Antidepressant-induced membrane trafficking regulates blood-brain barrier permeability.

As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other AD classes bidirectionally regulate fluid-phase uptake at therapeutic concentrations and below. We further characterize membrane trafficking induced by a canonical SSRI fluvoxamine to show that it involves enhancement of clathrin-mediated endocytosis, endosomal system, and exocytosis. RNA sequencing analysis showed few fluvoxamine-associated differences, consistent with the effect being independent of gene expression. Fluvoxamine-induced increase in membrane trafficking boosted transcytosis in cell-based blood-brain barrier models, while a single injection of fluvoxamine was sufficient to enable brain accumulation of a fluid-phase fluorescent tracer in vivo. These findings reveal modulation of membrane trafficking by ADs as a possible cellular mechanism of action and indicate their clinical repositioning potential for regulating drug delivery to the brain.

The neuropeptide landscape of human prefrontal cortex.

Human prefrontal cortex (hPFC) is a complex brain region involved in cognitive and emotional processes and several psychiatric disorders. Here, we present an overview of the distribution of the peptidergic systems in 17 subregions of hPFC and three reference cortices obtained by microdissection and based on RNA sequencing and RNAscope methods integrated with published single-cell transcriptomics data. We detected expression of 60 neuropeptides and 60 neuropeptide receptors in at least one of the hPFC subregions. The results reveal that the peptidergic landscape in PFC consists of closely located and functionally different subregions with unique peptide/transmitter-related profiles. Neuropeptide-rich PFC subregions were identified, encompassing regions from anterior cingulate cortex/orbitofrontal gyrus. Furthermore, marked differences in gene expression exist between different PFC regions (>5-fold; cocaine and amphetamine-regulated transcript peptide) as well as between PFC regions and reference regions, for example, for somatostatin and several receptors. We suggest that the present approach allows definition of, still hypothetical, microcircuits exemplified by glutamatergic neurons expressing a peptide cotransmitter either as an agonist (hypocretin/orexin) or antagonist (galanin). Specific neuropeptide receptors have been identified as possible targets for neuronal afferents and, interestingly, peripheral blood-borne peptide hormones (leptin, adiponectin, gastric inhibitory peptide, glucagon-like peptides, and peptide YY). Together with other recent publications, our results support the view that neuropeptide systems may play an important role in hPFC and underpin the concept that neuropeptide signaling helps stabilize circuit connectivity and fine-tune/modulate PFC functions executed during health and disease.

Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus.

Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer's disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways.

A phase Ib/II randomized, open-label drug repurposing trial of glutamate signaling inhibitors in combination with chemoradiotherapy in patients with newly diagnosed glioblastoma: the GLUGLIO trial protocol.

BACKGROUND: Glioblastoma is the most common and most aggressive malignant primary brain tumor in adults. Glioblastoma cells synthesize and secrete large quantities of the excitatory neurotransmitter glutamate, driving epilepsy, neuronal death, tumor growth and invasion. Moreover, neuronal networks interconnect with glioblastoma cell networks through glutamatergic neuroglial synapses, activation of which induces oncogenic calcium oscillations that are propagated via gap junctions between tumor cells. The primary objective of this study is to explore the efficacy of brain-penetrating anti-glutamatergic drugs to standard chemoradiotherapy in patients with glioblastoma. METHODS/DESIGN: GLUGLIO is a 1:1 randomized phase Ib/II, parallel-group, open-label, multicenter trial of gabapentin, sulfasalazine, memantine and chemoradiotherapy (Arm A) versus chemoradiotherapy alone (Arm B) in patients with newly diagnosed glioblastoma. Planned accrual is 120 patients. The primary endpoint is progression-free survival at 6 months. Secondary endpoints include overall and seizure-free survival, quality of life of patients and caregivers, symptom burden and cognitive functioning. Glutamate levels will be assessed longitudinally by magnetic resonance spectroscopy. Other outcomes of interest include imaging response rate, neuronal hyperexcitability determined by longitudinal electroencephalography, Karnofsky performance status as a global measure of overall performance, anticonvulsant drug use and steroid use. Tumor tissue and blood will be collected for translational research. Subgroup survival analyses by baseline parameters include segregation by age, extent of resection, Karnofsky performance status, O6-methylguanine DNA methyltransferase (MGMT) promotor methylation status, steroid intake, presence or absence of seizures, tumor volume and glutamate levels determined by MR spectroscopy. The trial is currently recruiting in seven centers in Switzerland. TRIAL REGISTRATION: NCT05664464. Registered 23 December 2022.

Differences in the effects of a startle stimulus on rate of force development between resistance-trained rock climbers and untrained individuals: Evidence for reticulospinal adaptations?

The aim of the present cross-sectional study was to determine if chronic rock climbing and climbing-specific resistance training (RT) would modify the reticulospinal tract (RST) efficacy. Sixteen healthy, elite level climbers (CL; n = 16, 5 F; 29.8 ± 6.7 years) with 12 ± 7 years of climbing and climbing-specific RT experience and 15 healthy recreationally active participants (CON; n = 15, 4 F; 24.6 ± 5.9 years), volunteered for the study. We quantified RST efficacy by comparing the effects of a startle stimulus over reaction time (Rtime ) and measured rate of force development (RFD) and surface electromyography (sEMG) in representative muscles during powerful hand grip contractions. Both groups performed two Rtime tasks while performing rapid, powerful gripping with the right hand (Task 1) or during 3-s-long maximal voluntary right hand grip contractions in response to an imperative visual signal alone (V), or combined with a auditory-non startle stimulus (A) or/and startling auditory stimulus (S). We also tested the reproducibility of these responses on two separate days in CON. Intersession reliability ranged from 0.34 to 0.96 for all variables. The CL versus CON was 37% stronger (p = 0.003). The S stimulus decreased Rtime and increased RFD and sEMG in both groups during both tasks (all p < 0.001). Rtime was similar between groups in all conditions. However, CL had a greater RFD from 50 to 100 ms compared with CON only after the S stimulus in both tasks (p < 0.05, d = 0.85-0.96). The data tentatively suggest that chronic rock climbing and climbing-specific RT might improve RST efficacy, by increasing RST input to the α-motoneurons.

Association Between Foundation Strength and Weightlifting Exercises in Highly Trained Weightlifters: Support for a General Strength Component.

ABSTRACT: Zecchin, A, Puggina, EF, Hortobágyi, T, and Granacher, U. Association between foundation strength and weightlifting exercises in highly trained weightlifters: support for a general strength component. J Strength Cond Res 37(7): 1375-1381, 2023-In addition to specific weightlifting exercises (i.e., clean and jerk and snatch), foundation strength exercises (i.e., overhead press, front squat, and deadlift) constitute an integral part of the weightlifters' training regime. The unexamined concept behind this training plan is that foundation strength exercises are associated with clean and jerk and snatch performance, implying the existence of a general strength component. We thus determined the relationship between performance in foundation strength exercises (overhead press, front squat, and deadlift) and weightlifting exercises (clean and jerk and snatch) in weightlifters. Well-trained weightlifters ( N = 19, age: 26.8 ± 4.4 years; body mass index: 27.6 ± 2.3 kg·m -2 ; and training history: 4.6 ± 0.8 years) performed 1 repetition maximum tests (1RM) in foundation strength and weightlifting exercises, over 14 days, in a randomized order. We observed significant correlations in 1RM performance between the overhead press and snatch ( r = 0.69), front squat and snatch ( r = 0.73), overhead press and clean and jerk ( r = 0.67), and front squat and clean and jerk ( r = 0.72, all r values: p < 0.01). No significant correlations were found for 1RM performance between the snatch and deadlift or between the clean and jerk and deadlift ( r- range: 0.20-0.58; p > 0.05). Stepwise linear regression revealed that 1RM performance in the overhead press and front squat explained 62% of the variance in snatch 1RM performance ( F = 5.51; p < 0.04). Overhead press and front squat 1RM performance explained 59% of the variance in the clean and jerk 1RM performance ( F = 5.14; p < 0.04). Our results demonstrate the existence of a general strength component between selected foundation strength exercises and weightlifting performance. However, the use of the front squat and overhead press to increase 1RM performance in weightlifting exercises needs to be determined in future research using a different methodological approach (i.e., longitudinal protocols), given that the observed correlations do not necessarily imply causation.

Measures of Physical Fitness Improve Prediction of Kayak and Canoe Sprint Performance in Young Kayakers and Canoeists.

ABSTRACT: Gäbler, M, Prieske, O, Elferink-Gemser, MT, Hortobágyi, T, Warnke, T, and Granacher, U. Measures of physical fitness improve prediction of kayak and canoe sprint performance in young kayakers and canoeists. J Strength Cond Res 37(6): 1264-1270, 2023-Markers of talent selection and predictors of performance in canoe and kayak sprint are not yet well defined. We aimed to determine the combination of variables (i.e., demographic, anthropometric, and physical fitness) that most accurately predicts sprint performance (i.e., 500- and 2000-m race time) in semielite, young kayakers and canoeists ( n = 39, age 13 year, 10F). The level of significance was set at p < 0.05. Linear regression analyses identified boat type (i.e., kayak or canoe), skeletal muscle mass, and average power during a 2-minute bench pull test, normalized to body mass, as predictors of 2000-m race time (R 22000 m = 0.69, Akaike information criterion [AIC] = 425) and together with vertical jump height, as predictors of 500-m race time (R 2500 m = 0.87, AIC = 255). This was an improvement over models containing solely demographic variables (R 2500 m = 0.66, AIC = 293; R 22000 m = 0.44, AIC = 446) and over models containing demographic and anthropometric variables (R 2500m = 0.79, AIC = 277; R 22000 m = 0.56, AIC = 437). Race time showed the strongest semipartial correlations with the 2-minute bench pull test (0.7 ≤ r ≤ 0.9). Adding physical fitness data (i.e., 2-minute bench pull test) to demographic and anthropometric data improves the prediction accuracy of race times in young kayak and canoe athletes. The characteristics of physical fitness tests should resemble as much as possible the biomechanical (e.g., prime movers) and metabolic (e.g., duration) demands of the sport.

[Isolated IgG4 hypertrophic pachymeningitis with cranial nerve involvement].

IgG4-related (IgG4-RD) disease is a relatively newly identified, chronic autoimmune disorder that can affect any organ system. The disease is relatively rare. It has mostly systemic presentation, however it can also appear in isolated form in one single organ. In our report, we demonstrate an elderly male patient's case with IgG4-RD presented in the form of diffuse meningeal inflammation and hypertrophic pachymeningitis with one-sided cranial nerve and intraventricular involvement.

Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus-pericoerulear complex by three-dimensional imaging.

Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer's disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0-6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer's disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau.

The dualistic role of the purinergic P2Y12-receptor in an in vivo model of Parkinson's disease: Signalling pathway and novel therapeutic targets.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative condition; characterized with the degeneration of the nigrostriatal dopaminergic pathway and neuroinflammation. During PD progression, microglia, the resident immune cells in the central nervous system (CNS) display altered activity, but their role in maintaining PD development has remained unclear to date. The purinergic P2Y12-receptor (P2Y12R), which is expressed on the microglia in the CNS has been shown to regulate microglial activity and responses; however, the function of the P2Y12R in PD is unknown. Here we show that MPTP-induced PD symptoms in mice are associated with marked neuroinflammatory changes and P2Y12R contribute to the activation of microglia and progression of the disease. Surprisingly, while pharmacological or genetic targeting of the P2Y12R augments acute mortality in MPTP-treated mice, these interventions protect against the neurodegenerative cell loss and the development of neuroinflammation in vivo. Pharmacological inhibition of receptors during disease development reverses the symptoms of PD and halts disease progression. We found that P2Y12R regulates ROCK and p38 MAPK activity and control cytokine production. Our principal finding is that the receptor has a dualistic role in PD: functional P2Y12Rs are essential to initiate a protective inflammatory response, since the lack of the receptor leads to reduced survival; however, at later stages of neurodegeneration, P2Y12Rs are apparently responsible for maintaining the activated state of microglia and stimulating pro-inflammatory cytokine response. Understanding protective and detrimental P2Y12R-mediated actions in the CNS may reveal novel approaches to control neuroinflammation and modify disease progression in PD.

Karyopherin abnormalities in neurodegenerative proteinopathies.

Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, α-synuclein, TAR DNA binding protein-43, fused in sarcoma and mutant huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins' phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases. Recent advances into the underlying pathogenic mechanisms have associated mislocalization and aberrant accumulation of disease-related proteins with defective nucleocytoplasmic transport and its mediators called karyopherins. These studies identify karyopherin abnormalities in amyotrophic lateral sclerosis, frontotemporal dementia, Alzheimer's disease, and synucleinopathies including Parkinson's disease and dementia with Lewy bodies, that range from altered expression levels to the subcellular mislocalization and aggregation of karyopherin α and ß proteins. The reported findings reveal that in addition to their classical function in nuclear import and export, karyopherins can also act as chaperones by shielding aggregation-prone proteins against misfolding, accumulation and irreversible phase-transition into insoluble aggregates. Karyopherin abnormalities can, therefore, be both the cause and consequence of protein mislocalization and aggregate formation in degenerative proteinopathies. The resulting vicious feedback cycle of karyopherin pathology and proteinopathy identifies karyopherin abnormalities as a common denominator of onset and progression of neurodegenerative disease. Pharmacological targeting of karyopherins, already in clinical trials as therapeutic intervention targeting cancers such as glioblastoma and viral infections like COVID-19, may therefore represent a promising new avenue for disease-modifying treatments in neurodegenerative proteinopathies.

Age- and muscle-specific reliability of muscle architecture measurements assessed by two-dimensional panoramic ultrasound.

BACKGROUND: Age-related changes in muscle properties affect daily functioning, therefore a reliable assessment of such properties is required. We examined the effects of age on reliability, muscle quality and interrelation among muscle architecture (MA) parameters of the gastrocnemius medialis (GM), tibialis anterior (TA), and vastus lateralis (VL) muscles. METHODS: Three raters scored ultrasound (US) scans of 12 healthy younger and older adults, on fascicle length (FL), pennation angle (PA) and muscle thickness (MT). Intra- and inter-rater reliability of MA measures in rest and contraction was assessed by intraclass correlation coefficients (ICC) and standard error of measurements (SEM, SEM%). The relationship between MA parameters was examined using Pearson correlation coefficients. Muscle quality (MQ) was examined using mean pixel intensity. RESULTS: Reliability was moderate to excellent for TA in both groups (ICCs: 0.64-0.99, SEM% = 1.6-14.8%), and for VL in the younger group (ICCs: 0.67-0.98, SEM% = 2.0-18.3%). VL reliability was poor to excellent in older adults (ICCs: 0.22-0.99, SEM% = 2.7-36.0%). For GM, ICCs were good to excellent (ICCs: 0.76-0.99) in both groups, but GM SEM% were higher in older adults (SEM%Younger = 1.5-10.7%, SEM%Older = 1.6-28.1%). Muscle quality was on average 19.0% lower in older vs. younger adults. In both groups, moderate to strong correlations were found for VL FL and MT (r ≥ 0.54), and TA PA and MT (r ≥ 0.72), while TA FL correlated with MT (r ≥ 0.67) in younger adults only. CONCLUSIONS: In conclusion, age- and muscle-specificities were present in the relationships between MT and PA, and MT and FL at rest. Furthermore, the reliability of MA parameters assessed with 2D panoramic US is acceptable. However, the level of reliability varies with age, muscle and MA measure. In older adults notably, the lowest reliability was observed in the VL muscle. Among the MA parameters, MT appears to be the simplest and most easily reproducible parameter in all muscles and age groups.

Comparative Effectiveness of 4 Exercise Interventions Followed by 2 Years of Exercise Maintenance in Multiple Sclerosis: A Randomized Controlled Trial.

OBJECTIVE: To determine the effects of exergaming (EXE) on quality of life (QOL), motor, and clinical symptoms in multiple sclerosis (MS). We compared the effects of EXE, balance (BAL), cycling (CYC), proprioceptive neuromuscular facilitation (PNF), and a standard care wait-listed control group on clinical and motor symptoms and quality of life (QOL) in people with MS (PwMS) and determined the effects of subsequent maintenance programs for 2 years in a hospital setting. DESIGN: A randomized controlled trial, using before-after test design. SETTING: University hospital setting. PARTICIPANTS: Of 82 outpatients with MS, 70 were randomized (N=70), and 68 completed the study. INTERVENTIONS: The initial high-intensity and high-frequency interventions consisted of 25 one-hour sessions over 5 weeks. After the 5-week-long initial intervention, the 2-year-long maintenance programs followed, consisting of 3 sessions per week, each for 1 hour. MAIN OUTCOME MEASURES: The primary outcome: Multiple Sclerosis Impact Scale (MSIS-29). SECONDARY OUTCOMES: Measures 5 aspects of health-related QOL (EuroQol 5-Dimension questionnaire), Beck Depression Inventory, 6-minute walk test (6MWT), Berg Balance Scale (BBS), Tinetti Assessment Tool (TAT), and static BAL (center of pressure). RESULTS: MSIS-29 improved most in EXE (11 points), BAL (6), and CYC (6) (all P<.05). QOL improved most in EXE (3 points), CYC, and BAL (2) (all P<.05). TAT and BBS improved significantly (P<.05) but similarly (P>.05) in EXE, BAL, and CYC. 6MWT improved most in EXE (57m), BAL (32m), and CYC (19m) (all P<.001). Standing sway did not change. Maintenance programs further increased the initial exercise-induced gains, robustly in EXE. CONCLUSIONS: A total of 25 sessions of EXE, BAL, CYC, and PNF, in this order, improved clinical and motor symptoms and QOL, and subsequent 2-year-long thrice weekly maintenance programs further slowed symptom worsening and improved QOL. EXE was the most and PNF was the least effective to improve clinical symptoms, motor function, and QOL in PwMS.

Voluntary suppression of associated activity decreases force steadiness in the active hand.

Unilateral muscle contractions are often accompanied by the activation of the ipsilateral hemisphere, producing associated activity (AA) in the contralateral homologous muscles. However, the functional role of AA is not fully understood. We determined the effects of voluntary suppression of AA in the first dorsal interosseous (FDI), on force steadiness during a constant force isometric contraction of the contralateral FDI. Participants (n = 17, 25.5 years) performed two trials of isometric FDI contractions as steadily as possible. In Trial 1, they did not receive feedback or explicit instructions for suppressing the AA in the contralateral homologous FDI. In Trial 2, participants received feedback and were asked to voluntarily suppress the AA in the contralateral nontarget FDI. During both trials, corticospinal excitability and motor cortical inhibition were measured. The results show that participants effectively suppressed the AA in the nontarget contralateral FDI (-71%), which correlated with reductions in corticospinal excitability (-57%), and the suppression was also accompanied by increases in inhibition (27%) in the ipsilateral motor cortex. The suppression of AA impaired force steadiness, but the decrease in force steadiness did not correlate with the magnitude of suppression. The results show that voluntary suppression of AA decreases force steadiness in the active hand. However, due to the lack of association between suppression and decreased steadiness, we interpret these data to mean that specific elements of the ipsilateral brain activation producing AA in younger adults are neither contributing nor detrimental to unilateral motor control during a steady isometric contraction.

Extracellular matrix changes in corneal opacification vary depending on etiology.

Purpose: The purpose of this study is to examine the expression of tenascin-C and matrilin-2 in three different disorders, which frequently require corneal transplantation. These pathological conditions include bullous keratopathy (BK), Fuchs' endothelial corneal dystrophy (FECD), and corneal scarring in herpetic keratitis. Methods: Histological sections of corneal buttons removed during keratoplasty were analyzed in BK (n = 20), FECD (n = 9), herpetic keratitis (n = 12), and cadaveric control (n = 10) groups with light microscopy following chromogenic immunohistochemistry. The sections were evaluated by three investigators, and semiquantitative scoring (0 to 3+) was applied according to standardized methods at 400X magnification. Each layer of the cornea was investigated; moreover, the stroma was subdivided into subepithelial, middle, and pre-Descemet's membrane areas for more detailed analysis. Results: Excessive epithelial and stromal expression of tenascin-C was identified in all investigated conditions; the results were most pronounced in the pre-Descemet's membrane. Regarding matrilin-2, when examined in BK, there was increased labeling intensity in the epithelium (p<0.001) and stromal layers (p<0.05), and a decrease in the endothelium (p<0.001). In the other investigated conditions, only a low degree of stromal localization (p<0.05) of matrilin-2 was detected. Conclusions: The expression of tenascin-C and matrilin-2 differs when examined in various corneal pathologies resulting in opacification. Both molecules seem to be involved in regeneration and wound healing of the corneal matrix in these diseases.

Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study.

Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., "absent" vs. "present") and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff's α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff's α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

The Interaction between Mobility Status and Exercise Specificity in Older Adults.

Many adults older than 60 yr experience mobility limitations. Although physical exercise improves older adults' mobility, differences in baseline mobility produce large variations in individual responses to interventions, and these responses could further vary by the type and dose of exercise. Here, we propose an exercise prescription model for older adults based on their current mobility status.

Effects of Exercise Dose and Detraining Duration on Mobility at Late Midlife: A Randomized Clinical Trial.

BACKGROUND: Office workers near retirement tend to be sedentary and can be prone to mobility limitations and diseases. We examined the dose effects of exergaming volume and duration of detraining on motor and cognitive function in office workers at late midlife to reduce sedentariness and mobility limitations. METHODS: In an assessor-blinded randomized trial, 160 workers aged 55-65 years performed physically active video games in a nonimmersive form of virtual reality (exergaming) in small, supervised groups for 1 h, 1×, 2×, or 3×/week for 8 weeks followed by detraining for 8 and 16 weeks. Exergaming comprises high-intensity, full-body sensorimotor coordination, balance, endurance, and strengthening exercises. The primary outcome was the 6-minute walk test (6MWT), and secondary outcomes were body mass, self-reported physical activity, sleep quality, Berg Balance Scale, Short Physical Performance Battery, fast gait speed, dynamic balance, heart rate recovery after step test, and 6 cognitive tests. RESULTS: The 3 groups were not different in any of the outcomes at baseline (all p > 0.05). The outcomes were stable and had acceptable reliability (intraclass correlation coefficients ≥0.334) over an 8-week control period. Training produced an inverted U-shaped dose response of no (1×), most (2×), and medium (3×/week) effects of exergaming volume in most motor and selected cognitive outcomes. The distance walked in the 6MWT (primary outcome) increased most (94 m, 19%, p < 0.05), medium (57 m, 12%, p < 0.05), and least (4 m, 1%) after exergaming 2×, 3×, or 0× (control) (all different p < 0.05). The highest responders tended to retain the exercise effects over 8 weeks of detraining, independent of training volume. This maintenance effect was less consistent after 16 weeks of detraining. CONCLUSION: Less was more during training and lasted longer after detraining. A medium dose volume of exergaming produced the largest clinically meaningful improvements in mobility and selected cognitive tests in 60-year-old office workers with mild mobility limitations and intact cognition.

High Frequency and Intensity Rehabilitation in 641 Subacute Ischemic Stroke Patients.

OBJECTIVES: To determine the effects of exergaming on quality of life (QoL), motor, and clinical symptoms in subacute stroke patients. DESIGN: A pseudorandomized controlled trial, using a before-after test design. SETTING: University hospital. PARTICIPANTS: Subacute, ischemic stroke outpatients (N=3857), 680 of whom were randomized and 641 completed the study. INTERVENTIONS: We determined the effects of 5 times a week twice daily (EX2; 50 sessions; n=286) and once daily (EX1; 25 sessions; n=272) exergaming and low-intensity standard care (control [CON]; 25 sessions; n=83) on clinical, mobility, blood pressure (BP), and QoL outcomes. MAIN OUTCOME MEASURES: The primary outcome was Modified Rankin Scale. Secondary outcomes were activities of daily living, 5 aspects of health-related QoL, Beck Depression Inventory, 6-minute walk test (6MWT), Berg Balance Scale (BBS), and static balance (center of pressure). RESULTS: During exercise, the peak heart rate was 134, 134, and 126 beats per minute in the EX2, EX1, and CON groups, respectively. mRS improved similarly in the EX2 (-1.8; effect size, d=-4.0) and EX1 (-1.4; d=-2.6) groups, but more than in the CON group (-0.7; d=-0.6). QoL, Barthel Index, BBS, 6MWT, and standing posturography improved more in the EX2 group and the same in the EX1 and CON groups. Systolic and diastolic resting BP decreased more in the EX2 and EX1 groups than in the CON group. The intervention effects did not differ between men (n=349) and women (n=292). CONCLUSIONS: Twice daily compared with once daily high-intensity exergaming or once daily lower intensity standard care produced superior effects on clinical and motor symptoms, BP, and QoL in male and female subacute ischemic stroke participants.

Training load but not fatigue affects cross-education of maximal voluntary force.

The purpose of this study was to determine the effects of training load (25% vs. 75% of one repetition maximum [1RM]) and fatigue (failure vs. non-failure) during four weeks of unilateral knee extension resistance training (RT) on maximal voluntary force in the trained and the untrained knee extensors. Healthy young adults (n = 42) were randomly assigned to control (CON, n = 9, 24 ± 4.3 years), low-load RT to failure (LLF, n = 11, 21 ± 1.3 years, three sets to failure at 25% of 1RM), high-load RT to failure (HLF, n = 11, 21 ± 1.4 years, three sets to failure at 75% of 1RM), and high-load RT without failure (HLNF, n = 11, 22 ± 1.5 years, six sets of five repetitions at 75% of 1RM) groups. Before and after the four weeks of training, 1RM, maximal voluntary isometric force, and corticospinal excitability (CSE) were measured. 1RM in the trained (20%, d = 0.70, 15%, d = 0.61) and the untrained knee extensors (5%, d = 0.27, 6%, d = 0.26) increased only in the HLF and HLNF groups, respectively. MVIC force increased only in the trained leg of the HLF (5%, d = 0.35) and HLNF groups (12%, d = 0.67). CSE decreased in the VL of both legs in the HLNF group (-19%, d = 0.44) and no changes occurred in the RF. In conclusion, high- but not low-load RT improves maximal voluntary force in the trained and the untrained knee extensors and fatigue did not further enhance these adaptations. Voluntary force improvements were unrelated to CSE changes in both legs.