Rate Of Brain Atrophy Research Articles

Dynamics of choroid plexus volume is associated with the presence and development of fatigue in multiple sclerosis

BackgroundImmune-mediated processes are implicated in the pathogenesis of fatigue, a common symptom in multiple sclerosis (MS). The choroid plexus (CP) regulates central nervous system (CNS) immune homeostasis and undergoes volumetric...

Magnetic Resonance Imaging Measures to Track Atrophy Progression in Progressive Supranuclear Palsy in Clinical Trials.

Several magnetic resonance imaging (MRI) measures have been suggested as progression biomarkers in progressive supranuclear palsy (PSP), and some PSP staging systems have been recently proposed. Comparing structural MRI measures and staging systems in tracking atrophy progression in PSP and estimating the sample size to use them as endpoints in clinical trials. Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) patients with one-year-follow-up longitudinal brain MRI were selected from the placebo arms of international trials (NCT03068468, NCT01110720, NCT01049399) and the DescribePSP cohort. The discovery cohort included patients from the NCT03068468 trial; the validation cohort included patients from other sources. Multisite age-matched healthy controls (HC) were included for comparison. Several MRI measures were compared: automated atlas-based volumetry (44 regions), automated planimetric measures of brainstem regions, and four previously described staging systems, applied to volumetric data. Of 508 participants, 226 PSP patients including discovery (n = 121) and validation (n = 105) cohorts, and 251 HC were included. In PSP patients, the annualized percentage change of brainstem and midbrain volume, and a combined index including midbrain, frontal lobe, and third ventricle volume change, were the progression biomarkers with the highest effect size in both cohorts (discovery: >1.6; validation cohort: >1.3). These measures required the lowest sample sizes (n < 100) to detect 30% atrophy progression, compared with other volumetric/planimetric measures and staging systems. This evidence may inform the selection of imaging endpoints to assess the treatment efficacy in reducing brain atrophy rate in PSP clinical trials, with automated atlas-based volumetry requiring smaller sample size than staging systems and planimetry to observe significant treatment effects. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Serum NfL and GFAP as biomarkers of progressive neurodegeneration in TBI.

We examined spatial patterns of brain atrophy after mild, moderate, and severe traumatic brain injury (TBI), the relationship between progression of brain atrophy with initial traumatic axonal injury (TAI), cognitive outcome, and with serum biomarkers of brain injury. A total of 143 patients with TBI and 43 controls were studied cross-sectionally and longitudinally up to 5 years with multiple assessments, which included brain magnetic resonance imaging, cognitive testing, and serum biomarkers. TBI patients showed progressive volume loss regardless of injury severity over several years, andTAI was independently associated with accelerated brain atrophy. Cognitive performance improved over time. Higher baseline serum neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) were associated with greater rate of brain atrophy over 5 years. Spatial patterns of atrophy differ by injury severity and TAI is associated with the progression of brain atrophy. Serum NfL and GFAP show promise as non-invasive prognostic biomarkers of progressive neurodegeneration in TBI. In this longitudinal study of patient with mild, moderate, and severe traumatic brain injury (TBI) who were assessed with paired magnetic resonance imaging (MRI), blood biomarkers, and cognitive assessments, we found that brain atrophy after TBI is progressive and continues for many years even after a mild head trauma without signs of brain injury on conventional MRI. We found that spatial pattern of brain atrophy differs between mild, moderate, and severe TBI, where in patients with mild TBI , atrophy is mainly seen in the gray matter, while in those with moderate to severe brain injury atrophy is predominantly seen in the subcortical gray matter and whiter matter. Cognitive performance improves over time after a TBI. Serum measures of neurofilament light or glial fibrillary acidic protein are associated with progression of brain atrophy after TBI.

Relationship between cortical brain atrophy, delirium, and long-term cognitive decline in older surgical patients

In older patients, delirium after surgery is associated with long-term cognitive decline (LTCD). The neural substrates of this association are unclear. Neurodegenerative changes associated with dementia are possible contributors. We investigated the relationship between brain atrophy rates in Alzheimer’s disease (AD) and cognitive aging signature regions from magnetic resonance imaging before and one year after surgery, LTCD assessed by the general cognitive performance (GCP) score over 6 years post-operatively, and delirium in 117 elective surgery patients without dementia (mean age = 76). The annual change in cortical thickness was 0.2(1.7) % (AD-signature p = 0.09) and 0.4(1.7) % (aging-signature p = 0.01). Greater atrophy was associated with LTCD (AD-signature: beta(CI) = 0.24(0.06–0.42) points of GCP/mm of cortical thickness; p < 0.01, aging-signature: beta(CI) = 0.55(0.07–1.03); p = 0.03). Atrophy rates were not significantly different between participants with and without delirium. We found an interaction with delirium severity in the association between atrophy and LTCD (AD-signature: beta(CI) = 0.04(0.00–0.08), p = 0.04; aging-signature: beta(CI) = 0.08(0.03–0.12), p < 0.01). The rate of cortical atrophy and severity of delirium are independent, synergistic factors determining postoperative cognitive decline in the elderly.

Long-term neuroprotective effects of natalizumab and fingolimod in multiple sclerosis: Evidence from real-world clinical data

BackgroundThe long-term effect of high efficacy disease modifying therapy (DMT) on neurodegeneration in people with multiple sclerosis (pwMS) is largely unknown. The aim of this study was to evaluate the long-term effect of natalizumab (NTZ) or fingolimod (FTY) therapy on the evolution of brain atrophy compared to moderate efficacy DMT in a real-world clinical setting. MethodsA total of 438 pwMS with 2,439 MRI exams during treatment were analyzed: 252 pwMS treated with moderate efficacy DMT, 130 with NTZ and 56 with FTY. Evolution of brain atrophy was analyzed over an average follow-up of 6.6 years after treatment initiation. Brain segmentation was performed on clinical 3D-FLAIRs using SynthSeg and regional brain volume changes over time were compared between the treatment groups. ResultsTotal brain, white matter and deep gray matter atrophy rates did not differ between moderate efficacy DMTs, NTZ and FTY. Annualized ventricle growth rates were lower in pwMS treated with NTZ (1.1 %/year) compared with moderate efficacy DMT (2.4 %/year, p < 0.001) and similar to FTY (2.0 %/year, p = 0.051). Cortical atrophy rates were lower in NTZ (-0.08 %/year) compared with moderate efficacy DMT (-0.16 %/year, p = 0.048). ConclusionIn a real-world clinical setting, pwMS treated with NTZ had slower ventricular expansion and cortical atrophy compared to those treated with moderate efficacy DMT.

Brain Atrophy Rate Is Associated with Disability Progression in MS (P11-6.015)

Brain Atrophy Rate Is Associated with Disability Progression in MS (P11-6.015)

Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the “power training in older multiple sclerosis patients (PoTOMS) randomized control trial

IntroductionApproximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. MethodsThe presented ‘Power Training in Older MS patients (PoTOMS)’ trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and disseminationThe presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

Identification of Parkinson's disease subtypes with distinct brain atrophy progression and its association with clinical progression.

Parkinson's disease (PD) patients suffer from progressive gray matter volume (GMV) loss, but whether distinct patterns of atrophy progression exist within PD are still unclear. This study aims to identify PD subtypes with different rates of GMV loss and assess their association with clinical progression. This study included 107 PD patients (mean age: 60.06 ± 9.98 years, 70.09% male) with baseline and ≥ 3-year follow-up structural MRI scans. A linear mixed-effects model was employed to assess the rates of regional GMV loss. Hierarchical cluster analysis was conducted to explore potential subtypes based on individual rates of GMV loss. Clinical score changes were then compared across these subtypes. Two PD subtypes were identified based on brain atrophy rates. Subtype 1 (n = 63) showed moderate atrophy, notably in the prefrontal and lateral temporal lobes, while Subtype 2 (n = 44) had faster atrophy across the brain, particularly in the lateral temporal region. Furthermore, subtype 2 exhibited faster deterioration in non-motor (MDS-UPDRS-Part Ⅰ, β = 1.26±0.18, P=0.016) and motor (MDS-UPDRS-Part Ⅱ, β = 1.34±0.20, P=0.017) symptoms, autonomic dysfunction (SCOPA-AUT, β = 1.15±0.22, P=0.043), memory (HVLT-Retention, β = -0.02±0.01, P=0.016) and depression (GDS, β = 0.26±0.083, P=0.019) compared to subtype 1. The study has identified two PD subtypes with distinct patterns of atrophy progression and clinical progression, which may have implications for developing personalized treatment strategies.

Exploring the effects of extended interval dosing of natalizumab and drug concentrations on brain atrophy in multiple sclerosis.

Extended interval dosing (EID) of natalizumab treatment is increasingly used in multiple sclerosis. Besides the clear anti-inflammatory effect, natalizumab is considered to have neuroprotective properties as well. This study aimed to study the longitudinal effects of EID compared to standard interval dosing (SID) and natalizumab drug concentrations on brain atrophy. Patients receiving EID or SID of natalizumab with a minimum radiological follow-up of 2 years were included. Changes in brain atrophy measures over time were derived from clinical routine 3D-Fluid Attenuated Inversion Recovery (FLAIR)-weighted magnetic resonance imaging (MRI) scans using SynthSeg. We found no differences between EID (n = 32) and SID (n = 50) for whole brain (-0.21% vs -0.16%, p = 0.42), ventricular (1.84% vs 1.13%, p = 0.24), and thalamic (-0.32% vs -0.32%, p = 0.97) annualized volume change over a median follow-up of 3.2 years. No associations between natalizumab drug concentration and brain atrophy rate were found. We found no clear evidence that EID compared to SID or lower natalizumab drug concentrations have a negative impact on the development of brain atrophy over time.

Early cerebral amyloid-β accumulation and hypermetabolism are associated with subtle cognitive deficits before accelerated cerebral atrophy

AimsAlzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aβ) in the brain. The deposition of Aβ is believed to initiate a detrimental cascade, including cerebral hypometabolism, accelerated brain atrophy, and cognitive problems—ultimately resulting in AD. However, the timing and causality of the cascade resulting in AD are not yet fully established. Therefore, we examined whether early Aβ accumulation affects cerebral glucose metabolism, atrophy rate, and age-related cognitive decline before the onset of neurodegenerative disease.MethodsParticipants from the Metropolit 1953 Danish Male Birth Cohort underwent brain positron emission tomography (PET) imaging using the radiotracers [11C]Pittsburgh Compound-B (PiB) (N = 70) and [18F]Fluorodeoxyglucose (FDG) (N = 76) to assess cerebral Aβ accumulation and glucose metabolism, respectively. The atrophy rate was calculated from anatomical magnetic resonance imaging (MRI) scans conducted presently and 10 years ago. Cognitive decline was examined from neurophysiological tests conducted presently and ten or 5 years ago.ResultsHigher Aβ accumulation in AD-critical brain regions correlated with greater visual memory decline (p = 0.023). Aβ accumulation did not correlate with brain atrophy rates. Increased cerebral glucose metabolism in AD-susceptible regions correlated with worse verbal memory performance (p = 0.040).ConclusionsAβ accumulation in known AD-related areas was associated with subtle cognitive deficits. The association was observed before hypometabolism or accelerated brain atrophy, suggesting that Aβ accumulation is involved early in age-related cognitive dysfunction. The association between hypermetabolism and worse memory performance may be due to early compensatory mechanisms adapting for malfunctioning neurons by increasing metabolism.

Longitudinal biomarkers in Dementia with Lewy bodies: A systematic review and meta‐analysis

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease (AD). DLB is a clinically and biologically heterogeneous disease, and little is known about longitudinal trajectories of patients with DLB. Disease progression can be measured with biomarkers capturing structural, functional, and pathological processes, aiding in understanding disease mechanism and discovering potential drug targets. We aimed to perform a systematic review to explore longitudinal patterns of biomarkers in DLB.MethodsSearches were conducted within five different databases, including cohort studies and case series on DLB patients with repeated measures of fluid or imaging biomarkers, and at least six months follow‐up. Fourteen studies were included (Figure 1), reporting data on longitudinal MRI, DaT‐Scan, PiB and flortaucipir‐PET, plasma p‐tau, and HMPAO SPECT, with up to 2,5 years of follow‐up (Table 1). No data on cerebrospinal fluid biomarkers were available. We could only perform a meta‐analysis on annualized brain atrophy rates, with a random effect model and standardized mean differences (SMD).ResultsProgressive putaminal atrophy is seen in DLB patients, even when DaT‐scans are initially normal. In the meta‐analysis, brain atrophy rates were not significantly higher in pure DLB compared to cognitively unimpaired controls, with the exception of accelerated ventricular expansion rates (SMD 0.57 [0.03‐1.10], p = 0.04, 2 studies, 58 patients). Autopsy‐confirmed AD copathology resulted in greater global atrophy rates compared to pure DLB (SMD 0.72 [0.21‐1.31], p = 0.006, Figure 2), similar to AD. AD copathology accelerates temporal lobe and striatal atrophy rates. In one study, brain amyloid accumulation in DLB initially accelerated and then decelerated, similar to AD and cognitively unimpaired subjects, with absolute SUVr lower than AD. In another study, brain tau accumulation rate correlated with brain atrophy rates in the middle temporal pole in DLB patients.ConclusionsOnly a few studies reported longitudinal data on biomarkers in DLB. DLB patients do not have significantly higher brain atrophy rates compared to controls, while the presence of AD copathology accelerates global and regional atrophy. Future studies with longer follow‐ups and multimodal biomarkers are needed to further characterize disease progression and elucidate clinical and biological heterogeneity.

Leveraging systems biology approaches and single‐nucleus RNA‐seq to study sex differences in AD

AbstractBackgroundThere is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences in the rates of cognitive decline and brain atrophy. Sex‐related differences in AD‐associated genes are starting to emerge, but these have not been systematically studied at cell‐type‐specific transcriptome‐wide expression levels. We leveraged single‐nucleus RNA‐seq (snRNA‐seq) and systems biology approaches to identify transcriptomic modules in human brains and determine the modules associated with sex‐AD interactions.MethodsWe studied snRNA‐seq data from the parietal cortex of 67 pathologically confirmed controls, sporadic AD (sAD), autosomal dominant AD (ADAD), and other neurodegenerative samples from the Knight ADRC and DIAN cohorts1, and used Celda2 to co‐cluster cells and genes into subpopulations and modules. This approach identified clusters that correspond to previously described cell types1. We used linear mixed models to identify those modules associated with a sex‐AD interaction. For each nominally significant (P&lt;0.05) module, we isolated the top genes that accounted for 80% of the module expression signature and tested each for a sex‐AD interaction.ResultsWhen run on 38,584 astrocytes, Celda split 13,302 genes into 65 gene modules. Module L17 was nominally significant (P = 0.04), with 55 out of 194 genes accounting for ∼80% of the module signature. After multiple testing correction, two genes, ENTREP1/FAM189A2 (Adj.P = 1.57´10−2) and CD38 (Adj.P = 1.80´10−2), showed a significant sex‐sAD interaction in expression (Figure 1, Table 1). ENTREP1 facilitates the removal of the chemokine receptor CXCR4 from the plasma membrane reducing the downstream effects of CXCL12/CXCR4 signaling3 including astrocytic inflammation response4 and release of glutamate as a gliotransmitter5. Studies have linked ENTREP16 and CXCL12/CXCR47 to neurodegeneration. CD38 expression is influenced by cytokine and chemokines released by senescent cells, which increase with age, AD, and other neurodegenerative diseases8. Increased expression of CD38 increases proinflammatory cytokine release and reduces NAD‐dependent enzyme activity, increasing DNA mutations, mitochondrial dysfunction, and oxidative stress. Knockouts of CD38 in mouse showed significant decreases in Aβ plaque load and soluble Aβ levels9.ConclusionThese results suggest that the known neurodegenerative genes ENTREP1 and CD38 are uniquely modulated by biological sex in relation to AD within astrocytes potentially contributing to the clinical differences seen between males and females.

White matter hyperintensity volume changes are associated with progressive hippocampal atrophy in Insight 46: the neuroscience sub‐study of the MRC National Survey of Health and Development, the British 1946 birth cohort

AbstractBackgroundWhite matter hyperintensity volume (WMHV) is a presumed marker of cerebrovascular disease associated with ageing, Alzheimer’s disease (AD) and vascular dementia. Higher baseline WMHV is associated with increased brain atrophy rate, with disproportionate effects in the hippocampus – a region affected early in AD. Understanding the relationships between longitudinal change in WMHV and hippocampal atrophy, while accounting for AD and cardiovascular risk factors, will increase our understanding of the multifactorial disease processes occurring during the early stages of AD.MethodRate of change in WMHV was calculated using Bayesian Model Selection (BaMoS) and total hippocampal atrophy rate was calculated using the Boundary Shift Integral (BSI), measured concurrently between two time‐points. Participants with major neurological disorders were excluded. Linear regression was used to test whether rates of WMHV change predicted rates of hippocampal atrophy while adjusting for total intracranial volume (TIV), sex and age. Further models adjusted for baseline PET amyloid‐β (Aβ) standard uptake value ratio (SUVR), ApoE‐e4 carrier status, and Framingham heart study cardiovascular risk (FHS‐CVS) aged 69, and tested for interactions with rate of WMHV change.Result308 individuals with high‐resolution isotropic MRI data at two time‐points were analysed in this study (Table 1). For every 1ml/year increase in WMHV there was an associated 0.013ml/year decrease in total hippocampal volume (Table 2, Model 1). This association remained when adjusting for Aβ SUVR (Table 2, Model 2), ApoE‐e4 status (Table 2, Model 3), and FHS‐CVS (Table 2, Model 4). A separate semi‐partial correlation analysis showed 4.6% of variance in rate of hippocampal atrophy was uniquely explained by rate of WMHV change when accounting for TIV, sex and age. There were no significant interactions between rate of WMHV change and Aβ, ApoE‐e4 or FHS‐CVS in relation to hippocampal atrophy rate.ConclusionIncreases in WMHV were significantly associated with progressive hippocampal atrophy accounting for head size, age and sex. These associations were not materially changed when adjusting for amyloid deposition, ApoE‐e4 or cardiovascular risk factors. These results suggest systemic processes that contribute to WMH development also contribute to hippocampal atrophy. Further work is required to determine the processes that drive this relationship.

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack

The relationship of small vessel disease burden on cerebral and regional brain atrophy rates and cognitive performance over one year of follow-up after transient ischemic attack

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Associations between peripheral hearing ability at age 70, brain atrophy and cognitive decline in adults born in the same week of 1946

AbstractBackgroundPeripheral hearing impairment has been proposed as a risk factor for dementia. However, the relationship between hearing ability, neurodegeneration and cognitive decline, and the extent to which pathological processes associated with increased risk of specific causes of dementia, such as β‐amyloid and small vessel disease, influence these relationships, is unclear.MethodData were analysed from 287 cognitively normal adults born in the same week of 1946 who underwent pure tone audiometry testing at baseline (mean age = 70.6 years), with cognitive assessment and brain imaging at baseline and at follow‐up on average 2.4 years later. Peripheral hearing impairment was defined as a pure tone average of greater than 25 decibels in the best hearing ear. Rates of change for whole brain, hippocampal and ventricle volume were estimated from structural MRI using the Boundary Shift Integral. Cognition was assessed using the Pre‐clinical Alzheimer’s Cognitive Composite. Regression models were performed to evaluate how baseline hearing impairment associated with subsequent brain atrophy and cognitive decline after adjustment for a range of variables including baseline β‐amyloid deposition (assessed using florbetapir‐PET) and baseline small vessel disease burden (estimated using white matter hyperintensity volume).Results111 out of 287 participants were defined as having peripheral hearing impairment. Hearing impaired individuals demonstrated faster rates of whole brain atrophy (p = 0.031 – figure/table 1) compared with those with normal hearing. Peripheral hearing impairment did not predict change in PACC performance, but there was evidence of an interaction between hearing impairment and whole brain atrophy rates in terms of effect on change in PACC performance. Specifically, faster rates of whole brain atrophy predicted greater cognitive decline in participants with hearing impairment (p = 0.004), whilst there was no evidence of an association between cognitive change and atrophy in participants with preserved hearing (figure/table 2). There was no evidence that β‐amyloid deposition or white matter hyperintensity volume modified these relationships.ConclusionWe present evidence of associations between peripheral hearing ability at age 70, brain atrophy and cognitive decline independent of β‐amyloid and small vessel disease, suggesting hearing may associate with brain health via mechanisms distinct from those typically implicated in pre‐clinical Alzheimer’s disease and vascular cognitive impairment.

Longitudinal brain atrophy rates in presymptomatic genetic frontotemporal dementia

AbstractBackgroundIn light of upcoming clinical trials for genetic frontotemporal dementia (FTD), it is important to identify at what age brain atrophy rates start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We aimed to investigate longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD, using normative brain volumetry software.Method34 GRN, eight MAPT, and 14 C9orf72 presymptomatic mutation carriers underwent longitudinal volumetric T1‐weighted MRI of the brain with a one‐ to two‐year interval (mean number of scans = 3.5, SD = 1.6). Images were automatically analyzed with Quantib® ND which consisted of volume measurements (CSF and grey + white matter) of lobes (left, right, and combined), cerebellum, and hippocampus. All volumes were compared to reference centile curves based on a large population‐derived sample of non‐demented individuals (n = 4951). Mixed‐effects models were fitted to analyze atrophy rates of the different gene groups as a function of age, and were corrected for sex, head coil, and scanner software version.ResultAtrophy rates of the total brain, frontal lobe, and temporal lobe differed between gene groups (all p&lt;0.002). GRN mutation carriers declined faster than the reference centile curves for all brain areas, though relative volumes remained between 5th and 75th percentile between the ages of 45 – 70. In MAPT mutation carriers, frontal lobe volume was already at the 5th percentile at age 45, and showed further decline between the ages 50‐60. Temporal lobe volume started in the 50th percentile at age 45, but showed fastest decline over time compared to other brain structures. Frontal, temporal, parietal and cerebellar volume already started below the 5th percentile compared to the reference centile curves at age 45 for C9orf72 mutation carriers, but there was minimal decline over time until the age of 60.ConclusionWe provide evidence for longitudinal brain atrophy in the presymptomatic stage of genetic FTD. The affected brain areas and the age after which atrophy rates start to accelerate and diverge from normal aging slopes differed between gene groups. These results highlight the value of normative volumetry software for disease‐tracking and staging biomarkers in genetic FTD.

Proteomics and relationship with axonal pathology in multiple sclerosis: 5-year diffusion tensor imaging study.

Blood-based biomarkers can be economic and easily accessible tools for monitoring and predicting disease activity in multiple sclerosis. The objective of this study was to determine the predictive value of a multivariate proteomic assay for concurrent and future microstructural/axonal brain pathology in a longitudinal study of a heterogeneous group of people with multiple sclerosis. A proteomic analysis was obtained on serum samples from 202 people with multiple sclerosis (148 relapsing-remitting and 54 progressive) at baseline and 5-year follow-up. The concentration of 21 proteins related to multiple pathways of multiple sclerosis pathophysiology was derived using Proximity Extension Assay on the Olink platform. Patients were imaged on the same 3T MRI scanner at both timepoints. Тhe rate of whole brain, white matter and grey matter atrophy over the 5-year follow-up was determined using the multi-timepoint Structural Image Evaluation, using Normalisation, of Atrophy algorithms. Lesion burden measures were also assessed. The severity of microstructural axonal brain pathology was quantified using diffusion tensor imaging. Fractional anisotropy and mean diffusivity of normal-appearing brain tissue, normal-appearing white matter, grey matter, T2 and T1 lesions were calculated. Age, sex and body mass index-adjusted step-wise regression models were used. Glial fibrillary acidic protein was the most common and highest-ranked proteomic biomarker associated with greater concurrent microstructural central nervous system alterations (P < 0.001). The rate of whole brain atrophy was associated with baseline levels of glial fibrillary acidic protein, protogenin precursor, neurofilament light chain and myelin oligodendrocyte (P < 0.009), whereas grey matter atrophy was associated with higher baseline neurofilament light chain, higher osteopontin and lower protogenin precursor levels (P < 0.016). Higher baseline glial fibrillary acidic protein level was a significant predictor of future severity of the microstructural CNS alterations as measured by normal-appearing brain tissue fractional anisotropy and mean diffusivity (standardized β = -0.397/0.327, P < 0.001), normal-appearing white matter fractional anisotropy (standardized β = -0.466, P < 0.0012), grey matter mean diffusivity (standardized β = 0.346, P < 0.011) and T2 lesion mean diffusivity (standardized β = 0.416, P < 0.001) at the 5-year follow-up. Serum levels of myelin-oligodendrocyte glycoprotein, neurofilament light chain, contactin-2 and osteopontin proteins were additionally and independently associated with worse concomitant and future axonal pathology. Higher glial fibrillary acidic protein levels were associated with future disability progression (Exp(B) = 8.65, P = 0.004). Multiple proteomic biomarkers are independently associated with greater severity of axonal brain pathology as measured by diffusion tensor imaging in multiple sclerosis. Baseline serum glial fibrillary acidic protein levels can predict future disability progression.

Disability progression and worse cognitive status are associated with higher concurrent brain atrophy rates (P13-3.007)

<h3>Objective:</h3> To determine associations between brain atrophy rate and clinical outcome measures in multiple sclerosis (MS). <h3>Background:</h3> The determination and treatment of neurodegenerative aspects of MS remains a challenge. One indirect form of assessment is the whole brain atrophy rate as determined by longitudinal MRI. Integration of brain atrophy rate assessments into clinical practice is hampered by multiple technical and translational factors, including incomplete clinical validation. It remains unclear to what extent clinical assessments are reflected and associated with this measure. <h3>Design/Methods:</h3> In a large retrospective observational cohort, we used FSL-SIENA to determine annualized percent brain volume change (aPBVC) from longitudinal clinical 3T MRI obtained using a uniform hardware and software acquisition protocol. Clinical outcomes, including confirmed disability progression, the 9-hole peg test (9HPT), the symbol digit modalities test (SDMT), and the timed-25-foot walk (T25w) were determined from retrospective chart review. SDMT, 9HPT, and T25w were averaged between the first and second MRI sessions to produce a single number. Using forward regression models, we assessed clinical predictors of aPBVC, including CDP and secondary clinical outcome measures, as independent variables along with age of onset and type of MS. <h3>Results:</h3> 123 patients met inclusion criteria (102 RMS, 21 PMS; mean age = 36 ±SD 11) with available clinical and MRI data. In univariable analyses, confirmed disability progression showed the strongest association with concurrent aPBVC (β=0.31, p &lt;0.001), followed by the SDMT (β=0.27, p=0.006) whereas 9HPT and T25 were not significant (p&gt;0.05). Change in EDSS and cross-sectional SDMT both remained significantly associated in multivariable models (p=0.008 and p=0.04, respectively). <h3>Conclusions:</h3> Both disability progression as well as the SDMT are independently associated with the observed brain atrophy rate. <b>Disclosure:</b> Dr. Garcia-Dominguez has nothing to disclose. Dr. Hemond has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for VIVIO Health. Dr. Hemond has stock in VIVIO Health. The institution of Dr. Hemond has received research support from Consorium of Multiple Sclerosis Centers. The institution of Dr. Hemond has received research support from National Multiple Sclerosis Society. The institution of Dr. Hemond has received research support from National Center for Advancing Translational Sciences, National Institutes of Health. The institution of Dr. Hemond has received research support from University of Massachusetts Memorial Medical Center. The institution of Dr. Hemond has received research support from National Institute Of Neurological Disorders And Stroke of the National Institutes of Health. Dr. Hemond has received personal compensation in the range of $0-$499 for serving as a Member of Data Safety and Monitoring Board with National Institute Of Neurological Disorders And Stroke of the National Institutes of Health.

Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial (NCT03269071, EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale ≥6.5, age 18–55 years, disease duration 2–20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients.