Abstract: “Parkinson’s disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles. An early-onset form of Parkinson’s disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson’s disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1−/− mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson’s disease, which highlights the relevance of the gut–brain axis in the disease.”
Matheoud D, Cannon T, Voisin A, Penttinen A-M, et al: Intestinal infection triggers Parkinson’s disease-like symptoms in Pink1−/− mice. Nature [Epub ahead of print, July 17, 2019; doi:10.1038/s41586-019-1405-y].
Summary: Migraine is a prevalent disorder, affecting 15.1% of the world’s population. In most cases, the migraine attacks are sporadic; however, some individuals experience a gradual increase in attack frequency over time, and up to 2% of the general population develops chronic migraine. The mechanisms underlying this chronicity are unresolved but are hypothesized to involve a degree of inflammation. In this article, the authors review the relevant literature related to inflammation and migraine, from the initiation of attacks to chronification. They propose that the increase in migraine frequency leading to chronic migraine involves neurogenic neuroinflammation, possibly entailing increased expression of cytokines via activation of protein kinases in neurons and glial cells of the trigeminovascular system. Evidence from preclinical research supports this view. The implications for migraine therapy are discussed.
Edvinsson L, Haanes KA and Warfvinge K: Does inflammation have a role in migraine? Nature Reviews Neurology [Epub ahead of print, July 1, 2019: doi: 10.1038/s41582-019-0216-y.]
“Public health is a priority for the Chinese Government. Evidence-based decision making for health at the province level in China, which is home to a fifth of the global population, is of paramount importance. This analysis uses data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 to help inform decision making and monitor progress on health at the province level. …
Stroke and ischaemic heart disease were the leading causes of death and DALYs (Disability-Adjusted Life-Years) at the national level in China in 2017. Age-standardised DALYs per 100 000 population decreased by 33·1% (95% uncertainty interval [UI] 29·8 to 37·4) for stroke and increased by 4·6% (–3·3 to 10·7) for ischaemic heart disease from 1990 to 2017. Age-standardised stroke, ischaemic heart disease, lung cancer, chronic obstructive pulmonary disease, and liver cancer were the five leading causes of YLLs (Years of Life Lost) in 2017. Musculoskeletal disorders, mental health disorders, and sense organ diseases were the three leading causes of YLDs (Years Lived with Disabilities) in 2017, and high systolic blood pressure, smoking, high-sodium diet, and ambient particulate matter pollution were among the leading four risk factors contributing to deaths and DALYs. All provinces had higher than expected DALYs per 100 000 population for liver cancer, with the observed to expected ratio ranging from 2·04 to 6·88. The all-cause age-standardised DALYs per 100 000 population were lower than expected in all provinces in 2017, and among the top 20 level 3 causes were lower than expected for ischaemic heart disease, Alzheimer’s disease, headache disorder, and low back pain. The largest percentage change at the national level in age-standardised SEVs (Summary Exposure Values) among the top ten leading risk factors was in high body-mass index (185%, 95% UI 113·1 to 247·7]), followed by ambient particulate matter pollution (88·5%, 66·4 to 116·4).
Interpretation: China has made substantial progress in reducing the burden of many diseases and disabilities. Strategies targeting chronic diseases, particularly in the elderly, should be prioritised in the expanding Chinese health-care system.”
Zhou M, Wang H, Zeng X et al.: Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet [Epub ahead of print, June 24, 2019; pii: S0140-6736(19)30427-1. doi: 10.1016/S0140-6736(19)30427-1].
Some people experience auditory sensations when seeing visual flashes or movements. This prevalent synaesthesia-like visually evoked auditory response could result either from overexuberant cross-activation between brain areas and/or reduced inhibition of normally occurring cross-activation. The authors of this paper have used transcranial alternating current stimulation to test these theories. Their results suggest that “hearing” visual stimuli may depend on disinhibition of normally occurring sensory cross-activation, and that this may be expressed more strongly in some individuals. Furthermore, endogenous alpha- and gamma-frequency oscillations in the brain may respectively inhibit or promote this cross-activation.
Fassnidge C, Ball D, Kazaz Z, Knudsen S, Spicer A, Tipple A, Freeman E: Hearing through Your Eyes: Neural Basis of Audiovisual Cross-activation, Revealed by Transcranial Alternating Current Stimulation. J. Cognitive Neuroscience 31(6):922-935 (2019).
Abstract: “Sleep is essential to all animals with a nervous system. Nevertheless, the core cellular function of sleep is unknown, and there is no conserved molecular marker to define sleep across phylogeny. Time-lapse imaging of chromosomal markers in single cells of live zebrafish revealed that sleep increases chromosome dynamics in individual neurons but not in two other cell types. Manipulation of sleep, chromosome dynamics, neuronal activity, and DNA double-strand breaks (DSBs) showed that chromosome dynamics are low and the number of DSBs accumulates during wakefulness. In turn, sleep increases chromosome dynamics, which are necessary to reduce the amount of DSBs. These results establish chromosome dynamics as a potential marker to define single sleeping cells, and propose that the restorative function of sleep is nuclear maintenance.”
Zada D, Bronshtein I, Lerer-Goldshtein T, Garini Y and Applebaum L: Sleep increases chromosome dynamics to enable reduction of accumulating DNA damage in single neurons. Nature Comm. 10(1): 895 (2019); doi: 10.1038/s41467-019-08806-w.
Abstract: “Cerebral blood flow is reduced early in Alzheimer’s disease (AD). Because most of the vascular resistance within the brain is in capillaries, this could reflect dysfunction of contractile pericytes on capillary walls. Here we used live and rapidly-fixed biopsied human tissue to establish disease-relevance, and rodent experiments to define mechanism. We found that, in humans with cognitive decline, amyloid β (Aβ) constricts brain capillaries at pericyte locations. This was caused by Aβ generating reactive oxygen species, which evoked the release of endothelin-1 (ET) that activated pericyte ETA receptors. Capillary, but not arteriole, constriction also occurred in vivo in a mouse model of Alzheimer’s disease. Thus, inhibiting the capillary constriction caused by Aβ could potentially reduce energy lack and neurodegeneration in AD.”
Nortley R, Korte N, Izquierdo P, Hirunpattarasilp C, Mishra A, Jaunmuktane Z, Kyrargyri V, Pfeiffer T, Khennouf L, Madry C, Gong H, Richard-Loendt A, Huang W, Saito T, Saido TC, Brandner S, Sethi H, Attwell D: Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes. Science [Epub ahead of print, June 20, 2019; pii: eaav9518. doi: 10.1126/science.aav9518 ].
Abstract: “The past decade has seen a dramatic expansion of the field of prodromal Parkinson’s disease (PD). Ten years ago, there were only six known prodromal markers of disease, none of which had more than two studies documenting diagnostic value. We now have at least 16 markers, with as many as 10 prospective studies for a single marker. This review summarizes the major advances over the last decade and speculates about the advances we will see in the decade to come. The most notable advances over the last decade came through the study of high-risk cohorts (REM sleep behavior disorder and later genetic and autonomic cohorts), the generation of more representative population-based cohorts for studying prodromal PD, major advances in neuroimaging of early disease stages, the emerging likelihood that tissue biopsy will be able to diagnose prodromal PD, and the coalescence of prodromal markers into discrete criteria. As the next decade dawns, we await increasing precision of sensitivity and specificity estimates of known markers, the discovery of new biomarkers of prodromal disease, improvements in diagnosis using combined methods/criteria (with increasing recognition of prodromal PD as one stage of the full PD spectrum), and ultimately the development of neuroprotective therapy that can be provided at the earliest stages of disease.”
Postuma, RB and Berg, D: Prodromal Parkinson’s disease: the decade past, the decade to come. Mov. Disord. 34: 665–675 (2019).
Summary: “Some of the most effective new pharmaceutical drugs are highly complex biological molecules. To make such therapies less expensive and more broadly available, drug developers seek to fashion biosimilars — good-enough copies that can be produced at large scale.” The following is a collection of articles which highlight this important new field of research…….
Abstract: “Multiple sclerosis (MS) is characterized by inflammatory insults that drive neuroaxonal injury. However, knowledge about neuron-intrinsic responses to inflammation is limited. By leveraging neuron-specific messenger RNA profiling, we found that neuroinflammation leads to induction and toxic accumulation of the synaptic protein bassoon (Bsn) in the neuronal somata of mice and patients with MS. Neuronal overexpression of Bsn in flies resulted in reduction of lifespan, while genetic disruption of Bsn protected mice from inflammation-induced neuroaxonal injury. Notably, pharmacological proteasome activation boosted the clearance of accumulated Bsn and enhanced neuronal survival. Our study demonstrates that neuroinflammation initiates toxic protein accumulation in neuronal somata and advocates proteasome activation as a potential remedy.”
Schattling B, Engler JB, Volkmann C, Rothammer N, Woo MS, Petersen M, Winkler I, Kaufmann M, Rosenkranz SC, Fejtova A, Thomas U, Bose A, Bauer S, Träger S, Miller KK, Brück W, Duncan KE, Salinas G, Soba P, Gundelfinger ED, Merkler D and Friese MA: Basson Proteinopathy drives neurodegeneration in multiple sclerosis. Nature Neuroscience 22(6): 887-896 (2019).
Abstract: “Mental health and well-being are consistently influenced-directly or indirectly-by multiple environmental exposures. In this review, we have attempted to address some of the most common exposures of the biophysical environment, with a goal of demonstrating how those factors interact with central structures and functions of the brain and thus influence the neurobiology of depression. We emphasize biochemical mechanisms, observational evidence, and areas for future research. Finally, we include aspects of contextual environments-city living, nature, natural disasters, and climate change-and call for improved integration of environmental issues in public health science, policies, and activities. This integration is necessary for reducing the global pandemic of depression.”
Van den Bosch M and Meyer-Lindenberg A: Environmental Exposures and Depression: Biological Mechanisms and Epidemiological Evidence. Annu. Rev. Public Health 40: 239-259 (2019).