Novel Imaging Biomarker for Neuroinflammation in Alzheimer's Disease

Introduction and Summary of the Thesis Alzheimer’s disease (AD) is the most common form of dementia, affecting approximately 50 million people worldwide, with projections suggesting this number could triple by 2050. An estimated 32 million cases are attributed to AD dementia, 69 million to prodromal AD, and 315 million to preclinical AD, totaling 416 million across the AD continuum (15). This contin-uum begins with an asymptomatic phase, which may precede the onset of symptoms by decades, during which pathological changes can be detected through biomarkers. As the disease progresses to the clinical phase, cognitive functions decline, accompanied by fur-ther changes in these biomarkers (2). Key symptoms include memory impairment, speech difficulties, disorientation in space and time, unusual behavior, lack of routines, delusions, and diminished motivation. As the disease progresses, patients become increasingly de-pendent on assistance with daily activities (11). On a molecular level, the major pathological hallmarks of AD include senile plaques made of amyloid-beta (Aβ), tau tangles formed by hyperphosphorylated tau, neurodegeneration and neuroinflammation (38,43). A central fea-ture of AD pathophysiology is neurodegeneration, which results from the death of neurons associated with inflammatory processes involving microglia and astrocytes (25,49). Age is the main risk factor for developing AD and women are two to three times more likely than men to develop AD after the age of 65 (1). Modifiable risk factors such as hypertension, diabetes, smoking, and obesity may influence cognitive decline, with lifestyle changes po-tentially benefiting women more than men (30). In the early stages of cognitive impairment, women often present difficulties in verbal memory and word-finding, rather than episodic memory problems typically seen in men. Additionally, sex differences in biomarkers, includ-ing blood, cerebrospinal fluid (CSF), and neuroimaging, may help reveal the underlying bi-ological mechanisms contributing to these disparities in AD between men and women (1). Diagnosing Alzheimer’s disease (AD) typically involves a comprehensive approach combin-ing clinical assessment, cognitive testing, medical history review and neuroimaging. A phy-sician will begin with a clinical evaluation, gathering information about the patient's symp-toms and changes in cognitive and behavioral functioning, often alongside discussions with family members or caregivers. Cognitive tests, such as the Mini-Mental State Examination (MMSE) or Montreal Cognitive Assessment (MoCA), are used to assess memory, language, and other cognitive functions (3,10). Neuroimaging techniques, like MRI or PET scans, help identify brain structural changes, like atrophy, or functional changes in brain hemodynamics, X characteristic of AD (21). Additionally, fluid biomarkers in blood and cerebrospinal fluid (CSF) can be measured to exclude other conditions and to assess the presence of AD-related proteinopathies due to amyloid and tau accumulation (44). In recent years, the National Institute on Aging (NIA) and the International Working Group (IWG-2) have developed crite-ria for the early diagnosis of AD that integrate biomarkers and imaging data. These criteria recommend a multidisciplinary approach that includes imaging modalities, biochemical tests, and neuropsychological evaluation to detect AD in its earliest stages (4). The prognosis for Alzheimer's disease (AD) is normally progressive and irreversible, with individuals typically living 3 to 10 years after diagnosis, though some might live longer (48). The disease gradually causes cognitive and functional decline, with individuals eventually requiring full assistance with daily activities and experiencing severe memory loss (8). While there is no cure for AD, medications such as cholinesterase inhibitors and N-methyl-D-as-partate (NMDA) antagonists can sometimes help manage symptoms and temporarily slow progression (28,41). Despite these treatments, AD ultimately results in substantial cognitive and physical decline. Supportive care, including a combination of medication and caregiving, is essential in enhancing the quality of life for individuals with the disease. Biomarkers A variety of clinical biomarkers are available for diagnosis: In CSF, Aβ42, Aβ42/Aβ40, total (t)-tau/Aβ40, phosphor (p)-tau 181, p-tau 217, p-tau231, p-tau205, neurofilament light chain (NfL) and glial fibrillary acidic protein GFAP are measurable. Blood-based samples can also reveal biomarkers like Aβ42/Aβ40, p-tau 217, p-tau205, %p-tau217, microtubule-binding re-peat region (MTBR)-tau243, GFAP and NfL (36,13,7,18). For cases with a familial history of AD, genetic testing can help identify genetic risk factors, including presenilin 1 (PSEN1), PSEN2, and amyloid precursor protein (APP). A major risk gene for sporadic AD is apolipo-protein E ε4 (APOE) ε4 (9,6). Imaging biomarkers are also crucial in diagnosing AD. Positron emission tomography (PET) tracers help pinpoint the location of protein aggregation, with FDG PET being the most com-monly used. PET has emerged as a powerful tool for in vivo visualizing amyloid, tau depo-sition, infarction and neuroinflammation employing the translocator protein (TSPO) tracer while providing essential insights into the underlying mechanisms of neurodegeneration (50). Chapter 1 delves into the details of various Aβ and tau PET tracers and reviews the XI advancements in amyloid and tau PET imaging in the context of AD and other tauopathies, highlighting their preclinical and clinical utility and challenges (32). Magnetic Resonance Imaging (MRI) is a valuable tool in the diagnosis of AD, primarily used to detect structural and functional changes in the brain. In AD, MRI can reveal atrophy, particularly in areas such as the hippocampus and cortex, which are crucial for memory and cognitive functions. MRI can also detect infarctions and white matter hyperintensities, which are areas of in-creased signal intensity in the white matter that may be associated with vascular changes or small vessel disease, commonly seen in AD and other types of dementia (18). Neuroinflammation in AD Neuroinflammation plays a pivotal role in AD, with astrocytes and microglia as key contrib-utors (16). Upon activation, these cells undergo morphological changes and express pro-inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) (45). According to the amyloid cascade hypothesis, Aβ accumulation is the initial step in AD pathophysiology (20). In the early stages, microglia respond protectively, but as the disease progresses, chronic cytokine release shifts their behavior toward a pro-inflammatory pheno-type (27). This shift leads to neuronal damage and neurodegeneration. AD patients with a short-lived protective phase may be more vulnerable to severe inflammatory responses (27). Given neuroinflammation’s critical role in disease progression, identifying a specific bi-omarker to detect brain inflammation is essential. Currently, TSPO, found on the outer mitochondrial membrane, is a marker that allows in vivo PET imaging of microglia location and density (46). However, increased TSPO density does not necessarily correlate with microglial activation (30). Thus, there is a need for a more reliable biomarker for neuroinflammation. As the main goal of this doctoral project is to identify a novel imaging biomarker for neuroinflammation in AD, our research investigated the PET tracer [18F]SMBT-1, which targets monoamine oxidase B (MAO-B) in astrocytes, microglia and neurons, and performed immunohistochemistry (IHC) with pro-inflammatory markers such as MAO-B, TSPO, and C3D (15). Astrocytes, the predominant glial cell type in the brain, play vital roles in maintaining blood-brain barrier (BBB) integrity, regulating blood flow, supporting neuronal energy needs, and regulating synaptic functions (26). In AD, reactive astrocytes contribute to neuroinflamma-tion (14). Reactive astrocytes can be assessed through CSF markers such as GFAP (29). XIl Both astrocytes and microglia accumulate around Aβ plaques and tau tangles (40). Addi-tionally, MAO-B is upregulated in reactive astrocytes, making it a target for neurodegenera-tive disease treatment (33,5). Chapter 2 explores MAO-B as a potential tracer for labeling astrocyte reactivity (23) and investigates the relationship between neuroinflammation, as visualized by [18F]SMBT-1 imaging, and other critical AD pathologies, including tracers for amyloid-beta ([18F]florbetapir), tau deposition ([18F]flortaucipir), alterations in glucose me-tabolism ([18F]FDG), and TSPO expression ([18F]DPA-714), using these PET tracers in APP/PS1 and 3×TG mouse models. By examining these interactions, we aim to provide a deeper understanding of how astrocytic reactivity correlates with features of AD, potentially introducing a new biomarker for AD and therapeutic strategies for the disease. The purinergic P2X7 receptor (P2X7R) is a receptor expressed on both microglia and as-trocytes that is activated by adenosine triphosphate (ATP) when it reaches a certain thresh-old (12). A PET study using a P2X7R tracer found increased standardized uptake values (SUVR) in the cortex of rTg4560 mice (24), suggesting P2X7R expression might be in-creased in the presence of neuroinflammation. Chapter 3 explores the levels of P2X7R and GFAP expression in the hippocampus of AD patients and investigates its association with amyloid and tau pathologies. Investigation into which subtypes of glial cells express P2X7R is a crucial part of this study. By understanding the relationship between purinergic signaling and hallmark features of AD, this research could shed light on novel biomarkers aimed at mitigating the disease’s progression. Brain Perfusion in P301L Mice of Tauopathy Magnetic resonance imaging (MRI) is a powerful tool for assessing structural changes, such as cortical and hippocampal atrophy

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