Meningiomas are one of the most frequent intracranial tumours, with 13 histological types and three grades according to the 2007 WHO Classi?cation 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.
Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are characterized by the presence of ?-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 ?-synuclein, phosphorylated tau (phosphotau) and A? 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 ?-synuclein load. Patients also had varying degrees of senile A? plaque and phosphotau pathology. Regression analyses pointed to a combined pathology (A? plaque plus phosphotau plus ?-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 ?-synuclein-induced neurodegeneration alone but senile plaque and phosphorylated tau pathology also contribute to the overall deficits.
The growth promoting effects of eccentric (ECC) contractions are well documented but it is unknown if the rate of stretch per se plays a role in such muscular responses in healthy aging human skeletal muscle. We tested the hypothesis that exercise training of the quadriceps muscle with low rate ECC and high rate ECC contractions in the form of stretch-shortening cycles (SSCs) but at equal total mechanical work would produce rate-specific adaptations in healthy old males age 60-70. Both training programs produced similar improvements in maximal voluntary isometric (6%) and ECC torque (23%) and stretch-shortening cycle function (reduced contraction duration [24%] and enhanced elastic energy storage [12%]) (p<0.05). The rate of torque development increased 30% only after SSC exercise (p<0.05). Resting testosterone and cortisol levels were unchanged but after each program the acute exercise-induced cortisol levels were 12-15% lower (p<0.05). Both programs increased quadriceps size 2.5% (p<0.05). It is concluded that both ECC and SSC exercise training produces favorable adaptations in healthy old males' quadriceps muscle. Although the rate of muscle tension during the SSC vs. ECC contractions was about 4-fold greater, the total mechanical work seems to regulate the hypetrophic, hormonal, and most of the mechanical adaptations. However, SSC exercise was uniquely effective in improving a key deficiency of aging muscle, i.e., its ability to produce force rapidly.
The BrainNet Europe consortium assessed the reproducibility in the assignment of the type of frontotemporal lobar degeneration (FTLD) with TAR DNA-binding protein (TDP) 43 following current recommendations. The agreement rates were influenced by the immunohistochemical (IHC) method and by the classification strategy followed. p62-IHC staining yielded good uniform quality of stains, but the most reliable results were obtained implementing specific Abs directed against the hallmark protein TDP43. Both assessment of the type and the extent of lesions were influenced by the Abs and by the quality of stain. Assessment of the extent of the lesions yielded poor results repeatedly; thus, the extent of pathology should not be used in diagnostic consensus criteria. Whilst 31 neuropathologists typed 30 FTLD-TDP cases, inter-rater agreement ranged from 19 to 100 per cent, being highest when applying phosphorylated TDP43/IHC. The agreement was highest when designating Type C or Type A/B. In contrast, there was a poor agreement when attempting to separate Type A or Type B FTLD-TDP. In conclusion, we can expect that neuropathologist, independent of his/her familiarity with FTLD-TDP pathology, can identify a TDP43-positive FTLD case. The goal should be to state a Type (A, B, C, D) or a mixture of Types (A/B, A/C or B/C). Neuropathologists, other clinicians and researchers should be aware of the pitfalls whilst doing so. Agreement can be reached in an inter-laboratory setting regarding Type C cases with thick and long neurites, whereas the differentiation between Types A and B may be more troublesome.
The loss of zinc transporter 3 (ZnT3) has been implicated in age-related cognitive decline in mice, and the protein has been associated with plaques. We investigated the levels of ZnT3 and postsynaptic density protein 95 (PSD95), a marker of the postsynaptic terminal, in people with Parkinson's disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer's disease (AD, n = 16), and controls (n = 24), using semiquantitative western blotting and immunohistochemistry in 3 cortical regions. Standardized cognitive assessments during life and semiquantitative scoring of amyloid ? (A?), tau, and ?-synuclein at postmortem were used to investigate the relationship between ZnT3 and PSD95, cognition and pathology. Associations were observed between ZnT3 and PSD95 levels in prefrontal cortex and cognitive impairment (p = 0.001 and p = 0.002, respectively) and between ZnT3 levels in the parietal cortex and cognitive impairment (p = 0.036). Associations were also seen between ZnT3 levels in cingulate cortex and severity of A? (p = 0.003) and tau (p = 0.011) pathologies. DLB and PDD were characterized by significant reductions of PSD95 (p < 0.05) and ZnT3 (p < 0.001) in prefrontal cortex compared with controls and AD. PSD95 levels in the parietal cortex were found to be decreased in AD cases compared with controls (p = 0.02) and PDD (p = 0.005). This study has identified Zn(2+) modulation as a possible novel target for the treatment of cognitive impairment in DLB and PDD and the potential for synaptic proteins to be used as a biomarker for the differentiation of DLB and PDD from AD.
Objective: To determine the association between the 5 subscales of the Multidimensional Fatigue Inventory (MFI-20) and physical function in late mid-life. Design: Cross-sectional study. Subjects: A population-based sample of adults who participated in the Copenhagen Aging and Midlife Biobank population cohort (n?=?4,964; age 49-63 years). Methods: Self-reported fatigue was measured using the MFI-20 comprising: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. Handgrip strength and chair rise tests were used as measures of physical function. Multiple logistic regression analyses were used to determine the associations between handgrip strength and the chair rise test with the MFI-20 subscales, adjusted for potential confounders. Results: After adjustments for potential confounders, handgrip strength was associated with physical fatigue (adjusted odds ratio (OR) 0.75 (95% confidence interval (CI) 0.66-0.86); p???0.001) and reduced motivation (adjusted OR 0.85 (95% CI 0.75-0.96); p???0.05), but not with the other subscales. After these adjustments, the chair rise test was associated with physical fatigue (adjusted OR 0.61 (0.53-0.69); p???0.001), general fatigue (adjusted OR 0.72 (0.62-0.84); p???0.001), reduced activity (adjusted OR 0.79 (0.70-0.90); p???0.001) and reduced motivation (adjusted OR 0.84 (0.74-0.95); p???0.01), but not with mental fatigue. Subgroup analyses for sex did not show statistically significant different associations between physical function and fatigue. Conclusion: The present study supports the physiological basis of 4 subscales of the MFI-20. The association between fatigue and function was independent of gender.
Depression is a common symptom in dementia with Lewy bodies (DLB), Parkinson disease dementia (PDD), and Alzheimer disease (AD), yet its molecular basis remains unclear and current antidepressants do not appear to be effective. Cerebral zinc has been implicated in depression and synaptic dysfunction. We investigated the relationship between synaptic zinc regulation (for which zinc transporter 3 [ZnT3] is responsible) and depression in a large clinicopathologic study.
We examined the susceptibility of fast and slow twitch muscle fibers in the quadriceps muscle to eccentric exercise-induced muscle damage. Nine healthy men (age: 22.5 ± 1.6 years) performed maximal eccentric quadriceps contractions at 120°·s-1 over a 120° of knee joint range of motion for 6 consecutive days. Biopsies were taken from the vastus lateralis muscle before repeated bouts of eccentric exercise on the third and seventh day. Immunohistochemical procedures were used to determine fiber composition and fibronectin activity. Creatine kinase (CK) and lactate dehydrogenase (LDH) were determined in serum. Average torque was calculated in each day for each subject. Relative to baseline, average torque decreased 37.4% till day 3 and increased 43.0% from the day 3 to day 6 (p < 0.001). Creatine kinase and LDH were 70.6 and 1.5 times higher on day 3 and 75.5 and 1.4 times higher on day 6. Fibronectin was found in fast fibers in subjects with high CK level on day 3 and 7 after exercise, but on day 7, fibronectin seemed in both slow and fast fibers except in muscles of 2 subjects with high fast fiber percentage. Peak torque and muscle fiber-type composition measured at baseline showed a strong positive association on day 3 (r = 0.76, p < 0.02) and strong negative association during recovery between day 3 and day 6 (r = -0.76, p < 0.02), and day 1 and day 6 (r = 0.84, p < 0.001). We conclude that the damage of fast fibers preceded the damage of slow fibers, and muscles with slow fiber dominance were more susceptible to repeated bouts of eccentric exercise than fast fiber dominance muscles. The data suggest that the responses to repeated bouts of eccentric exercise are fiber-type-dependent in the quadriceps muscle, which can be the basis for the design of individualized strength training protocols.
Pontocerebellar hypoplasia (PCH) represents a group of neurodegenerative disorders with prenatal onset. Eight subtypes have been described thus far (PCH1-8) based on clinical and genetic features. Common characteristics include hypoplasia and atrophy of the cerebellum, variable pontine atrophy, and severe mental and motor impairments. PCH1 is distinctly characterized by the combination with degeneration of spinal motor neurons. Recently, mutations in the exosome component 3 gene (EXOSC3) have been identified in approximately half of the patients with PCH subtype 1.
It has been unclear whether ischemic stroke induces neurogenesis or neuronal DNA rearrangements in the human neocortex. Using immunohistochemistry; transcriptome, genome and ploidy analyses; and determination of nuclear bomb test-derived (14)C concentration in neuronal DNA, we found neither to be the case. A large proportion of cortical neurons displayed DNA fragmentation and DNA repair a short time after stroke, whereas neurons at chronic stages after stroke showed DNA integrity, demonstrating the relevance of an intact genome for survival.
We examined a behavioral mechanism of how increases in leg strength improve healthy old adults' gait speed. Leg press strength training improved maximal leg press load 40% (p?=?0.001) and isometric strength in 5 group of leg muscles 32% (p?=?0.001) in a randomly allocated intervention group of healthy old adults (age 74, n?=?15) but not in no-exercise control group (age 74, n?=?8). Gait speed increased similarly in the training (9.9%) and control (8.6%) groups (time main effect, p?=?0.001). However, in the training group only, in line with the concept of biomechanical plasticity of aging gait, hip extensors and ankle plantarflexors became the only significant predictors of self-selected and maximal gait speed. The study provides the first behavioral evidence regarding a mechanism of how increases in leg strength improve healthy old adults' gait speed.
Although recent studies point to the involvement of the primary motor cortex in postural control, it is unknown if age-related deterioration of postural control is associated with changes in motor cortical circuits. We examined the interaction between age and sensory condition in the excitability of intracortical motor pathways as indexed by short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) during standing.
Classical studies in animal preparations suggest a strong role for spinal control of posture. In humans it is now established that the cerebral cortex contributes to postural control of unperturbed and perturbed standing. The age-related degeneration and accompanying functional changes in the brain, reported so far mainly in conjunction with simple manual motor tasks, may also affect the mechanisms that control complex motor tasks involving posture. This review outlines the age-related structural and functional changes at spinal and cortical levels and provides a mechanistic analysis of how such changes may be linked to the behaviorally manifest postural deficits in old adults. The emerging picture is that the age-related reorganization in motor control during voluntary tasks, characterized by differential modulation of spinal reflexes, greater cortical activation and cortical disinhibition, is also present during postural tasks. We discuss the possibility that this reorganization underlies the increased coactivation and dual task interference reported in elderly. Finally, we propose a model for future studies to unravel the structure-function-behavior relations in postural control and aging.
A hallmark of the age-related neural reorganization is that old versus young adults execute typical motor tasks by a more diffuse neural activation pattern including stronger ipsilateral activation during unilateral tasks. Whether such changes in neural activation are present already at middle age and affect bimanual interactions is unknown. We compared the amount of associated activity, i.e., muscle activity and force produced by the non-task hand and motor evoked potentials (MEPs) produced by magnetic brain stimulation between young (mean 24?years, n?=?10) and middle-aged (mean 50?years, n?=?10) subjects during brief unilateral (seven levels of % maximal voluntary contractions, MVCs) and bilateral contractions (4?×?7 levels of % MVC combinations), and during a 120-s-long MVC of sustained unilateral index finger abduction. During the force production, the excitability of the ipsilateral (iM1) or contralateral primary motor cortex (cM1) was assessed. The associated activity in the "resting" hand was ~2-fold higher in middle-aged (28% of MVC) versus young adults (11% of MVC) during brief unilateral MVCs. After controlling for the background muscle activity, MEPs in iM1 were similar in the two groups during brief unilateral contractions. Only at low (bilateral) forces, MEPs evoked in cM1 were 30% higher in the middle-aged versus young adults. At the start of the sustained contraction, the associated activity was higher in the middle-aged versus young subjects and increased progressively in both groups (30 versus 15% MVC at 120?s, respectively). MEPs were greater at the start of the sustained contraction in middle-aged subjects but increased further during the contraction only in young adults. Under these experimental conditions, the data provide evidence for the reorganization of neural control of unilateral force production as early as age 50. Future studies will determine if the altered neural control of such inter-manual interactions are of functional significance.
To 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 < 0.05). In each of the 3 stretch-load conditions, muscle damage affected short-range stiffness less than isometric and peak SSC torque (p < 0.05), providing evidence for a selective impairment in contractile function after muscle damage. With greater SSC stretch-load peak, SSC torque deficit increased linearly, whereas short-range stiffness deficit was unaffected. Efficiency declined only at the 180-J condition (p < 0.05) as a result of decreased positive work (p < 0.05). It was concluded that intense exercise produced microtrauma in the muscle, and a selective loss of force generating capacity, which suggests greater damage to the contractile machinery. Practitioners may expect greater acute impairment of force generation in movements that use large loads in their daily training drills. However, altered knee flexion strategy during SSC may compensate for the force deficit, preserving mechanical efficiency at smaller stretch-loads.
Herpes simplex virus encephalitis (HSVE) is a rare and life-threatening infection. The clinical signs are diverse and often misleading regarding the aetiology. However, focal seizure with fewer and typical CT/MRI finding should always raise the possibility of HSVE as early diagnosis and antiviral therapy is crucial. Before the advent of molecular techniques and high-tech imaging histological examination from multiple brain biopsies were often necessary. Although nowadays PCR and other molecular methods may provide an aetiological diagnosis some cases need neuropathological verification. Due to the high IgG seropositivity rate in the population the plasma IgG titer is not diagnostic and elevation of its plasma level requires several weeks. We report the case of a 25-years old male patient who initially presented with epileptic fits. There was no final diagnosis and causal treatment in the district general hospital. The patient was admitted to our institution in comatose state on day 9; the initiated diagnostic tests and therapy could not save the patient who died next day. The autopsy and subsequent neuropathological examination revealed HSVE. We present a flowchart on diagnostic work-up and special techniques to aid diagnosis in suspected viral encephalitis.
Glial tumours represent the most frequent type of primary brain cancers. Gliomas are characterized by heterogeneity that makes the diagnosis, histological classification and the choosing of correct therapy more difficult. Despite the advances in developing therapeutic strategies patients with malignant gliomas have a poor prognosis; therefore glial tumours represent one of the most important areas of cancer research. There are no detailed data on the epidemiology of gliomas in Hungary.
The WHO grade I. and II. low-grade gliomas represent nearly the 15% of all primary brain tumors. These tumours contain clinically, hisologically and molecularly distinct tumor types. According to their histologic characteristic, grade II glial tumours are the diffuse astrocytoma, oligodendroglioma and oligoastrocytoma subgroups; the ependymal tumors are not included in this study.
The usual local recurrence of primary brain tumors is mainly due to the infiltration of adjacent brain parenchyma by the glioma cells. This invasive feature of the tumors makes total surgical excision impossible and also decreases the efficacy of focal radiotherapy. Interestingly, intracerebral metastases originating from many anaplastic tumors of other organs perform very moderate peritumoral infiltration, therefore radical resection can be routinely achieved and focal irradiation, even stereotactic radiotherapy, provides good tumor control. Differences in the effectiveness of treatment between the two tumor types derive from the remarkably different extent of peritumoral infiltration. Thus significant molecular biological research has been dealing with the infiltrative activity of various brain tumors and many attempts were made to develop anti-invasive drugs for oncotherapy. This review summarizes the results of these studies, describing cellular and molecular events of brain tumor invasion and according potential oncotherapeutic possibilities.
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.
The aging process results in a number of functional (e.g., deficits in balance and strength/power performance), neural (e.g., loss of sensory/motor neurons), muscular (e.g., atrophy of type-II muscle fibers in particular), and bone-related (e.g., osteoporosis) deteriorations. Traditionally, balance and/or lower extremity resistance training were used to mitigate these age-related deficits. However, the effects of resistance training are limited and poorly translate into improvements in balance, functional tasks, activities of daily living, and fall rates. Thus, it is necessary to develop and design new intervention programs that are specifically tailored to counteract age-related weaknesses. Recent studies indicate that measures of trunk muscle strength (TMS) are associated with variables of static/dynamic balance, functional performance, and falls (i.e., occurrence, fear, rate, and/or risk of falls). Further, there is preliminary evidence in the literature that core strength training (CST) and Pilates exercise training (PET) have a positive influence on measures of strength, balance, functional performance, and falls in older adults.
Although an authoritative panel recommended the use of ergometer rowing as a non-weight-bearing form of exercise for obese adults, the biomechanical characterization of ergometer rowing is strikingly absent. We examined the interaction between body mass index (BMI) relative to the lower extremity biomechanics during rowing in 10 normal weight (NW, BMI 18-25), 10 overweight (OW, BMI 25-30 kg·m-2), and 10 obese (OB, BMI> 30 kg·m-2) participants. The results showed that BMI affects joint kinematics and primarily knee joint kinetics. The data revealed that high BMI leads to unfavorable knee joint torques, implying increased loads of the medial compartment in the knee joint that could be avoided by allowing more variable foot positioning on future designs of rowing ergometers.
Mutations in the gene encoding Fused in Sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. FUS is a predominantly nuclear DNA- and RNA-binding protein that is involved in RNA processing. Large FUS-immunoreactive inclusions fill the perikaryon of surviving motor neurons of ALS patients carrying mutations at post-mortem. This sequestration of FUS is predicted to disrupt RNA processing and initiate neurodegeneration. Here, we demonstrate that C-terminal ALS mutations disrupt the nuclear localizing signal (NLS) of FUS resulting in cytoplasmic accumulation in transfected cells and patient fibroblasts. FUS mislocalization is rescued by the addition of the wild-type FUS NLS to mutant proteins. We also show that oxidative stress recruits mutant FUS to cytoplasmic stress granules where it is able to bind and sequester wild-type FUS. While FUS interacts with itself directly by protein-protein interaction, the recruitment of FUS to stress granules and interaction with PABP are RNA dependent. These findings support a two-hit hypothesis, whereby cytoplasmic mislocalization of FUS protein, followed by cellular stress, contributes to the formation of cytoplasmic aggregates that may sequester FUS, disrupt RNA processing and initiate motor neuron degeneration.
Genome-wide association studies have pointed to clusterin (apolipoprotein J) as being linked to the occurrence of Alzheimers disease (AD); studies have identified the protein as a possible biomarker. The association between clusterin and senile plaques in AD brain is well known, and clusterin levels in AD brain are 40% higher than that in control subjects. The present study investigates, immunohistochemically, the association between clusterin and A? peptides in AD and control cortex. A unique and specific association between clusterin and A?40 was observed in plaques in the cerebral cortex from AD subjects in that only plaques that contained A?40 showed clusterin immunoreactivity, while the many plaques with A?42 alone lacked clusterin labeling. Cerebrovascular A? in AD brain generally lacked A?42 but was positively labeled by both the A?40 and the clusterin antibodies. In control subjects, however, A?40 was absent from plaques, although very occasional plaques were found to be labeled by both the A?42 and the clusterin antibodies. Overall, in AD, but not aged control brain, clusterin was associated specifically with the A?40 form of A? in the brain. The lack of clusterin in association with A?42 may be a significant feature in neuronal loss and neurodegeneration in the disease state.
We examined whether unilateral exercise creates perception bias in the non-exercised limb and ascertained whether rTMS applied to the primary motor cortex (M1) interferes with this perception. All participants completed 4 interventions: 1) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand (EX), 2) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand whilst receiving rTMS over the contralateral M1 (rTMS+EX); 3) 15-min of rTMS over the trained M1 (rTMS) and 4) 15-min rest (Rest). Pre and post-interventions, the error of force output production, the perception of effort (RPE), motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were measured in both hands. EX did not alter the error of force output production in the trained hand (?3%; P>0.05); however, the error of force output production was reduced in the untrained hand (?12%; P<0.05). rTMS+EX and rTMS alone did not show an attenuation in the error of force output production in either hand. EX increased RPE in the trained hand (9.1±0.5 vs. 11.3±0.7; P<0.01) but not the untrained hand (8.8±0.6 vs. 9.2±0.6; P>0.05). RPE was significantly higher after rTMS+EX in the trained hand (9.2±0.5 vs. 10.7±0.7; P<0.01) but ratings were unchanged in the untrained hand (8.5±0.6 vs. 9.2±0.5; P>0.05). The novel finding was that exercise alone reduced the error in force output production by over a third in the untrained hand. Further, when exercise was combined with rTMS the transfer of force perception was attenuated. These data suggest that the contralateral M1 of the trained hand might, in part, play an essential role for the transfer of force perception to the untrained hand.
Sit-to-stand is a fundamental activity of daily living, which becomes increasingly difficult with advancing age. Due to severe loss of leg strength old adults are required to change the way they rise from a chair and maintain stability. Here we examine whether old compared to young adults differently prioritize task-important performance variables and whether there are age-related differences in the use of available motor flexibility. We applied the uncontrolled manifold analysis to decompose trial-to-trial variability in joint kinematics into variability that stabilizes and destabilizes task-important performance variables. Comparing the amount of variability stabilizing and destabilizing task-important variables enabled us to identify the variable of primary importance for the task. We measured maximal isometric voluntary force of three muscle groups in the right leg. Independent of age and muscle strength, old and young adults similarly prioritized stability of the ground reaction force vector during sit-to-stand. Old compared to young adults employed greater motor flexibility, stabilizing ground reaction forces during sit-to-sand. We concluded that freeing those degrees of freedom that stabilize task-important variables is a strategy used by the aging neuromuscular system to compensate for strength deficits.
There is ample evidence that physical and cognitive performance are related, but the results of studies investigating this relationship show great variability. Both physical performance and cognitive performance are constructs consisting of several subdomains, but it is presently unknown if the relationship between physical and cognitive performance depends on subdomain of either construct and whether gender and age moderate this relationship. The aim of this study is to identify the strongest physical predictors of cognitive performance, to determine the specificity of these predictors for various cognitive subdomains, and to examine gender and age as potential moderators of the relationship between physical and cognitive performance in a sample of community-dwelling older adults. In total, 98 men and 122 women (average age 74.0±5.6 years) were subjected to a series of performance-based physical fitness and neuropsychological tests. Muscle strength, balance, functional reach, and walking ability (combined score of walking speed and endurance) were considered to predict cognitive performance across several domains (i.e. memory, verbal attention, visual attention, set-shifting, visuo-motor attention, inhibition and intelligence). Results showed that muscle strength was a significant predictor of cognitive performance for men and women. Walking ability and balance were significant predictors of cognitive performance for men, whereas only walking ability was significant for women. We did not find a moderating effect of age, nor did we find support for a differential effect of the physical predictors across different cognitive subdomains. In summary, our results showed a significant relationship between cognitive and physical performance, with a moderating effect of gender.
Resistance exercise has been shown to be a potent stimulus for neuromuscular adaptations. These adaptations are not confined to the exercising muscle and have been consistently shown to produce increases in strength and neural activity in the contralateral, homologous resting muscle; a phenomenon known as cross-education. This observation has important clinical applications for those with unilateral dysfunction given that cross-education increases strength and attenuates atrophy in immobilized limbs. Previous evidence has shown that these improvements in the transfer of strength are likely to reside in areas of the brain, some of which are common to the mirror neuron system (MNS). Here we examine the evidence for the, as yet, untested hypothesis that cross-education might benefit from observing our own motor action in a mirror during unimanual resistance training, thereby activating the MNS. The hypothesis is based on neuroanatomical evidence suggesting brain areas relating to the MNS are activated when a unilateral motor task is performed with a mirror. This theory is timely because of the growing body of evidence relating to the efficacy of cross-education. Hence, we consider the clinical applications of mirror training as an adjuvant intervention to cross-education in order to engage the MNS, which could further improve strength and reduce atrophy in dysfunctional limbs during rehabilitation.
The transactive response DNA binding protein (TDP-43) proteinopathies describe a clinico-pathological spectrum of multi-system neurodegeneration that spans motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and frontotemporal lobar degeneration (FTLD). We have identified four male patients who presented with the clinical features of a pure MND/ALS phenotype (without dementia) but who had distinctive cortical and cerebellar pathology that was different from other TDP-43 proteinopathies. All patients initially presented with weakness of limbs and respiratory muscles and had a family history of MND/ALS. None had clinically identified cognitive decline or dementia during life and they died between 11 and 32 months after symptom onset. Neuropathological investigation revealed lower motor neuron involvement with TDP-43-positive inclusions typical of MND/ALS. In contrast, the cerebral pathology was atypical, with abundant star-shaped p62-immunoreactive neuronal cytoplasmic inclusions in the cerebral cortex, basal ganglia and hippocampus, while TDP-43-positive inclusions were sparse. This pattern was also seen in the cerebellum where p62-positive, TDP-43-negative inclusions were frequent in granular cells. Western blots of cortical lysates, in contrast to those of sporadic MND/ALS and FTLD-TDP, showed high p62 levels and low TDP-43 levels with no high molecular weight smearing. MND/ALS-associated SOD1, FUS and TARDBP gene mutations were excluded; however, further investigations revealed that all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked MND/ALS and FTLD. We conclude that these chromosome 9-linked MND/ALS cases represent a pathological sub-group with abundant p62 pathology in the cerebral cortex, hippocampus and cerebellum but with no significant associated cognitive decline.
Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP-43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration.
We describe a patient with a history of longstanding primary generalised epilepsy, on anticonvulsant therapy, who presented with fever, headache, worsening seizures and hallucinations. Among various investigations, the patient had high CSF protein and ACE levels, leptomeningeal nodular enhancement on MRI brain and non-caseating granulomas in the brain and meninges on the biopsy. The patient was diagnosed with neurosarcoidosis. Subsequently, he was found to be panhypogammaglobulinaemic and was diagnosed with probable common variable immunodeficiency (CVID). The coexistence of common variable immunodeficiency and neurosarcoidosis is rare. Typically, non-caseating granulomas in CVID patients are localised in the lymphatic tissue and solid organs. To our knowledge, there are only five reports of the granulomas of the central nervous system (CNS) in CVID. We discuss the diagnostic difficulties in this case and review the literature.
In the absence of visual information, humans cannot maintain a straight walking path. We examined the hypothesis that step frequency during walking affects the magnitude of veering in healthy adults. Subject walked at a preferred (1.77 ± 0.18 Hz), low (0.8 × preferred, 1.41 ± 0.15 Hz), and high (1.2× preferred, 2.13 ± 0.20 Hz) step frequency with and without a blindfold. We compared the absolute differences between estimated and measured points of crossing a target line after 16 m of forward walking at the three step frequencies. There was no significant difference in veering when subjects walked at the different frequencies without a blindfold. However, the magnitude of veering was the smallest at the preferred (mean ± SE=91.6 ± 33.6 cm) compared with the low (204.3 ± 43.0 cm) and high (112.7 ± 34.0 cm) frequency gaits with a blindfold. Thus, walking at a preferred step frequency minimizes veering, which occurs in the absence of visual information. This phenomenon may be associated with the previously reported minimization of movement variability, energy cost, and attentional demand while walking at a preferred step frequency.
We examined the hypothesis that metabolic surgery-induced massive weight loss causes mass-driven and behavioral adaptations in the kinematics and kinetics of obese gait. Gait analyses were performed at three time points over ?1 yr in initially morbidly obese (mass: 125.7 kg; body mass index: 43.2 kg/m(2)) but otherwise healthy adults. Ten obese adults lost 27.1% ± 5.1 (34.0 ± 9.4 kg) weight by the first follow-up at 7.0 mo (±0.7) and 6.5 ± 4.2% (8.2 ± 6.0 kg) more by the second follow-up at 12.8 mo (±0.9), with a total weight loss of 33.6 ± 8.1% (42.2 ± 14.1 kg; P = 0.001). Subjects walked at a self-selected and a standard 1.5 m/s speed at the three time points and were also compared with an age- and gender-matched comparison group at the second follow-up. Weight loss increased swing time, stride length, gait speed, hip range of motion, maximal knee flexion, and ankle plantarflexion. Weight loss of 27% led to 3.9% increase in gait speed. An additional 6.5% weight loss led to an additional 7.3% increase in gait speed. Sagittal plane normalized knee torque increased and absolute ankle and frontal plane knee torques decreased after weight loss. We conclude that large weight loss produced mechanical plasticity by modifying ankle and knee torques and gait behavior. There may be a weight loss threshold of 30 kg limiting changes in gait kinematics. Implications for exercise prescription are also discussed.
Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimers disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)-dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)-dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration.
Cyclin-dependent kinase 5 is activated by small subunits, of which p35 is the most abundant. The functions of cyclin-dependent kinase 5 signalling in cognition and cognitive disorders remains unclear. Here, we show that in schizophrenia, a disorder associated with impaired cognition, p35 expression is reduced in relevant brain regions. Additionally, the expression of septin 7 and OPA1, proteins downstream of truncated p35, is decreased in schizophrenia. Mimicking a reduction of p35 in heterozygous knockout mice is associated with cognitive endophenotypes. Furthermore, a reduction of p35 in mice results in protein changes similar to schizophrenia post-mortem brain. Hence, heterozygous p35 knockout mice model both cognitive endophenotypes and molecular changes reminiscent of schizophrenia. These changes correlate with reduced acetylation of the histone deacetylase 1 target site H3K18 in mice. This site has previously been shown to be affected by truncated p35. By restoring H3K18 acetylation with the clinically used specific histone deacetylase 1 inhibitor MS-275 both cognitive and molecular endophenotypes of schizophrenia can be rescued in p35 heterozygous knockout mice. In summary, we suggest that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1.
In human movements muscles lengthen and then shorten, or occasionally shorten and then lengthen, but it is unclear whether the nature of neural activation of the initial phase influences the neural state of the subsequent phase. We examined whether contraction history modulates spinal excitability in the healthy human soleus muscle.
Retrograde messengers adjust the precise timing of neurotransmitter release from the presynapse, thus modulating synaptic efficacy and neuronal activity. 2-Arachidonoyl glycerol, an endocannabinoid, is one such messenger produced in the postsynapse that inhibits neurotransmitter release upon activating presynaptic CB(1) cannabinoid receptors. Cognitive decline in Alzheimers disease is due to synaptic failure in hippocampal neuronal networks. We hypothesized that errant retrograde 2-arachidonoyl glycerol signalling impairs synaptic neurotransmission in Alzheimers disease. Comparative protein profiling and quantitative morphometry showed that overall CB(1) cannabinoid receptor protein levels in the hippocampi of patients with Alzheimers disease remain unchanged relative to age-matched controls, and CB(1) cannabinoid receptor-positive presynapses engulf amyloid-?-containing senile plaques. Hippocampal protein concentrations for the sn-1-diacylglycerol lipase ? and ? isoforms, synthesizing 2-arachidonoyl glycerol, significantly increased in definite Alzheimers (Braak stage VI), with ectopic sn-1-diacylglycerol lipase ? expression found in microglia accumulating near senile plaques and apposing CB(1) cannabinoid receptor-positive presynapses. We found that microglia, expressing two 2-arachidonoyl glycerol-degrading enzymes, serine hydrolase ?/?-hydrolase domain-containing 6 and monoacylglycerol lipase, begin to surround senile plaques in probable Alzheimers disease (Braak stage III). However, Alzheimers pathology differentially impacts serine hydrolase ?/?-hydrolase domain-containing 6 and monoacylglycerol lipase in hippocampal neurons: serine hydrolase ?/?-hydrolase domain-containing 6 expression ceases in neurofibrillary tangle-bearing pyramidal cells. In contrast, pyramidal cells containing hyperphosphorylated tau retain monoacylglycerol lipase expression, although at levels significantly lower than in neurons lacking neurofibrillary pathology. Here, monoacylglycerol lipase accumulates in CB(1) cannabinoid receptor-positive presynapses. Subcellular fractionation revealed impaired monoacylglycerol lipase recruitment to biological membranes in post-mortem Alzheimers tissues, suggesting that disease progression slows the termination of 2-arachidonoyl glycerol signalling. We have experimentally confirmed that altered 2-arachidonoyl glycerol signalling could contribute to synapse silencing in Alzheimers disease by demonstrating significantly prolonged depolarization-induced suppression of inhibition when superfusing mouse hippocampi with amyloid-?. We propose that the temporal dynamics and cellular specificity of molecular rearrangements impairing 2-arachidonoyl glycerol availability and actions may differ from those of anandamide. Thus, enhanced endocannabinoid signalling, particularly around senile plaques, can exacerbate synaptic failure in Alzheimers disease.
The net metabolic cost of walking (C(w)) as well as the level of neural activation of agonist and antagonist leg muscles are higher in healthy old compared with young adults. This study examined the association between C(w) and agonist muscle activity and antagonist coactivity in young and old adults.
Optineurin (OPTN) is a multifunctional protein involved in vesicular trafficking, signal transduction and gene expression. OPTN mutations were described in eight Japanese patients with familial and sporadic amyotrophic lateral sclerosis (FALS, SALS). OPTN-positive inclusions co-localising with TDP-43 were described in SALS and in FALS with SOD-1 mutations, potentially linking two pathologically distinct pathways of motor neuron degeneration. We have explored the abundance of OPTN inclusions using a range of antibodies in postmortem tissues from 138 cases and controls including sporadic and familial ALS, frontotemporal lobar degeneration (FTLD) and a wide range of neurodegenerative proteinopathies. OPTN-positive inclusions were uncommon and detected in only 11/32 (34%) of TDP-43-positive SALS spinal cord and 5/15 (33%) of FTLD-TDP. Western blot of lysates from FTLD-TDP frontal cortex and TDP-43-positive SALS spinal cord revealed decreased levels of OPTN protein compared to controls (p < 0.05), however, this correlated with decreased neuronal numbers in the brain. Large OPTN inclusions were not detected in FALS with SOD-1 and FUS mutation, respectively, or in FTLD-FUS cases. OPTN-positive inclusions were identified in a few Alzheimers disease (AD) cases but did not co-localise with tau and TDP-43. Occasional striatal neurons contained granular cytoplasmic OPTN immunopositivity in Huntingtons disease (HD) but were absent in spinocerebellar ataxia type 3. No OPTN inclusions were detected in FTLD-tau and ?-synucleinopathy. We conclude that OPTN inclusions are relatively rare and largely restricted to a minority of TDP-43 positive ALS and FTLD-TDP cases. Our results do not support the proposition that OPTN inclusions play a central role in the pathogenesis of ALS, FTLD or any other neurodegenerative disorder.
This review provides evidence for the hypothesis that electrostimulation strength training (EST) increases the force of a maximal voluntary contraction (MVC) through neural adaptations in healthy skeletal muscle. Although electrical stimulation and voluntary effort activate muscle differently, there is substantial evidence to suggest that EST modifies the excitability of specific neural paths and such adaptations contribute to the increases in MVC force. Similar to strength training with voluntary contractions, EST increases MVC force after only a few sessions with some changes in muscle biochemistry but without overt muscle hypertrophy. There is some mixed evidence for spinal neural adaptations in the form of an increase in the amplitude of the interpolated twitch and in the amplitude of the volitional wave, with less evidence for changes in spinal excitability. Cross-sectional and exercise studies also suggest that the barrage of sensory and nociceptive inputs acts at the cortical level and can modify the motor cortical output and interhemispheric paths. The data suggest that neural adaptations mediate initial increases in MVC force after short-term EST.
TDP-43 is a predominantly nuclear RNA-binding protein that forms inclusion bodies in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). The mRNA targets of TDP-43 in the human brain and its role in RNA processing are largely unknown. Using individual nucleotide-resolution ultraviolet cross-linking and immunoprecipitation (iCLIP), we found that TDP-43 preferentially bound long clusters of UG-rich sequences in vivo. Analysis of RNA binding by TDP-43 in brains from subjects with FTLD revealed that the greatest increases in binding were to the MALAT1 and NEAT1 noncoding RNAs. We also found that binding of TDP-43 to pre-mRNAs influenced alternative splicing in a similar position-dependent manner to Nova proteins. In addition, we identified unusually long clusters of TDP-43 binding at deep intronic positions downstream of silenced exons. A substantial proportion of alternative mRNA isoforms regulated by TDP-43 encode proteins that regulate neuronal development or have been implicated in neurological diseases, highlighting the importance of TDP-43 for the regulation of splicing in the brain.
The cyclin-dependent kinase 5 activator p35 can be cleaved into p25. Formation of p25 has been suggested to contribute to neurodegeneration in Alzheimers disease (AD). However, overexpression of low levels of p25 in mice enhances memory formation. Therefore, it has been suggested that p25 formation might be an event early in AD to compensate for impairments in synaptic plasticity. Ongoing p25 formation has been hypothesized to contribute to neurodegeneration at the later stages of AD.
Although the squat exercise and its variations are commonly prescribed for anterior cruciate ligament rehabilitation, whether trunk position affects these ligament forces and strains during the squat is unclear. Our purpose was to evaluate the effects of trunk position on anterior cruciate ligament forces and strains during a single-leg squat.
Unilateral lengthening contractions provide a greater stimulus for neuromuscular adaptation than shortening contractions in the active and non-active contralateral homologous muscle, although little is known of the potential mechanism. Here we examined the possibility that corticospinal and spinal excitability vary in a contraction-specific manner in the relaxed right flexor carpi radialis (FCR) when humans perform unilateral lengthening and shortening contractions of the left wrist flexors at the same absolute force. Corticospinal excitability in the relaxed right FCR increased more during lengthening than shortening at 80% and 100% of maximum voluntary contraction (MVC). Short-interval intracortical inhibition diminished during shortening contractions, and it became nearly abolished during lengthening. Intracortical facilitation lessened during shortening but increased during lengthening. Interhemispheric inhibition to the non-active motor cortex diminished during shortening, and became nearly abolished during lengthening at 90% MVC. The amplitude of the Hoffman reflex in the relaxed right FCR decreased during and remained depressed for 20 s after lengthening and shortening of the left wrist flexors. We discuss the possibility that instead of the increased afferent input, differences in the descending motor command and activation of brain areas that link function of the motor cortices during muscle lengthening vs. shortening may cause the contraction-specific modulation of ipsilateral motor cortical output. In conclusion, ipsilateral motor cortex responses to transcranial magnetic stimulation are contraction-specific; unilateral lengthening and shortening contractions reduced contralateral spinal excitability, but uniquely modulated ipsilateral corticospinal excitability and the networks involved in intracortical and interhemispheric connections, which may have clinical implications.
Chronic unimanual motor practice increases the motor output not only in the trained but also in the nonexercised homologous muscle in the opposite limb. We examined the hypothesis that adaptations in motor cortical excitability of the nontrained primary motor cortex (iM1) and in interhemispheric inhibition from the trained to the nontrained M1 mediate this interlimb cross education.
Cis-regulatory variation is considered to be an important determinant of human phenotypic variability, including susceptibility to complex disease. Recent studies have shown that the effects of cis-regulatory polymorphism on gene expression can differ widely between tissues. In the present study, we tested whether the effects of cis-regulatory variation can also differ between regions of the adult human brain. We used relative allelic expression to measure cis-effects on the RNA expression of five candidate genes for neuropsychiatric illness (ZNF804A, NOS1, RGS4, AKT1 and TCF4) across multiple discrete brain regions within individual subjects. For all five genes, we observed significant differences in allelic expression between brain regions in several individual subjects, suggesting regional differences in the effects of cis-regulatory polymorphism to be a common phenomenon. As well as highlighting an important caveat for studies of regulatory polymorphism in the brain, our findings indicate that it is possible to delineate brain areas in which cis-regulatory variants are active. This may provide important insights into the fundamental biology of neuropsychiatric phenotypes with which such variants are associated.
Microglia activation is central to the neuroinflammation associated with neurological and neurodegenerative diseases, particularly because activated microglia are often a source of proinflammatory cytokines. Despite decade-long research, the molecular cascade of proinflammatory transformation of microglia in vivo remains largely elusive. Here, we report increased ?-catenin expression, a central intracellular component of WNT signaling, in microglia undergoing a proinflammatory morphogenic transformation under pathogenic conditions associated with neuroinflammation such as Alzheimers disease. We substantiate disease-associated ?-catenin signaling in microglia in vivo by showing age-dependent ?-catenin accumulation in mice with Alzheimers-like pathology (APdE9). In cultured mouse microglia expressing the WNT receptors Frizzled FZD(4,5,7,8) and LDL receptor-related protein 5/6 (LRP5/6), we find that WNT-3A can stabilize ?-catenin. WNT-3A dose dependently induces LRP6 phosphorylation with downstream activation of disheveled, ?-catenin stabilization, and nuclear import. Gene-expression profiling reveals that WNT-3A stimulation specifically increases the expression of proinflammatory immune response genes in microglia and exacerbates the release of de novo IL-6, IL-12, and tumor necrosis factor ?. In summary, our data suggest that the WNT family of lipoglycoproteins can instruct proinflammatory microglia transformation and emphasize the pathogenic significance of ?-catenin-signaling networks in this cell type.
Accurate identification of the onset of muscle activity is an important element in the biomechanical analysis of human movement. The purpose of this study was to determine if inclusion of the Teager-Kaiser energy operator (TKEO) in signal conditioning would increase the accuracy of popular electromyography (EMG) onset detection methods. Three methods, visual determination, threshold-based method, and approximated generalized likelihood ratio were used to estimate the onset of EMG burst with and without TKEO conditioning. Reference signals, with known onset times, were constructed from EMG signals collected during isometric contraction of the vastus lateralis (n = 17). Additionally, vastus lateralis EMG signals (n = 255) recorded during gait were used to evaluate a clinical application of the TKEO conditioning. Inclusion of TKEO in signal conditioning significantly reduced mean detection error of all three methods compared with signal conditioning without TKEO, using artificially generated reference data (13 vs. 98 ms, p < 0.001) and also compared with experimental data collected during gait (55 vs. 124 ms, p < 0.001). In conclusion, addition of TKEO as a step in conditioning surface EMG signals increases the detection accuracy of EMG burst boundaries.
Unilateral isometric muscle contractions increase motor-evoked potentials (MEPs) produced by transcranial magnetic stimulation not only in the contracting muscle but also in the resting contralateral homologous muscle. Corticospinal excitability in the M1 contralateral to the contracting muscle changes depending on the type of muscle contraction. Here, we investigated the possibility that corticospinal excitability in M1 ipsilateral to the contracting muscle is modulated in a contraction-type-dependent manner. To this end, we evaluated MEPs in the resting left flexor carpi radialis (FCR) during unilateral shortening, lengthening, and isometric muscle contractions of the right wrist flexors at 10, 20, and 30% of maximal isometric contraction force. To compare the effects of different unilateral contractions on MEPs between the contracting and resting sides, MEPs in the right FCR were recorded on two separate days. In a separate experiment, we investigated the contraction specificity of the crossed effect at the spinal level by recording H-reflexes from the resting left FCR during contraction of the right wrist flexors. The results showed that MEPs in the contracting right FCR were the smallest during lengthening contraction. By contrast, MEPs in the resting left FCR were the largest during lengthening contraction, whereas the H-reflex was similar in the resting left FCR during the three types of muscle contraction. These results suggest that different types of unilateral muscle contraction asymmetrically modulate MEP size in the resting contralateral homologous muscle and in the contracting muscle and that this regulation occurs at the supraspinal level.
Trans-activation response DNA-binding protein (TDP-43) accumulation is the major component of ubiquitinated protein inclusions found in patients with amyotrophic lateral sclerosis, and frontotemporal lobar degeneration with TDP-43 positive ubiquitinated inclusions, recently relabelled the TDP-43 proteinopathies. TDP-43 is predominantly located in the nucleus, however, in disease it mislocalizes to the cytoplasm where it aggregates to form hallmark pathological inclusions. The identification of TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis cases confirms its pathogenic role; but it is wild-type TDP-43 that is deposited in the vast majority of TDP-43 proteinopathies, implicating other unknown factors for its mislocalization and aggregation. One such mechanism may be defective nuclear import of TDP-43 protein, as a disruption of its nuclear localization signal leads to mislocalization and aggregation of TDP-43 in the cytoplasm. In order to explore the factors that regulate the nuclear import of TDP-43, we used a small interfering RNA library to silence 82 proteins involved in nuclear transport and found that knockdowns of karyopherin-beta1 and cellular apoptosis susceptibility protein resulted in marked cytoplasmic accumulation of TDP-43. In glutathione S-transferase pull-down assays, TDP-43 bound to karyopherin-alphas, thereby confirming the classical nuclear import pathway for the import of TDP-43. Analysis of the expression of chosen nuclear import factors in post-mortem brain samples from patients with TDP-43 positive frontotemporal lobar degeneration, and spinal cord samples from patients with amyotrophic lateral sclerosis, revealed a considerable reduction in expression of cellular apoptosis susceptibility protein in frontotemporal lobar degeneration. We propose that cellular apoptosis susceptibility protein associated defective nuclear transport may play a mechanistic role in the pathogenesis of the TDP-43 positive frontotemporal lobar degeneration.
Because anterior cruciate ligament (ACL) injuries can occur during deceleration maneuvers, biomechanics research has been focused on the lower extremity kinetic chain. Trunk mass and changes in trunk position affect lower extremity joint torques and work during gait and landing, but how the trunk affects knee joint and muscle forces is not well understood.
Giant cell tumour (GCT) of bone is an uncommon primary bone neoplasm typically occurring at the epiphyses of long bones in young adults. They are osteolytic neoplasms with approximate local recurrence rates of 25%, and 2% of patients develop pulmonary metastases. These tumours appear very rarely in the skull, with those few reported cases arising predominantly in the sphenoid and occasionally the temporal bones. They demonstrate benign histological features, but are locally aggressive and surgical excision is the treatment of choice. It is widely believed that giant cell tumours should be distinguished from other giant cell lesions, importantly central giant cell reparative granulomata (CGCG) which are thought to have a lower recurrence rate and for which no cases of malignant transformation or metastases have been reported. Investigators have noted that giant cell lesions in the skull bones may be unique and that GCT and CGCG may be part of a spectrum of a single disease process. We present a case of a giant cell tumour of the temporal bone which illustrates and re-emphasises this concept and review the literature on these lesions.
A 15 years old girl of African origin was admitted with a history of headaches and a generalised tonic seizure. Her clinical examination including fundoscopy was normal. She claimed she had been assaulted. Within a few hours of her admission she was found dead in her bed during the ward round. Cardiopulmonary resuscitation was unsuccessful. At post-mortem, the major organs showed no pathological changes and neck dissection showed no abnormality. Neuropathological examination after formalin fixation revealed a cystic lesion in the fourth ventricle, ependymitis and acute hydrocephalus. Histology showed parts of the parasite Taenia solium and the diagnosis was neurocysticercosis. This case highlights the need for forensic and general pathologists as well as forensic medical examiners and paediatricians to be aware of neurocysticercosis as a possible cause of sudden death in the presence of normal clinical findings and negative autopsy, especially in patients from Asian, African or South American countries. As cysticercosis is the commonest cause of seizures in the developing world, neurocysticercosis needs to be considered as a cause of sudden and unexpected death in any patient with a history of headaches and/or seizures.
Alterations in cholinergic activity have not been systematically studied in types of cerebrovascular disease. We examined cholinergic function at postmortem, focussing on stroke and vascular dementia (VaD).
The transactive response (TAR) DNA binding protein 43 (TDP-43) has been recently implicated as a major component of ubiquitinated inclusions in amyotrophic lateral sclerosis (ALS, motor neuron disease: MND) and ALS-related disorders. In this study, we examined abnormal TDP-43 pathology in 13 sporadic ALS (SALS), six familial ALS (FALS) with and without Cu/Zn superoxide dismutase (SOD1) mutations (SOD1-FALS and non-SOD1-FALS), Guam ALS, two frontotemporal lobar degeneration with MND/ALS (FTLD-MND/ALS), one FTLD with ubiquitin-only-immunoreactive inclusions (FTLD-U) and two progressive supranuclear palsy (PSP). Sections from the spinal cord were processed for immunohistochemistry using antibodies against TDP-43, ubiquitin, p62, cystatin C, phosphorylated tau protein (P-tau; AT8), alpha-synuclein and phosphorylated neurofilament protein (P-NF). In 12 out of 13 SALS and both Guam ALS cases ubiquitin and p62-immunoreactive (IR) neuronal inclusions co-localized with TDP-43. In three out of four SOD1-FALS and one of two non-SOD1-FALS cases, TDP-43-IR inclusions were absent despite the presence of p62 and/or ubiquitin-IR inclusions. However, a single TDP-43-IR neuronal inclusion co-localized with p62 and ubiquitin in one SOD1-FALS (His48Gln) case. Except for one neuron in a Guam case, all TDP-43-IR neuronal inclusions were negative for P-tau (AT8). TDP-43-IR glial inclusions and neurites were also demonstrated. The TDP-43 is a consistent component of the ubiquitinated inclusions in SALS and Guam ALS, but TDP-43-IR inclusions are absent or scarce in SOD1-FALS.
Vascular dementia accounts for approximately 15-20% of all dementias. In addition, a significant subset of people with Alzheimers disease have concurrent cerebrovascular disease. Vascular dementia is caused by different cerebrovascular morphological abnormalities including large artery territory infarction (multi-infarct vascular dementia) and sub-cortical ischaemic vascular dementia. Despite this distinction, there is a lack of studies examining the neurochemistry of individual vascular dementia subtypes. Serotonin is believed to play an important role in cognition, and serotonin receptors may provide a novel target for future anti-dementia therapeutics. This study aimed to determine levels of two serotonin receptors in subtypes of vascular dementia and relate any changes to cognition. We have determined, using saturation radioligand binding, the binding parameters (affinity and maximal binding) of ((3)H)-WAY 100635 binding to 5-HT(1A) receptors and ((3)H)-ketanserin binding to 5-HT(2A) receptors in post-mortem tissue from the frontal and temporal cortices of patients with either multi-infarct vascular dementia, sub-cortical ischaemic vascular dementia, mixed Alzheimers disease/vascular dementia or stroke no dementia (SND). 5-HT(1A) and 5-HT(2A) receptor binding was significantly increased in the temporal cortex of patients with either multi-infarct vascular dementia or SND, compared to age-matched controls. 5-HT(1A) receptor maximal binding in the temporal cortex was also positively correlated with cognition as determined by Mini-Mental State Examination (MMSE) and Cambridge Assessment of Mental Health for the Elderly scores (CAMCOG). These results reveal an important distinction between the neurochemistry of multi-infarct vascular dementia/SND and sub-cortical ischaemic vascular dementia, suggesting that pharmacological manipulation of serotonin offers the possibility to develop novel therapies for stroke and multi-infarct vascular dementia patients. The results also highlight the importance of the cortical 5-HT(1A) receptor in mediating cognition.
Differentiated neurons display specific biochemical, physiological and morphological properties that apparently prevent them from further cell division. Nevertheless, expression of cell cycle modulators persists after neuronal differentiation and is upregulated under stress conditions, such as trophic factor deprivation, oxidative stress and the presence of DNA damaging agents. This apparent reactivation of the cell cycle has been postulated as a sine qua non for neuronal death in response to those stress conditions, particularly in Alzheimers disease. However, the physiological and pathogenic implications of a putative neuronal cell cycle are far from clear. Here, we discuss the notion of the neuronal cell cycle as a mediator of cell death, with particular emphasis on Alzheimers disease.
Although there is consensus that the central nervous system mediates the increases in maximal voluntary force (maximal voluntary contraction, MVC) produced by resistance exercise, the involvement of the primary motor cortex (M1) in these processes remains controversial. We hypothesized that 1-Hz repetitive transcranial magnetic stimulation (rTMS) of M1 during resistance training would diminish strength gains. Forty subjects were divided equally into five groups. Subjects voluntarily (Vol) abducted the first dorsal interosseus (FDI) (5 bouts x 10 repetitions, 10 sessions, 4 wk) at 70-80% MVC. Another group also exercised but in the 1-min-long interbout rest intervals they received rTMS [Vol+rTMS, 1 Hz, FDI motor area, 300 pulses/session, 120% of the resting motor threshold (rMT)]. The third group also exercised and received sham rTMS (Vol+Sham). The fourth group received only rTMS (rTMS_only). The 37.5% and 33.3% gains in MVC in Vol and Vol+Sham groups, respectively, were greater (P = 0.001) than the 18.9% gain in Vol+rTMS, 1.9% in rTMS_only, and 2.6% in unexercised control subjects who received no stimulation. Acutely, within sessions 5 and 10, single-pulse TMS revealed that motor-evoked potential size and recruitment curve slopes were reduced in Vol+rTMS and rTMS_only groups and accumulated to chronic reductions by session 10. There were no changes in rMT, maximum compound action potential amplitude (M(max)), and peripherally evoked twitch forces in the trained FDI and the untrained abductor digiti minimi. Although contributions from spinal sources cannot be excluded, the data suggest that M1 may play a role in mediating neural adaptations to strength training.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.
The authors discuss the clinical and molecular genetic aspects of genetically determined neuromuscular disorders of some Roma families living in Hungary. Among the autosomal recessively inherited spinal muscular atrophic (SMA) group, 8 Caucasian children had the typical 7-8 exonal deletions of the SMA gene, but only 2 patients belonged to the Roma population. There was no difference in the molecular genetic findings among the Caucasian and the Roma SMA patients. All of them had 7-8 exonal deletions of the SMA gene. We wanted to call attention to the founder mutation of the Roma population in 7 patients suffering from congenital myasthenia (CMS) from 3 Roma families. The 1267G deletion for CMS was detected by molecular genetic method. Clinical onset was pubertal and relatively slow progression of specific and phenotypic features for this founder mutation of acetyl-cholin receptor epsylon gene. In 2 patients (sister and brother) the sarcoglycanopathy 2C type C283Q mutation was proven in one Roma family suffering from limb-girdle muscular dystrophy (LGMD). Two out of the three facioscapular-humeral dystrophy (FSHD) Roma families carried 21.8 kb and 18.5 kb alleles in FSHD A1 gene (D4S139). In one family together with prenatal diagnosis founder mutation in FSHD A1 gene was detected, according to the autosomal dominant (AD) inheritance. In (F2) prenatal diagnosis was carried out, 18.5 kb/18.5 kb homozygosity was proven in the fetus, so the pregnancy was interrupted. In the CMS, LGMD and FSHD Roma patients ancient typical Roma founder mutations were found.
beta-Amyloid (A-beta) related pathology shows a range of lesions which differ both qualitatively and quantitatively. Pathologists, to date, mainly focused on the assessment of both of these aspects but attempts to correlate the findings with clinical phenotypes are not convincing. It has been recently proposed in the same way as iota and alpha synuclein related lesions, also A-beta related pathology may follow a temporal evolution, i.e. distinct phases, characterized by a step-wise involvement of different brain-regions. Twenty-six independent observers reached an 81% absolute agreement while assessing the phase of A-beta, i.e. phase 1 = deposition of A-beta exclusively in neocortex, phase 2 = additionally in allocortex, phase 3 = additionally in diencephalon, phase 4 = additionally in brainstem, and phase 5 = additionally in cerebellum. These high agreement rates were reached when at least six brain regions were evaluated. Likewise, a high agreement (93%) was reached while assessing the absence/presence of cerebral amyloid angiopathy (CAA) and the type of CAA (74%) while examining the six brain regions. Of note, most of observers failed to detect capillary CAA when it was only mild and focal and thus instead of type 1, type 2 CAA was diagnosed. In conclusion, a reliable assessment of A-beta phase and presence/absence of CAA was achieved by a total of 26 observers who examined a standardized set of blocks taken from only six anatomical regions, applying commercially available reagents and by assessing them as instructed. Thus, one may consider rating of A-beta-phases as a diagnostic tool while analyzing subjects with suspected Alzheimers disease (AD). Because most of these blocks are currently routinely sampled by the majority of laboratories, assessment of the A-beta phase in AD is feasible even in large scale retrospective studies.
Old adults execute single-joint voluntary movements with heightened antagonist muscle coactivation and altered timing between agonist and antagonist muscles. It is less clear if old adults adopt similar strategies during the most common form of activity of daily living, gait, and if age and gait velocity interact. We compared antagonist muscle activation amplitude and onset, offset, and activation duration of the vastus lateralis, biceps femoris, tibialis anterior, and gastrocnemius lateralis from surface EMG in 17 young (age 19-25) and 17 old adults (age 71-85) while walking at 1.2, 1.5, and 1.8m/s. All participants were healthy and highly mobile. The activation level of the four muscles when each acted as the antagonist was, on the average, 83% higher in old vs young adults (for each muscle p<0.05). In two of four muscles this activation increased with gait velocity in young but not in old adults. The inter-burst interval between TA and GL was two-fold (83 ms) longer in young vs old adults and at higher gait velocities it became 14% (24 ms) shorter in young but 51% (31 ms) longer in old adults (interaction, p=0.015). It is concluded that there is an interaction between age and gait velocity in the amplitude and timing of antagonist muscle coactivation.
In the present study we investigated displacement, time, velocity and acceleration history of center of mass (COM) and electrical activity of knee extensors to estimate the dominance of the factors influencing the vertical velocity in squat jumps (SJs), countermovement jumps (CMJs) and drop jumps (DJs) performed with small (40°) and large (80°) range of joint motion (SROM and LROM). The maximum vertical velocity (v4) was 23.4% (CMJ) and 7.8% (DJ) greater when the jumps were performed with LROM compared with SROM (p < 0.05). These differences are considerably less than it could be expected from the greater COM and knee angular displacement and duration of active state. This small difference can be attributed to the greater deceleration during eccentric phase (CMJ:32.1%, DJ:91.5%) in SROM than that in LROM. v4 was greater for SJ in LROM than for SJ in SROM indicating the significance of the longer active state and greater activation level (p < 0.001). The difference in v4 was greater between SJ and CMJ in SROM (38.6%) than in LROM (9.0%), suggesting that elastic energy storage and re-use can be a dominant factor in the enhancement of vertical velocity of CMJ and DJ compared with SJ performed with SROM.
There is an association between gait performance and spinal alignment in elderly females but it is unclear if this association is gender-dependent and postural changes would also predict gait performance in healthy elderly males. We measured thoracic kyphosis angle (TKA), LLA as indices of spinal alignment and maximal walking speed (WS), timed up and go test (TUG), 10-m obstacle walking time, and 6-min walk distance as indices of gait performance in healthy old males (n=124, age 73.0 ± 7.2 years). Knee extensor strength and one-leg standing time with eyes open were measures of physical function. The LLA but not TKA correlated with performance in each of the 4 gait test. Multiple-regression analyses showed that only the combination of knee extensor strength and LLA accounted for significant variation in gait performance. While previous studies showed that spinal alignment is associated with gait performance in elderly women, in healthy elderly males both functional (leg strength) and structural (spinal alignment) factors contribute to gait performance.
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