Very Preterm Early Motor Repertoire and Neurodevelopmental Outcomes at 8 Years.

BACKGROUND AND OBJECTIVES: Children born very preterm (<32 weeks' gestation) have more neurodevelopmental problems compared with term-born peers. Aberrant fidgety movements (FMs) are associated with adverse motor outcomes in children born very preterm. However, associations of aberrant FMs combined with additional movements and postures to give a motor optimality score-revised (MOS-R) with school-aged cognitive and motor outcomes are unclear. Our aim with this study was to determine those associations. METHODS: Of 118 infants born <30 weeks' gestation recruited into a randomized controlled trial of early intervention, 97 had a general movements assessment at 3 months' corrected age and were eligible for this study. Early motor repertoire including FMs and MOS-R were scored from videos of infant's spontaneous movement at 3 months' corrected age. At 8 years' corrected age, cognitive and motor performances were evaluated. Associations of early FMs and MOS-R with outcomes at 8 years were determined using linear regression. RESULTS: Seventy-eight (80%) infants with early motor repertoire data had neurodevelopmental assessments at 8 years. A higher MOS-R, and favorable components of the individual subscales of the MOS-R, including the presence of normal FMs, were associated with better performance for general cognition, attention, working memory, executive function and motor function at 8 years; eg, presence of normal FMs was associated with a 21.6 points higher general conceptual ability score (95% confidence interval: 12.8-30.5; P < .001) compared with absent FMs. CONCLUSIONS: Favorable early motor repertoire of infants born <30 weeks is strongly associated with improved cognitive and motor performance at 8 years.

Prediction of Cognitive Ability With Social Determinants in Children of Low Birth Weight.

BACKGROUND: Despite strong prevention efforts and advances in neonatal care in recent decades, low birth weight remains a serious public health problem in the United States, and survivors remain at increased risk for lifelong problems including cognitive deficits. Current regional and local strategies for referral often rely on variable thresholds for birth weight and gestational age that may be poor analogues to cognitive risk. Improving early referral criteria offers many benefits, including improved cognitive outcomes for children and improved cost-effectiveness and resource utilization in resource-limited communities. OBJECTIVES: We hypothesized that social determinants measurable at birth or at birth hospital discharge, when combined with birth weight and gestational age, would offer an improvement over birth weight and gestational age alone in predicting cognitive test scores in school-aged children with low birth weight. METHODS: We conducted a secondary analysis using a birth cohort of children from the Fragile Families and Child Wellbeing Study. We created a panel of maternal, familial, and community-level social determinant indicators from the data and examined associations with cognitive measures assessed at age of 9 years. RESULTS: The final social determinant model was statistically significant and explained 35% of the total variance in composite test scores. The "standard care" model (birth weight and gestational age) only explained 9% of the variance. DISCUSSION: Assessment of social determinants may offer improvement over traditional referral criteria to identify children most at risk of cognitive deficits after low birth weight.

Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial.

Importance: The potential benefit of novel skeletal muscle anabolic agents to improve physical function in people with sarcopenia and other muscle wasting diseases is unknown. Objective: To confirm the safety and efficacy of bimagrumab plus the new standard of care on skeletal muscle mass, strength, and physical function compared with standard of care alone in community-dwelling older adults with sarcopenia. Design, Setting, and Participants: This double-blind, placebo-controlled, randomized clinical trial was conducted at 38 sites in 13 countries among community-dwelling men and women aged 70 years and older meeting gait speed and skeletal muscle criteria for sarcopenia. The study was conducted from December 2014 to June 2018, and analyses were conducted from August to November 2018. Interventions: Bimagrumab 700 mg or placebo monthly for 6 months with adequate diet and home-based exercise. Main Outcomes and Measures: The primary outcome was the change in Short Physical Performance Battery (SPPB) score after 24 weeks of treatment. Secondary outcomes included 6-minute walk distance, usual gait speed, handgrip strength, lean body mass, fat body mass, and standard safety parameters. Results: A total of 180 participants were recruited, with 113 randomized to bimagrumab and 67 randomized to placebo. Among these, 159 participants (88.3%; mean [SD] age, 79.1 [5.3] years; 109 [60.6%] women) completed the study. The mean SPPB score increased by a mean of 1.34 (95% CI, 0.90 to 1.77) with bimagrumab vs 1.03 (95% CI, 0.53 to 1.52) with placebo (P = .13); 6-minute walk distance increased by a mean of 24.60 (95% CI, 7.65 to 41.56) m with bimagrumab vs 14.30 (95% CI, -4.64 to 33.23) m with placebo (P = .16); and gait speed increased by a mean of 0.14 (95% CI, 0.09 to 0.18) m/s with bimagrumab vs 0.11 (95% CI, 0.05 to 0.16) m/s with placebo (P = .16). Bimagrumab was safe and well-tolerated and increased lean body mass by 7% (95% CI, 6% to 8%) vs 1% (95% CI, 0% to 2%) with placebo, resulting in difference of 6% (95% CI, 4% to 7%) (P < .001). Conclusions and Relevance: This randomized clinical trial found no significant difference between participants treated with bimagrumab vs placebo among older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, with physical function improving in both groups. Bimagrumab treatment was safe, well-tolerated, increased lean body mass, and decreased fat body mass. The effects of sarcopenia, an increasing cause of disability in older adults, can be reduced with proper diet and exercise. Trial Registration: ClinicalTrials.gov Identifier: NCT02333331; EudraCT number: 2014-003482-25.

Prior exercise protects against oxidative stress and motor deficit in a rat model of Parkinson's disease.

This study investigated if a prior long-term physical exercise protocol protects the substantia nigra and the striatum against oxidative stress and motor deficits in a Parkinson Disease model induced by 6-hydroxydopamine. Three animal treatment groups were included in the study: sham; 6-hydroxydopamine and 6-hydroxydopamine/exercise. Previously to the intrastriatal lesion by 6-hydroxydopamine, rats in the exercise groups performed a swimming program for 18 weeks. The rats were submitted to behavioral tests before and after intrastriatal 6-hydroxydopamine injection. The oxidative stress was analyzed by Thiobarbituric Acid Reactive Substances and Glutathione reductase activity methods. The exercise decreased lipid peroxidation and increased glutathione reductase activity in the substantia nigra. In contrast, in the striatum, exercise increased lipid peroxidation and decreased glutathione reductase activity. Exercise increased contralateral rotations and reduces immobility levels at 14 days post lesion. The exercise prior to 6-OHDA lesion had protective action only in substantia nigra against oxidative stress.

Development Through the Lens of a Perception-Action-Cognition Connection: Recognizing the Need for a Paradigm Shift in Clinical Reasoning.

Clinical assessment of movement and posture guides the decision-making process in designing interventions for infants and children with movement disorders. Clinical reasoning is influenced by the therapist's understanding of developmental processes. The views of development grounded in perception-action, dynamic systems, and neuronal group selection theories are well recognized in current literature and supported by a large body of research. Based on the available evidence, intervention must be task-specific, repetitive, and highly salient to the child. Furthermore, it must honor spontaneous exploration and active problem-solving, enhance the child's ability to perceive environmental affordances, and target optimal variability and adaptability of movement and posture. However, a neuromaturational approach to developmental assessment and intervention that relies on "teaching" motor milestones and emphasizes the importance of correcting movement patterns in infants and children developing atypically is still prevalent in the clinic. This perspective paper will: (1) examine evidence in support of a paradigm shift from neuromaturational views toward bringing the concepts of grounded cognition, variability, complexity, and adaptability to the forefront of clinical reasoning; and (2) introduce the Perception-Action Approach as a method of assessment and intervention that may serve as an agent of such a shift by augmenting knowledge translation for the clinician.

The microRNA miR-7a-5p ameliorates ischemic brain damage by repressing α-synuclein.

Ischemic stroke, which is caused by a clot that blocks blood flow to the brain, can be severely disabling and sometimes fatal. We previously showed that transient focal ischemia in a rat model induces extensive temporal changes in the expression of cerebral microRNAs, with a sustained decrease in the abundance of miR-7a-5p (miR-7). Here, we evaluated the therapeutic efficacy of a miR-7 mimic oligonucleotide after cerebral ischemia in rodents according to the Stroke Treatment Academic Industry Roundtable (STAIR) criteria. Rodents were injected locally or systemically with miR-7 mimic before or after transient middle cerebral artery occlusion. Decreased miR-7 expression was observed in both young and aged rats of both sexes after cerebral ischemia. Pre- or postischemic treatment with miR-7 mimic decreased the lesion volume in both sexes and ages studied. Furthermore, systemic injection of miR-7 mimic into mice at 30 min (but not 2 hours) after cerebral ischemia substantially decreased the lesion volume and improved motor and cognitive functional recovery with minimal peripheral toxicity. The miR-7 mimic treatment substantially reduced the postischemic induction of α-synuclein (α-Syn), a protein that induces mitochondrial fragmentation, oxidative stress, and autophagy that promote neuronal cell death. Deletion of the gene encoding α-Syn abolished miR-7 mimic-dependent neuroprotection and functional recovery in young male mice. Further analysis confirmed that the transcript encoding α-Syn was bound and repressed by miR-7. Our findings suggest that miR-7 mimics may therapeutically minimize stroke-induced brain damage and disability.

Maternal preconception weight trajectories, pregnancy complications and offspring's childhood physical and cognitive development.

There is limited evidence on the association between maternal preconception body mass index (BMI) trajectories and pregnancy complications and child development. This study examined the relationships of maternal BMI trajectories, diabetes and hypertensive disorders during pregnancy and offspring's childhood physical and cognitive development. Data were from the Australian Longitudinal Study on Women's Health and the Mothers and their Children's Health study (n=771). Women's preconception BMI trajectories were identified using group-based trajectory modelling. Children's physical and cognitive development (up to the average age of 5 years) were obtained from the Ages and Stages Questionnaire (suspected gross motor delay) and the Australian Early Development Census (AEDC). Generalized estimating equation models, adjusted for maternal sociodemographic and lifestyle factors, were used for analyses. Three distinct BMI trajectories were identified (normative, chronically overweight and chronically obese). Children born to chronically obese women were more likely to be classified as developmentally vulnerable/at-risk on AEDC domains; gross and fine motor skills [risk ratio (RR)=1.64, 95% confidence interval (CI): 1.04, 2.61] and communication skills and general knowledge (RR=1.71, 95% CI: 1.09, 2.68). They also had an elevated risk of suspected gross motor delay (RR=2.62, 95% CI: 1.26, 5.44) compared with children born to women with a normative BMI trajectory. Maternal diabetes or hypertensive disorders during pregnancy were not associated with child outcomes. Maternal preconception BMI trajectories were associated with poorer childhood development. This study finding underscores the importance of excessive weight gain prevention throughout the reproductive stage of life.

N-Propargyl Caffeamide (PACA) Ameliorates Dopaminergic Neuronal Loss and Motor Dysfunctions in MPTP Mouse Model of Parkinson's Disease and in MPP+-Induced Neurons via Promoting the Conversion of proNGF to NGF.

Insufficient production of nerve growth factor (NGF) is implicated in Parkinson's disease (PD). We recently discovered that caffeic acid derivative N-propargyl caffeamide (PACA) not only potentiated NGF-induced neurite outgrowth but also attenuated 6-hydroxydopamine neurotoxicity in neuronal culture. The aim of the present study was to investigate whether PACA could increase NGF levels against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) neurotoxicity in a mouse PD model. We induced parkinsonism in mice by intraperitoneal injection of MPTP for seven consecutive days. Animal motor functions were assessed by rotarod test and pole test. Our results showed that PACA ameliorated motor impairments in MPTP-challenged mice. Based on Western blot analysis and/or immunofluorescence staining of NGF and tyrosine hydroxylase (TH), PACA preserved TH levels in the midbrain substantia nigra pars compacta. PACA also increased NGF expression while it decreased proNGF accumulation. Interestingly, NGF was widely induced in the midbrains including astrocytes. To elucidate the mechanisms by which PACA induces NGF, we focused on the effects of PACA on two neurotrophic signaling pathways, the PI3K and MEK pathways. We found that PACA induced the phosphorylation of Akt, ERK, and CREB against MPTP-mediated alterations. Importantly, PACA increased NGF levels and subsequently induced TrkA activation in MPTP-treated mice. Consistently, PACA also increased NGF levels in dopaminergic PC12 cells and primary rat midbrain neurons against N-methyl-4-phenylpyridinium iodide (MPP+) toxicity. ERK and PI3K inhibitors attenuated the effects of PACA on NGF levels. Collectively, our results suggest that PACA may rescue NGF insufficiency via sequential activation of PI3K/Akt, ERK1/2, and CREB signaling pathways. Graphical Abstract ᅟ.

Effectiveness of a Timing and Coordination Group Exercise Program to Improve Mobility in Community-Dwelling Older Adults: A Randomized Clinical Trial.

Importance: Timing and coordination exercises may be an important addition to community-based health promotion exercise programs to improve walking in older adults. Objective: To compare the effectiveness of the On the Move group exercise program, which focuses on the timing and coordination of movement, with a seated strength, endurance, and flexibility program (usual care) at improving function, disability, and walking ability of older adults. Design, Setting, and Participants: Cluster-randomized, single-blind intervention trial. Thirty-two independent living facilities, senior apartment buildings, and senior community centers were randomized to On the Move (16 sites; 152 participants) or usual care (16 sites; 146 participants). Participants were 65 years or older, able to ambulate independently with a gait speed of at least 0.60 m/s, able to follow 2-step commands, and were medically stable. Interventions: Exercise classes were 50 minutes, twice a week for 12 weeks and had 10 or fewer participants per class. On the Move consisted of warm-up, timing and coordination (stepping and walking patterns), strengthening, and stretching exercises. The usual-care program consisted of warm-up, strength, endurance, and stretching exercises. Main Outcomes and Measures: The primary outcomes were self-report of function and disability (Late Life Function and Disability Instrument) and mobility (6-minute walk distance and gait speed) assessed by blinded individuals. Results: Participants (mean [SD] age, 80.0 [8.1] years) were mostly female (251 [84.2%]) and white (249 [83.6%]) and had a mean (SD) of 2.8 (1.4) chronic conditions. Intervention groups were similar on baseline characteristics. Postintervention, 142 (93.4%) participants in On the Move and 139 (95.2%) participants in usual care completed testing. On the Move had greater mean (SD) improvements than the usual-care group in gait speed (0.05 [0.13] vs -0.01 [0.11] m/s; adjusted difference = 0.05 [0.02] m/s; P = .002) and 6-minute walk distance (20.6 [57.1] vs 4.1 [55.6] m; adjusted difference = 16.7 [7.4] m; P = .03). Attendance was greater in the usual-care program compared with On the Move (95 [65.1%] vs 76 [50.0%] attended ≥20 classes; P = .03). There were no significant differences in any of the other primary or secondary outcomes. Conclusions and Relevance: The On the Move group exercise program was more effective at improving mobility than a usual-care exercise program, despite lower attendance. Additional research examining the impact of the intervention on long-term disability outcomes is needed before recommending routine implementation into clinical practice. Trial Registration: clinicaltrials.gov Identifier: NCT01986647.

Treadmill interventions in children under six years of age at risk of neuromotor delay.

BACKGROUND: Delayed motor development may occur in children with Down syndrome, cerebral palsy, general developmental delay or children born preterm. It limits the child's exploration of the environment and can hinder cognitive and social-emotional development. Literature suggests that task-specific training, such as locomotor treadmill training, facilitates motor development. OBJECTIVES: To assess the effectiveness of treadmill interventions on locomotor development in children with delayed ambulation or in pre-ambulatory children (or both), who are under six years of age and who are at risk for neuromotor delay. SEARCH METHODS: In May 2017, we searched CENTRAL, MEDLINE, Embase, six other databases and a number of trials registers. We also searched the reference lists of relevant studies and systematic reviews. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that evaluated the effect of treadmill intervention in the target population. DATA COLLECTION AND ANALYSIS: Four authors independently extracted the data. Outcome parameters were structured according to the International Classification of Functioning, Disability and Health model. MAIN RESULTS: This is an update of a Cochrane review from 2011, which included five trials. This update includes seven studies on treadmill intervention in 175 children: 104 were allocated to treadmill groups, and 71 were controls. The studies varied in population (children with Down syndrome, cerebral palsy, developmental delay or at moderate risk for neuromotor delay); comparison type (treadmill versus no treadmill; treadmill with versus without orthoses; high- versus low-intensity training); study duration, and assessed outcomes. Due to the diversity of the studies, only data from five studies were used in meta-analyses for five outcomes: age of independent walking onset, overall gross motor function, gross motor function related to standing and walking, and gait velocity. GRADE assessments of quality of the evidence ranged from high to very low.The effects of treadmill intervention on independent walking onset compared to no treadmill intervention was population dependent, but showed no overall effect (mean difference (MD) -2.08, 95% confidence intervals (CI) -5.38 to 1.22, 2 studies, 58 children; moderate-quality evidence): 30 children with Down syndrome benefited from treadmill training (MD -4.00, 95% CI -6.96 to -1.04), but 28 children at moderate risk of developmental delay did not (MD -0.60, 95% CI -2.34 to 1.14). We found no evidence regarding walking onset in two studies that compared treadmill intervention with and without orthotics in 17 children (MD 0.10, 95% CI -5.96 to 6.16), and high- versus low-intensity treadmill interventions in 30 children with Down syndrome (MD -2.13, 95% -4.96 to 0.70).Treadmill intervention did not improve overall gross motor function (MD 0.88, 95% CI -4.54 to 6.30, 2 studies, 36 children; moderate-quality evidence) or gross motor skills related to standing (MD 5.41, 95% CI -1.64 to 12.43, 2 studies, 32 children; low-quality evidence), and had a negligible improvement in gross motor skills related to walking (MD 4.51, 95% CI 0.29 to 8.73, 2 studies, 32 children; low-quality evidence). It led to improved walking skills in 20 ambulatory children with developmental delay (MD 7.60, 95% CI 0.88 to 14.32, 1 study) and favourable gross motor skills in 12 children with cerebral palsy (MD 8.00, 95% CI 3.18 to 12.82). A study which compared treadmill intervention with and without orthotics in 17 children with Down syndrome suggested that adding orthotics might hinder overall gross motor progress (MD -8.40, 95% CI -14.55 to -2.25).Overall, treadmill intervention showed a very small increase in walking speed compared to no treadmill intervention (MD 0.23, 95% CI 0.08 to 0.37, 2 studies, 32 children; high-quality evidence). Treadmill intervention increased walking speed in 20 ambulatory children with developmental delay (MD 0.25, 95% CI 0.08 to 0.42), but not in 12 children with cerebral palsy (MD 0.18, 95% CI -0.09 to 0.45). AUTHORS' CONCLUSIONS: This update of the review from 2011 provides additional evidence of the efficacy of treadmill intervention for certain groups of children up to six years of age, but power to find significant results still remains limited. The current findings indicate that treadmill intervention may accelerate the development of independent walking in children with Down syndrome and may accelerate motor skill attainment in children with cerebral palsy and general developmental delay. Future research should first confirm these findings with larger and better designed studies, especially for infants with cerebral palsy and developmental delay. Once efficacy is established, research should examine the optimal dosage of treadmill intervention in these populations.

The effect of intervening hospitalizations on the benefit of structured physical activity in promoting independent mobility among community-living older persons: secondary analysis of a randomized controlled trial.

BACKGROUND: Among older persons, disability is often precipitated by intervening illnesses and injuries leading to hospitalization. In the Lifestyle Interventions and Independence for Elders (LIFE) Study, a structured moderate-intensity physical activity program, compared with a health education program, was shown to significantly reduce the amount of time spent with major mobility disability (MMD) over the course of 3.5 years. We aimed to determine whether the benefit of the physical activity program in promoting independent mobility was diminished in the setting of intervening hospitalizations. METHODS: We analyzed data from a single-blinded, parallel group randomized trial (ClinicalTrials.gov: NCT01072500). In this trial, 1635 sedentary persons, aged 70-89 years, who had functional limitations but were able to walk 400 m, were randomized from eight US centers between February 2010 and December 2013: 818 to physical activity (800 received intervention) and 817 to health education (805 received intervention). Intervening hospitalizations and MMD, defined as the inability to walk 400 m, were assessed every 6 months for up to 3.5 years. RESULTS: For both the physical activity and health education groups, intervening hospitalizations were strongly associated with the initial onset of MMD and inversely associated with recovery from MMD, defined as a transition from initial MMD onset to no MMD. The benefit of the physical activity intervention did not differ significantly based on hospital exposure. For onset of MMD, the hazard ratios (HR) were 0.79 (95% confidence interval [CI] 0.58-1.1) and 0.77 (0.62-0.95) in the presence and absence of intervening hospitalizations, respectively (P-interaction, 0.903). For recovery of MMD, the magnitude of effect was modestly greater among participants who were hospitalized (HR 1.5, 95% CI 0.71-3.0) than in those who were not hospitalized (HR 1.2, 95% CI 0.88-1.7), but this difference did not achieve statistical significance (P-interaction, 0.670). CONCLUSIONS: Intervening hospitalizations had strong deleterious effects on the onset of MMD and recovery from MMD, but did not diminish the beneficial effect of the LIFE physical activity intervention in promoting independent mobility. To achieve sustained benefits over time, structured physical activity programs should be designed to accommodate acute illnesses and injuries leading to hospitalizations given their high frequency in older persons with functional limitations. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01072500 .

Preventing mobility disability in Europe: a health economics perspective from the SPRINTT study.

In a global context of population aging, gaining better knowledge of the mechanisms leading to loss of autonomy has become a major objective, notably with the aim of implementing effective preventive health policies. The concept of frailty, originally introduced in gerontology and geriatrics as a precursor state to functional dependency, appears as a useful tool in this specific context. The "Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies" (SPRINTT) project will provide a unique opportunity to explore health economics issues associated with frailty. In terms of health economics, the loss of autonomy approach retained here focuses on the economic and social causes and consequences of the onset of frailty in older adults, and examines the challenges not only in terms of health system efficiency but also in terms of social protection.

Neuroprotective potential of curcumin in combination with piperine against 6-hydroxy dopamine induced motor deficit and neurochemical alterations in rats.

AIM AND OBJECTIVE: 6-hydroxy dopamine (6-OHDA) is a neurotoxin which on intranigral administration produces severe nigrostriatal damage with motor and cognitive deficit in animals. Curcumin (CMN) in combination with bioenhancer piperine (PP) in 6-hydroxydopamine-induced Parkinsonian rats was used to investigate the antioxidant, neuromodulatory and neuroprotective mechanisms. MATERIALS AND METHODS: Hemi-Parkinson's rat model was developed with intranigral infusion of 6-OHDA (8 µg/2 µl, once, unilaterally), treatment with CMN (25 and 50 mg/kg) and combination of PP (2.5 mg/kg) with CMN (25 mg/kg) was given daily for 21 days starting from the 7th day after 6-OHDA infusion. The behavioral (locomotor, grip strength, and narrow beam walk) parameters were studied on weekly basis. On 22nd day, isolated brain preparations were subjected to biochemical (lipid peroxidation, glutathione, and nitrite), neuroinflammatory (IL-1ß, IL-6, and TNF- α), and neurochemical (DA, NE, 5- HT, GABA, Glutamate, DOPAC, HVA, and 5-HIAA) analysis. RESULTS: Oral administration of CMN had significantly prevented behavioral, neuroinflammatory, and neurochemical changes and preserved the antioxidant potential of the nigrostriatum in rats treated with 6-OHDA. CONCLUSION: In the present study, PP and CMN had afforded a better neuroprotective effect compared to alone treatment on behavior, biochemical, neuroinflammatory, and neurochemical parameters in rats.

Importance of Initiating a "Tummy Time" Intervention Early in Infants With Down Syndrome.

PURPOSE: This study compared differences in motor development in infants with Down syndrome beginning a tummy time intervention before 11 weeks of age and after 11 weeks of age. METHODS: Nineteen infants with Down syndrome participated in tummy time until they could independently transition in and out of sitting. Motor development was assessed monthly using the Bayley III Motor Scales and compared between the groups. RESULTS: A difference in motor development between early and late groups is apparent 1, 2, and 3 months following intervention initiation. CONCLUSION: Early implemented tummy time was effective in reducing motor delay in young infants with Down syndrome and is a prudent first step in intervention.

"Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies".

Manganese (Mn) is an essential heavy metal. However, Mn's nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and its molecular actions in the brain as well as promising neuroprotective strategies. The authors focused on reporting findings regarding Mn transport mechanisms, Mn effects on cholinergic system, behavioral alterations induced by Mn exposure and studies of neuroprotective strategies against Mn intoxication. We report that exposure to Mn may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such as mutation in the transporter SLC30A10. Accumulation of Mn occurs mainly in the basal ganglia and leads to a syndrome called manganism, whose symptoms of cognitive dysfunction and motor impairment resemble Parkinson's disease (PD). Various neurotransmitter systems may be impaired due to Mn, especially dopaminergic, but also cholinergic and GABAergic. Several proteins have been identified to transport Mn, including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin and ferroportin and allow its accumulation in the central nervous system. Parallel to identification of Mn neurotoxic properties, neuroprotective strategies have been reported, and these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols and non-characterized components), iron chelating agents, precursors of glutathione (GSH), and synthetic compounds that can experimentally afford protection against Mn-induced neurotoxicity.

Socioeconomic differences in the benefits of structured physical activity compared with health education on the prevention of major mobility disability in older adults: the LIFE study.

BACKGROUND: Evidence is lacking on whether health-benefiting community-based interventions differ in their effectiveness according to socioeconomic characteristics. We evaluated whether the benefit of a structured physical activity intervention on reducing mobility disability in older adults differs by education or income. METHODS: The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicentre, randomised trial that compared a structured physical activity programme with a health education programme on the incidence of mobility disability among at-risk community-living older adults (aged 70-89 years; average follow-up of 2.6 years). Education (≤ high school (0-12 years), college (13-17 years) or postgraduate) and annual household income were self-reported (<$24 999, $25 000 to $49 999 and ≥$50 000). The risk of disability (objectively defined as loss of ability to walk 400 m) was compared between the 2 treatment groups using Cox regression, separately by socioeconomic group. Socioeconomic group×intervention interaction terms were tested. RESULTS: The effect of reducing the incidence of mobility disability was larger for those with postgraduate education (0.72, 0.51 to 1.03; N=411) compared with lower education (high school or less (0.93, 0.70 to 1.24; N=536). However, the education group×intervention interaction term was not statistically significant (p=0.54). Findings were in the same direction yet less pronounced when household income was used as the socioeconomic indicator. CONCLUSIONS: In the largest and longest running trial of physical activity amongst at-risk older adults, intervention effect sizes were largest among those with higher education or income, yet tests of statistical interactions were non-significant, likely due to inadequate power. TRIAL REGISTRATION NUMBER: NCT01072500.

An active video game intervention does not improve physical activity and sedentary time of children at-risk for developmental coordination disorder: a crossover randomized trial.

BACKGROUND: Children with developmental coordination disorder (DCD) are highly inactive and sedentary. The purpose of this study was to assess the impact of a home-based active video game intervention on objectively measured physical activity and sedentary behaviour in children at risk for DCD. METHODS: In a crossover randomized clinical trial, 21 children (mean age 11.0, SD 1.0; n = 11 girls) in Perth, Western Australia participated in two 16-week periods: no active video games (AVGs) control period and AVGs intervention period. Two active input consoles were provided to participants along with a selection of non-violent AVGs for participants to play at home. Participants wore accelerometers at baseline and following each period to determine minutes of sedentary, light, moderate and vigorous times in addition to self-reported types of activities in a diary. Linear mixed models, adjusted for the order of periods, compared physical activity and sedentary time during the last week of each period. RESULTS: There were no significant differences between the intervention and control periods in time spent in sedentary (decrease of -1.0 min/day during the intervention period, 95%CI -12.1, 10.1), light (increase of 2.2 min/day, 95%CI -8.8, 13.2), moderate (decrease of 0.7 min/day, 95%CI -4.6, 3.3) or vigorous (decrease of -0.6 min/day, 95%CI -1.6, 0.4). CONCLUSIONS: Among children at risk for DCD, participating in this AVG intervention did not improve objectively measured physical activity and sedentary time.

Early developmental intervention programmes provided post hospital discharge to prevent motor and cognitive impairment in preterm infants.

BACKGROUND: Infants born preterm are at increased risk of developing cognitive and motor impairment compared with infants born at term. Early developmental interventions have been provided in the clinical setting with the aim of improving overall functional outcomes for these infants. Long-term benefits of these programmes remain unclear. OBJECTIVES: Primary objective To compare the effectiveness of early developmental intervention programmes provided post hospital discharge to prevent motor or cognitive impairment in preterm (< 37 weeks) infants versus standard medical follow-up of preterm infants at infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Secondary objectives To perform subgroup analyses to determine the following.• Effects of gestational age, birth weight and brain injury (periventricular leukomalacia (PVL)/intraventricular haemorrhage (IVH)) on cognitive and motor outcomes when early intervention is compared with standard follow-up. ∘ Gestational age: < 28 weeks, 28 to < 32 weeks, 32 to < 37 weeks. ∘ Birth weight: < 1000 grams, 1000 to < 1500 grams, 1500 to < 2500 grams. ∘ Brain injury: absence or presence of grade III or grade IV IVH or cystic PVL (or both) or an abnormal ultrasound/magnetic resonance image (MRI) before initiation of the intervention.• Effects of interventions started during inpatient stay with a post-discharge component versus standard follow-up care.• Effects of interventions focused on the parent-infant relationship, infant development or both compared with standard follow-up care.To perform sensitivity analysis to identify the following.• Effects on motor and cognitive impairment when early developmental interventions are provided within high-quality randomised trials with low risk of bias for sequence generation, allocation concealment, blinding of outcome measures and selective reporting bias. SEARCH METHODS: The search strategy of the Cochrane Neonatal Review Group was used to identify randomised and quasi-randomised controlled trials of early developmental interventions provided post hospital discharge. Two review authors independently searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Advanced, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO and EMBASE (1966 to August 2015). SELECTION CRITERIA: Studies included had to be randomised or quasi-randomised controlled trials of early developmental intervention programmes that began within the first 12 months of life for infants born before 37 weeks' gestational age. Interventions could commence on an inpatient basis but had to include a post-discharge component for inclusion in this review. Outcome measures were not prespecified, other than that they had to assess cognitive outcomes, motor outcomes or both. Rates of cerebral palsy were documented. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted and entered data. Cognitive and motor outcomes were pooled by four age groups: infancy (zero to < three years), preschool age (three to < five years), school age (five to < 18 years) and adulthood (≥ 18 years). Meta-analysis using RevMan 5.1 was carried out to determine the effects of early developmental interventions at each age range. Subgroup analyses focused on gestational age, birth weight, brain injury, commencement of the intervention, focus of the intervention and study quality. MAIN RESULTS: Twenty-five studies met the inclusion criteria (3615 randomly assigned participants). Only 12 of these studies were randomised controlled trials with appropriate allocation concealment. Variability was evident with regard to focus and intensity of the intervention, participant characteristics and length of follow-up. Meta-analysis led to the conclusion that intervention improved cognitive outcomes at infancy (developmental quotient (DQ): standardised mean difference (SMD) 0.32 standard deviations (SDs), 95% confidence interval (CI) 0.16 to 0.47; P value < 0.001; 16 studies; 2372 participants) and at preschool age (intelligence quotient (IQ); SMD 0.43 SDs, 95% CI 0.32 to 0.54; P value < 0.001; eight studies; 1436 participants). However, this effect was not sustained at school age (IQ: SMD 0.18 SDs, 95% CI -0.08 to 0.43; P value = 0.17; five studies; 1372 participants). Heterogeneity between studies for cognitive outcomes at infancy and at school age was significant. With regards to motor outcomes, meta-analysis of 12 studies showed a significant effect in favour of early developmental interventions at infancy only; however, this effect was small (motor scale DQ: SMD 0.10 SDs, 95% CI 0.01 to 0.19; P value = 0.03; 12 studies; 1895 participants). No effect was noted on the rate of cerebral palsy among survivors (risk ratio (RR) 0.82, 95% CI 0.52 to 1.27; seven studies; 985 participants). Little evidence showed a positive effect on motor outcomes in the long term, but only five included studies reported outcomes at preschool age (n = 3) or at school age (n = 2). AUTHORS' CONCLUSIONS: Early intervention programmes for preterm infants have a positive influence on cognitive and motor outcomes during infancy, with cognitive benefits persisting into preschool age. A great deal of heterogeneity between studies was due to the variety of early developmental intervention programmes tested and to gestational ages of included preterm infants; thus, comparisons of intervention programmes were limited. Further research is needed to determine which early developmental interventions are most effective in improving cognitive and motor outcomes, and to discern the longer-term effects of these programmes.

Loss of VGLUT3 Produces Circadian-Dependent Hyperdopaminergia and Ameliorates Motor Dysfunction and l-Dopa-Mediated Dyskinesias in a Model of Parkinson's Disease.

The striatum is essential for many aspects of mammalian behavior, including motivation and movement, and is dysfunctional in motor disorders such as Parkinson's disease. The vesicular glutamate transporter 3 (VGLUT3) is expressed by striatal cholinergic interneurons (CINs) and is thus well positioned to regulate dopamine (DA) signaling and locomotor activity, a canonical measure of basal ganglia output. We now report that VGLUT3 knock-out (KO) mice show circadian-dependent hyperlocomotor activity that is restricted to the waking cycle and is due to an increase in striatal DA synthesis, packaging, and release. Using a conditional VGLUT3 KO mouse, we show that deletion of the transporter from CINs, surprisingly, does not alter evoked DA release in the dorsal striatum or baseline locomotor activity. The mice do, however, display changes in rearing behavior and sensorimotor gating. Elevation of DA release in the global KO raised the possibility that motor deficits in a Parkinson's disease model would be reduced. Remarkably, after a partial 6-hydroxydopamine (6-OHDA)-mediated DA depletion (∼70% in dorsal striatum), KO mice, in contrast to WT mice, showed normal motor behavior across the entire circadian cycle. l-3,4-dihydroxyphenylalanine-mediated dyskinesias were also significantly attenuated. These findings thus point to new mechanisms to regulate basal ganglia function and potentially treat Parkinson's disease and related disorders. SIGNIFICANCE STATEMENT: Dopaminergic signaling is critical for both motor and cognitive functions in the mammalian nervous system. Impairments, such as those found in Parkinson's disease patients, can lead to severe motor deficits. Vesicular glutamate transporter 3 (VGLUT3) loads glutamate into secretory vesicles for neurotransmission and is expressed by discrete neuron populations throughout the nervous system. Here, we report that the absence of VGLUT3 in mice leads to an upregulation of the midbrain dopamine system. Remarkably, in a Parkinson's disease model, the mice show normal motor behavior. They also show fewer abnormal motor behaviors (dyskinesias) in response to l-3,4-dihydroxyphenylalanine, the principal treatment for Parkinson's disease. The work thus suggests new avenues for the development of novel treatment strategies for Parkinson's disease and potentially other basal-ganglia-related disorders.

Ferulic acid pretreatment mitigates MPTP-induced motor impairment and histopathological alterations in C57BL/6 mice.

CONTEXT: Ferulic acid (FA) is a potent ubiquitous plant antioxidant found in cereals such as brown rice, whole wheat, and oats. Phytochemical-based antioxidants are shown to be effective in neurodegenerative diseases. This study hypothesizes that supplementation of FA might combat oxidative stress-induced Parkinson's disease (PD). OBJECTIVE: To explore the effect of FA on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced neurotoxicity. MATERIALS AND METHODS: Mice were randomized into five groups: Group I mice served as control. Group II mice received 5 × MPTP [25 mg/kg body weight (i.p.)] in saline 24 h apart starting from the 3rd day and continued till the last day of the experimental period of 7 d. In addition to MPTP injections, mice in Groups III, IV, and V were given FA at a dose of 20, 40, and 80 mg, respectively, for 7 d. Mice were subjected to a battery of behavioral tests along with histological investigations. RESULTS: Our histological findings revealed that MPTP administration enhanced Bax/Bcl2 ratio and microglial cells activation reflecting induction of apoptosis and inflammation, respectively. This dopaminergic neuronal loss caused impairment in motor balance and coordination in MPTP mice as assessed by various behavioral tests. FA at a dose of 40 mg/kg/d body weight effectively attenuated MPTP-induced neurotoxicity. DISCUSSION: Antioxidant, free-radical quenching, and anti-inflammatory activities of FA could contribute to its neuroprotective effect. CONCLUSION: This study provides elementary evidence for the neuroprotective action of FA against MPTP-induced PD in mice and warrants further studies.