Indiana University School of Medicine (IUSM) is the largest medical school in the United States, with over 1,800 medical students and more than 3,000 residents and fellows in training. Founded in 1903, the school maintains a comprehensive research portfolio spanning basic neuroscience, translational medicine, and clinical trials for neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and related disorders. The institution's research programs emphasize the intersection of sleep biology, neuroinflammation, and protein aggregation pathologies that characterize these conditions["@iu-som-2023"].
The School of Medicine is headquartered in Indianapolis with eight regional campuses across Indiana:
Indiana University School of Medicine has established a leading research program investigating the bidirectional relationship between sleep disturbances and neurodegenerative disease. This research direction emerged from observations that sleep fragmentation and reduced slow-wave sleep are among the earliest detectable changes in both Alzheimer's disease and Parkinson's disease, often preceding clinical diagnosis by years or decades[@elder2010].
The IUSM Sleep and Brain Health research program examines how sleep-dependent glymphatic clearance mechanisms are impaired in neurodegenerative conditions. The glymphatic system, first characterized by Iliff and colleagues, represents a brain-wide waste clearance pathway that operates primarily during sleep, when interstitial space expands by more than 60%, facilitating the removal of metabolic waste products including amyloid-beta and tau proteins[@iliff2014][@xie2013].
Research conducted in collaboration with the Stark Neurosciences Research Institute has demonstrated that glymphatic function is significantly impaired in mouse models of Alzheimer's disease, particularly in limbic system structures critical for memory formation[@yuede2020]. This work has established that amyloid-beta accumulation in the brain parenchyma correlates with reduced perivascular aquaporin-4 (AQP4) polarization, compromising the convective bulk flow that drives waste clearance[@boken2021].
Clinical studies at IUSM have documented that patients with mild cognitive impairment and early-stage Alzheimer's disease show reduced cerebrospinal fluid turnover rates compared to age-matched controls, suggesting that impaired glymphatic clearance may contribute to protein aggregation even in prodromal disease stages[@zhen2022]. The Sleep and Neurodegeneration research program has proposed that enhancing glymphatic function through sleep optimization, exercise, or pharmacological interventions could slow disease progression.
The Alzheimer's disease research program at IUSM encompasses multiple investigative directions spanning basic science, biomarker development, and clinical trials. Key research areas include:
Amyloid and Tau Biology: IUSM investigators study the molecular mechanisms underlying amyloid-beta aggregation and tau hyperphosphorylation, with emphasis on identifying therapeutic targets that might prevent or reverse these pathological processes. Current projects examine the role of sleep deprivation in accelerating amyloid plaque formation, building on seminal work demonstrating that a single night of sleep deprivation increases amyloid burden in healthy adults[@shokri-kojori2018].
Neuroinflammation: The neuroinflammation research program investigates how chronic microglial activation contributes to neurodegeneration. IUSM researchers have characterized the temporal sequence of inflammatory changes in Alzheimer's disease models, demonstrating that pro-inflammatory cytokines emerge early in disease pathogenesis and may serve as therapeutic targets or biomarkers[@wilson2023].
Vascular Contributions: Recognizing that vascular dysfunction and neurodegenerative processes interact bidirectionally, IUSM investigators study the neurovascular unit in Alzheimer's disease, examining how blood-brain barrier breakdown, reduced cerebral blood flow, and vascular risk factors contribute to disease progression[@barucker2018][@zhang2017].
The Parkinson's disease research program at IUSM focuses on understanding alpha-synuclein pathology, Lewy body formation, and mechanisms of dopaminergic neuron degeneration. The Stark Neurosciences Research Institute houses investigators studying:
Alpha-Synuclein Aggregation: Research examines the conformational changes in alpha-synuclein that lead to fibril formation and Lewy body pathology. Studies investigate how cellular quality control mechanisms (autophagy, ubiquitin-proteasome system) fail in PD, leading to protein aggregate accumulation.
Cell-Based Therapies: IUSM investigators are developing cell replacement strategies for Parkinson's disease, including dopaminergic neuron transplantation and induced pluripotent stem cell (iPSC) approaches. Research addresses challenges related to cell survival, integration, and immune compatibility following transplantation[@kolb2019].
Sleep Disorders in PD: Recognizing that sleep disturbances are among the most common non-motor symptoms of Parkinson's disease, with up to 90% of PD patients experiencing insomnia, REM sleep behavior disorder, or excessive daytime sleepiness, IUSM researchers investigate how these symptoms relate to underlying disease pathology and whether they may serve as biomarkers or therapeutic targets[@bacik2022].
The Stark Neurosciences Research Institute serves as the hub for neuroscience research at IUSM, bringing together over 100 faculty investigators across departments of Neurology, Neuroscience, Psychiatry, Radiology, and Biomedical Engineering. The Institute provides:
The Indiana Alzheimer's Disease Research Center (IADRC), funded by the National Institute on Aging, conducts comprehensive research on the biology, diagnosis, and treatment of Alzheimer's disease and related disorders. The Center:
This specialized center provides comprehensive care while conducting clinical trials and observational studies in Parkinson's disease and related movement disorders. The Center:
IUSM faculty have made significant contributions to understanding neurodegenerative disease mechanisms and developing new therapeutic approaches:
Indiana University has been particularly influential in establishing the link between sleep disturbances and Alzheimer's disease pathogenesis. The research program has demonstrated that orexin (hypocretin) neurons, which regulate arousal and wakefulness, also modulate amyloid-beta production[@kang2023]. This work suggests that optimizing sleep architecture or targeting orexin signaling might reduce amyloid accumulation in at-risk individuals.
The clinical research program has documented that REM sleep behavior disorder (RBD) precedes the motor symptoms of Parkinson's disease by years or decades in many patients, suggesting that RBD may represent an early prodromal phase of synucleinopathy[@postuma2019]. This observation has important implications for early intervention strategies.
IUSM investigators study tau propagation and seeding mechanisms in Alzheimer's disease and primary tauopathies. Research has characterized how pathological tau spreads through connected neural circuits, with implications for understanding disease progression and developing interventions targeting tau pathology[@friedman2018].
IUSM conducts numerous clinical trials for neurodegenerative diseases through the Indiana Clinical and Translational Sciences Institute (CTSI) and the research centers described above:
The school maintains a Clinical Trials Office that provides:
IUSM offers extensive training in neurodegenerative disease research through multiple programs:
IUSM's distributed campus model serves Indiana's healthcare needs while providing unique research opportunities. The regional campuses train medical students who return to practice in underserved areas of the state, creating a network of clinicians familiar with neurodegenerative disease management in rural and suburban communities[@tynes2013].
The regional campuses also participate in clinical trials, expanding access for Indiana residents to cutting-edge therapies while generating diverse patient cohorts for research studies.
IUSM maintains active collaborations with:
The neurodegeneration research program at IUSM is expanding in several key directions: