Posted December 15, 2023

Environmental and Gut-Brain Axis Determinants of Cognitive Outcomes in PD

Dr. Vikram Khurana, M.D., Brigham and Women's Hospital
Dr. Beate Ritz, M.D., Ph.D., University of California, Los Angeles
Dr. Laura Cox, Ph.D., Brigham and Women's Hospital

Dr. Vikram Khurana
(Photo Provided)

Dr. Beate Ritz
(Photo Provided)

Dr. Laura Cox
(Photo Provided)

Parkinson’s disease (PD) is a progressive neurological disease characterized by a variety of motor and non-motor symptoms such as the hallmark tremor, cognitive dysfunction, stiffness, and constipation. The bacterial composition of the gut, commonly referred to as the gut microbiome, is among the principle causes for constipation and is now being examined for its role in the development and worsening of cognitive impairments associated with PD. The environment of the gut is dependent on multiple factors including diet choices and, consequently, exposure to different pesticides. With support from a fiscal year 2022 Synergistic Idea Award, researchers Drs. Vikram Khurana, Beate Ritz, and Laura Cox seek to apply different areas of expertise to determine if diet and exposures to pesticides are potential mechanisms that drive pathology in the brain, causing a portion of the cognitive decline observed in PD.

Link:
Public and Technical Abstracts: Environmental and Gut-Brain Axis Determinants of Cognitive Outcomes in PD

Figure 1: This proposal brings together complementary and synergistic research teams. The Ritz group at UCLA is gathering highly quantitative data “from the field.” They are measuring the “exposome” across three large counties in California, for example environmental toxicants or dietary factors that alter the gut flora (or “microbiome”). They then ask what the relationship is between these factors and cognitive and mental health outcomes in patients with Parkinson’s disease. These epidemiological studies do not get the “how” of this relationship. To get at the mechanism, and test hypotheses that arise from this work, Dr Ritz’s group will work in this project with teams at Harvard Medical School and Brigham and Women’s Hospital. The Khurana lab has deep expertise in modeling the disease using patient stem-cells. These cells can be converted into different types of brain cells, electrically active neurons versus glia that dictate inflammatory states in the brain. The powerful system allows the lab to test hypotheses about the ways in which pesticides and gut microbes can alter brain states and at the same time create human cellular models for discovering new drugs. The Cox lab at BWH/Harvard will bring strong expertise in microbiology to the group and will work to identify which of the gut microbes are likely to be most important in dictating cognitive outcomes in Parkinson’s disease. The Cox lab also brings to bear mouse models on the project to understand interactions between pesticides and gut microbes in a more physiologic animal exposure paradigm. Map adapted from Paul and Krolewski Nat Communications 2023. Graphics created with BioRender.com

APOE and Lipid Mechanisms Relevant to Cognitive Dysfunction in Parkinson's Disease

Dr. Ole Isacson, M.D., McLean Hospital
Dr. Penelope Hallett, Ph.D., McLean Hospital

Dr. Ole Isacson
(Photo Provided)

Dr. Penelope Hallett
(Photo Provided)

Every year, approximately 90,000 people are diagnosed with Parkinson’s disease (PD) in the United States. This represents a 50% increase in incidence compared to a decade ago.¹ Currently, no effective interventions exist to reduce or prevent the debilitating cognitive deficits associated with PD. Research conducted by Drs. Ole Isacson and Penelope Hallett found that a particular protein, called apoliopoprotien E (APOE), and an enzyme, called glucocerebroside (GBA1), are both implicated in the deterioration of nerve cells observed in PD and PD-associated dementia. With support from a fiscal year 2022 Synergistic Idea Award, Drs. Isacson and Hallett plan to build on their previous research wherein they identified elevated levels of lipids in the brains of people with PD. For this project, Dr. Isacson and Dr. Hallett seek to identify how the relationship between APOE and GBA1 impacts cognitive dysfunction in PD. Investigation into this interaction may lead to the discovery of new biomarkers for PD-associated dementia, which can be targeted for treatment.

References:
¹https://www.parkinson.org/understanding-parkinsons/statistics

Link:
Public and Technical Abstracts: APOE and Lipid Mechanisms Relevant to Cognitive Dysfunction in Parkinson's Disease

Figure 2: Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis. Cellular apolipoprotein E (ApoE) levels are increased in the brain following experimentally induced lipid load, reflecting the brain lipid elevations seen in Parkinson’s disease and dementia. Brain slices from 3 month old wildtype mice after daily injection of GBA1 inhibitor for 18 days were stained for ApoE and co-stained with the astrocyte marker GFAP and microglial marker Iba1. Images show cortical layer V (LV). Image from Fig. 1 of Connolly KJ et al., Cells 2023 doi: 10.3390/cells12212564

Modeling Cognitive Dysfunction in Parkinson's Disease and the Impact of Exercise

Dr. Sheila Fleming, Ph.D., Northeast Ohio Medical University
Dr. Caryl Sortwell, Ph.D., Michigan State University

Parkinson’s disease (PD) is routinely referred to as a movement disorder. However, patients with PD also exhibit several non-motor signs such as cognitive impairments, which can be more disabling than the movement dysfunction. Research into the causes of cognitive impairment is a priority given the fact that there are no treatment options available to slow or stop progression of this aspect of PD, and because cognitive impairments significantly reduce a patient’s quality of life. With support from a fiscal year 2022 Synergistic Idea Award, Drs. Sheila Fleming and Caryl Sortwell are investigating the impact of exercise on the presence of abnormal alpha-synuclein (a-Syn), a cardinal pathological feature observed in PD, and cognitive function in an animal model of PD. The benefits of exercise on motor function and cognition in healthy adults are widely accepted, and emerging evidence suggests the value of exercise to maintain mobility and function in people with PD. For this study, the team will examine the effect of a-Syn pathology in brain regions important for cognitive function on behaviors such as attention, cognitive flexibility, and memory. In addition, treadmill exercise will be implemented to determine its effect on cognitive behaviors and levels of a-Syn pathology. Finally, they will identify potential genes associated with a-Syn pathology in the brain regions important in cognitive function. This research provides the framework for a treatment approach that has high translatability, since exercise is a low-risk, low-cost intervention that is feasible for the vast majority of patients to complete independently, and for most clinics to implement across the United States.

Link:
Public and Technical Abstracts: Modeling Cognitive Dysfunction in Parkinson's Disease and the Impact of Exercise

Dr. Sheila Fleming's Lab Team

Dr. Caryl Sortwell's Lab Team

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