MiR-146a in ALS: Contribution to Early Peripheral Nerve Degeneration and Relevance as Disease Biomarker.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive, irreversible loss of upper and lower motor neurons (UMNs, LMNs). MN axonal dysfunctions are emerging as relevant pathogenic events since the early ALS stages. However, the exact molecular mechanisms leading to MN axon degeneration in ALS still need to be clarified. MicroRNA (miRNA) dysregulation plays a critical role in the pathogenesis of neuromuscular diseases. These molecules represent promising biomarkers for these conditions since their expression in body fluids consistently reflects distinct pathophysiological states. Mir-146a has been reported to modulate the expression of the NFL gene, encoding the light chain of the neurofilament (NFL) protein, a recognized biomarker for ALS. Here, we analyzed miR-146a and Nfl expression in the sciatic nerve of G93A-SOD1 ALS mice during disease progression. The miRNA was also analyzed in the serum of affected mice and human patients, the last stratified relying on the predominant UMN or LMN clinical signs. We revealed a significant miR-146a increase and Nfl expression decrease in G93A-SOD1 peripheral nerve. In the serum of both ALS mice and human patients, the miRNA levels were reduced, discriminating UMN-predominant patients from the LMN ones. Our findings suggest a miR-146a contribution to peripheral axon impairment and its potential role as a diagnostic and prognostic biomarker for ALS.

Diabetes Mellitus and Cognition: Pathway Analysis in the MEMENTO Cohort.

OBJECTIVE: To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS: The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aß42/Aß40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. RESULTS: There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION: In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.

Neurodegeneration in Niemann-Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment.

Niemann-Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.

Brain energy metabolism and neurodegeneration: hints from CSF lactate levels in dementias.

Mitochondrial dysfunction is pivotal in the development of neurodegenerative dementias, causing cellular death alongside disease-specific pathogenic cascades. Holding cerebrospinal fluid (CSF) lactates as an indirect measure of brain metabolic activity, we first compared CSF lactate levels from patients with Alzheimer's disease (AD)-stratified according to the ATN system and epsilon genotype-frontotemporal dementia (FTD) and dementia with Lewy body (DLB) to findings from healthy controls. With respect to controls, we detected lower CSF lactates in patients with AD and FTD but comparable levels in patients with DLB. Second, a correlation analysis between CSF lactates and biomarkers of neurodegeneration identified an inverse correlation between lactates and levels of t-tau and p-tau only in the Alzheimer's continuum. The reduction of CSF lactate correlates to the advent of tauopathy and cellular death in AD, implying that Aß pathology alone is not sufficient to induce neuronal metabolic impairment. The metabolic impairment in FTD patients has a similar explanation, as it is likely due to fast neuronal degeneration in the disease. The absence of CSF lactate reduction in patients with DLB may be related to the prevalent subcortical localization of the pathology.

Broadening the spectrum phenotype of TBCE-related neuron neurodegeneration.

BACKGROUND: Severe loss of TBCE function has been related to two well-known dysmorphic syndromes, while TBCE hypomorphic variants have been linked to neurodegenerative conditions due to perturbed microtubule dynamics and homeostasis, with signs of central and peripheral nervous system involvement. METHOD: We report on an Italian female originating from Southern Italy who presented early-onset regression and neurodegeneration, with neurological features of tetraparesis and signs of peripheral nervous system involvement. Her brain MRI revealed white matter involvement. RESULTS: Analyzing all known hypomyelination leukodystrophies related genes, two mutations in TBCE (NM_001079515) were detected: the missense variant c.464 T > A; p. (Ile155Asn) and the frameshift variant c.924del; p. (Leu309Ter), in compound heterozygosity, already reported in the literature in patients coming from the same geographical area. The clinical phenotype of the proposita was more severe and with an earlier onset than the majority of the patients reported so far. CONCLUSIONS: Next Generation Sequencing is becoming increasingly necessary to assess unusual phenotypes, with the opportunity to establish prognosis and disease mechanisms, and facilitating differential diagnosis.

Methodological considerations of evaluating the rate of presynaptic dopaminergic denervation in Parkinson disease with radiotracers: Analysis of the PPMI data.

ABSTRACT: Many previous studies have estimated the rate of dopaminergic denervation in Parkinson disease (PD) via imaging studies. However, they lack the considerations of onset age, disease duration at onset, gender, and dopaminergic denervation due to normal aging. Herein, using a large prospective cohort, we estimated the rate of dopaminergic denervation in PD patients, compared with an age- and gender-matched normal control group.One hundred forty-one normal controls and 301 PD patients were enrolled. Striatal specific binding ratios (SBRs) of I-123 FP-CIT single positron emission tomography images were analyzed according to the age of onset, gender, and the duration of motor symptoms.In the PD group, symptom duration was significantly correlated with caudate SBRs, but with putamen SBRs (P  < .05, R2 = 0.02). Moreover, was significantly inversely related to caudate SBRs, but not with putamen SBRs (P  < .05, R2 = 0.02). Patients of different age onsets did not show any significant correlation between symptom durations and striatal SBRs. In the age-matched group, no significant relationship was observed between symptom duration and percent decrease of caudate SBRs, but there was a significant relationship between symptom duration and percent decrease of the putamen SBRs (P  < .01, R2 = 0.06). There was no significant relationship between the symptom duration and the percent decrease of striatal SBRs in the age- and gender-matched group.The significance and R2 values from the regression analysis between symptom duration, age, and dopaminergic denervation are low. This suggests that, contrary to previous knowledge, there is a relatively weak association between dopaminergic denervation and age or symptom duration.

Neurodegeneration, Alzheimer's disease biomarkers, and longitudinal verbal learning and memory performance in late middle age.

This study examined the effect of neurodegeneration, and its interaction with Alzheimer's disease (AD) cerebrospinal fluid biomarkers, on longitudinal verbal learning and memory performance in cognitively unimpaired (CU) late middle-aged adults. Three hundred and forty-two CU adults (cognitive baseline mean age = 58.4), with cerebrospinal fluid and structural MRI, completed 2-10 (median = 5) cognitive assessments. Learning and memory were assessed using the Rey Auditory Verbal Learning Test (RAVLT). We used sequential comparison of nested linear mixed effects models to analyze the data. Model selection preserved a significant ptau181/Aß42 × global atrophy × age interaction; individuals with less global atrophy and lower ptau181/Aß42 levels had less learning and delayed recall decline than individuals with more global atrophy and/or higher levels of ptau181/Aß42. The hippocampal volume × age × ptau181/Aß42 interaction was not significant. Findings suggest that in a sample of CU late middle-aged adults, individuals with AD biomarkers, global atrophy, or both evidence greater verbal learning and memory decline than individuals without either risk factor.

Neurofilament light chain as a potential biomarker for monitoring neurodegeneration in X-linked adrenoleukodystrophy.

X-linked adrenoleukodystrophy (X-ALD), the most frequent monogenetic disorder of brain white matter, is highly variable, ranging from slowly progressive adrenomyeloneuropathy (AMN) to life-threatening inflammatory brain demyelination (CALD). In this study involving 94 X-ALD patients and 55 controls, we tested whether plasma/serum neurofilament light chain protein (NfL) constitutes an early distinguishing biomarker. In AMN, we found moderately elevated NfL with increased levels reflecting higher grading of myelopathy-related disability. Intriguingly, NfL was a significant predictor to discriminate non-converting AMN from cohorts later developing CALD. In CALD, markedly amplified NfL levels reflected brain lesion severity. In rare cases, atypically low NfL revealed a previously unrecognized smoldering CALD disease course with slowly progressive myelin destruction. Upon halt of brain demyelination by hematopoietic stem cell transplantation, NfL gradually normalized. Together, our study reveals that blood NfL reflects inflammatory activity and progression in CALD patients, thus constituting a potential surrogate biomarker that may facilitate clinical decisions and therapeutic development.

MAdCAM-1 mediates retinal neuron degeneration in experimental colitis through recruiting gut-homing CD4+ T cells.

Extra-intestinal manifestations (EIMs) of the eyes are found in IBD patients, but the underlying pathogenesis remains unknown. To investigate the pathogenesis of IBD-associated retinal dysfunction, chronic colitis was induced in mice by oral administration of dextran sodium sulfate (DSS). Electroretinography (ERG) was performed to evaluate retinal function. Retinal neuron degeneration was analyzed by immunohistochemistry. Colitic mice displayed aberrant amplitudes of ERG a-, b-wave and oscillatory potentials (OP). Importantly, we observed severe degeneration of bipolar and ganglion cells. In contrast, outer retinal neurons (mainly photoreceptor cells) are mildly affected by colitis. Moreover, retinal inflammatory responses were significantly upregulated during colitis, including microglia activation, lymphocyte infiltration and cytokine/chemokine production. Notably, mucosal addressin cell adhesion molecule 1 (MAdCAM-1) was upregulated in retinal microvessels, especially the superficial and deep plexuses, and recruited gut-homing CD4+ T cells to be co-localized with bipolar and ganglion cells during colitis. Expectedly, in vivo depletion of CD4+ T cells or blockade of MAdCAM-1 greatly alleviated colitis-induced retinal inflammatory responses and neuron degeneration. Therefore, our data provide novel insight into the pathogenesis of IBD-associated retinal dysfunction, and targeted immune therapy directly against MAdCAM-1 might provide a novel approach in the management of eye EIM of IBD.

The degeneration of upper and lower motor neuron from the perspective of clinical neurological examination and MRI-electromyography manifold detection in amyotrophic lateral sclerosis.

OBJECTIVE: The aim of this study was to explore the upper motor neurons (UMN) and lower motor neurons (LMN) degeneration in amyotrophic lateral sclerosis (ALS) from the perspective of the clinical neurological examination and MRI-electromyography manifold detection, respectively. METHODS: The clinical data, cortical thickness of corresponding areas in different body regions in MRI and electromyography data were collected from 108 classical ALS patients. RESULTS: The kappa value of UMN and LMN involvement signs in the bulbar region (0.31) was higher than that of the left upper limb (-0.13), right upper limb (-0.27), left lower limb (-0.05) and right lower limb (-0.08). The cortical thickness in the positive LMN damage group was thinner than that of the negative LMN damage group in the left head-face area (P < 0.05; Cohen's d = 0.84); however, cortical thickness showed no significant differences in the right head-face, bilateral tongue-larynx, upper-limb, trunk and lower-limb areas between LMN-damage-positive and LMN-damage-negative groups. CONCLUSION: The degeneration of motor neuron could be independent through UMN and LMN levels. The degenerative process was not only confined to UMN and LMN levels but can also expand to white matter fiber tracts. Thus, the degeneration of UMN and LMN might be independent of the motor system's three-dimensional anatomy.

Positron Emission Tomography (PET) and Neuroimaging in the Personalized Approach to Neurodegenerative Causes of Dementia.

Generally, dementia should be considered an acquired syndrome, with multiple possible causes, rather than a specific disease in itself. The leading causes of dementia are neurodegenerative and non-neurodegenerative alterations. Nevertheless, the neurodegenerative group of diseases that lead to cognitive impairment and dementia includes multiple possibilities or mixed pathologies with personalized treatment management for each cause, even if Alzheimer's disease is the most common pathology. Therefore, an accurate differential diagnosis is mandatory in order to select the most appropriate therapy approach. The role of personalized assessment in the treatment of dementia is rapidly growing. Neuroimaging is an essential tool for differential diagnosis of multiple causes of dementia and allows a personalized diagnostic and therapeutic protocol based on risk factors that may improve treatment management, especially in early diagnosis during the prodromal stage. The utility of structural and functional imaging could be increased by standardization of acquisition and analysis methods and by the development of algorithms for automated assessment. The aim of this review is to focus on the most commonly used tracers for differential diagnosis in the dementia field. Particularly, we aim to explore 18F Fluorodeoxyglucose (FDG) and amyloid positron emission tomography (PET) imaging in Alzheimer's disease and in other neurodegenerative causes of dementia.

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic dysfunction, and axonal injury relate to atrophy in structural brain regions specific to Alzheimer's disease.

INTRODUCTION: Patterns of atrophy can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures. METHODS: Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other. RESULTS: Increased phosphorylated tau (p-tau), total tau, and neurofilament light (P-values <.045) related to smaller signatures (indicating greater atrophy). Diagnosis and sex modified associations between p-tau and neurogranin (P-values<.05) and signatures, such that associations were stronger among participants with mild cognitive impairment and female participants. The strength of associations did not differ between signatures. DISCUSSION: Increased evidence of neurodegeneration, axonopathy, and tau phosphorylation relate to greater AD-related atrophy. Tau phosphorylation and synaptic dysfunction may be more prominent in AD-affected regions in females.

Neurofilament light chain and MRI volume parameters as markers of neurodegeneration in multiple sclerosis.

BACKGROUND: Neurofilament light chain (NfL) is considered a major marker of neurodegeneration and disease activity. Higher levels of NfL are associated with worse clinical outcomes and increased brain atrophy. In treated patients with Relapsing-Remitting Multiple Sclerosis (RRMS), we aimed to determine the level of NfL, an association between NfL and demographic, clinical and magnetic resonance imaging (MRI) characteristics as well as brain volume parameters. We wanted to confirm that level of NfL is clinically useful as biomarker of neurodegeneration and disease activity. METHODS: 56 treated RRMS patients were enrolled. Plasmatic levels of NfL (pNfL) were measured by SIMOA® technique. Clinical severity of MS was expressed by Expanded Disability Status Scale (EDSS), and volumetric analysis of MRI data was performed using Icobrain software. RESULTS: The mean pNfL level was significantly higher in MS patients than in healthy controls (14.73 ± 6.38 versus 6.67 ± 3.9, p<0.001). In patients, we did not find association between pNfL and MRI activity, number of new T2 lesions, and number of enhancing lesions. Levels of pNfL correlated significantly with atrophy of whole brain volume (Wbv), atrophy of grey matter volume (Gmv), and negatively with Wbv. We found significantly positive correlation between pNfL levels and EDSS. CONCLUSION: Study shows association of pNfL with Wbv, presence of brain atrophy and EDSS, and strong correlation of EDSS with multiple MRI volume parameters. We did not confirm association pNfL with disease activity. Our data suggest that pNfL and MRI volume parameters could be considered as biomarkers of neurodegeneration in MS.

Gradient subthalamic neurodegeneration and tau pathology in the hypoglossal nucleus as essential pathological markers of progressive supranuclear palsy - Richardson syndrome.

Progressive supranuclear palsy - Richardson syndrome (PSP-RS) was first described in 1964 by Steele et al. Tau pathology has not been reported in the hypoglossal nuclei of PSP-RS patients, whereas Steele et al. described gliosis with no remarkable neuronal losses in the hypoglossal nucleus. This study aimed to investigate the distribution and degree of tau pathology-associated neurodegeneration, with an emphasis on the hypoglossal nucleus, in patients with PSP-RS. Six clinicopathologically proven PSP-RS cases were included in this study. All patients were clinicopathologically and immunohistochemically re-evaluated. This study confirmed the following neuropathological characteristics of PSP-RS: (1) neurodegeneration usually affects the striatonigral system and cerebellar dentate nucleus; (2) the cerebellar afferent system in PSP-RS is affected by absent-to-mild neurodegeneration; and (3) the extent of tau distribution throughout the central nervous system is greater than the extent of neurodegeneration. Furthermore, we found that subthalamic neurodegeneration was more prominent in the ventromedial region than in the dorsolateral region. Nevertheless, the tau pathology showed no remarkable differences between these two sites. Interestingly, the tau pathology was frequently observed in the hypoglossal nuclei of PSP-RS patients. Gradient neurodegeneration of the subthalamus and tau pathology in the hypoglossal nucleus could be regarded as essential pathological features of PSP-RS.

[Basal ganglia calcification]. / Calcifications des noyaux gris centraux.

Calcifications of the basal ganglia are frequently seen on the cerebral CT scans and particularly in the globus pallidus. Their frequency increases physiologically with age after 50 years old. However, pathological processes can also be associated with calcium deposits in the gray nuclei, posterior fossa or white matter. Unilateral calcification is often related to an acquired origin whereas bilateral ones are mostly linked to an acquired or genetic origin that will be sought after eliminating a perturbation of phosphocalcic metabolism. In pathological contexts, these calcifications may be accompanied by neurological symptoms related to the underlying disease: Parkinson's syndrome, psychiatric and cognitive disorders, epilepsy or headache. The purpose of this article is to provide a diagnostic aid, in addition to clinical and biology, through the analysis of calcification topography and the study of different MRI sequences.

Elevated levels of BDNF and cathepsin-d as possible peripheral markers of neurodegeneration in plasma of patients with glutaric acidemia type I.

Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.

Objective subtle cognitive difficulties predict future amyloid accumulation and neurodegeneration.

OBJECTIVE: To determine the temporal sequence of objectively defined subtle cognitive difficulties (Obj-SCD) in relation to amyloidosis and neurodegeneration, the current study examined the trajectories of amyloid PET and medial temporal neurodegeneration in participants with Obj-SCD relative to cognitively normal (CN) and mild cognitive impairment (MCI) groups. METHOD: A total of 747 Alzheimer's Disease Neuroimaging Initiative participants (305 CN, 153 Obj-SCD, 289 MCI) underwent neuropsychological testing and serial amyloid PET and structural MRI examinations. Linear mixed effects models examined 4-year rate of change in cortical 18F-florbetapir PET, entorhinal cortex thickness, and hippocampal volume in those classified as Obj-SCD and MCI relative to CN. RESULT: Amyloid accumulation was faster in the Obj-SCD group than in the CN group; the MCI and CN groups did not significantly differ from each other. The Obj-SCD and MCI groups both demonstrated faster entorhinal cortical thinning relative to the CN group; only the MCI group exhibited faster hippocampal atrophy than CN participants. CONCLUSION: Relative to CN participants, Obj-SCD was associated with faster amyloid accumulation and selective vulnerability of entorhinal cortical thinning, whereas MCI was associated with faster entorhinal and hippocampal atrophy. Findings suggest that Obj-SCD, operationally defined using sensitive neuropsychological measures, can be identified prior to or during the preclinical stage of amyloid deposition. Further, consistent with the Braak neurofibrillary staging scheme, Obj-SCD status may track with early entorhinal pathologic changes, whereas MCI may track with more widespread medial temporal change. Thus, Obj-SCD may be a sensitive and noninvasive predictor of encroaching amyloidosis and neurodegeneration, prior to frank cognitive impairment associated with MCI.

Serum creatinine is a biomarker of progressive denervation in spinal muscular atrophy.

OBJECTIVE: Identifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA. METHODS: We examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 (SMN2) copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE). RESULTS: Patients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93-2.49; p < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52-1.82; p < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31-1.58; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.8-fold (95% CI 1.57-2.11; p < 0.0001) higher Crn levels compared to patients with SMA with 2 SMN2 copies and 1.4-fold (95% CI 1.24-1.58; p < 0.0001) higher Crn levels compared to patients with SMA with 3 SMN2 copies. Patients with SMA with 3 SMN2 copies had 1.4-fold (95% CI 1.21-1.56; p < 0.0001) higher Crn levels than patients with SMA with 2 SMN2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters (p < 0.0001) and positive associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, SMN2 copies, HFMS, CMAP, and MUNE. CONCLUSIONS: These findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.

Cerebrospinal fluid neurogranin in an inducible mouse model of neurodegeneration: A translatable marker of synaptic degeneration.

Synapse impairment is thought to be an early event in Alzheimer's disease (AD); dysfunction and loss of synapses are linked to cognitive symptoms that precede neuronal loss and neurodegeneration. Neurogranin (Ng) is a somatodendritic protein that has been shown to be reduced in brain tissue but increased in the cerebrospinal fluid (CSF) of AD patients compared to age-matched controls. High levels of CSF Ng have been shown to reflect a more rapid AD progression. To gauge the translational value of Ng as a biomarker, we developed a new, highly sensitive, digital enzyme-linked immunosorbent assay (ELISA) on the Simoa platform to measure Ng in both mouse and human CSF. We investigated and confirmed that Ng levels are increased in the CSF of patients with AD compared to controls. In addition, we explored how Ng is altered in the brain and CSF of transgenic mice that display progressive neuronal loss and synaptic degeneration following the induction of p25 overexpression. In this model, we found that Ng levels increased in CSF when neurodegeneration was induced, peaking after 2 weeks, while they decreased in brain. Our data suggest that CSF Ng is a biomarker of synaptic degeneration with translational value.