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We determined the effects of wearing an above-knee compression garment (CG) on knee joint position sense. Healthy young adults (n = 24, age = 27.46 +/- 4.65 years) performed a passive knee position-matching task on an isokinetic dynamometer with each leg separately. We determined the magnitude of compression by measuring anatomical thigh cross sectional area (CSA) in standing using magnetic resonance imaging. Wearing the CG compressed CSA by 2% (t = 2.91, p = 0.010, Cohen's d = 0.68). Repeated measures ANOVA (rANOVA) with three repetition factors (condition: CG, no CG; leg: right dominant, left non-dominant; and target angles: 30 degrees, 45 degrees, 60 degrees) revealed an effect of angles (p

Aging contributes to cellular stress and neurodegeneration. Our understanding is limited regarding the tissue-restricted mechanisms providing protection in postmitotic cells throughout life. Here, we show that spinal cord motoneurons exhibit a high abundance of asymmetric dimethyl arginines (ADMAs) and the presence of this posttranslational modification provides protection against environmental stress. We identify protein arginine methyltransferase 8 (PRMT8) as a tissue-restricted enzyme responsible for proper ADMA level in postmitotic neurons. Male PRMT8 knock-out mice display decreased muscle strength with aging due to premature destabilization of neuromuscular junctions. Mechanistically, inhibition of methyltransferase activity or loss of PRMT8 results in accumulation of unrepaired DNA double-stranded breaks and decrease in the cAMP response-element-binding protein 1 (CREB1) level. As a consequence, the expression of CREB1-mediated prosurvival and regeneration-associated immediate early genes is dysregulated in aging PRMT8 knock-out mice. The uncovered role of PRMT8 represents a novel mechanism of stress tolerance in long-lived postmitotic neurons and identifies PRMT8 as a tissue-specific therapeutic target in the prevention of motoneuron degeneration. SIGNIFICANCE STATEMENT Although most of the cells in our body have a very short lifespan, postmitotic neurons must survive for many decades. Longevity of a cell within the organism depends on its ability to properly regulate signaling pathways that counteract perturbations, such as DNA damage, oxidative stress, or protein misfolding. Here, we provide evidence that tissue-specific regulators of stress tolerance exist in postmitotic neurons. Specifically, we identify protein arginine methyltransferase 8 (PRMT8) as a cell-type-restricted arginine methyltransferase in spinal cord motoneurons (MNs). PRMT8-dependent arginine methylation is required for neuroprotection against age-related increased of cellular stress. Tissue-restricted expression and the enzymatic activity of PRMT8 make it an attractive target for drug development to delay the onset of neurodegenerative disorders.

Background Behavioural and psychological symptoms in dementia (BPSD) form an important sub-syndrome of dementia. We assessed the frequency and severity of BPSD in a random sample of Hungarian treatment-naïve dementia patients. Furthermore, we examined the relationship between cognitive symptoms and BPSD and the pattern of BPSD in specific types of dementias. Methods Patients (n=131) were classified into 3 groups: Alzheimer’s (AD), vascular (VD), and mixed (MD) dementia. The Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and Neuropsychiatric Inventory (NPI) neuropsychological tests were employed. Results Mean age and MMSE score did not differ significantly among groups. BPSD was frequent (100% prevalence, NPI mean total Frequency score: 14.58, SD=7.55); abnormal motor behaviour showed the highest frequency. Hallucinations and delusions were related to the aetiology of dementia and were independent of the level of cognitive deterioration, whereas irritability, sleep-wake cycle dysfunctions, and eating-appetite change were associated with cognitive deterioration and were independent from aetiology. Both aberrant motor behaviour and disinhibition were significantly associated with aetiology and cognitive deterioration. Conclusions BPSD symptoms are significant constituents of dementia syndromes, affecting quality of life and substantially contributing to the caregiver’s burden. Specific symptom patterns can be identified in different types of dementia.

Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2–10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.

Purpose: Age-related slowing of gait speed predicts many clinical conditions in later life. We examined the kinematic and kinetic mechanisms of how lower extremity power training increases healthy old adults' gait speed.Methods: We randomly allocated old adults to a training (age 74.3 y, 9 males, 6 females) and a control group (age 73.6 y, 3 males, 4 females) and compared the biomechanics of habitual and fast gait before and after 16 sessions (8 weeks) of lower extremity power training.Results: Training increased maximal leg press load by similar to 40% (P Conclusion: Increases in leg muscle power increased healthy old adults' gait speed through correlated increases in stride length and ankle plantarflexor work generation.

There is currently no test to directly and easily measure dynamic balance during walking in old adults. We examined the idea that distance of beam walking with and without cognitive dual-tasking could detect age differences in dynamic balance. Healthy old (n = 16, 71.2 y) and young (n = 20, 22.0 y) volunteers walked 3 times on 4-m long beams first without (single-tasking) then with a calculation task (dual-tasking) in order of decreasing beam width (12, 8, 4 cm). There was a Group (old, young) by Beam width (4, 8, 12 cm) by Task (single-, dual-tasking) interaction (F = 4.0, p = 0.026) for beam walking distance (primary outcome). Beam walking distance decreased similarly with decreasing beam width while single-tasking (12 cm: 3.88 m, 8 cm: 3.62 m, 4 cm: 2.49 m) and dual-tasking (12 cm: 3.87 m, 8 cm: 3.76 m, 4 cm: 2.59 m) in young adults. Beam walking distance decreased substantially and most on the narrowest beam while single-tasking (12 cm: 3.85 m, 8 cm: 3.72 m, 4 cm: 1.46 m) but decreased even more on the two narrowest beams during dual-tasking (12 cm 3.91 m, 8 cm: 2.63 m, 4 cm: 0.66 m) in old adults. Video analyses revealed that step length decreased in young while both step number and step length decreased in old adults. Beam width but not dual-tasking affected young adults' beam walking distance whereas both beam width and dual-tasking affected substantially and interactively old adults' beam walking distance and velocity. The results suggest that, if validated and cognitive performance also quantified, beam walking distance and walking velocity in single- and dual-tasking conditions could be a diagnostic tool of walking balance and cognitive impairment in aging.

Psychotic symptoms may occur in any dementia, including Alzheimer’s disease (AD), but are particularly common in Lewy body dementia (LBD). The mechanisms of psychotic symptoms are largely unknown. Psychosis has been found to be associated with more severe AD and Lewy body pathology in patients with AD and cerebrovascular disease-related vasculopathy.1 One form of vascular pathology, cerebral amylod angiopathy (CAA), is defined as deposits of amyloid in the vessel walls that increase risk of haemorrhage and ischaemia. CAA contributes to neurodegeneration, but its relation to clinical symptoms and course in dementia is not fully understood.2 The aim of this study was to investigate the postmortem pathological correlates of severe psychotic symptoms in moderate AD and LBD, which were followed annually from the time of diagnosis until death. This is a 12-year prospective follow-up study of dementia ending in neuropathological examination. The 223 patients of the dementia study in Western Norway (Demvest) were diagnosed as mild dementia and followed annually with standardised clinical assessments until death. Patient were diagnosed according to standardised clinical criteria for AD3 and DLB4 or Parkinson's disease dementia (PDD) (both combined as LBD) and mild dementia defined as Mini Mental Status Examination (MMSE) score of at least 20 or a Clinical Dementia Rating scale(CDR) global score=1. The procedures are described in detail elsewhere.5 All comparisons are between groups are based on pathological defined diagnosis. The validated Norwegian 12-item Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Presence of severe psychosis was based on the first 5 years after diagnosis and MMSE value above 10. NPI score of >4 on either item 1 (delusions) or 2 (hallucinations) was used as clinical significant cut-off. …

Alpha-synuclein (α-syn) aggregations are the key pathological hallmark of dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), but are also frequently present in Alzheimer’s disease (AD). Much remains unknown about the role of α-syn in the synapse and the wider role of synaptic dysfunction in these dementias. Changes in concentrations of key ‘SNAP (Soluble N-ethylmaleimide Sensitive Factor Attachment Protein) Receptor’ (SNARE) proteins as a consequence of alterations in the aggregation state of α-syn may contribute to synaptic dysfunction in patients with DLB, PDD, and AD and result in impaired cognition. We have studied a large cohort (n = 130) of autopsy confirmed DLB, PDD, AD, and control brains. Using semi-quantitative western blotting, we have demonstrated significant changes across the diagnostic groups of DLB, PDD, and AD in the SNARE and vesicle proteins syntaxin, Munc18, VAMP2, and monomeric α-syn in the prefrontal cortex, with a significant reduction of Munc18 in AD patients (p < 0.001). This correlated to the final MMSE score before death (p = 0.016). We also identified a significant negative correlation between the duration of dementia and the levels of the binding partners VAMP2 (p = 0.0004) and monomeric α-syn (p = 0.0002). Our findings may indicate that an upregulation of SNARE complex related proteins occurs in the early stages of disease as an attempt at compensating for failing synapses, prior to widespread deposition of pathological α-syn.

When humans voluntarily activate a muscle, intracortical inhibition decreases. Such a decrease also occurs in the presence of a postural challenge and more so with increasing age. Here, we examined age-related changes in motor cortical activity during postural and non-postural contractions with varying levels of postural challenge. Fourteen young (age 22) and twelve old adults (age 70) performed three conditions: (1) voluntary contraction of the soleus muscle in sitting and (2) leaning forward while standing with and (3) without being supported. Subthreshold transcranial magnetic stimulation was applied to the soleus motor area suppressing ongoing EMG, as an index of motor cortical activity. The area of EMG suppression was similar to 60% smaller (p 0.05). Even though in absolute terms young compared with old adults leaned farther (p = 0.018), there was no age effect or an age by condition interaction in EMG suppression. Leaning closer to the maximum without support correlated with less EMG suppression (rho = -0.44, p = 0.034). We conclude that the critical factor inmodulating motor cortical activity was postural challenge and not contraction aim or posture. Age did not affect the motor control strategy as quantified by the modulation of motor cortical activity, but the modulation appeared at a lower task difficulty with increasing age. (C) 2015 Elsevier Inc. All rights reserved.

Background: Walking speed decreases in old age. Even though old adults regularly participate in exercise interventions, we do not know how the intervention-induced changes in physical abilities produce faster walking. The Potsdam Gait Study (POGS) will examine the effects of 10 weeks of power training and detraining on leg muscle power and, for the first time, on complete gait biomechanics, including joint kinematics, kinetics, and muscle activation in old adults with moderate mobility disability. Methods/Design: POGS is a randomized controlled trial with two arms, each crossed over, without blinding. Arm 1 starts with a 10-week control period to assess the reliability of the tests and is then crossed over to complete 25-30 training sessions over 10 weeks. Arm 2 completes 25-30 exercise sessions over 10 weeks, followed by a 10-week follow-up (detraining) period. The exercise program is designed to improve lower extremity muscle power. Main outcome measures are: muscle power, gait speed, and gait biomechanics measured at baseline and after 10 weeks of training and 10 weeks of detraining. Discussion: It is expected that power training will increase leg muscle power measured by the weight lifted and by dynamometry, and these increased abilities become expressed in joint powers measured during gait. Such favorably modified powers will underlie the increase in step length, leading ultimately to a faster walking speed. POGS will increase our basic understanding of the biomechanical mechanisms of how power training improves gait speed in old adults with moderate levels of mobility disabilities.

Background: Habitual walking speed predicts many clinical conditions later in life, but it declines with age. However, which particular exercise intervention can minimize the age-related gait speed loss is unclear. Purpose: Our objective was to determine the effects of strength, power, coordination, and multimodal exercise training on healthy old adults' habitual and fast gait speed. Methods: We performed a computerized systematic literature search in PubMed and Web of Knowledge from January 1984 up to December 2014. Search terms included 'Resistance training', 'power training', 'coordination training', 'multimodal training', and 'gait speed (outcome term). Inclusion criteria were articles available in full text, publication period over past 30 years, human species, journal articles, clinical trials, randomized controlled trials, English as publication language, and subject age C65 years. The methodological quality of all eligible intervention studies was assessed using the Physiotherapy Evidence Database (PEDro) scale. We computed weighted average standardized mean differences of the intervention-induced adaptations in gait speed using a random-effects model and tested for overall and individual intervention effects relative to no-exercise controls. Results: A total of 42 studies (mean PEDro score of 5.0 +/- 1.2) were included in the analyses (2495 healthy old adults; age 74.2 years [64.4-82.7]; body mass 69.9 +/- 4.9 kg, height 1.64 +/- 0.05 m, body mass index 26.4 +/- 1.9 kg/m(2), and gait speed 1.22 +/- 0.18 m/s). The search identified only one power training study, therefore the subsequent analyses focused only on the effects of resistance, coordination, and multimodal training on gait speed. The three types of intervention improved gait speed in the three experimental groups combined (n = 1297) by 0.10 m/s (+/- 0.12) or 8.4 % (+/- 9.7), with a large effect size (ES) of 0.84. Resistance (24 studies; n = 613; 0.11 m/s; 9.3 %; ES: 0.84), coordination (eight studies, n = 198; 0.09 m/s; 7.6 %; ES: 0.76), and multimodal training (19 studies; n = 486; 0.09 m/s; 8.4 %, ES: 0.86) increased gait speed statistically and similarly. Conclusions: Commonly used exercise interventions can functionally and clinically increase habitual and fast gait speed and help slow the loss of gait speed or delay its onset., Zweitveröffentlichungen der Universität Potsdam : Humanwissenschaftliche Reihe; 840

The embryonal tumor with abundant neuropil and true rosettes is a rare and highly malignant variant of embryonal brain tumors. It usually affects infants and young children under the age of 4 years and exhibits a very aggressive course with a dismal prognosis. For the 68 cases reported to date the mean age at diagnosis was 25.42 months (range 3-57 months). Survival data are available for 48 children (including our case): the median overall survival is 13.0 months, though 6 (9%) of the children have had a relative long survival (>30 months). The aggressive combined treatment, involving primary surgical tumor removal, adjuvant polychemotherapy, including high-dose chemotherapy with stem cell transplantation, radiotherapy and radiochemotherapy, might play an important role in the longer survival. We have performed a literature review and we present here a multimodal-treated case of a 2- year-old girl with a long survival, who was reoperated when recurrence occurred. The residual tumor demonstrated a good response to temozolomide radiochemotherapy (craniospinal axis + boost) and followed by maintenance temozolomide. The described complex aggressive treatment option might be considered for future cases of this tumor entity.

Aim The unfolded protein response (UPR) is a pro-survival defence mechanism induced during periods of endoplasmic reticulum stress, and it has recently emerged as an attractive therapeutic target across a number of neurodegenerative conditions, but has not yet been studied in synuclein disorders. Methods The level of a key mediator of the UPR pathway, glucose-regulated protein 78 (GRP78), also known as binding immunoglobulin protein (BiP), was measured in post mortem brain tissue of patients with dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) in comparison with Alzheimer's disease (AD) and age-matched controls using Western blot. The UPR activation was further confirmed by immunohistochemical detection of GRP78/BiP and phosphorylated protein kinase RNA-like endoplasmic reticulum (ER) kinase (p-PERK). Results GRP78/BiP was increased to a greater extent in DLB and PDD patients compared with AD and control subjects in cingulate gyrus and parietal cortex. However, there were no changes in the prefrontal and temporal cortices. There was a significant positive correlation between GRP78/BiP level and α-synuclein pathology in the cingulate gyrus, while AD-type pathology showed an inverse correlation relationship in the parietal cortex. Conclusion Overall, these results give emphasis to the role of UPR in Lewy body dementias, and suggest that Lewy body degeneration, in combination with AD-type pathologies, is associated with increased UPR activation to a greater extent than AD alone, possibly as a consequence of the increasing load of ER proteins. This work also highlights a novel opportunity to explore the UPR as a therapeutic target in synuclein diseases.

We tested the hypothesis that an all-out-effort 200-m front-crawl swim trial affects competitive swimmers' shoulder joint position sense. On Day 1, we measured shoulder joint position sense before and after the swim trial, and on Day 2 before and after 2 min of seated rest. On both days, shoulder joint position sense was measured in the seated position using electromagnetic movement sensors in a position-matching paradigm. An investigator abducted participants' left (reference) shoulder joint in the frontal plane to test angles of 90 degrees, 135 degrees, and 180 degrees. Participants then actively abducted the right (indicator) shoulder joint to match the position of the left, reference arm. After the 200-m all-out front-crawl swim trial, the indicator relative to the reference angle differed by 4.4 degrees toward adduction at the 180 degrees (vertical) testing position (P

Forceful, unilateral contractions modulate corticomotor paths targeting the resting, contralateral hand. However, it is unknown whether mirror-viewing of a slowly moving but forcefully contracting hand would additionally affect these paths. Here we examined corticospinal excitability and short-interval intracortical inhibition (SICI) of the right-ipsilateral primary motor cortex (M1) in healthy young adults under no-mirror and mirror conditions at rest and during right wrist flexion at 60% maximal voluntary contraction (MVC). During the no-mirror conditions neither hand was visible, whereas in the mirror conditions participants looked at the right hand's reflection in the mirror. Corticospinal excitability increased during contractions in the left flexor carpi radialis (FCR) (contraction 0.41 mV vs. rest 0.21 mV) and extensor carpi radialis (ECR) (contraction 0.56 mV vs. rest 0.39 mV), but there was no mirror effect (FCR: P = 0.743, ηp2= 0.005; ECR: P = 0.712, ηp2= 0.005). However, mirror-viewing of the contracting and moving wrist attenuated SICI relative to test pulse in the left FCR by ∼9% compared with the other conditions ( P < 0.05, d ≥ 0.62). Electromyographic activity in the resting left hand prior to stimulation was not affected by the mirror (FCR: P = 0.255, ηp2= 0.049; ECR: P = 0.343, ηp2= 0.035) but increased twofold during contractions. Thus viewing the moving hand in the mirror and not just the mirror image of the nonmoving hand seems to affect motor cortical inhibitory networks in the M1 associated with the mirror image. Future studies should determine whether the use of a mirror could increase interlimb transfer produced by cross-education, especially in patient groups with unilateral orthopedic and neurological conditions.

We describe an atypical neuropathological phenotype of sporadic Creutzfeldt-Jakob disease in a 76-year-old man. The clinical symptoms were characterized by progressive dementia, gait ataxia, rigidity and urinary incontinence. The disease duration was 6 weeks. MRI did not show prominent atrophy or hyperintensities in cortical areas, striatum or thalamus. Biomarker examination of the cerebrospinal fluid deviated from that seen in pure Alzheimer's disease. Triphasic waves in the EEG were detected only later in the disease course, while 14-3-3 assay was positive. PRNP genotyping revealed methionine homozygosity (MM) at codon 129. Neuropathology showed classical CJD changes corresponding to the MM type 1 cases. However, a striking feature was the presence of abundant kuru-type plaques in the white matter. This rare morphology was associated with neuropathological signs of intranuclear inclusion body disease and advanced stage of argyrophilic grain disease. These alterations did not show correlation with each other, thus seemed to develop independently. This case further highlights the complexity of neuropathological alterations in the ageing brain.

Age-related decline in muscle strength can compromise shoulder function, which could increase the effort needed to perform activities of daily living (ADLs). The purpose of this cross-sectional study was to determine for the first time the relative shoulder effort during ADLs in healthy young and older adults.Ten healthy young adults and ten healthy older adults were tested for maximal isokinetic torque and on a set of ADL tasks. Using inverse dynamics, the shoulder torques during ADLs were referenced to the maximal isokinetic torque and relative effort was determined.Older compared to younger adults had >40% lower isokinetic shoulder abduction strength. The ratio of peak joint torque during six ADLs over the maximal isokinetic torque, i.e., relative effort, was higher in old (similar to 52%) compared with young adults (similar to 22%, p Healthy older compared with younger adults perform most ADL tasks involving the shoulder joint with nearly twice the level of relative effort. The concomitant reductions in maximal shoulder isokinetic torque and increases in relative effort may be related to the high prevalence of musculoskeletal pain and shoulder dysfunction in old age reported in epidemiological studies. (C) 2018 Elsevier Ltd. All rights reserved.

Melanin-concentrating hormone (MCH) is a cyclic 19 amino acid orexigenic hypothalamic peptide. MCH is located in the lateral and dorsal hypothalamus, as well as in the zona incerta. In mammals MCH increases food intake, contributes to regulation of energy balance, temperature, reproductive function, endocrine homeostasis and biological rhythms. Several studies have proved the significance of MCH in obesity, diabetes and depression. Although the peptide is well-characterized in mouse models, much less is known about its functions in avians. In birds the MCH system especially in the lateral and basal hypothalamus has important connections to the limbic system and it coordinates the vegetative and endocrine functions, as well as the emotional behaviour. Pharmacological modulation of MCH system could contribute to the therapy of eating disorders and improve agricultural efficiency regarding avians. Reviewing the current knowledge on MCH system in human, rodents and avians may stimulate a new wave of studies in the field.

See Attems and Jellinger (doi:10.1093/brain/awx360) for a scientific commentary on this article.Cognitive changes occurring throughout the pathogenesis of neurodegenerative diseases are directly linked to synaptic loss. We used in-depth proteomics to compare 32 post-mortem human brains in the prefrontal cortex of prospectively followed patients with Alzheimer's disease, Parkinson's disease with dementia, dementia with Lewy bodies and older adults without dementia. In total, we identified 10 325 proteins, 851 of which were synaptic proteins. Levels of 25 synaptic proteins were significantly altered in the various dementia groups. Significant loss of SNAP47, GAP43, SYBU (syntabulin), LRFN2, SV2C, SYT2 (synaptotagmin 2), GRIA3 and GRIA4 were further validated on a larger cohort comprised of 92 brain samples using ELISA or western blot. Cognitive impairment before death and rate of cognitive decline significantly correlated with loss of SNAP47, SYBU, LRFN2, SV2C and GRIA3 proteins. Besides differentiating Parkinson's disease dementia, dementia with Lewy bodies, and Alzheimer's disease from controls with high sensitivity and specificity, synaptic proteins also reliably discriminated Parkinson's disease dementia from Alzheimer's disease patients. Our results suggest that these particular synaptic proteins have an important predictive and discriminative molecular fingerprint in neurodegenerative diseases and could be a potential target for early disease intervention.

Objective Plasticity of the central nervous system likely underlies motor learning. It is however unclear, whether plasticity in cortical motor networks is motor learning stage-, activity-, or connectivity-dependent. Methods From electroencephalography (EEG) data, we quantified effective connectivity by the phase slope index (PSI), neuronal activity by event-related desynchronization, and sensorimotor integration by N30 during the stages of visuomotor skill acquisition, consolidation, and interlimb transfer. Results Although N30 amplitudes and event-related desynchronization in parietal electrodes increased with skill acquisition, changes in PSI correlated most with motor performance in all stages of motor learning. Specifically, changes in PSI between the premotor, supplementary motor, and primary motor cortex (M1) electrodes correlated with skill acquisition, whereas changes in PSI between electrodes representing M1 and the parietal and primary sensory cortex (S1) correlated with skill consolidation. The magnitude of consolidated interlimb transfer correlated with PSI between bilateral M1s and between S1 and M1 in the non-practiced hemisphere. Conclusions Spectral and temporal EEG measures but especially PSI correlated with improvements in complex motor behavior and revealed distinct neural networks in the acquisition, consolidation, and interlimb transfer of motor skills. Significance A complete understanding of the neuronal mechanisms underlying motor learning can contribute to optimizing rehabilitation protocols.

Alzheimer’s disease (AD) is a neurodegenerative disorder with cognitive impairment. Physical exercise has long been proven to be beneficial in the disorder. The present study was designed to examine the effect of voluntary exercise on spatial memory, imaging, and pathological abnormalities. Particular focus has been given to the role of heme oxygenase-1 (HO-1)—an important cellular cytoprotectant in preserving mental acuity—using an aging rat model of dementia. Male and female Wistar rats were segregated into six groups—namely, (i) aged sedentary (control) females (ASF, n=8); (ii) aged sedentary (control) males (ASM, n=8); (iii) aged running females (ARF, n=8); (iv) aged running males (ARM, n=8); (v) young control females (YCF, n=8); and (vi) young control males (YCM, n=8). Rats in the ARF and ARM groups had free access to a standardized inbuilt running wheel during the 3-month evaluation period. Spatial memory was investigated using the Morris Water Test, imaging and pathological alterations were assessed using positron emission tomography (PET) imaging and histopathological examinations (H&E, Congo red staining), respectively, and HO-1 enzyme activity assays were also conducted. The outcomes suggest that voluntary physical exercise mitigates impaired spatial memory and neuropathological changes exhibited by the aging sedentary group, via elevated HO-1 activity, contributing to the antioxidant capacity in the aging brain.

Peritumoral infiltration is characteristic of astrocytomas even in low-grade tumors. Tumor cells migrate to neighbouring tissue and cause recurrence. The extracellular matrix (ECM) plays a role in tumor invasion; expression levels of its components' have been linked to tumor invasion. This study determines the mRNA and protein expression of 20 invasion-related ECM components by examining non-tumor brain; grade I-II-III astrocytoma and glioblastoma samples. Expression levels were measured by QRT-PCR and mass-spectroscopy. The connection between the expression pattern and tumor grade is statistically analyzed. During the analysis of data, key molecules (brevican, cadherin-12, fibronectin and integrin-β1) correlating the most with tumor grade were selected. While the mRNA level of brevican, ErbB2, fibronectin, integrin-β1 and versican discriminates low-grade from high-grade gliomas, of proteins RHAMM, integrin-α1 and MMP2 seems important. The expression pattern was found to be distinctive for tumor grade, as statistical classifiers are capable of identifying an unknown sample's grade using them. Furthermore, normal brain and glioma expression patterns, along with low-grade astrocytoma and glioblastoma samples, differ the most. Determining the invasion-related molecules' expression profile provides extra information regarding the tumor's clinical behavior. Additionally, identifying molecules playing a key role in glioma invasion could uncover potential therapeutic targets in the future.

Amyotrophic lateral sclerosis (ALS) is the major motor neuron disorder. The hallmark features are progressive, irreversible motor neuron loss leading to denervation atrophy of muscles and death, usually within 5 years of disease onset. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43, or FUS; rarely the disease is caused by mutation of the respective genes. Frontotemporal lobar degeneration (FTLD) is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively. The characteristic aggregate-forming protein in non-tau FTLD is either TDP-43 or FUS. It has been known for several years that frontotemporal dementia (or less severe forms of cognitive impairment) may coexist with ALS. Recent discoveries in genetics (e.g., C9orf72 mutation) and the subsequent neuropathologic characterization have revealed remarkable overlap between ALS and non-tau FTLD also at a molecular level, indicating common molecular pathways in pathogenesis. After a historic overview we demonstrate and compare the macroscopic and microscopic appearances and molecular characteristics with emphasis on genetic background, neuroanatomic distribution, and morphology of abnormal protein aggregates and their possible association with specific mutations. The clinicopathologic classifications and correlations are also discussed.

Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications.A központi idegrendszeri tumorok többsége sporadikus és csak ritkán mutat családon belüli halmozódást. A tumorokkal kapcsolatba hozható családi daganatszindrómák általában autoszomális domináns öröklődésmenetet követnek. A kialakuló daganatok jellemzően a sporadikus tumoroknál fiatalabb korban jelentkeznek, bilaterálisak, multiplexek vagy multifokálisak. A betegségek hátterében olyan gének mutációi állnak, amelyek a sejtciklus szabályozásában, a sejtnövekedésben és -differenciációban, illetve a DNS hibajavításában játszanak szerepet. A sporadikus tumorok kialakulásáért felelős molekuláris eltérések teljes feltérképezéséhez, illetve terápiás célpontok kifejlesztéséhez hozzájárul az öröklődő tumorszindrómák mutációinak vizsgálata is. A szerzők összefoglaló közleményükben a központi idegrendszer daganataira hajlamosító legfontosabb örökletes tumorszindrómákat és azok molekuláris genetikai jellemzőit mutatják be. Orv. Hetil., 2015, 156(5), 171–177.

Meningiomas represent nearly one-third of all adult primary brain tumours. According to their clinical and histologic appearance, they can be divided into WHO grades I-III. Almost 90% of meningiomas are benign, showing favourable response to conventional therapies, however, patients diagnosed with grade 2 and 3 tumours may have a poor prognosis. In addition, high frequency of tumour recurrence renders treatments more challenging even in benign meningiomas. Molecular-pathological profiling of meningiomas could lead to development of more effective therapies. Although the cytogenetic background of these tumours are already well-characterised, the majority of related genes and mutations is still unknown. Recently, high-throughput techniques enabled better characterisation of mechanisms involved in meningioma development, progression and recurrence. Furthermore, epigenetic dysregulation could offer new opportunities for both diagnosis and treatment of meningiomas. We provide a comprehensive overview of cytogenetic and molecular genetic defects as well as epigenetic alterations in meningiomas. Many of these may serve as biomarker or therapeutic target in the near future.

When two tasks are performed simultaneously, performance often declines in one or both tasks. These so-called dual-task costs are more pronounced in old than in young adults. One proposed neurological mechanism of the dual-task costs is that old compared with young adults tend to execute single-tasks with higher brain activation. In the brain regions that are needed for both tasks, the reduced residual capacity may interfere with performance of the dual-task. This competition for shared brain regions has been called structural interference. The purpose of the study was to determine whether structural interference indeed plays a role in the age-related decrease in dual-task performance. Functional magnetic resonance imaging (fMRI) was used to investigate 23 young adults (20-29 years) and 32 old adults (66-89 years) performing a calculation (serial subtraction by seven) and balance-simulation (plantar flexion force control) task separately or simultaneously. Behavioral performance decreased during the dual-task compared with the single-tasks in both age groups, with greater dual-task costs in old compared with young adults. Brain activation was significantly higher in old than young adults during all conditions. Region of interest analyses were performed on brain regions that were active in both tasks. Structural interference was apparent in the right insula, as quantified by an age-related reduction in upregulation of brain activity from single-to dual-task. However, the magnitude of upregulation did not correlate with dual-task costs. Therefore, we conclude that the greater dual-task costs in old adults were probably not due to increased structural interference.

Amyotrophic lateral sclerosis (ALS) is the major motor neuron disorder. The hallmark features are progressive, irreversible motor neuron loss leading to denervation atrophy of muscles and death, usually within 5 years of disease onset. The hallmark proteins of the pathognomonic inclusions are SOD-1, TDP-43, or FUS; rarely the disease is caused by mutation of the respective genes. Frontotemporal lobar degeneration (FTLD) is genetically, neuropathologically, and clinically heterogeneous and may present as a dementia with three major clinical syndromes dominated by behavioral, language, and motor disorders, respectively. The characteristic aggregate-forming protein in non-tau FTLD is either TDP-43 or FUS. It has been known for several years that frontotemporal dementia (or less severe forms of cognitive impairment) may coexist with ALS. Recent discoveries in genetics (e.g., C9orf72 mutation) and the subsequent neuropathologic characterization have revealed remarkable overlap between ALS and non-tau FTLD also at a molecular level, indicating common molecular pathways in pathogenesis. After a historic overview we demonstrate and compare the macroscopic and microscopic appearances and molecular characteristics with emphasis on genetic background, neuroanatomic distribution, and morphology of abnormal protein aggregates and their possible association with specific mutations. The clinicopathologic classifications and correlations are also discussed.

BACKGROUND The first consensus criteria for dementia with Lewy bodies (DLB) published in 1996 were revised in 2005, partly because the original clinical criteria had suboptimal sensitivity. Few studies have assessed the accuracy of the 2005 criteria applied prospectively in newly diagnosed patients who have been followed longitudinally. OBJECTIVE To explore the correlation between clinical and pathological diagnoses in patients with DLB and Parkinson's disease with dementia (PDD). METHODS From a prospective referral cohort study with enriched recruitment of patients with DLB and PDD, we included the first 56 patients coming to autopsy. Patients had mild dementia at inclusion and were followed annually until death with standardized clinical assessments. Pathological assessment was performed blind to clinical information according to standardized protocols and consensus criteria for DLB. RESULTS 20 patients received a pathological diagnosis of Lewy body disease; the corresponding clinical diagnoses were probable DLB (n = 11), PDD (n = 5), probable (n = 2) or possible (n = 2) Alzheimer's disease (AD). Of 14 patients with a clinical diagnosis of probable DLB, 11 had DLB/PDD and 3 had AD at pathology. One patient with clinically possible DLB fulfilled criteria for pathological AD. Sensitivity, specificity, positive predictive value, and negative predictive values for probable DLB were 73%, 93%, 79%, and 90%. CONCLUSION Our findings suggest that the international clinical consensus criteria for DLB perform reasonably well. However, false positive and false negative diagnoses still occur, indicating that the criteria need to be improved, that biomarkers may be needed, and that neuropathological feedback is vital to improve accuracy.

Malignant melanoma is one of the most aggressive tumors which often gives metastasis to distant organs thereby limiting the chances of survival. Brain metastasis occurs in nearly half of the advanced tumors. In order to improve outcome early diagnosis is important. The discovery and better understanding of genetic and epigenetic changes is essential for developing new effective therapies, which can designate promising therapeutic targets. Melanoma most often is caused by gene mutations of the mitogen-activated protein kinase pathway, the phosphatidylinositol 3-kinase signaling pathway, and the cell cycle regulatory molecules, respectively. The molecular process of brain metastasis has not been fully elucidated. In our review we summarize the genetic alterations and molecular mechanisms playing a role in the development of melanoma and its brain metastasis. Orv Hetil. 2017; 158(28): 1083-1091.

Background/aim The most common malignant primary brain tumor is glioblastoma which infiltrates the peritumoral brain, while secondary brain metastases are well demarcated malignancies. Previous research has proved the pivotal role of the changes in the extracellular matrix (ECM) in cancer cell invasion. Materials and methods The mRNA expression of 40 ECM molecules was determined using qRT-PCR in 54 fresh-frozen glioblastoma and brain metastasis samples. Seventy-two samples were used to determine the levels of 20 ECM proteins. Results The mRNA and protein expression pattern of the studied tumors differs greatly. Linear discriminant analysis of mRNA expression identified samples based on their mRNA expression profile with 92.3% probability and highlighted the role of some molecules as their level greatly influenced sample identification. Conclusion Different tumor types with different invasiveness differ in the composition of their ECM and this can be used to identify samples. Furthermore, some ECM molecules greatly contribute to tumor invasiveness and could be targets of anti-invasive oncotherapy.

Background: Gait speed declines with increasing age, but it is unclear if gait speed preferentially correlates with leg muscle strength or mass. Objective: We determined the relationship between gait speed and (1) leg muscle strength measured at 3 lower extremity joints and (2) leg lean tissue mass (LTM) in healthy young (age: 25 years, n = 20) and old (age: 70 years, n = 20) adults. Methods: Subjects were tested for maximal isokinetic hip, knee, and ankle extension torque, leg LTM by bioimpedance, and gait performance (i.e., gait speed, stride length) at preferred and maximal gait speeds. Results: We found no evidence for a preferential relationship between gait performance and leg muscle strength compared with gait performance and leg LTM in healthy young and old adults. In old adults, hip extensor strength only predicted habitual gait speed (R2 = 0.29, p = 0.015), whereas ankle plantarflexion strength only predicted maximal gait speed and stride length (both R2 = 0.40, p = 0.003). Conclusions: Gait speed did not preferentially correlate with leg muscle strength or leg LTM, favoring neither outcome for predicting mobility. Thus, we recommend that both leg muscle strength and leg LTM should be tested and trained complementarily. Further, hip and ankle extension torque predicted gait performance, and thus we recommend to test and train healthy old adults by functional integrated multiarticular rather than monoarticular lower extremity strength exercises.

Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia. The accurate diagnosis is often possible only by neuropathological examination. The morphologic hallmarks are the presence of α-synuclein-rich Lewy bodies and Lewy neurites, identical to those seen in Parkinson's disease (PD) and Parkinson's disease dementia (PDD). Neurotransmitter deficits, synaptic and ubiquitin-proteasome system (UPS) dysfunction play major role in the pathomechanism. Characteristic symptoms are cognitive fluctuation, parkinsonism and visual hallucinations. Due to the often atypical clinical presentation novel imaging techniques and biomarkers could help the early diagnosis. Although curative treatment is not available, therapies can improve quality of life. Clinicopathological studies are important in exploring pathomechanisms, ensuring accurate diagnosis and identifying therapeutic targets. Orv Hetil. 2017; 158(17): 643-652.

Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus’ cortex were selected as regions of interest from Parkinson’s disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer’s disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p

Advancing age affects gait adaptability, but it is unclear if such adaptations to split-belt perturbations are already affected at middle-age. Changes in neuromuscular control, that already start at middle-age, may underlie the age-related changes in gait adaptation. Thus, we examined the effects of age on adaptations in gait and muscle activation patterns during split-belt walking in healthy young and middle-aged adults. Young (23.3 ± 3.13 years) and middle-aged adults (55.3 ± 2.91 years) walked on an instrumented split-belt treadmill. Both age groups adapted similarly by reducing asymmetry in step length and double support time. Surface EMG was recorded from eight leg muscles bilaterally. Principal Component Analysis (PCA) was applied to the EMG data of all subjects, for the fast and slow leg separately, to identify muscle activation patterns. The principal components consisted of i.e. temporal projections that were analyzed with Statistical Parametric Mapping (SPM). The functional muscle groups, identified by PCA, increased activation during early adaptation and post-adaptation, and decreased activation over time similarly in both age groups. Extra activation peaks of the plantar- and dorsiflexors suggest a role in gait modulation during split-belt walking. Both young and middle-aged adults re-established gait symmetry and showed adaptation effects in the muscle activation patterns. Since the adaptation of muscle activation patterns parallels adaptation of gait symmetry, changes in muscle activation likely underlie the changes in step parameters during split-belt adaptation. In conclusion, split-belt adaptation, in terms of gait and muscle activation patterns, is still preserved at middle-age, suggesting that age-related differences occur later in the lifespan.

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of α-synuclein-containing Lewy bodies and Lewy neurites. However, both dementias also show variable degrees of Alzheimer's disease (AD) pathology (senile plaques and neurofibrillary tangles), particularly in areas of the cortex associated with higher cognitive functions. This study investigates the contribution of the individual and combined pathologies in determining the rate of cognitive decline. Cortical α-synuclein, phosphorylated tau (phosphotau) and Aβ plaque pathology in 34 PDD and 55 DLB patients was assessed semi-quantitatively in four regions of the neocortex. The decline in cognition, assessed by Mini Mental State Examination, correlated positively with the cortical α-synuclein load. Patients also had varying degrees of senile Aβ plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (Aβ plaque plus phosphotau plus α-synuclein-positive features), particularly in the prefrontal cortex (BA9) and temporal lobe neocortex with the superior and middle temporal gyrus (BA21, 22), being a major determining factor in the development of dementia. Thus, cognitive decline in Lewy body dementias is not a consequence of α-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.

We examined the effects of whole-body mechanical vibration (WBV) on indices of motoneuronal excitability at rest and during muscle contraction in healthy humans. Real and sham WBV at 30 Hz had no effect on reflexes measured during muscle contraction. Real WBV at 30 and 50 Hz depressed the H-reflex ∼45%. These depressions diminished across the five inter-bout rest intervals. The depression converted to 27% and 7% facilitation over the 15-min long recovery period following real WBV at 30 and 50 Hz, respectively. The depression, measured during the inter-bout rest, correlated r = 0.48 (P = 0.007) with the subsequent facilitation, measured during the follow-up. The depression produced by sham vs real WBV was significant but less (23%), recovered faster, and the facilitation was absent in the 15-min long follow-up period. WBV produced time-varying depression followed by facilitation of the H-reflex at rest. A lack of change in volitional wave suggests that WBV did not affect the efferent neural drive.

ALS and FTD are progressive neurodegenerative diseases, often characterised by cytoplasmic aggregation of TDP-43. Nuclear import of TDP-43 occurs via the classical pathway in which karyopherin alphas (KPNAs) act as adaptor proteins. KPNA4 has been identified as the strongest interactor of TDP-43, and karyopherins co-localise with the aberrant cytoplasmic aggregates in ALS/FTD.This study explored how KPNA4 is affected in the spinal cord of sporadic-ALS (n=8), C9ORF72-ALS cases (n=7) as compared to control (n=6) and in the frontal cortex of sporadic-FTD (n=8), C9ORF72-FTD (n=8), and Tau-FTD (n=8) as compared to control (n=8). Quantitative western blotting was used to analyse whether KPNA4 differed between the protein samples from post-mortem tissue.Soluble levels of KPNA4 were significantly lower in the spinal cord of sporadic-ALS patients compared to control (D=0.4321, CI= 0.124–0.7401, p=0.0086), in the frontal cortex of sporadic-FTD patients compared to control (D=0.258, 95% CI=0.065–0452, p= 0.01) and in the frontal cortex of Tau-FTD patients compared to control (D= 0.22, CI= 0.03–0.42, p= 0.022) but not in C9ORF72 ALS/FTD.The results show a statistically significant downregulation of KPNA4 in sporadic ALS/FTD and Tau-FTD, suggesting KPNA4 could be forming insoluble aggregates or that the translation of KPNA4 mRNA may be reduced.

Inclusion body myositis is a slowly progressive myopathy affecting predominantly the middle-aged and older patient population. It is a major form of the idiopathic inflammatory myopathies which are chronic systemic autoimmune diseases characterized by symmetrical proximal muscle weakness. Unfortunately, there is no effective therapy yet; however, the early diagnosis is essential to provide treatment options which may significantly slow the progression of the disease. In our case-based clinicopathological study the importance of the close collaboration between the clinician and the neuropathologist is emphasised.

Meningiomas are one of the most frequent intracranial tumours, with 13 histological types and three grades according to the 2007 WHO Classification of Tumours of the Central Nervous System. p53, as one of the most potent tumour suppressor proteins, plays a role in nearly 50% of human tumours. Poly(ADP-ribose) polymerase (PARP) is a DNA repair enzyme with high ATP demand. It plays a role in apoptosis by activating an apoptosis inducing factor, and in necrosis by consuming NAD+ and ATP. Only PARP1 has been investigated in detail in tumours out of the 17 members of the PARP superfamily; however, its role has not been studied in meningiomas yet. The aim of this study was to determine the role of p53 and PARP1 in meningiomas of different grade and to establish whether there is any correlation between the p53 and PARP1 expression. Both PARP1 and p53 have been expressed in all examined meningiomas. PARP1 labelled grade II tumours with a higher intensity as compared to grade I and III neoplasms, respectively. An increased p53 expression was noted in grade III meningiomas. There was no statistical correlation between p53 and PARP1 expression. Our data indicate that both PARP1 and p53 activation is a feature in meningiomas of higher grade, PARP1 overexpression being an early, whereas p53 overexpression, a late event in tumour progression.

Nemaline myopathy is a type of the heterogeneous group of congenital myopathies. Generalized hypotonia, weakness, and delayed motor development are the main clinical features of the typical congenital form. Histopathology shows characteristic nemaline rods in the muscle biopsy. Mutations in at least 7 genes, including nebulin gene ( NEB), proved to be responsible for this muscle disease. We present a boy with nemaline myopathy type 2 (NEM2) caused by compound heterozygosity for 2 novel mutations, a deletion and a duplication in the NEB gene. The deletion was inherited from the father and the duplication from the mother. Testing all family members supports genetic counseling.

Vaczi, M, Racz, L, Hortobagyi, T, and Tihanyi, J. Dynamic contractility and efficiency impairments in stretch-shortening cycle are stretch-load-dependent after training-induced muscle damage. J Strength Cond Res 27(8): 2171-2179, 2013To determine the acute task and stretch-load dependency of neuromuscular impairments after muscle-damaging exercises, we examined the magnitude of strength deficits in isometric and stretch-shortening cycle (SSC) contractions after a single bout of exercise. Ten trained men performed 90 unilateral isokinetic eccentric-concentric knee extensions on a dynamometer. Plasma creatine kinase activity, muscle soreness, maximal isometric torque, short-range stiffness, and peak torque in the eccentric phase of the SSC contraction at 3 stretch-loads (120, 150, and 180 J) were determined in the quadriceps before and 24 hours after exercise. During SSC, positive mechanical work and efficiency were also calculated. Creatine kinase and soreness increased at 24 hours (p

We accomplish activities of daily living through a combination of or isolated isometric, shortening (concentric), lengthening (eccentric) contractions regarded as fundamental patterns of muscle activation. It has been widely recognized that a unique neural strategy may control lengthening contractions but it is still unclear if this neural strategy is uniform across muscles. Here we review evidence for task-specific differences in neural control of muscle lengthening and shortening as indexed by surface electromyographic activity, corticospinal excitability, anatomical properties, and motor unit behavior. The emerging hypothesis is that the neural control of task-specificity associated with muscle lengthening and shortening may not be uniform across all healthy human muscles.