Neurological patients confronting climate change: A potential role for the glymphatic system and sleep.

Interest in the health consequences of climate change (global warming, heatwaves) has increased in the neurological community. This review addresses the impact of elevated ambient temperatures and heatwaves on patients with neurological and mental health disorders, including multiple sclerosis, synucleinopathies, dementia, epilepsies, mental health, and stroke. Patients with such conditions are highly vulnerable during heatwaves because of functional disorders affecting sleep, thermoregulation, autonomic system reactivity, mood, and cognitive ability. Several medications may also increase the risk of heatstroke. Special attention is devoted to the involvement of common underlying mechanisms, such as sleep and the glymphatic system. Disease prevention and patient care during heatwaves are major issues for caregivers. Beyond the usual recommendations for individuals, we favor artificially induced acclimation to heat, which provides preventive benefits with proven efficacy for healthy adults.

Heatwaves and human sleep: Stress response versus adaptation.

The World Meteorological Organization considers a heatwave as "a period of statistically unusual hot weather persisting for a number of days and nights". Accompanying the ongoing global climate change, sharp heatwave bouts occur worldwide, growing in frequency and intensity, and beginning earlier in the season. Heatwaves exacerbate the risk of heat-related illnesses, hence human morbidity and mortality, particularly in vulnerable elderly and children. Heat-related illnesses present a continuum from normothermic (prickly heat, heat edema, heat cramps, heat tetany) to hyperthermic syndromes (from heat syncope and heat exhaustion to lethal heat stroke). Heat stroke may occur through passive heating and/or exertional exercise. "Normal sleep", such as observed in temperate conditions, is altered during heatwaves. Brisk excessive heat bouts shorten and fragment human sleep. Particularly, deep N3 sleep (formerly slow-wave sleep) and REM sleep are depleted, such as in other stressful situations. The resultant sleep loss is deleterious to cognitive performance, emotional brain function, behavior, and susceptibility to chronic health conditions and infectious diseases. Our group has previously demonstrated that sleep constitutes an adaptive mechanism during climatic heat acclimatization. In parallel, artificial heat acclimation procedures have been proposed in sports and military activities, and for the elderly. Other preventive actions should be considered, such as education and urban heat island cooling (vegetation, white paint), thus avoiding energy-hungry air conditioning.

Environmental neurology: Concepts and short history of an interdisciplinary approach to etiology, treatment and prevention.

Environmental Neurology (EN), a sub-discipline of Neurology and Neurological Sciences, favors an interdisciplinary collaboration allowing a holistic approach to understanding the impact of environmental factors on the nervous system and their relationship with neurological diseases. Several examples of diseases and conditions show the large scope of subjects addressed by EN. The EN sub-discipline focuses on both individual and population issues thus joining patient care and public health, respectively. Neuropathogenesis is addressed by several major questions: How do the environment and nervous system interact? Which exogenous factors can trigger neurological disease? When, where and how do they act? What are the therapeutic implications, and how can these disorders be controlled or prevented. To answer such questions, we address the incentive for, philosophy of and methods developed by EN, which seeks to safeguard Brain Health and, thus, the quality of life.

Endemic parkinsonism: clusters, biology and clinical features.

The term 'endemic parkinsonism' refers to diseases that manifest with a dominant parkinsonian syndrome, which can be typical or atypical, and are present only in a particular geographically defined location or population. Ten phenotypes of endemic parkinsonism are currently known: three in the Western Pacific region; two in the Asian-Oceanic region; one in the Caribbean islands of Guadeloupe and Martinique; and four in Europe. Some of these disease entities seem to be disappearing over time and therefore are probably triggered by unique environmental factors. By contrast, other types persist because they are exclusively genetically determined. Given the geographical clustering and potential overlap in biological and clinical features of these exceptionally interesting diseases, this Review provides a historical reference text and offers current perspectives on each of the 10 phenotypes of endemic parkinsonism. Knowledge obtained from the study of these disease entities supports the hypothesis that both genetic and environmental factors contribute to the development of neurodegenerative diseases, not only in endemic parkinsonism but also in general. At the same time, this understanding suggests useful directions for further research in this area.

New clues to the elusive aetiology of nodding syndrome.

Nodding syndrome is a paediatric epileptic encephalopathy of unknown aetiology that affects children in impoverished communities of Eastern Africa subject to internal displacement. Set in southcentral South Sudan, where nodding syndrome first surfaced circa 1990, an important new study of recent-onset cases of nodding syndrome examined parasitic, bacterial, viral, immune-mediated, metabolic and nutritional factors associated with the brain disease. Infection with the nematode Mansonella perstans, but not with Onchocerca volvulus, was the most prominent finding in nodding syndrome cases versus controls. While M. perstans is unlikely to be causal of nodding syndrome, investigation of the freshwater habitats, where insect-to-human transmission of the filarial larvae takes place, may reveal a clue as to the aetiology of this neurodegenerative disease. The culpable environmental agent(s) must be able to induce neuroinflammation and tau pathology preferentially in infants and children.

Association of N-nitrosodimethylamine exposure with cognitive impairment based on the clues of mice and humans.

N-nitrosodimethylamine (NDMA) is an environmental and food contaminant, but limited data to concern whether NDMA has adverse effects on the brain. This study first determined the concentration of NDMA in foods from aquaculture markets in Shenzhen, then analyzed the effects on C57BL/6 mice and further evaluated on the urine samples of elderly Chinese residents with normal cognition (NC, n = 144), cognitive decline (CD, n = 116) and mild cognitive impairment (MCI, n = 123). The excessive rate of NDMA in foods was 3.32% (27/813), with a exceeding range of 4.78-131.00 µg/kg. Behavioral tests showed that 60 days treatment of mice with 3 mg/kg NDMA reduced cognitive performance. Cognitive impairment in human was significantly associated with sex, educational levels, length of residence in Shenzhen, household registration, passive smoking, rice, fresh vegetables, bacon products. NDMA was detected in 55.4% (212/383) of urine samples, with a median concentration of 0.23 µg/L (1.20 × 10 -7-157.39 µg/L). The median concentration for NC, CD and MCI were 0.32, 0.27, and 0 µg/L, respectively. The urinary NDMA concentration had a strong negative correlation with cognitive impairment (Kendall's Tau-b = -0.89, P = 0.024). The median estimated daily intake (EDI) of NDMA was determined to be 6.63 ng/kg-bw/day. Taken together, there appears to be an association between NDMA and human and murine cognition, which provides a new clue to Alzheimer's disease (AD).

Lathyrism in Spain: Lessons from 68 publications following the 1936-39 Civil War.

After the end of the Spanish Civil War (1936-1939), an estimated 1,000 patients presented with lathyrism due to their excessive and prolonged consumption of grasspea (Lathyrus sativus L.) against the backdrop of poverty, drought, and famine. Based on 68 scientific communications between 1941 and 1962 by qualified medical professionals, the disease emerged in different geographical locations involving selective populations: (1) farmers from extensive areas of central Spain, traditionally producers and consumers of grasspea; (2) immigrants in the industrial belt of Catalonia and in the Basque Country, areas with little or no production of grasspea, which was imported from producing areas; (3) workers in Galicia, an area where the legume is neither produced nor consumed, who were seasonally displaced to high-production areas of grasspea in Castille; and (4) inmates of overcrowded postwar Spanish prisons. Original reports included failed attempts by Carlos Jiménez Díaz (1898-1967) to induce experimental lathyrism, the neuropathology of lathyrism in early stages of the disease in two patients, as reported by Carlos Oliveras de la Riva (1914-2007), and the special susceptibility of children to develop a severe form of lathyrism after relatively brief periods of consumption of the neurotoxic seed of L. sativus. In the Spanish Basque Country, L. cicera L. (aizkol) was cultivated exclusively as animal fodder. Patients who were forced to feed on this plant developed unusual manifestations of lathyrism, such as axial myoclonus and severe neuropsychiatric disorders, unknown in other regions of the country and previously unreported. The postwar epidemic of lathyrism in Spain represents the most extensively studied outbreak of this self-limiting but crippling upper motor neuron disease.

Empirical landscape genetic comparison of single nucleotide polymorphisms and microsatellites in three arid-zone mammals with high dispersal capacity.

Landscape genetics is increasingly transitioning away from microsatellites, with single nucleotide polymorphisms (SNPs) providing increased resolution for detecting patterns of spatial-genetic structure. This is particularly pertinent for research in arid-zone mammals due to challenges associated with unique life history traits, such as boom-bust population dynamics and long-distance dispersal capacities. Here, we provide a case study comparing SNPs versus microsatellites for testing three explicit landscape genetic hypotheses (isolation-by-distance, isolation-by-barrier, and isolation-by-resistance) in a suite of small, arid-zone mammals in the Pilbara region of Western Australia. Using clustering algorithms, Mantel tests, and linear mixed effects models, we compare functional connectivity between genetic marker types and across species, including one marsupial, Ningaui timealeyi, and two native rodents, Pseudomys chapmani and P. hermannsburgensis. SNPs resolved subtle genetic structuring not detected by microsatellites, particularly for N. timealeyi where two genetic clusters were identified. Furthermore, stronger signatures of isolation-by-distance and isolation-by-resistance were detected when using SNPs, and model selection based on SNPs tended to identify more complex resistance surfaces (i.e., composite surfaces of multiple environmental layers) in the best-performing models. While we found limited evidence for physical barriers to dispersal across the Pilbara for all species, we found that topography, substrate, and soil moisture were the main environmental drivers shaping functional connectivity. Our study demonstrates that new analytical and genetic tools can provide novel ecological insights into arid landscapes, with potential application to conservation management through identifying dispersal corridors to mediate the impacts of ongoing habitat fragmentation in the region.

Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology via lifetime exposome research.

The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.

Linking life history to landscape for threatened species conservation in a multiuse region.

Landscape-scale conservation that considers metapopulation dynamics will be essential for preventing declines of species facing multiple threats to their survival. Toward this end, we developed a novel approach that combines occurrence records, spatial-environmental data, and genetic information to model habitat, connectivity, and patterns of genetic structure and link spatial attributes to underlying ecological mechanisms. Using the threatened northern quoll (Dasyurus hallucatus) as a case study, we applied this approach to address the need for conservation decision-making tools that promote resilient metapopulations of this threatened species in the Pilbara, Western Australia, a multiuse landscape that is a hotspot for biodiversity and mining. Habitat and connectivity were predicted by different landscape characteristics. Whereas habitat suitability was overwhelmingly driven by terrain ruggedness, dispersal was facilitated by proximity to watercourses. Although there is limited evidence for major physical barriers in the Pilbara, areas with high silt and clay content (i.e., alluvial and hardpan plains) showed high resistance to dispersal. Climate subtlety shaped distributions and patterns of genetic turnover, suggesting the potential for local adaptation. By understanding these spatial-environmental associations and linking them to life-history and metapopulation dynamics, we highlight opportunities to provide targeted species management. To support this, we have created habitat, connectivity, and genetic uniqueness maps for conservation decision-making in the region. These tools have the potential to provide a more holistic approach to conservation in multiuse landscapes globally.

La conservación a nivel del paisaje que incluye las dinámicas metapoblacionales será esencial para prevenir la declinación de especies con múltiples amenazas a su supervivencia. Enfocados en este fin, desarrollamos una estrategia novedosa que combina los registros presenciales, datos espacio-ambientales e información genética para modelar la conectividad de hábitat y los patrones de estructura genética y conectar los atributos espaciales con los mecanismos ecológicos subyacentes. Usamos al cuol del norte (Dasyurus hallucatus) como estudio de caso para aplicar esta estrategia y abordar la necesidad de herramientas de decisión en la conservación que promuevan metapoblaciones resilientes de esta especie en la Pilbara de Australia Occidental, un paisaje multiusos que es un punto caliente para la biodiversidad y la minería. Diferentes características del paisaje pronosticaron la conectividad y el hábitat. Mientras que la escabrosidad del terreno causó enormemente la idoneidad del hábitat, la dispersión estuvo propiciada por la proximidad a los cauces. Aunque hay evidencias limitadas de barreras físicas importantes en la Pilbara, las áreas con un contenido elevado de limo y arcilla (es decir, planicies aluviales y de alio) mostraron una gran resistencia a la dispersión. La matización climática determinó la distribución y los patrones del recambio genético, lo que sugiere un potencial para la adaptación local. Si entendemos estas asociaciones espacio-ambientales y las conectamos con las dinámicas metapoblacionales y de historia de vida, podemos resaltar las oportunidades para proporcionar un manejo focalizado de la especie. Para respaldar esto hemos creado mapas de hábitat, conectividad y singularidad genética para las decisiones de conservación en la región. Estas herramientas tienen el potencial de proporcionar una estrategia más holística para la conservación en los paisajes multiusos de todo el mundo.

MGMT, a risk factor for both genetic and environmental forms of dementia.

MGMT, the gene coding for the DNA-repair protein O6 -methylguanine methyltransferase, which has been recently shown to be a risk factor for inherited forms of Alzheimer's disease (AD), notably among women, might also be linked to Western Pacific amyotrophic lateral sclerosis and Parkinsonism-dementia complex (ALS/PDC), one phenotype of which is an AD-like dementia. Guam ALS/PDC is strongly considered to be an environmental disorder caused by oral exposure to natural toxins (i.e., genotoxic/epigenotoxic chemicals), notably methylazoxymethanol (MAM) that alkylates guanine to form O6 -methylguanine, found in the seed of cycad plants traditionally used for food. Thus, the DNA-repair protein MGMT might participate in both AD and in the AD-related disorder ALS/PDC.

Covid-19: Early Cases and Disease Spread.

The emergence and global spread of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is critical to understanding how to prevent or control a future viral pandemic. We review the tools used for this retrospective search, their limits, and results obtained from China, France, Italy and the USA. We examine possible scenarios for the emergence of SARS-CoV-2 in the human population. We consider the Chinese city of Wuhan where the first cases of atypical pneumonia were attributed to SARS-CoV-2 and from where the disease spread worldwide. Possible superspreading events include the Wuhan-based 7th Military World Games on October 18-27, 2019 and the Chinese New Year holidays from January 25 to February 2, 2020. Several clues point to an early regional circulation of SARS-CoV-2 in northern Italy (Lombardi) as soon as September/October 2019 and in France in November/December 2019, if not before. With the goal of preventing future pandemics, we call for additional retrospective studies designed to trace the origin of SARS-CoV-2.

Protein pyrrole adducts are associated with elevated glucose indices and clinical features of diabetic diffuse neuropathies.

INTRODUCTION: Diabetic neuropathy is the most prevalent complication of diabetes mellitus. Although the precise etiology of this neurological disorder has yet to be defined, elevated blood glucose promotes anerobic glycolysis; this produces excess advanced glycation end-products, many of which have a pyrrole structure. Here, we test the hypothesis that protein pyrrole adducts are associated with elevated glucose indices and some clinical features of diabetic diffuse neuropathies. METHOD: We investigated the levels of plasma pyrrole adducts and adjusted urinary pyrrole adducts in a group of elderly persons (n = 516, age 60-79) residing in the District of Luohu, Shenzhen, China between 2017 and 2018. Symptoms of distal symmetric polyneuropathy (DSPN) and resting heart rate, a measure of autonomic nervous system function, were collected from participants (n = 258) with elevated glucose indices. RESULT: Protein pyrrole adducts showed a strong correlation with glucose indices before and after adjustment for age and estimated glomerular filtration rates. Stratified analysis showed that the medians and interquartile values of pyrrole adducts grew as glucose indices of the subgroups increased. Participants with symptoms of DSPN and sinus tachycardia presented elevated levels of plasma pyrrole adducts. CONCLUSION: This study provides a novel link between glucose indices and the etiology of diabetic diffuse neuropathies.

Preliminary seroprevalence study of neurotropic virus antibodies in Nodding syndrome.

Nodding syndrome (NS) is a mostly East African pediatric epileptiform encephalopathy of unknown etiology that shares some clinical features with measles-associated subacute sclerosing panencephalitis (SSPE) and progressive rubella panencephalitis. Two independent studies in northern Uganda identified an association between NS and prior measles infection, while an earlier study in South Sudan found an inverse association. We report preliminary serologic analyses of antibodies to measles (MV), rubella (RV), HSV-1, and CMV viruses in northern Ugandan children with NS and Household (HC) and Community (CC) Controls. Only MV-positive titers were significantly different (3-fold and > 2-fold) in NS relative to HC and HC + CC, respectively. While these results are consistent with greater prior measles infection in Ugandan persons with NS, further studies are needed to determine whether Measles virus (MV) plays any role in the etiology and pathogenesis of NS. Resolving this issue will be invaluable for the thousands of children at risk for this devastating yet often neglected condition.

Population genomics of a predatory mammal reveals patterns of decline and impacts of exposure to toxic toads.

Mammal declines across northern Australia are one of the major biodiversity loss events occurring globally. There has been no regional assessment of the implications of these species declines for genomic diversity. To address this, we conducted a species-wide assessment of genomic diversity in the northern quoll (Dasyurus hallucatus), an Endangered marsupial carnivore. We used next generation sequencing methods to genotype 10,191 single nucleotide polymorphisms (SNPs) in 352 individuals from across a 3220-km length of the continent, investigating patterns of population genomic structure and diversity, and identifying loci showing signals of putative selection. We found strong heterogeneity in the distribution of genomic diversity across the continent, characterized by (i) biogeographical barriers driving hierarchical population structure through long-term isolation, and (ii) severe reductions in diversity resulting from population declines, exacerbated by the spread of introduced toxic cane toads (Rhinella marina). These results warn of a large ongoing loss of genomic diversity and associated adaptive capacity as mammals decline across northern Australia. Encouragingly, populations of the northern quoll established on toad-free islands by translocations appear to have maintained most of the initial genomic diversity after 16 years. By mapping patterns of genomic diversity within and among populations, and investigating these patterns in the context of population declines, we can provide conservation managers with data critical to informed decision-making. This includes the identification of populations that are candidates for genetic management, the importance of remnant island and insurance/translocated populations for the conservation of genetic diversity, and the characterization of putative evolutionarily significant units.

An in-plane photoelectric effect in two-dimensional electron systems for terahertz detection.

Many mid- and far-infrared semiconductor photodetectors rely on a photonic response, when the photon energy is large enough to excite and extract electrons due to optical transitions. Toward the terahertz range with photon energies of a few milli-electron volts, classical mechanisms are used instead. This is the case in two-dimensional electron systems, where terahertz detection is dominated by plasmonic mixing and by scattering-based thermal phenomena. Here, we report on the observation of a quantum, collision-free phenomenon that yields a giant photoresponse at terahertz frequencies (1.9 THz), more than 10-fold as large as expected from plasmonic mixing. We artificially create an electrically tunable potential step within a degenerate two-dimensional electron gas. When exposed to terahertz radiation, electrons absorb photons and generate a large photocurrent under zero source-drain bias. The observed phenomenon, which we call the "in-plane photoelectric effect," provides an opportunity for efficient direct detection across the entire terahertz range.

Parkinsonism and motor neuron disorders: Lessons from Western Pacific ALS/PDC.

Recognized worldwide as an unusual "overlap" syndrome, Parkinsonism and motor neuron disease, with or without dementia, is best exemplified by the former high-incidence clusters of Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) in Guam, USA, in the Kii Peninsula of Honshu Island, Japan, and in Papua, Indonesia, on the western side of New Guinea. Western Pacific ALS/PDC is a disappearing neurodegenerative disorder with multiple and sometime overlapping phenotypes (ALS, atypical parkinsonism, dementia) that appear to constitute a single disease of environmental origin, in particular from exposure to genotoxins/neurotoxins in seed of cycad plants (Cycas spp.) formerly used as a traditional source of food (Guam) and/or medicine (Guam, Kii-Japan, Papua-Indonesia). Seed compounds include the principal cycad toxin cycasin, its active metabolite methylazoxymethanol (MAM) and a non-protein amino acid ß-N-methylamino-L-alanine (L-BMAA); each reproduces components of ALS/PDC neuropathology when individually administered to laboratory species in single doses perinatally (MAM, L-BMAA) or repeatedly for prolonged periods to young adult animals (L-BMAA). Human exposure to MAM, a potent DNA-alkylating mutagen, also has potential relevance to the high incidence of diverse mutations found among Guamanians with/without ALS/PDC. In sum, seven decades of intensive study of ALS/PDC has revealed field and laboratory approaches leading to discovery of disease etiology that are now being applied to sporadic neurodegenerative disorders such as ALS beyond the Western Pacific region. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna.

Genotoxic Damage During Brain Development Presages Prototypical Neurodegenerative Disease.

Western Pacific Amyotrophic Lateral Sclerosis and Parkinsonism-Dementia Complex (ALS/PDC) is a disappearing prototypical neurodegenerative disorder (tau-dominated polyproteinopathy) linked with prior exposure to phytogenotoxins in cycad seed used for medicine and/or food. The principal cycad genotoxin, methylazoxymethanol (MAM), forms reactive carbon-centered ions that alkylate nucleic acids in fetal rodent brain and, depending on the timing of systemic administration, induces persistent developmental abnormalities of the cortex, hippocampus, cerebellum, and retina. Whereas administration of MAM prenatally or postnatally can produce animal models of epilepsy, schizophrenia or ataxia, administration to adult animals produces little effect on brain structure or function. The neurotoxic effects of MAM administered to rats during cortical brain development (specifically, gestation day 17) are used to model the histological, neurophysiological and behavioral deficits of human schizophrenia, a condition that may precede or follow clinical onset of motor neuron disease in subjects with sporadic ALS and ALS/PDC. While studies of migrants to and from communities impacted by ALS/PDC indicate the degenerative brain disorder may be acquired in juvenile and adult life, a proportion of indigenous cases shows neurodevelopmental aberrations in the cerebellum and retina consistent with MAM exposure in utero. MAM induces specific patterns of DNA damage and repair that associate with increased tau expression in primary rat neuronal cultures and with brain transcriptional changes that parallel those associated with human ALS and Alzheimer's disease. We examine MAM in relation to neurodevelopment, epigenetic modification, DNA damage/replicative stress, genomic instability, somatic mutation, cell-cycle reentry and cellular senescence. Since the majority of neurodegenerative disease lacks a solely inherited genetic basis, research is needed to explore the hypothesis that early-life exposure to genotoxic agents may trigger or promote molecular events that culminate in neurodegeneration.