Risk Factor For Neurological Disorders Research Articles

Lifestyle neuropathology: how our behavior harms our brains and what we can do about it

an under-investigated area of research in neuropathology and neuroscience. One reason may be that neuroscientists have been educated in the belief that most neuropathological diseases are primarily due to genetic and cellular malfunctions that should be analyzed experimentally using cellular and molecular biological techniques. Helping to begin to address this deficiency, this issue of Acta Neuropathologica includes a cluster of review papers, each focusing on a behavioral risk factor for neurological disease, including obesity, brain injury induced by sporting activity, smoking, alcoholism, addiction to illegal drugs, stress, and reduced cognitive and social activity. The papers cover clinical and epidemiological data, human neuropathology, neuroimaging and experimental studies on mechanisms. It is hoped that this cluster of articles will encourage neuropathologists and other neuroscientists with an interest in neurological disease to engage in more interdisciplinary research, combining cellular and molecular biology with behavioral biology, epidemiology and biomarker analysis. Neuropathologists, as neuroscientists with both clinical and experimental expertise, are in a unique position to study experimentally the effects of modifying lifestyles using relevant models of disease and validating the results in clinicopathological studies using human tissues. Furthermore, the papers may stimulate all neuroscientists to contribute to the education of society regarding lifestyles that prevent disease and preserve a healthy brain. The most common neurological disorders, including Alzheimer’s disease, Parkinson’s disease, stroke and brain injury are not solely the result of fate or unfavorable genetics. In fact, major brain diseases such as Alzheimer’s disease and stroke are highly influenced by lifestyle patterns, such as smoking, obesity, education, and reduced cognitive, physical and social activity. Other harmful activities of life lead to brain impairment and pathology per se; these include alcoholism, use of illicit drugs, exposure to environmental toxins, chronic stress, and engagement in sports that feature repeated head impact. In addition, lifestyle factors may alter the relation of pathology to neurological symptoms. For example, more cognitive activity and better education may decrease the probability of dementia for any given level of neuropathology by increasing cognitive reserve. Beneficial lifestyle choices considerably reduce the risk of developing neurological disease. It has been estimated that 50 % of all Alzheimer’s disease might be prevented through reducing important risk factors, i.e., by not smoking, being physically and mentally active, combating low education, and properly treating or preventing chronic diseases and conditions such as hypertension, high cholesterol, diabetes, obesity in mid-life and depression. Similarly, up to 80 % of strokes are preventable by modifying lifestyle factors, such as increasing physical activity, modifying cholesterol levels, eating better, managing blood pressure and blood glucose, losing weight, and stopping smoking. Given the immense medical, social and economic burden of harmful patterns of lifestyle, it is remarkable that this is

Whole mitochondrial DNA variations in hippocampal surgical specimens and blood samples with high-throughput sequencing: A case of mesial temporal lobe epilepsy with hippocampal sclerosis

IntroductionHippocampal sclerosis is the most common lesion in patients with mesial temporal lobe epilepsy. Recently, there has been growing evidence on the involvement of mitochondria also in sporadic forms of epilepsy. In addition, it has been increasingly argued that mitochondrial dysfunction has an important role in epileptogenesis and seizure generation in temporal lobe epilepsy. Although mtDNA polymorphisms have been identified as potential risk factors for neurological diseases, the link between homoplasmy and heteroplasmy within tissues is not clear. We investigated whether mitochondrial DNA (mtDNA) polymorphisms are involved in a case report of a patient with mesial temporal lobe epilepsy-hippocampal sclerosis (MTLE-HS). DesignWe report the whole genome mtDNA deep sequencing results and clinical features of a 36-year-old woman with MTLE-HS. We used pyrosequencing technology to sequence a whole mitochondrial genome isolated from six different regions of her brain and blood. To assess the possible role of mitochondrial DNA variations in affected tissues, we compared all specimens from different regions of the hippocampus and blood. ResultsIn total, 35 homoplasmic and 18 heteroplasmic variations have been detected in 6 different regions of the hippocampus and in blood samples. While the samples did not display any difference in homoplasmic variations, it has been shown that hippocampus regions contain more heteroplasmic variations than blood. The number of heteroplasmic variations was highest in the CA2 region of the brain and accumulated in ND2, ND4 and ND5 genes. Also, dentate and subiculum regions of the hippocampus had similar heteroplasmic variation profiles. DiscussionWe present a new rare example of parallel mutation at 16223 position. Our case suggests that defects in mitochondrial function might be underlying the pathogenesis of seizures in temporal lobe epilepsy.

Prevalence and risk factors for neurological disorders in children aged 6 months to 2 years in northern India

To study prevalence and risk factors for neurological disorders--epilepsy, global developmental delay, and motor, vision, and hearing defects--in children aged 6 months to 2 years in northern India. A two-stage community survey for neurological disorders was conducted in rural and urban areas of Lucknow. After initial screening with a new instrument, the Lucknow Neurodevelopment Screen, screen positives and a random proportion of screen negatives were validated using predefined criteria. Prevalence was calculated by weighted estimates. Demographic, socio-economic, and medical risk factors were compared between validated children who were positive and negative for neurological disorders by univariate and logistic regression analysis. Of 4801 children screened (mean age [SD] 15.32mo [5.96]; 2542 males, 2259 females), 196 were positive; 190 screen positives and 269 screen negatives were validated. Prevalence of neurological disorders was 27.92 per 1000 (weighted 95% confidence interval 12.24-43.60). Significant risk factors (p≤0.01) for neurological disorders were higher age in months (p=0.010), lower mean number of appliances in the household (p=0.001), consanguineous marriage of parents (p=0.010), family history of neurological disorder (p=0.001), and infants born exceptionally small (parental description; p=0.009). On logistic regression, the final model included age (p=0.0193), number of appliances (p=0.0161), delayed cry at birth (p=0.0270), postneonatal meningoencephalitis (p=0.0549), and consanguinity (p=0.0801). Perinatal factors, lower socio-economic status, and consanguinity emerged as predictors of neurological disorders. These factors are largely modifiable.

Sleep loss as risk factor for neurologic disorders: A review

Sleep loss refers to sleep of shorter duration than the average baseline need of seven to eight hours per night. Sleep loss and sleep deprivation have severe effects on human health. In this article, we review the main aspects of sleep loss, taking into account its effects on the central nervous system. The neurocognitive and behavioral effects of sleep loss are well known. However, there is an increasing amount of research pointing to sleep deprivation as a risk factor for neurologic diseases, namely stroke, multiple sclerosis, Alzheimer's disease, headache, epilepsy, pain, and somnambulism. Conversely, sleep loss has been reported to be a potential protective factor against Parkinson's disease. The pathophysiology involved in this relationship is multiple, comprising immune, neuroendocrine, autonomic, and vascular mechanisms. It is extremely important to identify the individuals at risk, since recognition and adequate treatment of their sleep problems may reduce the risk of certain neurologic disorders.

Electric shocks at work in Europe: development of a job exposure matrix

ObjectivesElectric shocks have been suggested as a potential risk factor for neurological disease, in particular for amyotrophic lateral sclerosis. While actual exposure to shocks is difficult to measure, occurrence and...

Depression und neurologische Erkrankungen

In many neurological diseases a depressive syndrome is a characteristic sign of the primary disease or is an important comorbidity. Post-stroke depression, for example, is a common and relevant complication following ischemic brain infarction. Approximately 4 out of every 10 stroke patients develop depressive disorders in the course of the disease which have a disadvantageous effect on the course and the prognosis. On the other hand depression is also a risk factor for certain neurological diseases as was recently demonstrated in a meta-analysis of prospective cohort studies which revealed a much higher stroke risk for depressive patients. Furthermore, depression plays an important role in other neurological diseases with respect to the course and quality of life, such as Parkinson's disease, multiple sclerosis and epilepsy. This article gives a review of the most important epidemiological, pathophysiological and therapeutic aspects of depressive disorders as a comorbidity of neurological diseases and as a risk factor for neurological diseases.

Metabolic syndrome as a risk factor for neurological disorders.

The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. At the molecular level, metabolic syndrome is accompanied not only by dysregulation in the expression of adipokines (cytokines and chemokines), but also by alterations in levels of leptin, a peptide hormone released by white adipose tissue. These changes modulate immune response and inflammation that lead to alterations in the hypothalamic 'bodyweight/appetite/satiety set point,' resulting in the initiation and development of metabolic syndrome. Metabolic syndrome is a risk factor for neurological disorders such as stroke, depression and Alzheimer's disease. The molecular mechanism underlying the mirror relationship between metabolic syndrome and neurological disorders is not fully understood. However, it is becoming increasingly evident that all cellular and biochemical alterations observed in metabolic syndrome like impairment of endothelial cell function, abnormality in essential fatty acid metabolism and alterations in lipid mediators along with abnormal insulin/leptin signaling may represent a pathological bridge between metabolic syndrome and neurological disorders such as stroke, Alzheimer's disease and depression. The purpose of this review is not only to describe the involvement of brain in the pathogenesis of metabolic syndrome, but also to link the pathogenesis of metabolic syndrome with neurochemical changes in stroke, Alzheimer's disease and depression to a wider audience of neuroscientists with the hope that this discussion will initiate more studies on the relationship between metabolic syndrome and neurological disorders.

Development of a shock job exposure matrix based on reported electric accidents in Europe

ObjectivesElectric shocks has been raised as a potential risk factor for neurological disease and in particular for amyotrophic lateral sclerosis (ALS). While actual exposure to electric shocks cannot be measured,...

Pain Coping Strategies for Tension-Type Headache: Possible Implications for Insomnia?

Insomnia has been identified as a risk factor for tension-type headache, although the pathogenesis of sleep disturbance in this population is unclear. The present study examined pain-related self-management strategies in a nonclinical, young-adult sample for preliminary evidence to support a novel hypothesis for the development of insomnia in this population. Self-report data on triggers of headache, pain interference with sleep, and pain-related self-management strategies were analyzed for 32 women with tension-type headache and 33 women with minimal pain who served as controls. The results revealed that a significantly greater proportion of the headache group relative to the control group reported sleep problems as a trigger of headaches, stress as a trigger of headache, and going to sleep as a coping strategy for pain. The headache group also reported significantly higher ratings of pain interference with sleep. Going to sleep was the most commonly used self-management strategy (81%) by headache sufferers and also rated as the most effective strategy (5.5 out of 7.0). These findings suggest that a bidirectional relationship between sleep disturbance and headache is present in this young-adult sample. Furthermore, the frequent use of sleep as a self-management strategy for pain is consistent with the hypothesis that sleep-seeking behavior might be a mediating factor in the development of insomnia among people with tension-type headache. This hypothesis fits within the most widely accepted conceptual model of chronic insomnia and should be further investigated in individuals with both tension-type headache and insomnia.

Statin-Like Drugs for the Treatment of Brain Cholesterol Loss in Alzheimers Disease

Aging is one of the most significant risk factors for neurological disorders including Alzheimer's Disease (late-onset AD and sporadic AD), the most common form of dementia. AD is characterized by progressive atrophy and loss of neurons resulting in cognitive deficits, confusion and dementia, culminating in childlike helplessness and death. One of the major pathological hallmarks of the disease are amyloid plaques, composed primarly of insoluble fibrils of Abeta peptide: this molecule derives from the processing of the transmembrane amyloid precursor protein (APP) by different secretases and its production is a physiological event, but the anormal increase in Abeta levels appears to be toxic both in vitro and in vivo. Being APP cleavage a membrane event the involvement of lipids in alterations of this cleavage is assumable. Cholesterol is the most abundant lipid in cellular membranes and is an essential component of them, determining the fluidity and biophysical properties. In fact, genetic studies of the risk of AD have reported association with polymorphism in some cholesterol related genes like the allele epsilon4 of the apolipoprotein E, cholesterol 24-hydroxylase (CYP46A1), ATP-binding cassette transporter a1 (ABCA1) and the lipoprotein receptor-related protein (LRP). Moreover a recent publication shows a downregulation of Seladin-1 (which catalyze the last step of cholesterol biosynthesis) in affected neurons in Alzheimer's Disease. Post-mortem analysis of AD brains reveal a loss in cholesterol content and this make the therapeutical use of statin-like drugs quite a lot controversial. Taking together their clinical trials results and the large body of literature regarding lipid profile alterations in AD, it is actually unclear how much these agents can be helpful or not for affected patients.

Folate and Methylation Status in Relation to Phosphorylated Tau Protein(181P) and β-Amyloid(1–42) in Cerebrospinal Fluid

Increased plasma total homocysteine (tHcy) is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained. We evaluated concentrations of tHcy, S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), folate, and vitamin B(12) in cerebrospinal fluid (CSF) and plasma or serum from 182 patients with different neurological disorders. We measured concentrations of phosphorylated tau protein (P-tau)((181P)) and beta-amyloid(1-42) in the CSF. Aging was associated with higher concentrations of tHcy and SAH in the CSF, in addition to lower concentrations of CSF folate and lower SAM:SAH ratio. Concentrations of CSF SAH and CSF folate correlated significantly with those of P-tau (r = 0.46 and r = -0.28, respectively). Moreover, P-tau correlated negatively with SAM:SAH ratio (r = -0.40, P <0.001). The association between SAH and higher P-tau was observed in 3 age groups (<41, 41-60, and >60 years). CSF tHcy was predicted by concentrations of CSF cystathionine (beta = 0.478), folate (beta = -0.403), albumin (beta = 0.349), and age (beta = 0.298). tHcy concentration in the brain is related to age, B vitamins, and CSF albumin. Increase of CSF SAH is related to increased CSF P-tau; decreased degradation of P-tau might be a plausible explanation. Disturbed methyl group metabolism may be the link between hyperhomocysteinemia and neurodegeneration. Lowering tHcy and SAH might protect the brain by preventing P-tau accumulation.

Gestational Vitamin B Deficiency Leads to Homocysteine-Associated Brain Apoptosis and Alters Neurobehavioral Development in Rats

Hyperhomocysteinemia has been identified as a risk factor for neurological disorders. To study the influence of early deficiency in nutritional determinants of hyperhomocysteinemia on the developing rat brain, dams were fed a standard diet or a diet lacking methyl groups during gestation and lactation. Homocysteinemia progressively increased in the offspring of the deficient group and at 21 days reached 13.3+/-3.7 micromol/L versus 6.8+/-0.3 micromol/L in controls. Homocysteine accumulated in both neurons and astrocytes of selective brain structures including the hippocampus, the cerebellum, the striatum, and the neurogenic subventricular zone. Most homocysteine-positive cells expressed p53 and displayed fragmented DNA indicative of apoptosis. Righting reflex and negative geotaxis revealed a delay in the onset of integration capacities in the deficient group. Between 19 and 21 days, a poorer success score was recorded in deficient animals in a locomotor coordination test. A switch to normal food after weaning allowed restoration of normal homocysteinemia. Nevertheless, at 80 days of age, the exploratory behavior in the elevated-plus maze and the learning and memory behavior in the eight-arm maze revealed that early vitamin B deprivation is associated with persistent functional disabilities, possibly resulting from the ensuing neurotoxic effects of homocysteine.

Maternal infection and white matter toxicity

Studies examining maternal infection as a risk factor for neurological disorders in the offspring have suggested that altered maternal immune status during pregnancy can be considered as an adverse event in prenatal development. Infection occurring in the mother during the gestational period has been implicated in multiple neurological effects. The current manuscript will consider the issue of immune/inflammatory conditions during prenatal development where adverse outcomes have been linked to maternal systemic infection. The discussions will focus primary on white matter and oligodendrocytes as they have been identified as target processes. This white matter damage occurs in very early preterm infants and in various other human diseases currently being examined for a linkage to maternal or early developmental immune status. The intent is to draw attention to the impact of altered immune status during pregnancy on the offspring for the consideration of such contributing factors to the general assessment of developmental neurotoxicology.

The Involvement of Copper Transporter in Lead-induced Oxidative Stress in Astroglia

Lead (Pb), depositing primarily in astroglia in the brain, is a well-known neurotoxicant and a risk factor for neurologic disorders. Pb has been reported to induce oxidative stress by probably the disturbance of copper (Cu) homeostasis in astroglia. Thus, we hypothesized that Pb-induced oxidative stress is initiated by interfering with Cu transporter in astroglia. In this study, we observed Pb-induced oxidative stress as indicated by reactive oxygen species (ROS) augmentation and GRP78 and GRP94 protein induction, and it was parallel to Cu accumulation intracellularly by Pb. To further address Cu transporter as a potential Pb target, a heavy metal-binding (HMB) domain of Cu-transporting ATPase (Atp7a) was overexpressed and purified. Evidence showed that one molecule of HMB chelated 11 Pb ions or seven Cu ions and that Pb competed with Cu for binding to HMB. These findings suggest that Pb-induced oxidative stress results from the impairment of Cu metabolism by Pb targeting of Atp7a.

Aging and the brain: a new frontier.

With aging, both "normal" senescent age-related changes (ARCs) and late-onset diseases affect the brain, producing declines in performance. The brain as a postmitotic structure is particularly vulnerable to ARCs, and senescence is by far the most powerful risk factor for neurological diseases of the elderly such as sporadic Alzheimer's disease. The concept of senescence as an immutable result of the passage of time is yielding to understanding of the biology of ARCs. Both individual and species differences in longevity illustrate the variable effects of time. Whereas human life expectancy has been extended by prevention and treatment of specific diseases, life span can be altered by modifying the processes producing ARCs. Models of prolonged life span (eg, modifications of Caenorhabditis elegans longevity genes, restricted caloric intake) demonstrate the feasibility of extending longevity throughout the phylogenetic spectrum. Both programmed and variable factors produce ARCs. Cell survival depends on a balance of opposing factors--oncogene and anti-oncogene products, cyclins, growth factors, and so on; apoptotic death results when the balance shifts. Variable factors, including accumulation of oxygen free radicals, protein conformational changes, decline in chaperone functions, and secondary loss of mitochondrial energy production, can also result in neuronal degeneration. To prevent the increased neuronal vulnerability of senescence, ARCs must be modified. The "new frontier" in neurology is the challenge of understanding the changes of aging, both to determine their impact on disease and to prevent their consequences.

Differential Postmorbidity Mortality in Observational Studies of Risk Factors for Neurologic Disorders

Selection bias may be introduced in case-control or cross-sectional studies, and the impact on the observed associations may be dramatic. Many authors have examined this issue primarily in the context of subject source (e.g. referral bias). The potential bias encountered when a risk factor associated with outcome is also associated with an increase in mortality among cases greater than that among those not developing the disease (e.g. selective survival) is examined here. The potential for selective survival bias arising in observational studies is demonstrated in studies of the etiology of neonatal seizures and Parkinson's disease.