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The latest medical research on Neurodegenerative Disorders

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Regulation of disease-associated microglia in the optic nerve by lipoxin B4 and ocular hypertension.

Molecular Neurodegeneration

The resident astrocyte-retinal ganglion cell (RGC) lipoxin circuit is impaired during retinal stress, which includes ocular hypertension-induced neuropathy. Lipoxin B4 produced by homeostatic astrocytes directly acts on RGCs to increase survival and function in ocular hypertension-induced neuropathy. RGC death in the retina and axonal degeneration in the optic nerve are driven by the complex interactions between microglia and macroglia. Whether LXB4 neuroprotective actions include regulation of other cell types in the retina and/or optic nerve is an important knowledge gap.

Cellular targets and signaling of LXB4 in the retina were defined by single-cell RNA sequencing. Retinal neurodegeneration was induced by injecting silicone oil into the anterior chamber of mouse eyes, which induced sustained and stable ocular hypertension. Morphological characterization of microglia populations in the retina and optic nerve was established by MorphOMICs and pseudotime trajectory analyses. The pathways and mechanisms of action of LXB4 in the optic nerve were investigated using bulk RNA sequencing. Transcriptomics data was validated by qPCR and immunohistochemistry. Differences between experimental groups were assessed by Student's t-test and one-way ANOVA.

Single-cell transcriptomics identified microglia as a primary target for LXB4 in the healthy retina. LXB4 downregulated genes that drive microglia environmental sensing and reactivity responses. Analysis of microglial function revealed that ocular hypertension induced distinct, temporally defined, and dynamic phenotypes in the retina and, unexpectedly, in the distal myelinated optic nerve. Microglial expression of CD74, a marker of disease-associated microglia in the brain, was only induced in a unique population of optic nerve microglia, but not in the retina. Genetic deletion of lipoxin formation correlated with the presence of a CD74 optic nerve microglia population in normotensive eyes, while LXB4 treatment during ocular hypertension shifted optic nerve microglia toward a homeostatic morphology and non-reactive state and downregulated the expression of CD74. Furthermore, we identified a correlation between CD74 and phospho-phosphoinositide 3-kinases (p-PI3K) expression levels in the optic nerve, which was reduced by LXB4 treatment.

We identified early and dynamic changes in the microglia functional phenotype, reactivity, and induction of a unique CD74 microglia population in the distal optic nerve as key features of ocular hypertension-induced neurodegeneration. Our findings establish microglia regulation as a novel LXB4 target in the retina and optic nerve. LXB4 maintenance of a homeostatic optic nerve microglia phenotype and inhibition of a disease-associated phenotype are potential neuroprotective mechanisms for the resident LXB4 pathway.

Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders.

Molecular Neurodegeneration

Disturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review ar...

Supplementary and Premotor Cortical Activation During Manual Dexterity Involving Motor Imagery in Multiple Sclerosis: A Functional Near-Infrared Spectroscopy Study.

Neurorehabilitation and Neural Repair

Investigating brain activation during motor imagery (MI) tasks in people with multiple sclerosis (pwMS) can increase the knowledge of the neural mechanisms underlying motor dysfunction in MS and, hopefully, aid in developing improved rehabilitation strategies.

To investigate brain activation in the supplementary motor area and premotor cortex via functional near-infrared spectroscopy (fNIRS) during a hand manipulation task, and comparing MI with actual practice (AP) in pwMS.

Each subject completed a sequence of 4 consecutive manual dexterity trials wearing an fNIRS device. The tasks included the following conditions: AP dominant hand, MI dominant hand, AP non-dominant hand, and MI non-dominant hand.

Twenty pwMS (mean Expanded Disability Status Scale = 4.75 [3.0-6.5]) and 20 healthy controls (HC) participated in the study. According to the fNIRS timeline course, a similar increase (compared with baseline) was observed in the relative oxygenated hemoglobin (HbO) concentration during the MI and AP tasks, which was immediately followed by a decrease (for either hand) in the pwMS and the HC groups. A difference in the relative HbO concentration between the HC and pwMS was detected solely when the 2 groups mentally replicated the manual dexterity task movements in the MI condition (dominant hand). The increase was higher in the HC group (P = .030).

Despite exhibiting manual dexterity difficulties, pwMS demonstrated comparable neural activation patterns as the HCs during MI tasks in regions associated with motor planning and complex movement control, thus, suggesting that deficits in manual dexterity among pwMS may not solely originate from impairments in the motor planning processes.

Contribution of amyloid deposition from oligodendrocytes in a mouse model of Alzheimer's disease.

Molecular Neurodegeneration

The accumulation of β-amyloid (Aβ) peptides into insoluble plaques is an early pathological feature of Alzheimer's disease (AD). BACE1 is the sole β-secretase for Aβ generation, making it an attractive therapeutic target for AD therapy. While BACE1 inhibitors have been shown to reduce Aβ levels in people with AD, clinical trials targeting BACE1 have failed due to unwanted synaptic deficits. Understanding the physiological role of BACE1 in individual cell types is essential for developing effective BACE inhibitors for the treatment of AD. Recent single-cell RNA transcriptomic assays revealed that oligodendrocytes are enriched with genes required for generating Aβ. However, the contribution of oligodendrocytes to amyloid plaque burden in AD and the side effects of oligodendrocyte-specific Bace1 deletion remain to be explored.

We generated an oligodendrocyte-specific Bace1 knockout model (Bace1fl/fl;Olig2-Cre) to monitor potential disruptions in myelination using standard electron microscopy. Long-term potentiation (LTP) was monitored to measure synaptic integrity. We crossed the Bace1fl/fl;Olig2-Cre model with heterozygous AppNL-G-F/wt knock-in AD mice to generate AD mice lacking oligodendrocyte Bace1 (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt) and examined amyloid plaque number and insoluble Aβ levels and gliosis in these animals. Single nuclei RNA sequencing experiments were conducted to examine molecular changes in response to Bace1 deficiency in oligodendrocytes in the wild type or APP knock-in background.

Bace1 deletion in oligodendrocytes caused no change in myelin thickness in the corpus callosum but a marginal reduction in myelin sheath thickness of the optic nerve. Synaptic strength measured by LTP was not different between Bace1fl/fl;Olig2-Cre and age-matched Bace1fl/fl control animals, suggesting no major effect on synaptic plasticity. Intriguingly, deletion of Bace1 in 12-month-old heterozygous AD knock-in mice (Bace1fl/fl;Olig2-Cre; AppNL-G-F/wt mice) caused a significant reduction of amyloid plaques by ~ 33% in the hippocampus and ~ 29% in the cortex compared to age-matched AD mice (Bace1fl/fl;AppNL-G-F/wt). Insoluble Aβ1-40 and Aβ1-42 levels were reduced comparably while more astrocytes and microglia were observed in surrounding amyloid plaques. Unbiased single-nuclei RNA sequencing results revealed that deletion of oligodendrocyte Bace1 in APPNL-G-F/wt knock-in mice increased expression of genes associated with Aβ generation and clearance such as ADAM10, Ano4, ApoE, Il33, and Sort1.

Our results provide compelling evidence that the amyloidogenic pathway in oligodendrocytes contributes to Aβ plaque formation in the AD brain. While specifically targeting BACE1 inhibition in oligodendrocytes for reducing Aβ pathology in AD is likely challenging, this is a potentially explorable strategy in future studies.

Changes in the prognosis of CADASIL over time: a 23-year study in 555 individuals.

Neurology, Neurosurgery and Psychiatry

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of stroke and is associated with early-onset stroke and dementia. Whether its clinical phenotype is becoming milder with better risk factor treatments and other care improvements is unknown. In a large longitudinal CADASIL cohort, we determined whether the prognosis has changed over 23 years.

Patients were identified from the Cambridge CADASIL register and the UK Familial stroke study. Change in age at stroke over the time of recruitment was determined using linear mixed-effects model, and the impact of genetic and vascular risk factors on stroke and dementia risk was further evaluated using Cox proportional hazard regression.

A total of 555 patients with CADASIL were recruited between 2001 and 2023. The age of stroke onset significantly increased over time (p<0.001), with the mean age of stroke onset for patients recruited before 2016 (n=265) at 46.7±9.2 years and 51.6±9.5 years for those recruited since 2016 (n=290). Patients recruited since 2016 had lower risks of both stroke (HR 0.36, 95% CI 0.26 to 0.50, p<0.001) and dementia (HR 0.43, 95% CI 0.19 to 0.99, p=0.046) after adjusting for sex, hypertension history, smoking status, epidermal growth factor-like repeat position and calendar effect.

The clinical phenotype of CADASIL is improving. While this may be partly explained by reduced vascular risk factors such as smoking and the identification of milder cases, differences persisted after controlling for risk factors and mutation sites. These updated risk estimates should be used when counselling patients with CADASIL on prognosis.

CSF proteins of inflammation, proteolysis and lipid transport define preclinical AD and progression to AD dementia in cognitively unimpaired individuals.

Molecular Neurodegeneration

This preclinical AD CSF proteome study identified a panel of 12-CSF markers detecting amyloid positivity and clinical progression to AD with high a...

Prevalence of epilepsy: a population-based cohort study in Denmark with comparison to Global Burden of Disease (GBD) prevalence estimates.

Neurology, Neurosurgery and Psychiatry

The Global Burden of Disease Study (GBD) produces prevalence estimates for 'idiopathic epilepsy' (ie, of unknown aetiology) and 'secondary epilepsy' (ie, with known aetiology) but does not report prevalence by underlying aetiologies for 'secondary epilepsy'.

We used nationwide, population-based register data from Denmark to identify underlying causes of epilepsy and their contribution to prevalence of 'secondary epilepsy' and compared with global prevalence data from GBD 2019. We identified all persons with a hospital-based epilepsy diagnosis and a filled prescription for antiseizure medication between 1 January 2009 and 31 December 2018. Epilepsy was categorised into 'idiopathic' or 'secondary' and 'total epilepsy' as the sum of the two epilepsy categories.

On 31 December 2018, a total of 5 784 284 individuals (49.7% males) were living in Denmark including 40 336 with epilepsy (51.5% males). Perinatal conditions, traumatic brain injury, brain tumours and stroke were prominent underlying causes of 'secondary epilepsy'. The prevalence of 'total epilepsy' in Denmark was 697 (95% CI 691 to 704) per 100 000 population (264 (95% CI 260 to 269) for 'secondary epilepsy' and 433 (95% CI 428 to 438) for 'idiopathic epilepsy'). In the GBD 2019 Study, the prevalence of 'total epilepsy' in 2018 was 682 (95% uncertainty interval (UI) 586 to 784) per 100 000 population (359 (95% UI 324-397) for 'secondary epilepsy' and 324 (95% UI 249 to 404) for 'idiopathic epilepsy').

Prevalence estimates of 'total epilepsy', 'idiopathic epilepsy' and 'secondary epilepsy' in Denmark align with the GBD 2019 estimates. In future studies, it is suggested to explicitly include all types of epilepsy, including 'secondary epilepsy', which is currently estimated as sequelae (consequences) of underlying diseases.

Exploring the Complexity of Falls in People With Multiple Sclerosis: A Qualitative Study.

International J MS Care

The complexity of falls in people with multiple sclerosis (MS) needs further exploration to develop strategies to reduce fall risk. The aim of this study is to explore and describe factors contributing to falls and the complexity of fall situations in people with MS.

This longitudinal study used individual interviews shortly after prospective reporting of falls. Manifest analysis was used to describe frequency, place, and time of falls. The International Classification of Functioning, Disability and Health (ICF) was used for deductive content analyses to describe fall-inducing factors. Participants were adults with MS (N = 33) who had experienced falls during the past year and who did not use walking aids.

The 25 participants who fell during the study period reported 94 falls, mainly during the day (61%) and outdoors (56%). Fall situations were complex, with interaction between triggering and circumstantial factors related to all domains in the ICF, the impact of preceding factors, and fluctuating symptoms.

The complexity of fall situations can be more clearly understood and managed by considering the preceding activities and circumstances in addition to describing single risk factors. This may facilitate discussions of fall risk between health care professionals and people with MS. Individualized fall risk assessments and interventions that strengthen self-management are recommended.

Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience.

Molecular Neurodegeneration

Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer's disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood.

APOEε4 carriers and APOEε3 homozygotes enrolled in the Women's Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank.

A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers.

We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.

Reasons for Hospital Admission in Individuals With Multiple Sclerosis.

International J MS Care

Health care utilization is higher in individuals with multiple sclerosis (MS) than in the general population. However, there are limited data on the reasons for their hospital admissions. Our primary objective is to analyze the reasons for the hospitalization of individuals with MS with the goal of identifying preventable causes.

We conducted a retrospective analysis of a cohort of adults with a confirmed diagnosis of MS admitted to Duke University Hospital between January 2018 and January 2020. This yielded a cohort of 210 individuals. Data were analyzed using descriptive statistics.

The most common reason for admission was urinary tract infection (UTI; 10.3%). The average length of stay was 6.1 days for the individuals with MS vs 5.5 days for the general population. The 30-day readmission rates were 14.9% and 15.5%, respectively. A significant number of admitted patients were not on any disease-modifying therapy (DMT), and no difference in median age was identified between those with a DMT vs those without.

Length of stay and readmission rates were similar to those of the general population in this contemporary cohort. Given the prevalence of bladder dysfunction in MS, it is not surprising that a UTI was the most common reason for admission. Actively addressing management of and techniques for bladder dysfunction may decrease the admission rate for individuals with MS. Though we now have more treatment options for MS, many individuals with the highest health care utilization are not on a DMT. Future research is needed to identify the factors that can be addressed to support these patients and reduce preventable hospitalizations.

Polysomnographic Findings into Sleep Disorders in Essential Tremor and Essential Tremor Plus: A Comparison with Healthy Controls.

Journal of Movement Disorders

To explore sleep patterns in individuals with Essential Tremor (ET) and Essential Tremor Plus (ET-Plus), compared to healthy controls, and assess differences between ET and ET-Plus, given the lack of established polysomnography (PSG) data on these groups and the potential for sleep disturbances to serve as clinical markers.

We conducted a prospective cross-sectional study at NIMHANS, Bengaluru, from November 2021 to August 2023 on 45 patients (26 ET, 19 ET-Plus) and 45 controls. Tremor severity was assessed using TETRAS and FTMTRS, and sleep symptoms with ESS, PSQI, Mayo Sleep Questionnaire, RLS-Q, BQ, GAD-7 and PHQ-9. All cases and controls underwent overnight video PSG. Sleep scoring was manually done by a technically adequate sleep researcher and the first author following AASM (2022) guidelines with data analysed using R studio.

ET patients exhibited younger onset age (30.8 ± 16.7 years) compared to ET-Plus patients (46.8 ± 11.1 years). ET-Plus had higher TETRAS and FTMRS scores (P < 0.001) than ET. Both ET and ET-Plus patients exhibited poorer sleep quality, excessive daytime sleepiness, REM sleep behavior disorder (RBD), and Restless Legs Syndrome (RLS) symptoms compared to controls. PSG findings supported these clinical observations, showing elevated Apnea-Hypopnea Index (AHI), reduced Total Sleep Time (TST), prolonged REM latency, decreased sleep efficiency, increased N1 stage duration, and reduced N2/N3 durations and percentages in patients versus controls.

The study highlights significant sleep architecture abnormalities in both ET and ET-Plus patients as compared to healthy controls, with no differences between the ET groups.

Intensity-Dependent Effects of Low-Frequency Subthreshold rTMS on Primary Motor Cortex Excitability and Interhemispheric Inhibition in Elderly Participants: A Randomized Trial.

Neurorehabilitation and Neural Repair

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) protocols targeting primary motor cortex (M1) are used in rehabilitation of neurological diseases for their therapeutic potential, safety, and tolerability. Although lower intensity LF-rTMS can modulate M1 neurophysiology, results are variable, and a systematic assessment of its dose effect is lacking.

To determine the dose-response of LF-rTMS on stimulated and non-stimulated M1.

In a sham-controlled randomized double-blind crossover study the effect of LF-TMS protocols were determined in 20 right-handed older healthy participants. In 3 sessions, 1 Hz rTMS at 80% (rTMS80), 90% (rTMS90) of motor threshold or sham stimulation were applied to left upper extremity M1. Outcome measures were curve parameters of the stimulus-response curve (maximum motor evoked potential [MEPMAX], slope and the intensity to evoke 50% MEPMAX), short-interval intracortical inhibition (SICI), and interhemispheric inhibition (IHI).

Within LF-rTMS sessions, rTMS90, increased MEPMAX in the stimulated M1. Furthermore, rTMS90, increased the slope in the non-stimulated M1. LF-rTMS effects on SICI were dependent on the participants' baseline SICI, hemisphere, and intensity of conditioning pulse. Finally, rTMS90 increased whereas rTMS80 decreased IHI, for both IHI directions. These changes were dependent on baseline IHI and hemisphere and were no longer significant when baseline IHI was accounted for.

Intensity of subthreshold LF-rTMS has differential effects on excitation and inhibition of stimulated and non-stimulated M1. The effects were small and were only demonstrated within the LF-rTMS sessions but were not different when compared to sham. rTMS related changes in SICI and IHI were dependent on baseline level.

NCT02544503, NCT01726218.