Background: Traumas to the head and neck are common in sports and often affects otherwise healthy young individuals. Sports-related concussions (SRC), defined as a mild traumatic brain injury (mTBI), may inflict persistent neck and shoulder pain, and headache, but also more complex symptoms, such as imbalance, dizziness, and visual disturbances. These more complex symptoms are difficult to identify with standard health care diagnostic procedures.

Objective: To investigate postural control in a group of former elite athletes with persistent post-concussive symptoms (PPCS) at least 6 months after the incident.

Method: Postural control was examined using posturography during quiet stance and randomized balance perturbations with eyes open and eyes closed. Randomized balance perturbations were used to examine motor learning through sensorimotor adaptation. Force platform recordings were converted to reflect the energy used to maintain balance and spectrally categorized into total energy used, energy used for smooth corrective changes of posture (i.e., <0.1 Hz), and energy used for fast corrective movements to maintain balance (i.e., >0.1 Hz).

Results: The mTBI group included 20 (13 males, mean age 26.6 years) elite athletes with PPCS and the control group included 12 athletes (9 males, mean age 26.4 years) with no history of SRC. The mTBI group used significantly more energy during balance perturbations than controls: +143% total energy, p = 0.004; +122% low frequency energy, p = 0.007; and +162% high frequency energy, p = 0.004. The mTBI subjects also adapted less to the balance perturbations than controls in total (18% mTBI vs. 37% controls, p = 0.042), low frequency (24% mTBI vs. 42% controls, p = 0.046), and high frequency (6% mTBI vs. 28% controls, p = 0.040). The mTBI subjects used significantly more energy during quiet stance than controls: +128% total energy, p = 0.034; +136% low-frequency energy, p = 0.048; and +109% high-frequency energy, p = 0.015.

Conclusion: Athletes with previous mTBI and PPCS used more energy to stand compared to controls during balance perturbations and quiet stance and had diminished sensorimotor adaptation. Sports-related concussions are able to affect postural control and motor learning.

Background: Combining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence). MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia.

Methods: MET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes. The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded. Conclusion: MET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.

Symptoms of vestibular dysfunction such as dizziness and vertigo are common after sports-related concussions (SRC) and associated with a worse outcome and a prolonged recovery. Vestibular dysfunction after SRC can be because of an impairment of the peripheral or central neural parts of the vestibular system. The aim of the present study was to establish the cause of vestibular impairment in athletes with SRC who have persisting post-concussive symptoms (PPCS). We recruited 42 participants—21 athletes with previous SRCs and PPCS ≥6 months and 21 healthy athletic age- and sex-matched controls—who underwent symptom rating, a detailed test battery of vestibular function and 7T magnetic resonance imaging with diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) of cerebellar white matter tracts, and T1-weighted imaging for cerebellar volumetrics. Vestibular dysfunction was observed in 13 SRC athletes and three controls (p = 0.001). Athletes with vestibular dysfunction reported more pronounced symptoms on the Dizziness Handicap Inventory (DHI; p < 0.001) and the Hospital Anxiety and Depression Scale (HADS; p < 0.001). No significant differences in DTI metrics were found, while in DKI two metrics were observed in the superior and/or inferior cerebellar tracts. Cerebellar gray and white matter volumes were similar in athletes with SRC and controls. Compared with controls, pathological video head impulse test results (vHIT; p < 0.001) and cervical vestibular evoked myogenic potentials (cVEMP; p = 0.002) were observed in athletes with SRC, indicating peripheral vestibular dysfunction and specifically suggesting injury to the inferior vestibular nerve. In athletes with persisting symptoms after SRC, vestibular dysfunction is associated with injury to the inferior vestibular nerve.

Sports-related concussions may cause white matter injuries and persistent post-concussive symptoms (PPCS). We hypothesized that athletes with PPCS would have neurocognitive impairments and white matter abnormalities that could be revealed by advanced neuroimaging using ultra-high field strength diffusion tensor (DTI) and diffusion kurtosis (DKI) imaging metrics and cerebrospinal fluid (CSF) biomarkers. A cohort of athletes with PPCS severity limiting the ability to work/study and participate in sport school and/or social activities for ≥6 months completed 7T magnetic resonance imaging (MRI) (morphological T1-weighed volumetry, DTI and DKI), extensive neuropsychological testing, symptom rating, and CSF biomarker sampling. Twenty-two athletes with PPCS and 22 controls were included. Concussed athletes performed below norms and significantly lower than controls on all but one of the psychometric neuropsychology tests. Supratentorial white and gray matter, as well as hippocampal volumes did not differ between concussed athletes and controls. However, of the 72 examined white matter tracts, 16% of DTI and 35% of DKI metrics (in total 28%) were significantly different between concussed athletes and controls. DKI fractional anisotropy and axial kurtosis were increased, and DKI radial diffusivity and radial kurtosis decreased in concussed athletes when compared with controls. CSF neurofilament light (NfL; an axonal injury marker), although not glial fibrillary acidic protein, correlated with several diffusion metrics. In this first 7T DTI and DKI study investigating PPCS, widespread microstructural alterations were observed in the white matter, correlating with CSF markers of axonal injury. More white matter changes were observed using DKI than using DTI. These white matter alterations may indicate persistent pathophysiological processes following concussion in sport.

A sports-related concussion (SRC) is often caused by rapid head rotation at impact, leading to shearing and stretching of axons in the white matter and initiation of secondary inflammatory processes that may exacerbate the initial injury. We hypothesized that athletes with persistent post-concussive symptoms (PPCS) display signs of ongoing neuroinflammation, as reflected by altered profiles of cerebrospinal fluid (CSF) biomarkers, in turn relating to symptom severity. We recruited athletes with PPCS preventing sports participation as well as limiting work, school and/or social activities for ≥ 6 months for symptom rating using the Sport Concussion Assessment Tool, version 5 (SCAT-5) and for cognitive assessment using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Following a spinal tap, we analysed 27 CSF inflammatory biomarkers (pro-inflammatory chemokines and cytokine panels) by a multiplex immunoassay using antibodies as electrochemiluminescent labels to quantify concentrations in PPCS athletes, and in healthy age- and sex-matched controls exercising ≤ 2 times/week at low-to-moderate intensity. Thirty-six subjects were included, 24 athletes with PPCS and 12 controls. The SRC athletes had sustained a median of five concussions, the most recent at a median of 17 months prior to the investigation. CSF cytokines and chemokines levels were significantly increased in eight (IL-2, TNF-α, IL-15, TNF-β, VEGF, Eotaxin, IP-10, and TARC), significantly decreased in one (Eotaxin-3), and unaltered in 16 in SRC athletes when compared to controls, and two were un-detectable. The SRC athletes reported many and severe post-concussive symptoms on SCAT5, and 10 out of 24 athletes performed in the impaired range (Z < − 1.5) on cognitive testing. Individual biomarker concentrations did not strongly correlate with symptom rating or cognitive function. Limitations include evaluation at a single post-injury time point in relatively small cohorts, and no control group of concussed athletes without persisting symptoms was included. Based on CSF inflammatory marker profiling we find signs of ongoing neuroinflammation persisting months to years after the last SRC in athletes with persistent post-concussive symptoms. Since an ongoing inflammatory response may exacerbate the brain injury these results encourage studies of treatments targeting the post-injury inflammatory response in sports-related concussion.

Clinical burnout has been associated with impaired cognitive functioning; however, inconsistent findings have been reported regarding the pattern and magnitude of cognitive deficits. The aim of this systematic review and multivariate meta-analysis was to assess cognitive function in clinical burnout as compared to healthy controls and identify the pattern and severity of cognitive dysfunction across cognitive domains. We identified 17 studies encompassing 730 patients with clinical burnout and 649 healthy controls. Clinical burnout was associated with impaired performance in episodic memory (g = −0.36, 95% CI −0.57 to −0.15), short-term and working memory (g = −0.36, 95% CI −0.52 to −0.20), executive function (g = −0.39, 95% CI −0.55 to −0.23), attention and processing speed (g = −0.43, 95% CI −0.57 to −0.29) and fluency (g = −0.53, 95% CI −1.04 to −0.03). There were no differences between patients and controls in crystallized (k = 6 studies) and visuospatial abilities (k = 4). Our findings suggest that clinical burnout is associated with cognitive impairment across multiple cognitive domains. Cognitive dysfunction needs to be considered in the clinical and occupational health management of burnout to optimise rehabilitation and support return-to-work. 

Traumatic brain injury (TBI) or repeated sport-related concussions (rSRC) may lead to long-term memory impairment. Diffusion tensor imaging (DTI) is helpful to reveal global white matter damage but may underestimate focal abnormalities. We investigated the distribution of post-injury regional white matter changes after TBI and rSRC. Six patients with moderate/severe TBI, and 12 athletes with rSRC were included ≥6 months post-injury, and 10 (age-matched) healthy controls (HC) were analyzed. The Repeatable Battery for the Assessment of Neuropsychological Status was performed at the time of DTI. Major white matter pathways were tracked using q-space diffeomorphic reconstruction and analyzed for global and regional changes with a controlled false discovery rate. TBI patients displayed multiple classic white matter injuries compared with HC (p < 0.01). At the regional white matter analysis, the left frontal aslant tract, anterior thalamic radiation, and the genu of the corpus callosum displayed focal changes in both groups compared with HC but with different trends. Both TBI and rSRC displayed worse memory performance compared with HC (p < 0.05). While global analysis of DTI-based parameters did not reveal common abnormalities in TBI and rSRC, abnormalities to the fronto-thalamic network were observed in both groups using regional analysis of the white matter pathways. These results may be valuable to tailor individualized rehabilitative approaches for post-injury cognitive impairment in both TBI and rSRC patients.

In Sweden, traumatic brain injury (TBI) is a major cause of disability across all ages, and the need for rehabilitation and long-term follow-up is as important as in many other countries. This article presents the rehabilitation of TBI in Sweden. Strengths and weaknesses of TBI rehabilitation within the Swedish healthcare system are described, together with examples of research and development.

Purpose

To explore work related and personal facilitators and barriers for return to work (RTW) and stay at work after stroke.

Materials and methods

Twenty individuals post-stroke (median age 52 years; seven women) were interviewed in focus groups. Data were analyzed by using qualitative content analysis.

Results

An overall theme “Work conditions, support and changed personal priorities influenced RTW and stay at work after stroke” emerged and covered three categories: “Adjustments and flexibility at the work place facilitated RTW and a sustainable work situation”, “Psychosocial support and knowledge about stroke consequences facilitated work and reduced stress”, and “Changed view of work and other personal priorities”. Physical adjustments at the work place and flexibility in the work schedule were perceived facilitators. Support from family and colleagues were important, whereas lack of knowledge of stroke disabilities at the work place was perceived a barrier. Also changed personal priorities in relation to the work and the current life situation influenced RTW in various ways.

Conclusions

The individual’s opportunities to influence the work situation is a key factor for RTW and the ability to stay at work after stroke. Adjustments, flexibility, support, knowledge of stroke, and receptivity to a changed view of work are important for a sustainable work situation.

Transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation method to treat neurological and psychiatric diseases. However, its underlying neural mechanisms warrant further investigation. Indeed, dose–response interrelations are poorly understood. Placing explanted brain tissue, mostly from mice or rats, into a uniform direct current electric field (dcEF) is a well-established in vitro system to elucidate the neural mechanism of tDCS. Nevertheless, we will show that generating a defined, uniform, and constant dcEF throughout a brain slice is challenging. This article critically reviews the methods used to generate and calibrate a uniform dcEF. We use finite element analysis (FEA) to evaluate the widely used parallel electrode configuration and show that it may not reliably generate uniform dcEF within a brain slice inside an open interface or submerged chamber. Moreover, equivalent circuit analysis and measurements inside a testing chamber suggest that calibrating the dcEF intensity with two recording electrodes can inaccurately capture the true EF magnitude in the targeted tissue when specific criteria are not met. Finally, we outline why microfluidic chambers are an effective and calibration-free approach of generating spatiotemporally uniform dcEF for DCS in vitro studies, facilitating accurate and fine-scale dcEF adjustments. We are convinced that improving the precision and addressing the limitations of current experimental platforms will substantially improve the reproducibility of in vitro experimental results. A better mechanistic understanding of dose–response relations will ultimately facilitate more effective non-invasive stimulation therapies in patients.

Traumatic brain injury (TBI) and repeated sports-related concussions (rSRCs) are associated with an increased risk for neurodegeneration. Autopsy findings of selected cohorts of long-term TBI survivors and rSRC athletes reveal increased tau aggregation and a persistent neuroinflammation. To assess in vivo tau aggregation and neuroinflammation in young adult TBI and rSRC cohorts, we evaluated 9 healthy controls (mean age 26 ± 5 years; 4 males, 5 females), 12 symptomatic athletes (26 ± 7 years; 6 males, 6 females) attaining ≥ 3 previous SRCs, and 6 moderate-to severe TBI patients (27 ± 7 years; 4 males, 2 females) in a combined positron emission tomography (PET)/ magnetic resonance (MR) scanner ≥6 months post-injury. Dual PET tracers, [¹⁸F]THK5317 for tau aggregation and [¹¹C]PK11195 for neuroinflammation/microglial activation, were investigated on the same day. The Repeated Battery Assessment of Neurological Status (RBANS) scores, used for cognitive evaluation, were lower in both the rSRC and TBI groups (p<0.05). Neurofilament-light (NF-L) levels were increased in plasma and cerebrospinal fluid (CSF; p<0.05), and serum tau levels lower, in TBI although not in rSRC. In rSRC athletes, PET imaging showed increased neuroinflammation in the hippocampus and tau aggregation in the corpus callosum. In TBI patients, tau aggregation was observed in thalami, temporal white matter and midbrain; widespread neuroinflammation was found e.g. in temporal white matter, hippocampus and corpus callosum. In mixed-sex cohorts of young adult athletes with persistent post-concussion symptoms and in TBI patients, increased tau aggregation and neuroinflammation are observed at ≥ 6 months post-injury using PET. Studies with extended clinical follow-up, biomarker examinations and renewed PET imaging are needed to evaluate whether these findings progress to a neurodegenerative disorder or if spontaneous resolution is possible.

Electrical stimulation (ES) shows promise as a therapy to promote recovery and regeneration after spinal cord injury. ES therapy establishes beneficial electric fields (EFs) and has been investigated in numerous studies, which date back nearly a century. In this review, we discuss the various engineering approaches available to generate regenerative EFs through direct current electrical stimulation and very low frequency electrical stimulation. We highlight the electrode-tissue interface, which is important for the appropriate choice of electrode material and stimulator circuitry. We discuss how to best estimate and control the generated field, which is an important measure for comparability of studies. Finally, we assess the methods used in these studies to measure functional recovery after the injury and treatment. This work reviews studies in the field of ES therapy with the goal of supporting decisions regarding best stimulation strategy and recovery assessment for future work.

Introduction: Lifestyle interventions may prevent cognitive decline, but the sufficient dose of intervention activities and lifestyle changes is unknown. We investigated how intervention adherence affects cognition in the FINGER trial (pre-specified subgroup analyses).

Methods: FINGER is a multicenter randomized controlled trial examining the efficacy of multidomain lifestyle intervention (ClinicalTrials.gov NCT01041989). A total of 1260 participants aged 60 to 77 with increased dementia risk were randomized to a lifestyle intervention and control groups. Percentage of completed intervention sessions, and change in multidomain lifestyle score (self-reported diet; physical, cognitive, and social activity; vascular risk) were examined in relation to change in Neuropsychological Test Battery (NTB) scores.

Results: Active participation was associated with better trajectories in NTB total and all cognitive subdomains. Improvement in lifestyle was associated with improvement in NTB total and executive function.

Discussion: Multidomain lifestyle changes are beneficial for cognitive functioning, but future interventions should be intensive enough, and supporting adherence is essential.

Background: The number of people who suffer a stroke is increasing all over the world, and thus the healthcare system is faced with a continuing challenge to develop and modernize the rehabilitation for stroke patients. 

Aim: To review and synthesize literature on how stroke patients experience Virtual Reality (VR) in rehabilitation and its possible impact on the ability to perform activities in everyday life. 

Method: A systematic literature review to review and compile literature. The databases used for the collection of the articles are CINAHL, Medline, PubMed, Taylor & Francis Journals, AMED and PsycInfo, which resulted in 9 studies. The review of the articles was carried out according to the SBU’s review model on assessment of studies with qualitative methodology. After the quality review, a meta-synthesis was made of the included articles to answer the purpose of the study. 

The result: The literature review contains 9 studies with publication years 2015–2022. The meta- synthesis led to 24 first-level themes and four second-level themes: "VR creates positive and negative experiences", "Perceived advantages and disadvantages of using VR among stroke patients", "Improvement of functional ability in everyday life with the help of VR" and "The importance of context and support are emphasized”. An analysis of the second-level themes resulted in two third-level themes: "VR arouses interest, but has advantages as well as disadvantages" and "VR's importance in everyday life and social life for stroke patients". 

Conclusion: The review of the material resulted in 9 studies. On the basis of the studies, positive and negative experiences of VR in stroke patients emerged, among other things. Based on the study, there also remains a need for continued qualitative studies within the subject, which focus on stroke patients and their experiences of VR in order to contribute to an increased knowledge of the subject from an occupational therapy perspective. 

Background: Parkinson’s disease is generally asymptomatic at earlier stages. At an early stage, there is an extensive progression in the neuropathological hallmarks, although, at this stage, diagnosis is not possible with currently available diagnostic methods. Therefore, the pressing need is for susceptibility risk biomarkers that can aid in better diagnosis and therapeutics as well can objectively serve to measure the endpoint of disease progression. The role of small extracellular vesicles (sEV) in the progression of neurodegenerative diseases could be potent in playing a revolutionary role in biomarker discovery.

Methods: In our study, the salivary sEV were efficiently isolated by chemical precipitation combined with ultrafiltration from subjects (PD = 70, healthy controls = 26, and prodromal PD = 08), followed by antibody-based validation with CD63, CD9, GAPDH, Flotillin-1, and L1CAM. Morphological characterization of the isolated sEV through transmission electron microscopy. The quantification of sEV was achieved by fluorescence (lipid-binding dye-labeled) nanoparticle tracking analysis and antibody-based (CD63 Alexa fluor 488 tagged sEV) nanoparticle tracking analysis. The total alpha-synuclein (α-synTotal) in salivary sEVs cargo was quantified by ELISA. The disease severity staging confirmation for n = 18 clinically diagnosed Parkinson’s disease patients was done by 99mTc-TRODAT-single-photon emission computed tomography.

Results: We observed a significant increase in total sEVs concentration in PD patients than in the healthy control (HC), where fluorescence lipid-binding dye-tagged sEV were observed to be higher in PD (p = 0.0001) than in the HC using NTA with a sensitivity of 94.34%. In the prodromal PD cases, the fluorescence lipid-binding dye-tagged sEV concentration was found to be higher (p = 0.008) than in HC. This result was validated through anti-CD63 tagged sEV (p = 0.0006) with similar sensitivity of 94.12%. We further validated our findings with the ELISA based on α-synTotal concentration in sEV, where it was observed to be higher in PD (p = 0.004) with a sensitivity of 88.24%. The caudate binding ratios in 99mTc-TRODAT-SPECT represent a positive correlation with sEV concentration (r = 0.8117 with p = 0.0112).

Conclusions: In this study, for the first time, we have found that the fluorescence-tagged sEV has the potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD.

Objective: Congenital hyperinsulinism (CHI) is the most frequent cause of severe and persistent hypoglycaemia from birth. Understanding the pathophysiology and genetic defects behind hyperinsulinism and its complications provides clues to timely diagnosis and management. The aim of this study was to evaluate the underlying genetic aetiology of a specific Iranian pediatric cohort with CHI.

Methods: A total of 44 unrelated children, 20 girls and 24 boys, with an initial diagnosis or history of CHI from all regions of Iran were recruited between 2016 and 2019. Targeted next generation sequencing (tNGS) was performed for the genes found in about half of CHI patients.

Results: Mutations were identified in 24 cases (55%). Patients with a confirmed genetic cause were mainly diagnosed below age of one year old (p=0.01), had fewer other syndromic features, excluding seizure, (p=0.03), were less diazoxide responsive (p=0.04) and were more diazoxide unresponsive leading to pancreatectomy (p=0.007) compared to those with no identified mutations. Among 24 patients with identified genetic mutations, 17 (71%) had a mutation in ABCC8, 3 (12%) in KCNJ11, 3 (12%) in HADH, and 1 patient had a mutation in KMT2D. These included five novel mutations in ABCC8, KCNJ11, and KMT2D.

Conclusion: This is the biggest genetic study of CHI in Iran. A high frequency of recessive forms of CHI, especially HADH mutations, in our study could be due to a high rate of consanguineous marriage. We recommend tNGS to screen for all the CHI genes.

Objective: To examine whether the brain biomarkers total-tau (T-tau), glial fibrillary acidic protein (GFAP), and β-amyloid (Aβ) isomers 40 and 42 in plasma relate to the corresponding concentrations in cerebrospinal fluid (CSF), blood-brain barrier integrity, and duration of post-concussion syndrome (PCS) due to repetitive head impacts (RHI) in professional athletes.

Method: In this cross-sectional study, professional athletes with persistent PCS due to RHI (median of 1.5 years after recent concussion) and uninjured controls were assessed with blood and CSF sampling. The diagnosis of PCS was based on the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition). The athletes were enrolled through information flyers about the study sent to the Swedish hockey league (SHL) and the SHL Medicine Committee. The controls were enrolled through flyers at University of Gothenburg and Sahlgrenska University Hospital, Sweden. The participants underwent lumbar puncture and blood assessment at Sahlgrenska University Hospital. The main outcome measures were history of RHI and PCS severity (PCS> 1 year versus PCS< 1 year) in relation to plasma and CSF concentrations of T-tau, GFAP, Aβ40, and Aβ42. Plasma T-tau, GFAP, Aβ40, and Aβ42 were quantified using an ultrasensitive assay technology.

Results: A total of 47 participants (28 athletes [median age 28 years, range 18-52] with persistent PCS, due to RHI and 19 controls [median age, 25 years, range 21-35]) underwent paired blood and cerebrospinal fluid (CSF) sampling. T-tau, Aβ40 and Aβ42 concentrations measured in plasma did not correlate with the corresponding CSF concentrations, while there was a correlation between plasma and CSF levels of GFAP (r=0.45, p=0.020). There were no significant relationships between plasma T-tau, GFAP, and blood-brain barrier integrity as measured by CSF:serum albumin ratio. T-tau, GFAP, Aβ40, and Aβ42 measured in plasma did not relate to PCS severity. None of the markers measured in plasma correlated with number of concussions, except decreased Aβ42 in those with higher number of concussions (r=–0.40, p=0.04).

Conclusions: T-tau, GFAP, Aβ40 and Aβ42 measured in plasma do not correspond to CSF measures, and may have limited utility for the evaluation of the late effects of RHI, compared with when measured in CSF.

Electrical stimulation of ex vivo brain tissue slices has been a method used to understand mechanisms imparted by transcranial direct current stimulation (tDCS), but there are significant direct current electric field (dcEF) dosage and electrochemical by-product concerns in conventional experimental setups that may impact translational findings. Therefore, we developed an on-chip platform with fluidic, electrochemical, and magnetically-induced spatial control. Fluidically, the chamber geometrically confines precise dcEF delivery to the enclosed brain slice and allows for tissue recovery in order to monitor post-stimulation effects. Electrochemically, conducting hydrogel electrodes mitigate stimulation-induced faradaic reactions typical of commonly-used metal electrodes. Magnetically, we applied ferromagnetic substrates beneath the tissue and used an external permanent magnet to enable in situ rotational control in relation to the dcEF. By combining the microfluidic chamber with live-cell calcium imaging and electrophysiological recordings, we showcased the potential to study the acute and lasting effects of dcEFs with the potential of providing multi-session stimulation. This on-chip bioelectronic platform presents a modernized yet simple solution to electrically stimulate explanted tissue by offering more environmental control to users, which unlocks new opportunities to conduct thorough brain stimulation mechanistic investigations.

Parkinson’s disease (PD) is generally asymptomatic at earlier stages. The pressing need is for susceptibility risk biomarkers, which can aid in better diagnosis and therapeutics and objectively serve to measure the endpoint of disease progression. The role of exosomes in the progression of neurodegenerative diseases is already reported and its cargo could be potent in playing a revolutionary role in biomarker discovery. In our study, the salivary exosomes were efficiently isolated by chemical precipitation from subjects (PD=70, healthy controls=26, and probable PD=08) followed by antibody-based validation through CD63, CD9, GAPDH, flotillin 1, L1CAM, and calnexin. Morphological characterization of the isolated exosomes through transmission electron microscopy (TEM) was also analyzed. The exosome quantification via fluorescence and antibody-based nanoparticle tracking analysis (NTA) was performed. The total alpha-synuclein (α-syntotal) in salivary exosomal cargo was quantified by ELISA. The disease severity staging confirmation was done by 99mTc-TRODAT-SPECT. We observed a significant increase in total exosome concentration in PD patients to the healthy control (HC) where fluorescence-tagged exosomes were observed to be higher in PD (p<0.0001) than the HC using NTA with a sensitivity of 94.34%. These results was validated through exosomes tagged with antibody CD63 (p=0.006) with a similar sensitivity of 94.12%. We further validated our findings with the ELISA-based α-syntotal concentration in exosomes, which was observed to be higher in PD with a sensitivity of 88.24%. The striatal binding ratios in 99mTc-TRODAT-SPECT shown positive correlation with fluorescent exosomes concentration r=0.3000, α-syntotal concentration r=0.8000. In this study, conclusively we have found that the fluorescence-tagged exosomes has potential to screen the progression of disease with clinically acceptable sensitivity and can be a potent early detection method for PD.

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by Aβ plaques and neurofibrillary tangles. Chronic inflammation and synaptic dysfunction lead to disease progression and cognitive decline. Small extracellular vesicles (sEVs) are implicated in AD progression by facilitating the spread of pathological proteins and inflammatory cytokines. This study investigates synaptic dysfunction and neuroinflammation protein markers in plasma-derived sEVs (PsEVs), their association with Amyloid-β and tau pathologies, and their correlation with AD progression.

Methods: A total of 90 [AD = 35, mild cognitive impairment (MCI) = 25, and healthy age-matched controls (AMC) = 30] participants were recruited. PsEVs were isolated using a chemical precipitation method, and their morphology was characterized by transmission electron microscopy. Using nanoparticle tracking analysis, the size and concentration of PsEVs were determined. Antibody-based validation of PsEVs was done using CD63, CD81, TSG101, and L1CAM antibodies. Synaptic dysfunction and neuroinflammation were evaluated with synaptophysin, TNF-α, IL-1β, and GFAP antibodies. AD-specific markers, amyloid-β (1–42), and p-Tau were examined within PsEVs using Western blot and ELISA.

Results: Our findings reveal higher concentrations of PsEVs in AD and MCI compared to AMC (p < 0.0001). Amyloid-β (1–42) expression within PsEVs is significantly elevated in MCI and AD compared to AMC. We could also differentiate between the amyloid-β (1–42) expression in AD and MCI. Similarly, PsEVs-derived p-Tau exhibited elevated expression in MCI compared with AMC, which is further increased in AD. Synaptophysin exhibited downregulated expression in PsEVs from MCI to AD (p = 0.047) compared to AMC, whereas IL-1β, TNF-α, and GFAP showed increased expression in MCI and AD compared to AMC. The correlation between the neuropsychological tests and PsEVs-derived proteins (which included markers for synaptic integrity, neuroinflammation, and disease pathology) was also performed in our study. The increased number of PsEVs correlates with disease pathological markers, synaptic dysfunction, and neuroinflammation.

Conclusions: Elevated PsEVs, upregulated amyloid-β (1–42), and p-Tau expression show high diagnostic accuracy in AD. The downregulated synaptophysin expression and upregulated neuroinflammatory markers in AD and MCI patients suggest potential synaptic degeneration and neuroinflammation. These findings support the potential of PsEV-associated biomarkers for AD diagnosis and highlight synaptic dysfunction and neuroinflammation in disease progression.

Primary Objective

Traumatic brain injury (TBI) and sports-related concussion (SRC) may result in chronic functional and neuroanatomical changes. We tested the hypothesis that neuroimaging findings (cerebral blood flow (CBF), cortical thickness, and 1H-magnetic resonance (MR) spectroscopy (MRS)) were associated to cognitive function, TBI severity, and sex.

Research Design

Eleven controls, 12 athletes symptomatic following ≥3SRCs and 6 patients with moderate-severe TBI underwent MR scanning for evaluation of cortical thickness, brain metabolites (MRS), and CBF using pseudo-continuous arterial spin labeling (ASL). Cognitive screening was performed using the RBANS cognitive test battery.

Main Outcomes and Results

RBANS-index was impaired in both injury groups and correlated with the injury severity, although not with any neuroimaging parameter. Cortical thickness correlated with injury severity (p = 0.02), while neuronal density, using the MRS marker ((NAA+NAAG)/Cr, did not. On multivariate analysis, injury severity (p = 0.0003) and sex (p = 0.002) were associated with CBF. Patients with TBI had decreased gray (p = 0.02) and white matter (p = 0.02) CBF compared to controls. CBF was significantly lower in total gray, white matter and in 16 of the 20 gray matter brain regions in female but not male athletes when compared to female and male controls, respectively.

Conclusions

Injury severity correlated with CBF, cognitive function, and cortical thickness. CBF also correlated with sex and was reduced in female, not male, athletes. Chronic CBF changes may contribute to the persistent injury mechanisms in TBI and rSRC.