is not fully understood. The aim of this study was to investigate the longitudinal association between astrocyte function and glucose metabolism in Alzheimer's disease. METHODS: The current investigation combined longitudinal PET data from patients with autosomal dominant Alzheimer's disease, including data on astrocyte function (11C-deuterium-L-deprenyl binding) and glucose metabolism (18F-fluorodeoxyglucose uptake). Research participants included 7 presymptomatic and 4 symptomatic mutation carriers (age 44.9 ± 9.8 years and 58.0 ± 3.7 years, respectively) and 16 noncarriers (age 51.1 ± 14.2 years). Eight carriers and eight noncarriers underwent longitudinal follow-up PET imaging at an average of 2.8 ± 0.2 and 3.0 ± 0.5 years from baseline, respectively. RESULTS: Longitudinal decline in astrocyte function as measured using 11C-deuterium-L-deprenyl PET was significantly associated with progressive hypometabolism (18F-fluorodeoxyglucose uptake) in mutation carriers; no significant association was observed in noncarriers. CONCLUSION: The emerging data shift the accepted wisdom that decreases in cerebral metabolism measured with 18F-fluorodeoxyglucose solely reflect neuronal injury, and places astrocytes more centrally in the development of Alzheimer's disease.

Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging.

PURPOSE: Several tracers have been designed for tracking the abnormal accumulation of tau pathology in vivo. Recently, concerns have been raised about the sources of off-target binding for these tracers; inconclusive data propose binding for some tracers to monoamine oxidase B (MAO-B). METHODS: Molecular docking and dynamics simulations were used to estimate the affinity and free energy for the binding of several tau tracers (FDDNP, THK523, THK5105, THK5317, THK5351, T807 [aka AV-1451, flortaucipir], T808, PBB3, RO-948, MK-6240, JNJ-311 and PI-2620) to MAO-B. These values were then compared with those for safinamide (MAO-B inhibitor). PET imaging was used with the tau tracer [18F]THK5317 and the MAO-B tracer [11C]DED in five patients with Alzheimer's disease to investigate the MAO-B binding component of this first generation tau tracer in vivo. RESULTS: The computational modelling studies identified a binding site for all the tau tracers on MAO-B; this was the same site as that for safinamide. The binding affinity and free energy of binding for the tau tracers to MAO-B was substantial and in a similar range to those for safinamide. The most recently developed tau tracers MK-6240, JNJ-311 and PI-2620 appeared, in silico, to have the lowest relative affinity for MAO-B. The in vivo investigations found that the regional distribution of binding for [18F]THK5317 was different from that for [11C]DED, although areas of suspected off-target [18F]THK5317 binding were detected. The binding relationship between [18F]THK5317 and [11C]DED depended on the availability of the MAO-B enzyme. CONCLUSIONS: The developed tau tracers show in silico and in vivo evidence of cross-interaction with MAO-B; the MAO-B component of the tracer binding was dependent on the regional concentration of the enzyme.

Associations Between APOE Variants, Tau and α-Synuclein.

Neurodegenerative diseases are characterized by the aggregation and deposition of misfolded proteins in the brain, most prominently amyloid-ß (Aß), tau and α-synuclein (α-syn), and are thus referred to as proteinopathies. While tau is a hallmark of Alzheimer's disease (AD) and other non-AD tauopathies, and α-synuclein is the pathological feature of the spectrum of synucleinopathies including Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB), the presence of co-pathologies is very frequent in all these diseases. Positive and synergistic associations between the different types of protein deposits have been reported, leading to worse prognosis and cognitive decline. A large variation in phenotypic clinical presentation of these diseases, largely due to the frequent presence of co-pathologies, makes differential diagnosis challenging. The observed clinico-pathological overlaps suggest common underlying mechanisms, in part due to shared genetic risk factors. The ε4 allele of the apolipoprotein (APOE) gene is one of the major genetic risk factors for the sporadic forms of proteinopathies, but the biological mechanisms linking APOE, tau and α-syn are not fully understood. This chapter describes current experimental evidence on the relationships between APOE variants, tau and α-syn, from clinical studies on fluid biomarkers and positron emission tomography (PET) imaging, and from basic experimental studies in cellular/molecular biology and animal models. The chapter focuses on recent advances and identifies knowledge gaps. In particular, no PET tracer for assessment of brain α-syn deposits is yet available, although it is subject of intense research and development, therefore experimental evidence on in vivo α-syn levels is based on measures in the cerebrospinal fluid (CSF) and plasma. Moreover, tau PET imaging studies comparing the patterns of tracer retention in synucleinopathies versus in other proteinopathies are scarce and much is still unknown regarding the relationships between APOE variants and fluid and/or imaging biomarkers of tau and α-syn. Further research incorporating multimodal imaging, fluid biomarkers and genetic factors will help elucidate the biological mechanisms underlying these proteinopathies, and contribute to differential diagnosis and patient stratification for clinical trials.

Longitudinal uncoupling of cerebral perfusion, glucose metabolism, and tau deposition in Alzheimer's disease.

INTRODUCTION: Cross-sectional findings using the tau tracer [18F]THK5317 (THK5317) have shown that [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) data can be approximated using perfusion measures (early-frame standardized uptake value ratio; ratio of tracer delivery in target to reference regions). In this way, a single PET study can provide both functional and molecular information. METHODS: We included 16 patients with Alzheimer's disease who completed follow-up THK5317 and FDG studies 17 months after baseline investigations. Linear mixed-effects models and annual percentage change maps were used to examine longitudinal change. RESULTS: Limited spatial overlap was observed between areas showing declines in THK5317 perfusion measures and FDG. Minimal overlap was seen between areas showing functional change and those showing increased retention of THK5317. DISCUSSION: Our findings suggest a spatiotemporal offset between functional changes and tau pathology and a partial uncoupling between perfusion and metabolism, possibly as a function of Alzheimer's disease severity.

Predicting Cognitive Decline across Four Decades in Mutation Carriers and Non-carriers in Autosomal-Dominant Alzheimer's Disease.

OBJECTIVES: The aim of this study was to investigate cognitive performance including preclinical and clinical disease course in carriers and non-carriers of autosomal-dominant Alzheimer's disease (adAD) in relation to multiple predictors, that is, linear and non-linear estimates of years to expected clinical onset of disease, years of education and age. METHODS: Participants from five families with early-onset autosomal-dominant mutations (Swedish and Arctic APP, PSEN1 M146V, H163Y, and I143T) included 35 carriers (28 without dementia and 7 with) and 44 non-carriers. All participants underwent a comprehensive clinical evaluation, including neuropsychological assessment at the Memory Clinic, Karolinska University Hospital at Huddinge, Stockholm, Sweden. The time span of disease course covered four decades of the preclinical and clinical stages of dementia. Neuropsychological tests were used to assess premorbid and current global cognition, verbal and visuospatial functions, short-term and episodic memory, attention, and executive function. RESULTS: In carriers, the time-related curvilinear trajectory of cognitive function across disease stages was best fitted to a formulae with three predictors: years to expected clinical onset (linear and curvilinear components), and years of education. In non-carriers, the change was minimal and best predicted by two predictors: education and age. The trajectories for carriers and non-carriers began to diverge approximately 10 years before the expected clinical onset in episodic memory, executive function, and visuospatial function. CONCLUSIONS: The curvilinear trajectory of cognitive functions across disease stages was mimicked by three predictors in carriers. In episodic memory, executive and visuospatial functions, the point of diverging trajectories occurred approximately 10 years ahead of the clinical onset compared to non-carriers. (JINS, 2017, 23, 195-203).

Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-ß, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-ß plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear mixed-effects models, fibrillar amyloid-ß plaque deposition was first observed in the striatum of presymptomatic autosomal dominant Alzheimer's disease carriers from 17 years before expected symptom onset; at about the same time, astrocytosis was significantly elevated and then steadily declined. Diverging from the astrocytosis pattern, amyloid-ß plaque deposition increased with disease progression. Glucose metabolism steadily declined from 10 years after initial amyloid-ß plaque deposition. Patients with sporadic mild cognitive impairment who were (11)C-Pittsburgh compound B-positive at baseline showed increasing amyloid-ß plaque deposition and decreasing glucose metabolism but, in contrast to autosomal dominant Alzheimer's disease carriers, there was no significant longitudinal decline in astrocytosis over time. The prominent initially high and then declining astrocytosis in autosomal dominant Alzheimer's disease carriers, contrasting with the increasing amyloid-ß plaque load during disease progression, suggests astrocyte activation is implicated in the early stages of Alzheimer's disease pathology.

Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study.

PURPOSE: Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aß) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aß deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. METHODS: PET imaging with the amyloid plaque tracer (11)C-AZD2184 and the astroglial tracer (11)C-deuterium-L-deprenyl ((11)C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aß deposition and astrocytosis by in vitro autoradiography using (3)H-AZD2184, (3)H-Pittsburgh compound B (PIB) and (3)H-L-deprenyl and immunostaining performed with antibodies for Aß42 and glial fibrillary acidic protein (GFAP) in sagittal brain sections. RESULTS: (11)C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal (11)C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography (3)H-AZD2184 and (3)H-PIB binding confirmed the in vivo findings with (11)C-AZD2184 and demonstrated age-dependent increases in Aß deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in (3)H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aß42 deposits in the cortex and hippocampus and more GFAP(+) reactive astrocytes in the hippocampus at 18-24 months than at 6 months in APPswe mice. CONCLUSION: The findings provide further in vivo evidence that astrocytosis occurs early in AD, preceding Aß plaque deposition.

Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-ß (Aß) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e., astrocytes and microglia, and neuroinflammatory response, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers is available to selectively target the different pathophysiological processes of AD. Along with the success of Aß PET and the more recent tau PET imaging, there is a great interest to develop PET tracers to image glial reactivity and neuroinflammation. While most research to date has focused on imaging microgliosis, there is an upsurge of interest in imaging reactive astrocytes in the AD continuum. There is increasing evidence that reactive astrocytes are morphologically and functionally heterogeneous, with different subtypes that express different markers and display various homeostatic or detrimental roles across disease stages. Therefore, multiple biomarkers are desirable to unravel the complex phenomenon of reactive astrocytosis. In the field of in vivo PET imaging in AD, the research concerning reactive astrocytes has predominantly focused on targeting monoamine oxidase B (MAO-B), most often using either 11C-deuterium-L-deprenyl (11C-DED) or 18F-SMBT-1 PET tracers. Additionally, imidazoline2 binding (I2BS) sites have been imaged using 11C-BU99008 PET. Recent studies in our group using 11C-DED PET imaging suggest that astrocytosis may be present from the early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aß deposition, glucose metabolism, and brain structural changes. It may also contribute to understanding the potential role of novel plasma biomarkers of reactive astrocytes, in particular the glial fibrillary acidic protein (GFAP), at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial response in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial reactivity and neuroinflammation as biomarkers with clinical application and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.

Continuous ß-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity.

BACKGROUND AND OBJECTIVES: Discordance between CSF and PET biomarkers of ß-amyloid (Aß) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aß-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aß, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories. METHODS: Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aß42 and global Aß-PET to a hyperbolic regression model, deriving a participant-specific Aß-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aß and positive values more aggregated relative to soluble Aß. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aß-aggregation scores. With linear mixed models, we assessed whether Aß-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years). RESULTS: The imbalance model could be fit (pseudo-R2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aß-aggregation scores were associated with larger ventricular volume (ß = 0.13, p < 0.001), male sex (ß = -0.18, p = 0.019), and homozygous APOE-ε4 carriership (ß = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (ß = 0.17, p < 0.001) and t-tau (ß = 0.16, p < 0.001), better baseline executive functioning (ß = 0.12, p < 0.001), and slower global cognitive decline (ß = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE-ε4, CSF t-tau, and, although modestly, with cognition. DISCUSSION: We propose a novel continuous model of Aß CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aß pools in 2 independent cohorts across the full Aß continuum. Aß-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.

Tracking reactive astrogliosis in autosomal dominant and sporadic Alzheimer's disease with multi-modal PET and plasma GFAP.

BACKGROUND: Plasma assays for the detection of Alzheimer's disease neuropathological changes are receiving ever increasing interest. The concentration of plasma glial fibrillary acidic protein (GFAP) has been suggested as a potential marker of astrocytes or recently, amyloid-ß burden, although this hypothesis remains unproven. We compared plasma GFAP levels with the astrocyte tracer 11C-Deuterium-L-Deprenyl (11C-DED) in a multi-modal PET design in participants with sporadic and Autosomal Dominant Alzheimer's disease. METHODS: Twenty-four individuals from families with known Autosomal Dominant Alzheimer's Disease mutations (mutation carriers = 10; non-carriers = 14) and fifteen patients with sporadic Alzheimer's disease were included. The individuals underwent PET imaging with 11C-DED, 11C-PIB and 18F-FDG, as markers of reactive astrogliosis, amyloid-ß deposition, and glucose metabolism, respectively, and plasma sampling for measuring GFAP concentrations. Twenty-one participants from the Autosomal Dominant Alzheimer's Disease group underwent follow-up plasma sampling and ten of these participants underwent follow-up PET imaging. RESULTS: In mutation carriers, plasma GFAP levels and 11C-PIB binding increased, while 11C-DED binding and 18F-FDG uptake significantly decreased across the estimated years to symptom onset. Cross-sectionally, plasma GFAP demonstrated a negative correlation with 11C-DED binding in both mutation carriers and patients with sporadic disease. Plasma GFAP indicated cross-sectionally a significant positive correlation with 11C-PIB binding and a significant negative correlation with 18F-FDG in the whole sample. The longitudinal levels of 11C-DED binding showed a significant negative correlation with longitudinal plasma GFAP concentrations over the follow-up interval. CONCLUSIONS: Plasma GFAP concentration and astrocyte 11C-DED brain binding levels followed divergent trajectories and may reflect different underlying processes. The strong negative association between plasma GFAP and 11C-DED binding in Autosomal Dominant and sporadic Alzheimer's disease brains may indicate that if both are markers of reactive astrogliosis, they may detect different states or subtypes of astrogliosis. Increased 11C-DED brain binding seems to be an earlier phenomenon in Alzheimer's disease progression than increased plasma GFAP concentration.

Cortical microstructural changes predict tau accumulation and episodic memory decline in older adults harboring amyloid.

INTRODUCTION: Non-invasive diffusion-weighted imaging (DWI) to assess brain microstructural changes via cortical mean diffusivity (cMD) has been shown to be cross-sectionally associated with tau in cognitively normal older adults, suggesting that it might be an early marker of neuronal injury. Here, we investigated how regional cortical microstructural changes measured by cMD are related to the longitudinal accumulation of regional tau as well as to episodic memory decline in cognitively normal individuals harboring amyloid pathology. METHODS: 122 cognitively normal participants from the Harvard Aging Brain Study underwent DWI, T1w-MRI, amyloid and tau PET imaging, and Logical Memory Delayed Recall (LMDR) assessments. We assessed whether the interaction of baseline amyloid status and cMD (in entorhinal and inferior-temporal cortices) was associated with longitudinal regional tau accumulation and with longitudinal LMDR using separate linear mixed-effects models. RESULTS: We find a significant interaction effect of the amyloid status and baseline cMD in predicting longitudinal tau in the entorhinal cortex (p = 0.044) but not the inferior temporal lobe, such that greater baseline cMD values predicts the accumulation of entorhinal tau in amyloid-positive participants. Moreover, we find a significant interaction effect of the amyloid status and baseline cMD in the entorhinal cortex (but not inferior temporal cMD) in predicting longitudinal LMDR (p < 0.001), such that baseline entorhinal cMD predicts the episodic memory decline in amyloid-positive participants. CONCLUSIONS: The combination of amyloidosis and elevated cMD in the entorhinal cortex may help identify individuals at short-term risk of tau accumulation and Alzheimer's Disease-related episodic memory decline, suggesting utility in clinical trials.

People with Alzheimer's disease have problems with their memory and ability to acquire and process knowledge. Understanding the earliest brain changes leading to these problems helps identify those likely to develop Alzheimer's disease early in the disease process. This study used a marker that measures the mobility of water in the brain to investigate how these changes can predict development of a protein named tau and changes in people's memory. The participants showed no signs of memory impairment at the beginning of the study, but some developed memory decline during follow-up. Greater mobility of water in certain brain areas predicted future increase in tau and decline in memory, indicating this measure could be used to identify people at risk of developing Alzheimer's disease.