Faculty Bibliography

Background: Levodopa-carbidopa intestinal gel (LCIG) is a long-term therapy for motor fluctuations in patients with advanced Parkinson's disease (PD). The aim of this analysis was to identify the baseline characteristics that predict "Off" time reduction in advanced PD patients treated with LCIG under routine clinical care in the GLORIA registry. Methods: Patients were followed under routine care for 24 months (M) with delivery of LCIG via percutaneous gastrojejunostomy. Analysis of covariance (ANCOVA) and logistic regression were performed to identify baseline characteristics that predict "Off" time reduction. Results: Compared to baseline, 86% (n/N = 131/152; mean ± SD baseline "Off" time: 3.4 ± 2.2 h) of M24 completers had ≥ 1 h reduction in "Off" time and 64% (n/N = 97/152; mean ± SD baseline "Off" time: 7.6 ± 2.9 h) had ≥ 3 h "Off" time reduction at M24. Most baseline characteristics were similar across responder subgroups; however, patients with ≥ 3 h "Off" time improvement had more "Off" time and less time with dyskinesia at baseline compared to patients with <3 h "Off" time reduction. Despite having less improvement in absolute "Off" h at M24, patients with <3 h "Off" time reduction experienced a 33% median reduction in "Off" time and a 44% median reduction in dyskinesia duration at M24, which was similar to the dyskinesia improvement observed among patients with ≥ 3 h "Off" time improvement (50% median reduction). Baseline "Off" time was both the best predictor of and the only significant factor associated with "Off" time improvement (P <0.0001). Conclusions: LCIG treatment led to clinically meaningful improvements in "Off" time in 86% of advanced PD patients and those with greater "Off" time are likely to experience the largest absolute reduction in hours "Off."

Parkinson's disease (PD) management requires the involvement of movement disorders experts, other medical specialists, and allied health professionals. Traditionally, multispecialty care has been implemented in the form of a multidisciplinary center, with an inconsistent clinical benefit and health economic impact. With the current capabilities of digital technologies, multispecialty care can be reshaped to reach a broader community of people with PD in their home and community. Digital technologies have the potential to connect patients with the care team beyond the traditional sparse clinical visit, fostering care continuity and accessibility. For example, video conferencing systems can enable the remote delivery of multispecialty care. With big data analyses, wearable and non-wearable technologies using artificial intelligence can enable the remote assessment of patients' conditions in their natural home environment, promoting a more comprehensive clinical evaluation and empowering patients to monitor their disease. These advances have been defined as technology-enabled care (TEC). We present examples of TEC under development and describe the potential challenges to achieve a full integration of technology to address complex care needs in PD.

Objectives/UNASSIGNED:Clinically relevant neuroanatomy is challenging to teach, learn and remember since many functionally important structures are visualized best using histology stains from serial 2D planar sections of the brain. In clinical patients, the locations of specific structures then must be inferred from spatial position and surface anatomy. A 3D MRI dataset of neuroanatomy has several advantages including simultaneous multi-planar visualization in the same brain, direct end-user manipulation of the data and image contrast identical to clinical MRI. We created 3D MRI datasets of the postmortem brain with high spatial and contrast resolution for simultaneous multi-planar visualization of complex neuroanatomy. Materials and Methods/UNASSIGNED:; time = 7 h). Besides resolution, this sequence has multiple adjustments to improve contrast compared to a clinical protocol, including 93% reduced turbo factor and 77% reduced effective echo time. Results/UNASSIGNED:This MRI microscopy protocol provided excellent contrast resolution of small nuclei and internal myelinated pathways within the basal ganglia, thalamus, brainstem, and cerebellum. Contrast was sufficient to visualize the presence and variation of horizontal layers in the cerebral cortex. 3D isotropic resolution datasets facilitated simultaneous multi-planar visualization and efficient production of specific tailored oblique image orientations to improve understanding of complex neuroanatomy. Conclusion/UNASSIGNED:structure visualization.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.