Axonal Integrity Research Articles

Downregulation of SF3B2 protects CNS neurons in models of multiple sclerosis.

Neurodegeneration induced by inflammatory stress in multiple sclerosis (MS) leads to long-term neurological disabilities that are not amenable to current immunomodulatory therapies. Here, we report that neuronal downregulation of Splicing factor 3b subunit 2 (SF3B2), a component of U2 small nuclear ribonucleoprotein (snRNP), preserves retinal ganglion cell (RGC) survival and axonal integrity in experimental autoimmune encephalomyelitis (EAE)-induced mice. By employing an invitro system recapitulating the inflammatory environment of MS lesion, we show that when SF3B2 levels are downregulated, cell viability and axon integrity are preserved in cortical neurons against inflammatory toxicity. Notably, knockdown of SF3B2 suppresses the expression of injury-response and necroptosis genes and prevents activation of Sterile Alpha and TIR Motif Containing 1 (Sarm1), a key enzyme that mediates programmed axon degeneration. Together, these findings suggest that the downregulation of SF3B2 is a novel potential therapeutic target to prevent secondary neurodegeneration in MS.

NEUROFILAMENT LIGHT CHAIN (NFL) AND GENERAL COGNITIVE ABILITY IN ADULTS APPROACHING MIDLIFE

Abstract Neurofilament light chain (NfL) is a biomarker indexing axonal integrity where small NfL variations may be associated with cognitive performance in early adulthood and high values associated with neurodegenerative disorders such as Alzheimer’s disease. In the Colorado Adoption/Twin Study of Lifespan behavioral development and cognitive aging (CATSLife1) individuals were tested at 28–49 years (M=33.1, SD=4.9). Quanterix Simoa assays of plasma NfL (pNfL) were measured in duplicate, and we included values for 1159 individuals where 1098 had available general cognitive ability scores and sociodemographic covariates. Unadjusted NfL values were consistent with other studies of early-mid adulthood (M = 5.9, SD = 3.1, range = 1.14 – 40.1 pg/mL) and 6% showed values outside expected normal reference limits (>10 pg/mL). After adjusting for technical covariates and skew, higher natural log-transformed pNfL was associated with age (r = 0.27) and female sex (r = 0.07). Moreover, adjusting for sociodemographic covariates, higher pNfL was associated with lower general cognitive ability (GCA) (r = -.06), where associations were more pronounced above the mean pNfL value (r = -.08). Multi-level regression analyses suggested that GCA-NfL associations were modified by age, whereby the worse performance was observed at higher ages and pNfL values (p <= 0.03), accounting for sibling relatedness and sociodemographic covariates. We observed small negative associations of higher plasma NfL and lower cognitive performance, where associations may become magnified with increasing age in early- to mid-adulthood.

Autophagic degradation of CNS myelin maintains axon integrity.

(Macro)autophagy is a major lysosome-dependent degradation mechanism which engulfs, removes and recycles unwanted cytoplasmic material, including damaged organelles and toxic protein aggregates. Although a few studies implicate autophagy in CNS demyelinating pathologies, its role, particularly in mature oligodendrocytes and CNS myelin, remains poorly studied. Here, using both pharmacological and genetic inhibition of the autophagic machinery, we provide evidence that autophagy is an essential mechanism for oligodendrocyte maturation in vitro. Our study reveals that two core myelin proteins, namely proteolipid protein (PLP) and myelin basic protein (MBP) are incorporated into autophagosomes in oligodendrocytes, resulting in their degradation. Furthermore, we ablated atg5, a core gene of the autophagic machinery, specifically in myelinating glial cells in vivo by tamoxifen administration (plp-Cre ERT2 ; atg5 f/f ) and showed that myelin maintenance is perturbed, leading to PLP accumulation. Significant morphological defects in myelin membrane such as decompaction accompanied with increased axonal degeneration are observed. As a result, the mice exhibit behavioral deficits. In summary, our data highlight that the maintenance of adult myelin homeostasis in the CNS requires the involvement of a fully functional autophagic machinery.

Aberrant claustrum structure in preterm-born neonates: an MRI study

The human claustrum is a gray matter structure in the white matter between insula and striatum. Previous analysis found altered claustrum microstructure in very preterm-born adults associated with lower cognitive performance. As the claustrum development is related to hypoxia–ischemia sensitive transient cell populations being at-risk in premature birth, we hypothesized that claustrum structure is already altered in preterm-born neonates.We studied anatomical and diffusion-weighted MRIs of 83 preterm- and 83 term-born neonates at term-equivalent age. Additionally, claustrum development was analyzed both in a spectrum of 377 term-born neonates and longitudinally in 53 preterm-born subjects. Data was provided by the developing Human Connectome Project.Claustrum development showed increasing volume, increasing fractional anisotropy (FA), and decreasing mean diffusivity (MD) around term both across term- and preterm-born neonates. Relative to term-born ones, preterm-born neonates had (i) increased absolute and relative claustrum volumes, both indicating increased cellular and/or extracellular matter and being in contrast to other subcortical gray matter regions of decreased volumes such as thalamus; (ii) lower claustrum FA and higher claustrum MD, pointing at increased extracellular matrix and impaired axonal integrity; and (iii) aberrant covariance between claustrum FA and MD, respectively, and that of distributed gray matter regions, hinting at relatively altered claustrum microstructure.Results together demonstrate specifically aberrant claustrum structure in preterm-born neonates, suggesting altered claustrum development in prematurity, potentially relevant for later cognitive performance.

Axonal degeneration in the anterior insular cortex is associated with Alzheimer’s co-pathology in Parkinson’s disease and dementia with Lewy bodies

BackgroundAxons, crucial for impulse transmission and cellular trafficking, are thought to be primary targets of neurodegeneration in Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Axonal degeneration occurs early, preceeding and exceeding neuronal loss, and contributes to the spread of pathology, yet is poorly described outside the nigrostriatal circuitry. The insula, a cortical brain hub, was recently discovered to be highly vulnerable to pathology and plays a role in cognitive deficits in PD and DLB. The aim of this study was to evaluate morphological features as well as burden of proteinopathy and axonal degeneration in the anterior insular sub-regions in PD, PD with dementia (PDD), and DLB.Methodsα-Synuclein, phosphorylated (p-)tau, and amyloid-β pathology load were evaluated in the anterior insular (agranular and dysgranular) subregions of post-mortem human brains (n = 27). Axonal loss was evaluated using modified Bielschowsky silver staining and quantified using stereology. Cytoskeletal damage was comprehensively studied using immunofluorescent multi-labelling and 3D confocal laser-scanning microscopy.ResultsCompared to PD and PDD, DLB showed significantly higher α-synuclein and p-tau pathology load, argyrophilic grains, and more severe axonal loss, particularly in the anterior agranular insula. Alternatively, the dysgranular insula showed a significantly higher load of amyloid-β pathology and its axonal density correlated with cognitive performance. p-Tau contributed most to axonal loss in the DLB group, was highest in the anterior agranular insula and significantly correlated with CDR global scores for dementia. Neurofilament and myelin showed degenerative changes including swellings, demyelination, and detachment of the axon-myelin unit.ConclusionsOur results highlight the selective vulnerability of the anterior insular sub-regions to various converging pathologies, leading to impaired axonal integrity in PD, PDD and DLB, disrupting their functional properties and potentially contributing to cognitive, emotional, and autonomic deficits.

Emerging mitochondrial-mediated mechanisms involved in oligodendrocyte development.

Oligodendrocytes are the myelinating glia of the central nervous system and are generated after oligodendrocyte progenitor cells (OPCs) transition into pre-oligodendrocytes and then into myelinating oligodendrocytes. Myelin is essential for proper signal transmission within the nervous system and axonal metabolic support. Although the intrinsic and extrinsic factors that support the differentiation, survival, integration, and subsequent myelination of appropriate axons have been well investigated, little is known about how mitochondria-related pathways such as mitochondrial dynamics, bioenergetics, and apoptosis finely tune these developmental events. Previous findings suggest that changes to mitochondrial morphology act as an upstream regulatory mechanism of neural stem cell (NSC) fate decisions. Whether a similar mechanism is engaged during OPC differentiation has yet to be elucidated. Maintenance of mitochondrial dynamics is vital for regulating cellular bioenergetics, functional mitochondrial networks, and the ability of cells to distribute mitochondria to subcellular locations, such as the growing processes of oligodendrocytes. Myelination is an energy-consuming event, thus, understanding the interplay between mitochondrial dynamics, metabolism, and apoptosis will provide further insight into mechanisms that mediate oligodendrocyte development in healthy and disease states. Here we will provide a concise overview of oligodendrocyte development and discuss the potential contribution of mitochondrial mitochondrial-mediated mechanisms to oligodendrocyte bioenergetics and development.

Distinct patterns of neurodegeneration after TBI and in Alzheimer’s disease

AbstractBackgroundTraumatic brain injury (TBI) is an established risk factor for dementia, with Alzheimer’s disease reportedly more prevalent post‐injury. Experimental injury models relate axonal injury to the generation of toxic proteinopathies including amyloid and hyperphosphorylated tau, but epidemiological data relating brain injury and Alzheimer’s disease specifically are inconsistent. Using longitudinal volumetric MRI, it is possible to assess commonalities and differences between chronic post‐traumatic neurodegeneration, Alzheimer’s disease and ageing in vivo, to better understand the long‐term consequences of TBI.MethodSerial volumetric T1‐weighted MRI was performed on two occasions a year apart in 55 patients after moderate‐severe TBI, a group of 23 age‐matched healthy volunteers, a group of 15 older healthy controls (healthy ageing group), as well as 45 patients with Alzheimer’s disease alongside 23 age‐matched controls comprising the MIRIAD dataset. Jacobian determinant (JD) brain atrophy rates in white, grey matter and CSF were quantified, spatial patterns defined and systematically compared between the groups. Diffusion imaging was acquired in TBI patients at baseline, facilitating the generation of the fractional anisotropy metric of axonal integrity via diffusion tensor imaging.ResultAtrophy rates were significantly increased in white matter only after TBI (P<0.01), in contrast to increases in both white matter and grey matter in Alzheimer’s disease (P<0.001). Common subcortical white matter regions showed atrophy in both Alzheimer’s disease and TBI, but deep white matter atrophy was TBI‐specific, and cortical atrophy Alzheimer’s disease‐specific. Post‐TBI atrophy patterns were distinct from ageing, which more closely resembled Alzheimer’s disease, and were predicted by the extent of axonal injury on diffusion tensor imaging at baseline (P<0.05).ConclusionNeurodegeneration after moderate‐severe TBI is distinct in location from both ageing and Alzheimer’s disease, with a characteristic central white matter predominance. This likely reflects the underlying spatial distribution of traumatic axonal injury, and may represent ongoing chronic Wallerian degeneration, and/or toxic proteinopathy‐driven neurodegeneration.

Spectral signatures associated with cognitive aging, APOE4, amyloid‐β and measures of axonal integrity in cognitively unimpaired adults

AbstractBackgroundOscillatory brain rhythms are a defining feature of neuronal activity that support cognition in humans. Previous studies that showed associations of spectral changes in individuals who harbor high risk for Alzheimer’s disease (AD) were limited to identify abnormalities within select brain regions defined apriori. Comprehensive whole‐brain spatiotemporal patterns of oscillatory changes associated with cognitive‐aging and with AD risk are only partly known. Our main goals were to understand how frequency specific spectral changes relate to cognitive abilities in normal aging and to identify oscillatory signatures that indicate pre‐symptomatic AD pathophysiological processes in cognitively unimpaired elderly.MethodsWe used magnetoencephalography (MEG) to study the spectral signatures within delta‐theta (2‐7Hz), alpha (8‐12Hz) and beta (13‐35Hz) oscillations, in cognitively unimpaired adults (n=70). Using a partial‐least‐square regression, we correlated spectral patterns to executive, memory, and processing‐speed abilities (n=40). Next, we compared the spectral signatures between amyloid‐β (Aβ)+ vs. Aβ‐ and between APOE‐Ɛ4+ vs. APOE‐Ɛ4‐, in sub‐cohorts evaluated with Aβ‐PET (n=46) and APOE4 (n=65), respectively. In a subset of participants (n=19), we also examined associations between spectral signatures and cerebrospinal fluid (CSF) markers indicating damage to: presynaptic (growth‐associated protein‐43, GAP43); postsynaptic (neurogranin, NG); axonal (neurofilament light chain, NFL), levels.ResultsAn age dependent, low‐grade, increase in alpha power and decrease in delta‐theta power were associated with better cognitive performance in memory, executive and processing speed (Figure‐1). APOE4+ individuals showed reduced alpha power within bilateral medial temporal and right precuneus, compared to APOE4‐. Aβ+ individuals showed a dual pattern of alpha change with increased frontal and reduced medial and lateral temporal cortex pattern and a frontally distributed increased delta‐theta power (Figure‐2). Higher CSF‐NFL was correlated with lower alpha power.ConclusionsOur findings demonstrate that higher alpha power indicates a positive spectral change towards better cognitive health in aging. Importantly, a reduced alpha power signature indicated early neurodegenerative changes, as demonstrated by: (1)Aβ+ individuals and APOE‐Ɛ4+ individuals showing reduced alpha power within the regions known for earliest tau accumulations; (2) lower alpha correlating with higher NFL, which reflects Aβ‐independent neurodegeneration. Collectively alpha signatures may indicate tau related neuropathology with aging and in early AD.

Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Cognition in Alzheimer’s Disease

AbstractBackgroundOverexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function. By inhibiting the translation of amyloid precursor protein, tau and alpha‐synuclein, our drug restored axonal transport, lowered inflammation, and protected nerve cells from dying in animal models. Buntanetap’s reversal of the toxic cascade leading to nerve cell death did preserve and/or restore full function in 7 different animal models of neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD).MethodIn a double blind, placebo controlled Phase2a study, early AD patients were randomized into 80mg Buntanetap (n = 10) or placebo (n = 5) QD for 25±2 days. We evaluated the safety, pharmacokinetics of Buntanetap, biomarkers, and its efficacy.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both healthy volunteers and AD/PD patients. In our recent double‐blind, placebo controlled Phase2a study, patients randomized to either 80mg QD Buntanetap or placebo we measured biomarkers in AD patients and showed that Buntanetap can lower neurotoxic proteins, improve axonal integrity and synaptic function, and lower inflammation. Buntanetap has also improved AD patients’ cognitive functions as measured by ADASCog11 and WAIS coding test after 25±2 days treatment.ConclusionThese encouraging data support our further development of Buntanetap as a potential treatment for Alzheimer’s disease. We are planning three double‐blind, placebo‐controlled studies, a short 3‐month dose‐finding trial and two long‐term 12‐ and 18‐month trials in early and moderate AD patients.

Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Motor Function in Parkinson’s Disease

AbstractBackgroundParkinson’s disease (PD) is a neurodegenerative disorder that affects predominately dopaminergic neurons in substantia nigra. Although alpha‐synuclein (αSYN) is the main component of Lewy bodies, TDP‐43, Aβ and tau are also detected in PD. Buntanetap has been shown to inhibit the translation of multiple neurotoxic proteins such as amyloid precursor protein, tau and alpha‐synuclein. It been shown in animal models to restore axonal transport, lower inflammation and protect nerve cells from dying. By reversing the toxic cascade leading to nerve cell death, Buntanetap preserves and restores full function in 7 different animal models of neurodegenerative diseases including PD.MethodIn our double‐blind, placebo‐controlled, dose‐finding Phase 2a trial, 5 different doses of Buntanetap (5mg, 10mg, 20mg, 40mg and 80mg QD) were tested compared to control after25±2 days treatment. Buntanetap’s safety, pharmacokinetics, biomarkers and efficacy were evaluated.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both in healthy volunteers and in AD/PD patient. In PD patients, Buntanetap lowers neurotoxic proteins, improves axonal integrity and synaptic function, and lowers inflammation. Buntanetap improves PD patients’ mobility shown by MDS‐UPDRS and WAIS coding test after 25±2 days treatment. Of the 5 different doses, 10 & 20mg Buntanetap QD showed the best clinical outcomes.ConclusionThese data supported us getting regulatory approval to develop next stage pivotal studies in larger population and for longer durations. The FDA consented us to move the development into two phase 3 clinical studies – one in early and one in advanced PD. Our first pivotal trial intends to treat 450 early PD patients at 1:1:1 ration for 10mg, 20mg Buntanetap QD or placebo for 6 months duration.

The Dual PDE7-GSK3β Inhibitor, VP3.15, as Neuroprotective Disease-Modifying Treatment in a Model of Primary Progressive Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune and degenerative disease with axonal damage and demyelination as its main features. Its dual neurological and autoimmune nature makes it a disease that is difficult to treat. Treatments that simultaneously stop the immune response while protecting and repairing the nervous system are urgent. That is of utmost importance for the primary progressive multiple sclerosis (PPMS), a rare and severe variant of MS, characterized by worsening neurological function from the onset of symptoms. In this sense, inhibitors of glycogen synthase kinase 3β (GSK3β) and phosphodiesterase 7 (PDE7) have recently shown great therapeutic potential for the treatment of demyelinating diseases. Here we investigated a dual inhibitor of these two targets, the small molecule VP3.15, in a preclinical model, which resembles primary-progressive MS (PPMS), the Theiler's mouse encephalomyelitis virus-induced demyelinated disease (TMEV-IDD). In our study, VP3.15 ameliorates the disease course improving motor deficits of infected mice. Chronic treatment with VP3.15 also showed significant efficacy in the immunomodulation process, as well as in the proliferation and differentiation of oligodendroglial precursors, improving the preservation of myelin and axonal integrity. Therefore, our results support a treatment with the safe VP3.15 as an integrative therapeutic strategy for the treatment of PPMS.

Complement inhibition prevents glial nodal membrane injury in a GM1 antibody-mediated mouse model.

The involvement of the complement pathway in Guillain-Barré syndrome pathogenesis has been demonstrated in both patient biosamples and animal models. One proposed mechanism is that anti-ganglioside antibodies mediate neural membrane injury through the activation of complement and the formation of membrane attack complex pores, thereby allowing the uncontrolled influx of ions, including calcium, intracellularly. Calcium influx activates the calcium-dependent protease calpain, leading to the cleavage of neural cytoskeletal and transmembrane proteins and contributing to subsequent functional failure. Complement inhibition has been demonstrated to provide effective protection from injury in anti-ganglioside antibody-mediated mouse models of axonal variants of Guillain-Barré syndrome; however, the role of complement in the pathogenesis of demyelinating variants has yet to be established. Thus, it is currently unknown whether complement inhibition would be an effective therapeutic for Guillain-Barré syndrome patients with injuries to the Schwann cell membrane. To address this, we recently developed a mouse model whereby the Schwann cell membrane was selectively targeted with an anti-GM1 antibody resulting in significant disruption to the axo-glial junction and cytoplasmic paranodal loops, presenting as conduction block. Herein, we utilize this Schwann cell nodal membrane injury model to determine the relevance of inhibiting complement activation. We addressed the early complement component C2 as the therapeutic target within the complement cascade by using the anti-C2 humanized monoclonal antibody, ARGX-117. This anti-C2 antibody blocks the formation of C3 convertase, specifically inhibiting the classical and lectin complement pathways and preventing the production of downstream harmful anaphylatoxins (C3a and C5a) and membrane attack complexes. Here, we demonstrate that C2 inhibition significantly attenuates injury to paranodal proteins at the node of Ranvier and improves respiratory function in ex vivo and in vivo Schwann cell nodal membrane injury models. In parallel studies, C2 inhibition also protects axonal integrity in our well-established model of acute motor axonal neuropathy mediated by both mouse and human anti-GM1 antibodies. These data demonstrate that complement inhibition prevents injury in a Schwann cell nodal membrane injury model, which is representative of neuropathies associated with anti-GM1 antibodies, including Guillain-Barré syndrome and multifocal motor neuropathy. This outcome suggests that both the motor axonal and demyelinating variants of Guillain-Barré syndrome should be included in future complement inhibition clinical trials.

Moderate-to-Vigorous Physical Activity is Related With Retinal Neuronal and Axonal Integrity in Persons With Multiple Sclerosis

Background Moderate-to-vigorous physical activity (MVPA) may confer benefits for axonal and/or neuronal integrity in adults with multiple sclerosis (MS). Purpose Examine the association between device-measured MVPA with optical coherence tomography (OCT) metrics of retinal nerve fiber layer (RNFL) thickness and total macular volume (TMV) in persons with and without MS. Methods Adults with MS (N = 41), along with sex-matched healthy control (HC) participants (N = 79), underwent measurements of retinal morphology via OCT and wore an accelerometer for a period of 7 days as a measure of MVPA. Results Persons with MS had significantly lower MVPA, RNFL thickness, and TMV compared with HCs. MVPA was correlated with RNFL (r = .38, P < .01) thickness and TMV (r = .49, P < .01). Hierarchical linear regression analyses indicated that addition of MVPA attenuated the Group effect on RNFL and TMV. MVPA accounted for 8% and 3% of the variance in TMV (β = .343, P < .01) and RNFL thickness (β = .217, P = .03), respectively. Conclusion MVPA was positively associated with axonal and neuronal integrity assessed by OCT and partially explained group differences in those metrics. These results present possible future targets for MS management by increasing MVPA.

Buntanetap, a Novel Translational Inhibitor of Multiple Neurotoxic Proteins, Proves to Be Safe and Promising in Both Alzheimer’s and Parkinson’s Patients

BackgroundPreviously we reported the clinical safety and pharmacological activity of buntanetap (known as Posiphen or ANVS401) in healthy volunteers and mild cognitive impaired (MCI) patients (21). The data supported continued clinical evaluation of buntanetap for treating Alzheimer’s Disease (AD). Neurodegenerative diseases such as AD and Parkinson’s disease (PD) share several pathological manifestations, including increased levels of multiple neurotoxic protein aggregates. Therefore, a treatment strategy that targets toxic species common to both disorders can potentially provide better clinical outcomes than attacking one neurotoxic protein alone. To test this hypothesis, we recently completed a clinical study in early AD and early PD participants and report the data here.ObjectivesWe evaluated safety, pharmacokinetics, biomarkers, and efficacy of buntanetap in treating early AD and PD patients.DesignDouble-blind, placebo-controlled, multi-center study.Setting13 sites in the US participated in this clinical trial. The registration number is NCT04524351 at ClinicalTrials.gov.Participants14 early AD patients and 54 early PD patients.InterventionAD patients were given either 80mg buntanetap or placebo QD. PD patients were given 5mg, 10mg, 20mg, 40mg, 80mg buntanetap or placebo QD.MeasurementsPrimary endpoint is safety and tolerability; secondary endpoint is pharmacokinetics of buntanetap in plasma; exploratory endpoints are 1) biomarkers in cerebrospinal fluid (CSF) in both AD and PD patients 2) psychometric tests specific for AD (ADAS-Cogs & WAIS coding test) or PD (MDS-UPDRS & WAIS coding test).ResultsBuntanetap was safe and well tolerated. Biomarker data indicated a trend in lowering levels of neurotoxic proteins and inflammatory factors and improving axonal integrity and synaptic function in both AD and PD cohorts. Psychometric tests showed statistically significant improvements in ADAS-Cog11 and WAIS coding in AD patients and MDS-UPDRS and WAIS coding in PD patients.ConclusionsBuntanetap is well tolerated and safe at doses up to 80mg QD in both AD and PD patients. Cmax and AUC increase with dose without evidence for a plateau up to 80mg QD. The drug shows promising evidence in exploratory biomarker and efficacy measures. Further evaluation of buntanetap in larger, longer-term clinical trials for the treatment of AD and PD are warranted.

Neurodegeneration Markers in the Cerebrospinal Fluid of 100 Patients with Schizophrenia Spectrum Disorder.

Schizophrenia spectrum disorders (SSD) can be associated with neurodegenerative processes causing disruption of neuronal, synaptic, or axonal integrity. Some previous studies have reported alterations of neurodegenerative markers (such as amyloid beta [Aβ], tau, or neurofilaments) in patients with SSD. However, the current state of research remains inconclusive. Therefore, the rationale of this study was to investigate established neurodegenerative markers in the cerebrospinal fluid (CSF) of a large group of patients with SSD. Measurements of Aβ1-40, Aß1-42, phospho- and total-tau in addition to neurofilament light (NFL), medium (NFM), and heavy (NFH) chains were performed in the CSF of 100 patients with SSD (60 F, 40 M; age 33.7 ± 12.0) and 39 controls with idiopathic intracranial hypertension (33 F, 6 M; age 34.6 ± 12.0) using enzyme-linked immunoassays. The NFM levels were significantly increased in SSD patients (P = .009), whereas phospho-tau levels were lower in comparison to the control group (P = .018). No other significant differences in total-tau, beta-amyloid-quotient (Aβ1-42/Aβ1-40), NFL, and NFH were identified. The findings argue against a general tauopathy or amyloid pathology in patients with SSD. However, high levels of NFM, which has been linked to regulatory functions in dopaminergic neurotransmission, were associated with SSD. Therefore, NFM could be a promising candidate for further research on SSD.

Structural brain changes in patients with persistent headache after COVID-19 resolution

Headache is among the most frequently reported symptoms after resolution of COVID-19. We assessed structural brain changes using T1- and diffusion-weighted MRI processed data from 167 subjects: 40 patients who recovered from COVID-19 but suffered from persistent headache without prior history of headache (COV), 41 healthy controls, 43 patients with episodic migraine and 43 patients with chronic migraine. To evaluate gray matter and white matter changes, morphometry parameters and diffusion tensor imaging-based measures were employed, respectively. COV patients showed significant lower cortical gray matter volume and cortical thickness than healthy subjects (p < 0.05, false discovery rate corrected) in the inferior frontal and the fusiform cortex. Lower fractional anisotropy and higher radial diffusivity (p < 0.05, family-wise error corrected) were observed in COV patients compared to controls, mainly in the corpus callosum and left hemisphere. COV patients showed higher cortical volume and thickness than migraine patients in the cingulate and frontal gyri, paracentral lobule and superior temporal sulcus, lower volume in subcortical regions and lower curvature in the precuneus and cuneus. Lower diffusion metric values in COV patients compared to migraine were identified prominently in the right hemisphere. COV patients present diverse changes in the white matter and gray matter structure. White matter changes seem to be associated with impairment of fiber bundles. Besides, the gray matter changes and other white matter modifications such as axonal integrity loss seemed subtle and less pronounced than those detected in migraine, showing that persistent headache after COVID-19 resolution could be an intermediate state between normality and migraine.

Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency.

In 2017, an inborn error of metabolism caused by recessive mutations in SGPL1 was discovered. The disease features steroid-resistant nephrotic syndrome, adrenal insufficiency, and neurological defects. The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration. SGPL1 encodes the pyridoxal-5’-phosphate (PLP) dependent enzyme sphingosine phosphate lyase (SPL), and the condition is now referred to as SPL insufficiency syndrome (SPLIS). SPL catalyzes the final step in the degradative pathway of sphingolipids in which the bioactive sphingolipid sphingosine-1-phosphate (S1P) is irreversibly degraded to a long chain aldehyde and phosphoethanolamine (PE). SPL guards the only exit point for sphingolipid metabolism, and its inactivation leads to accumulation of various types of sphingolipids which have biophysical roles in plasma membrane rafts and myelin, and signaling roles in cell cycle progression, vesicular trafficking, cell migration, and programmed cell death. In addition, the products of the SPL reaction have biological functions including regulation of autophagic flux, which is important in axonal and neuronal integrity. In this review, the neurological manifestations of SPLIS will be described, and insights regarding the neurological consequences of SPL insufficiency from the study of brain-specific SPL knockout mice and Drosophila SPL mutants will be summarized.

Microstructural imaging and transcriptomics of the basal forebrain in first-episode psychosis

Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p > 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Combined Effects of Synaptic and Axonal Integrity on Longitudinal Gray Matter Atrophy in Cognitively Unimpaired Adults.

Synaptic dysfunction and degeneration is a predominant feature of brain aging, and synaptic preservation buffers against Alzheimer disease (AD) protein-related brain atrophy. We tested whether CSF synaptic protein concentrations similarly moderate the effects of axonal injury, indexed by CSF neurofilament light [NfL]), on brain atrophy in clinically normal adults. Clinically normal older adults enrolled in the observational Hillblom Aging Network study at the UCSF Memory and Aging Center completed baseline lumbar puncture and longitudinal brain MRI (mean scan [follow-up] = 2.6 [3.7 years]). CSF was assayed for synaptic proteins (synaptotagmin-1, synaptosomal-associated protein 25 [SNAP-25], neurogranin, growth-associated protein 43 [GAP-43]), axonal injury (NfL), and core AD biomarkers (ptau181/Aβ42 ratio; reflecting AD proteinopathy). Ten bilateral temporoparietal gray matter region of interest (ROIs) shown to be sensitive to clinical AD were summed to generate a composite temporoparietal ROI. Linear mixed-effects models tested statistical moderation of baseline synaptic proteins on baseline NfL-related temporoparietal trajectories, controlling for ptau181/Aβ42 ratios. Forty-six clinically normal older adults (mean age = 70 years; 43% female) were included. Synaptic proteins exhibited small to medium correlations with NfL (r range: 0.10-0.36). Higher baseline NfL, but not ptau181/Aβ42 ratios, predicted steeper temporoparietal atrophy (NfL × time: β = -0.08, p < 0.001; ptau181/Aβ42 × time: β = -0.02, p = 0.31). SNAP-25, neurogranin, and GAP-43 significantly moderated NfL-related atrophy trajectories (-0.07 ≤ β's ≥ -0.06, p's < 0.05) such that NfL was associated with temporoparietal atrophy at high (more abnormal) but not low (more normal) synaptic protein concentrations. At high NfL concentrations, atrophy trajectories were 1.5-4.5 times weaker when synaptic protein concentrations were low (β range: -0.21 to -0.07) than high (β range: -0.33 to -0.30). The association between baseline CSF NfL and longitudinal temporoparietal atrophy is accelerated by synaptic dysfunction and buffered by synaptic integrity. Beyond AD proteins, concurrent examination of in vivo axonal and synaptic biomarkers may improve detection of neural alterations that precede overt structural changes in AD-sensitive brain regions.

Neurodegeneration in multiple sclerosis.

Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post-mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.