Browsing by Author "Erickson, Kirk I."

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    A blood-based marker of mitochondrial DNA damage in Parkinson's disease
    (American Association for the Advancement of Science, 2023) Qi, Rui; Sammler, Esther; Gonzalez-Hunt, Claudia P.; Barraza, Ivana; Pena, Nicholas; Rouanet, Jeremy P.; Naaldijk, Yahaira; Goodson, Steven; Fuzzati, Marie; Blandini, Fabio; Erickson, Kirk I.; Weinstein, Andrea M.; Lutz, Michael W.; Kwok, John B.; Halliday, Glenda M.; Dzamko, Nicolas; Padmanabhan, Shalini; Alcalay, Roy N.; Waters, Cheryl; Hogarth, Penelope; Simuni, Tanya; Smith, Danielle; Marras, Connie; Tonelli, Francesca; Alessi, Dario R.; West, Andrew B.; Shiva, Sruti; Hilfiker, Sabine; Sanders, Laurie H.; Oral and Maxillofacial Surgery and Hospital Dentistry, School of Dentistry
    Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.
  • Thumbnail Image
    Item
    Dose-response effects of exercise on mental health in community-dwelling older adults: Exploration of genetic moderators
    (Elsevier, 2024) Gujral, Swathi; Burns, Marcia; Erickson, Kirk I.; Rofey, Dana; Peiffer, Jeremiah J.; Laws, Simon M.; Brown, Belinda; Psychology, School of Science
    Background/objective: (1) Examine the role of exercise intensity on mental health symptoms in a community-based sample of older adults. (2) Explore the moderating role of genetic variation in brain-derived neurotrophic factor (BDNF) and apolipoprotein E (APOE) on the effects of exercise on mental health symptoms. Method: This study is a secondary analysis of a three-arm randomized controlled trial, comparing the effects of 6 months of high-intensity aerobic training vs. moderate-intensity aerobic training vs. a no-contact control group on mental health symptoms assessed using the Depression, Anxiety, and Stress Scale (DASS). The BDNF Val66Met polymorphism and APOE ε4 carrier status were explored as genetic moderators of exercise effects on mental health symptoms. Results: The exercise intervention did not influence mental health symptoms. The BDNF Val66Met polymorphism did not moderate intervention effects on mental health symptoms. APOE ε4 carrier status moderated the effect of intervention group on perceived stress over 6 months, such that APOE ε4 carriers, but not non-carriers, in the high-intensity aerobic training group showed a decline in perceived stress over 6 months. Conclusions: APOE ε4 carrier status may modify the benefits of high-intensity exercise on perceived stress such that APOE ε4 carriers show a greater decline in stress as a result of exercise relative to non-APOE ε4 carriers.
  • Thumbnail Image
    Item
    Estrogen, brain structure, and cognition in postmenopausal women
    (Wiley, 2021) Boyle, Christina P.; Raji, Cyrus A.; Erickson, Kirk I.; Lopez, Oscar L.; Becker, James T.; Gach, H. Michael; Kuller, Lewis H.; Longstreth, William, Jr.; Carmichael, Owen T.; Riedel, Brandalyn C.; Thompson, Paul M.; Radiology and Imaging Sciences, School of Medicine
    Declining estrogen levels before, during, and after menopause can affect memory and risk for Alzheimer's disease. Undesirable side effects of hormone variations emphasize a role for hormone therapy (HT) where possible benefits include a delay in the onset of dementia-yet findings are inconsistent. Effects of HT may be mediated by estrogen receptors found throughout the brain. Effects may also depend on lifestyle factors, timing of use, and genetic risk. We studied the impact of self-reported HT use on brain volume in 562 elderly women (71-94 years) with mixed cognitive status while adjusting for aforementioned factors. Covariate-adjusted voxelwise linear regression analyses using a model with 16 predictors showed HT use as positively associated with regional brain volumes, regardless of cognitive status. Examinations of other factors related to menopause, oophorectomy and hysterectomy status independently yielded positive effects on brain volume when added to our model. One interaction term, HTxBMI, out of several examined, revealed significant negative association with overall brain volume, suggesting a greater reduction in brain volume than BMI alone. Our main findings relating HT to regional brain volume were as hypothesized, but some exploratory analyses were not in line with existing hypotheses. Studies suggest lower levels of estrogen resulting from oophorectomy and hysterectomy affect brain volume negatively, and the addition of HT modifies the relation between BMI and brain volume positively. Effects of HT may depend on the age range assessed, motivating studies with a wider age range as well as a randomized design.
  • Thumbnail Image
    Item
    Genetic Risk Score Predicts Late-Life Cognitive Impairment
    (Hindawi, 2015-08-23) Wollam, Mariegold E.; Weinstein, Andrea M.; Saxton, Judith A.; Morrow, Lisa; Snitz, Beth; Fowler, Nicole R.; Suever Erickson, Barbara L.; Roecklein, Kathryn A.; Erickson, Kirk I.; Medicine, School of Medicine
    Introduction. A family history of Alzheimer's disease is a significant risk factor for its onset, but the genetic risk associated with possessing multiple risk alleles is still poorly understood. Methods. In a sample of 95 older adults (Mean age = 75.1, 64.2% female), we constructed a genetic risk score based on the accumulation of risk alleles in BDNF, COMT, and APOE. A neuropsychological evaluation and consensus determined cognitive status (44 nonimpaired, 51 impaired). Logistic regression was performed to determine whether the genetic risk score predicted cognitive impairment above and beyond that associated with each gene. Results. An increased genetic risk score was associated with a nearly 4-fold increased risk of cognitive impairment (OR = 3.824, P = .013) when including the individual gene polymorphisms as covariates in the model. Discussion. A risk score combining multiple genetic influences may be more useful in predicting late-life cognitive impairment than individual polymorphisms.