ABSTRACT
OBJECTIVE: While excessive daytime sleepiness (EDS) can predate the clinical diagnosis of Parkinson disease (PD), associations with underlying PD pathogenesis are unknown. Our objective is to determine if EDS is related to brain Lewy pathology (LP), a marker of PD pathogenesis, using clinical assessments of EDS with postmortem follow-up. METHODS: Identification of LP was based on staining for α-synuclein in multiple brain regions in a sample of 211 men. Data on EDS were collected at clinical examinations from 1991 to 1999 when participants were aged 72-97 years. RESULTS: Although EDS was more common in the presence vs absence of LP (p = 0.034), the association became stronger in neocortical regions. When LP was limited to the olfactory bulb, brainstem, and basal forebrain (Braak stages 1-4), frequency of EDS was 10% (4/40) vs 17.5% (20/114) in decedents without LP (p = 0.258). In contrast, compared to the absence of LP, EDS frequency doubled (36.7% [11/30], p = 0.023) when LP reached the anterior cingulate gyrus, insula mesocortex, and midfrontal, midtemporal, and inferior parietal neocortex (Braak stage 5). With further infiltration into the primary motor and sensory neocortices (Braak stage 6), EDS frequency increased threefold (51.9% [14/27], p < 0.001). Findings were similar across sleep-related features and persisted after adjustment for age and other covariates, including the removal of PD and dementia with Lewy bodies. CONCLUSIONS: The association between EDS and PD includes relationships with extensive topographic LP expansion. The neocortex could be especially vulnerable to adverse relationships between sleep disorders and aggregation of misfolded α-synuclein and LP formation.
Subject(s)
Lewy Bodies/pathology , Lewy Body Disease/pathology , Parkinson Disease/pathology , Sleep Wake Disorders/pathology , Aged , Aged, 80 and over , Brain/pathology , Dementia/pathology , Disorders of Excessive Somnolence/diagnosis , Disorders of Excessive Somnolence/pathology , Female , Humans , Lewy Body Disease/diagnosis , Male , Parkinson Disease/diagnosis , alpha-Synuclein/metabolismABSTRACT
BACKGROUND: Organochlorine pesticides are associated with an increased risk of Parkinson's disease. A preliminary analysis from the Honolulu-Asia Aging Study suggested that heptachlor epoxide, a metabolite from an organochlorine pesticide extensively used in Hawaii, may be especially important. This was a cross sectional analysis to evaluate the association of heptachlor epoxide and other organochlorine compounds with Lewy pathology in an expanded survey of brain organochlorine residues from the longitudinal Honolulu-Asia Aging Study. METHODS: Organochlorines were measured in frozen occipital or temporal lobes in 705 brains using gas chromatography with mass spectrometry. Lewy pathology was identified using hematoxylin and eosin- and α-synuclein immunochemistry-stained sections from multiple brain regions. RESULTS: The prevalence of Lewy pathology was nearly doubled in the presence versus the absence of heptachlor epoxide (30.1% versus 16.3%, P < 0.001). Although associations with other compounds were weaker, hexachlorobenzene (P = 0.003) and α-chlordane (P = 0.007) were also related to Lewy pathology. Most of the latter associations, however, were a result of confounding from heptachlor epoxide. Neither compound was significantly related to Lewy pathology after adjustment for heptachlor epoxide. In contrast, the association of heptachlor epoxide with Lewy pathology remained significant after adjustments for hexachlorobenzene (P = 0.013) or α-chlordane (P = 0.005). Findings were unchanged after removal of cases of PD and adjustment for age and other characteristics. CONCLUSIONS: Organochlorine pesticides are associated with the presence of Lewy pathology in the brain, even after exclusion of PD cases. Although most of the association is through heptachlor epoxide, the role of other organochlorine compounds is in need of clarification. © 2018 International Parkinson and Movement Disorder Society.
Subject(s)
Brain/drug effects , Heptachlor Epoxide/pharmacology , Hydrocarbons, Chlorinated/pharmacology , Lewy Body Disease/etiology , Pesticides/pharmacology , Aged , Brain/pathology , Cross-Sectional Studies , Gas Chromatography-Mass Spectrometry/methods , Humans , Hydrocarbons, Chlorinated/metabolism , Lewy Body Disease/pathology , Male , Middle Aged , Parkinson Disease/pathologyABSTRACT
Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as a means to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-ß plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.
Subject(s)
Brain/metabolism , Endoplasmic Reticulum Stress/drug effects , Membrane Proteins/pharmacology , Selenoproteins/pharmacology , tau Proteins/metabolism , Aged , Aged, 80 and over , Analysis of Variance , Cell Line, Tumor , Endoplasmic Reticulum Stress/physiology , Gene Expression Regulation/genetics , Glucose/pharmacology , Humans , Leucine/genetics , Membrane Proteins/genetics , Mutation/genetics , Neuroblastoma/pathology , Phosphorylation/drug effects , Proline/genetics , RNA, Messenger/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Selenoproteins/genetics , TransfectionABSTRACT
Cerebrovascular injury while on extracorporeal membrane oxygenation (ECMO) may be caused by excessive brain perfusion during hypoxemic reperfusion. Previous studies have postulated that the most vulnerable period of time for cerebrovascular injury is during the transfer period to ECMO. Therefore, our objective was to compare brain perfusion and hemodynamics in a piglet endotoxic shock ECMO model. The effect of ECMO flow on microcirculation of different brain regions was compared between 10 control pigs and six pigs (7-10 kg) administered IV endotoxin to achieve a drop in mean arterial blood pressure (MAP) of at least 30%. Cardiac output (CO), brain oxygen utilization, and microcirculatory blood flow (BF) were compared at baseline and 2 hours after ECMO stabilization. Matching ECMO delivery with baseline CO in control animals increased perfusion (p < 0.05) in all areas of the brain. In contrast, with endotoxin, ECMO returned perfusion closer to baseline levels in all regions of the brain and maintained brain tissue oxygen consumption. Both control and endotoxic pigs showed no evidence of acute neuronal necrosis in histologic cerebral cortical sections examined after 2 hours of ECMO. Results show that during endotoxic shock, transition to ECMO can maintain brain BF equally to all brain regions without causing overperfusion, and does not appear to cause brain tissue histopathologic changes (hemorrhage or necrosis) during the acute stabilization period after ECMO induction.
Subject(s)
Cerebrovascular Circulation , Extracorporeal Membrane Oxygenation , Shock, Septic/physiopathology , Animals , Cerebrovascular Circulation/physiology , Extracorporeal Membrane Oxygenation/methods , Female , Male , Microcirculation , SwineABSTRACT
OBJECTIVE: To examine frequencies and relationships of 5 common neuropathologic abnormalities identified at autopsy with late-life cognitive impairment and dementia in 2 different autopsy panels. METHODS: The Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS) are population-based investigations of brain aging that included repeated cognitive assessments and comprehensive brain autopsies. The neuropathologic abnormalities assessed were Alzheimer disease (AD) neuropathologic changes, neocortical Lewy bodies (LBs), hippocampal sclerosis, microinfarcts, and low brain weight. Associations with screening tests for cognitive impairment were examined. RESULTS: Neuropathologic abnormalities occurred at levels ranging from 9.7% to 43%, and were independently associated with cognitive impairment in both studies. Neocortical LBs and AD changes were more frequent among the predominantly Caucasian NS women, while microinfarcts were more common in the Japanese American HAAS men. Comorbidity was usual and very strongly associated with cognitive impairment. Apparent cognitive resilience (no cognitive impairment despite Braak stage V) was strongly associated with minimal or no comorbid abnormalities, with fewer neocortical AD lesions, and weakly with longer interval between final testing and autopsy. CONCLUSIONS: Total burden of comorbid neuropathologic abnormalities, rather than any single lesion type, was the most relevant determinant of cognitive impairment in both cohorts, often despite clinical diagnosis of only AD. These findings emphasize challenges to dementia pathogenesis and intervention research and to accurate diagnoses during life.
Subject(s)
Aging/pathology , Alzheimer Disease/diagnosis , Alzheimer Disease/epidemiology , Brain/pathology , Cognition Disorders/diagnosis , Cognition Disorders/epidemiology , Nuns , Aged , Aged, 80 and over , Aging/psychology , Alzheimer Disease/psychology , Asia/epidemiology , Cognition Disorders/psychology , Cohort Studies , Comorbidity , Female , Hawaii/epidemiology , Humans , Lewy Bodies/pathology , Nuns/psychologyABSTRACT
Subjects with Alzheimer's disease (AD) have elevated brain levels of the selenium transporter selenoprotein P (Sepp1). We investigated if this elevation results from increased release of Sepp1 from the choroid plexus (CP). Sepp1 is significantly increased in CP from AD brains in comparison to non-AD brains. Sepp1 localizes to the trans-Golgi network within CP epithelia, where it is processed for secretion. The cerebrospinal fluid from AD subjects also contains increased levels Sepp1 in comparison to non-AD subjects. These findings suggest that AD pathology induces increased levels of Sepp1 within CP epithelia for release into the cerebrospinal fluid to ultimately increase brain selenium.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Choroid Plexus/metabolism , Selenoprotein P/metabolism , Aged, 80 and over , Blotting, Western , Humans , Immunohistochemistry , MaleABSTRACT
OBJECTIVE: To determine how sleep-disordered breathing, nocturnal hypoxia, and changes in sleep architecture in the elderly may be related to the development of the neuropathologic correlates of dementia. METHODS: The Honolulu-Asia Aging Study is a prospective cohort study of Japanese American men in Honolulu, HI. We examined brain lesions at autopsy (Braak stage, neurofibrillary tangle and neuritic plaque counts, microinfarcts, generalized brain atrophy, lacunar infarcts, Lewy bodies [LBs], neuronal loss and gliosis in the locus ceruleus) in 167 participants who underwent polysomnography in 1999-2000 (mean age, 84 years) and died through 2010 (mean 6.4 years to death). Polysomnography measures included the apnea-hypopnea index, duration of apnea or hypopnea, duration of hypoxemia, minimum oxygen saturation (SpO2), duration of slow-wave sleep (SWS, non-REM stage N3), and arousals. RESULTS: Sleep duration with SpO2 <95% was associated with higher levels of microinfarcts (adjusted odds ratio [OR] 3.88, 95% confidence interval [CI] 1.10-13.76, comparing the highest to lowest quartiles of %sleep with SpO2 <95%). Greater SWS duration was associated with less generalized atrophy (adjusted OR 0.32, 95% CI 0.10-1.03, comparing highest to lowest quartiles of %sleep in SWS). LBs were less common with greater %sleep with SpO2 <95% (adjusted OR 0.17, 95% CI 0.04-0.78, comparing highest to lowest quartiles). Higher minimum SpO2 during REM sleep was associated with less gliosis and neuronal loss in the locus ceruleus. Cognitive scores declined less among men with greater SWS duration. CONCLUSIONS: The findings support a role for lower nocturnal oxygenation and SWS in the development of microinfarcts and brain atrophy, but not Alzheimer lesions or LBs.
Subject(s)
Brain/pathology , Death , Dementia/complications , Polysomnography/methods , Sleep Apnea Syndromes/complications , Sleep Apnea Syndromes/diagnosis , Aged , Aged, 80 and over , Asian , Autopsy , Brain Infarction/etiology , Brain Infarction/pathology , Chi-Square Distribution , Cohort Studies , Dementia/pathology , Humans , Male , Neurofibrillary Tangles/pathology , Neuropsychological Tests , Plaque, Amyloid/pathologyABSTRACT
Selenoproteins are important for normal brain function, and decreased function of selenoproteins can lead to impaired cognitive function and neurological disorders. This review examines the possible roles of selenoproteins in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and epilepsy. Selenium deficiency is associated with cognitive decline, and selenoproteins may be helpful in preventing neurodegeneration in AD. PD is associated with impaired function of glutathione peroxidase selenoenzymes. In HD, selenium deters lipid peroxidation by increasing specific glutathione peroxidases. Selenium deficiency increases risk of seizures in epilepsy, whereas supplementation may help to alleviate seizures. Further studies on the mechanisms of selenoprotein function will increase our understanding of how selenium and selenoproteins can be used in treatment and prevention of brain disorders.
Subject(s)
Brain Diseases/metabolism , Selenium/metabolism , Selenoproteins/metabolism , Animals , Brain Diseases/drug therapy , Humans , Selenium/therapeutic useABSTRACT
Oxidative stress and oxidized dopamine contribute to the degeneration of the nigrostriatal pathway in Parkinson's disease (PD). Selenoproteins are a family of proteins containing the element selenium in the form of the amino acid selenocysteine, and many of these proteins have antioxidant functions. We recently reported changes in expression of the selenoprotein, phospholipid hydroperoxide glutathione peroxidase GPX4 and its co-localization with neuromelanin in PD brain. To further understand the changes in GPX4 in PD, we examine here the expression of the selenium transport protein selenoprotein P (Sepp1) in postmortem Parkinson's brain tissue. Sepp1 in midbrain was expressed in neurons of the substantia nigra (SN), and expression was concentrated within the centers of Lewy bodies, the pathological hallmark of PD. As with GPX4, Sepp1 expression was significantly reduced in SN from PD subjects compared with controls, but increased relative to cell density. In putamen, Sepp1 was found in cell bodies and in dopaminergic axons and terminals, although levels of Sepp1 were not altered in PD subjects compared to controls. Expression levels of Sepp1 and GPX4 correlated strongly in the putamen of control subjects but not in the putamen of PD subjects. These findings indicate a role for Sepp1 in the nigrostriatal pathway, and suggest that local release of Sepp1 in striatum may be important for signaling and/or synthesis of other selenoproteins such as GPX4.
Subject(s)
Parkinson Disease/pathology , Putamen/metabolism , Selenoprotein P/metabolism , Substantia Nigra/metabolism , Aged, 80 and over , Analysis of Variance , Asian , Glutathione Peroxidase/metabolism , Hawaii , Humans , Male , Phospholipid Hydroperoxide Glutathione Peroxidase , Stereotaxic Techniques , Tyrosine 3-Monooxygenase/metabolism , alpha-Synuclein/metabolismABSTRACT
BACKGROUND: During extracorporeal membrane oxygenation (ECMO), circulation of blood across synthetic surfaces triggers an inflammatory response. Therefore, we evaluated the ability of continuous renal replacement therapy (CRRT) to remove cytokines and reduce the inflammatory response in a piglet hemorrhage-reperfusion ECMO model. METHODS: Three groups were studied: (i) uninjured controls (n = 11); (ii) hemorrhage-reperfusion while on venoarterial ECMO (30% hemorrhage with subsequent blood volume replacement within 60 min) (n = 8); (iii) treatment with CRRT after hemorrhage-reperfusion while on ECMO (n = 7). Hemodynamic parameters, oxygen utilization, and plasma and broncho-alveolar lavage (BAL) cytokine levels were recorded and lung tissue samples collected for histologic comparison. RESULTS: Whereas mean arterial pressures decreased among hemorrhage-reperfusion piglets, ECMO with CRRT did not significantly alter mean arterial pressures or systemic vascular resistance and was able to maintain blood flow as well as oxygen delivery after hemorrhage-reperfusion. Plasma interleukin (IL)-6 and IL-10, and BAL tumor necrosis factor (TNF)-α, IL-1ß, IL-6, IL-8, and IL-10 increased as a result of hemorrhage-reperfusion while on ECMO. After a 6-h period of CRRT, plasma IL-6 and BAL TNF-α, IL-6, and IL-8 levels decreased. CONCLUSION: Data suggest CRRT may decrease inflammatory cytokine levels during the initial phase of ECMO therapy following hemorrhage-reperfusion while maintaining cardiac output and oxygen utilization.
Subject(s)
Disease Models, Animal , Extracorporeal Membrane Oxygenation , Inflammation/therapy , Renal Replacement Therapy , Animals , Bronchoalveolar Lavage Fluid , Cytokines/metabolism , Hemodynamics , Oxygen/metabolism , SwineABSTRACT
BACKGROUND: Most central neurocytomas follow a benign clinical course. However, more aggressive variants have been described requiring additional surgical resection, radiation, or chemotherapy. Chemotherapy has rarely been used as an adjuvant therapy for central neurocytomas. METHODS: We report a case of a 20-year-old girl who underwent four subtotal resections, over the course of 3 years, for a large central neurocytoma that continued to progress. She was not a candidate for stereotactic radiosurgery, given the large tumor size. To avoid radiation injury in a young patient, she was treated with six cycles of chemotherapy including procarbazine, CCNU, and vincristine. Procarbazine was stopped after 2 cycles because of the development of a rash. Serial magnetic resonance imaging was used to follow treatment response. RESULTS: Her tumor started to decrease in size after 2 cycles of chemotherapy and continued to shrink until it stabilized after 5 cycles of chemotherapy. A small area of residual tumor with minimal enhancement persisted along the left lateral ventricle and remained stable for at least 16 months after the completion of chemotherapy. CONCLUSIONS: To our knowledge, this is only the fourth report describing the use of chemotherapy for progression of central neurocytomas as a treatment alternative to radiation therapy. The use of procarbazine, CCNU, and vincristine has not been previously described for the treatment of a central neurocytoma and presents an additional treatment option.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/drug therapy , Lomustine/therapeutic use , Neurocytoma/drug therapy , Procarbazine/therapeutic use , Vincristine/therapeutic use , Adolescent , Female , HumansABSTRACT
BACKGROUND: The determination of the form of prion disease and early diagnosis are important for prognostic, public health, and epidemiologic reasons. OBJECTIVE: To describe a patient with sporadic Creutzfeldt-Jakob disease (sCJD) who had a clinical history and initial electroencephalogram and magnetic resonance imaging findings consistent with variant CJD (vCJD). RESULTS: Results of a repeated electroencephalogram were suggestive of sCJD, and a subsequent brain biopsy confirmed this diagnosis. CONCLUSIONS: This case cautions against relying solely on T2- and diffusion-weighted pulvinar hyperintensity and clinical features to differentiate between vCJD and sCJD, and further supports established diagnostic criteria for vCJD.