Rate Of Brain Atrophy Research Articles

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.

Spotlight on the December 13 Issue

![Graphic][1]</img>#### Notable in Neurology This Week This issue features an article that examines the association of striatal dopamine depletion pattern and white matter networks in Parkinson disease; another investigates the prevalence and patterns of interfacility transfers after seizure-related emergency department visits. A featured Contemporary Issues in Practice, Education, & Research article presents a progress report of the National Institute of Neurological Disorders and Stroke's 2021–2026 Strategic Plan. ### Longitudinal Brain Atrophy Rates in Presymptomatic Carriers of Genetic Frontotemporal Dementia ![Graphic][2]</img> Identifying the timing of brain changes in genetic frontotemporal dementia (FTD) may improve diagnostics, care, … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif

Multiple sclerosis as a model to investigate SARS-CoV-2 effect on brain atrophy.

Data on structural brain changes after infection with SARS-CoV-2 is sparse. We postulate multiple sclerosis as a model to study the effects of SARS-CoV-2 on brain atrophy due to the unique availability of longitudinal imaging data in this patient group, enabling assessment of intraindividual brain atrophy rates. Global and regional cortical gray matter volumes were derived from structural MRIs using FreeSurfer. A linear model was fitted to the measures of the matching pre-SARS-CoV-2 images with age as an explanatory variable. The residuals were used to determine whether the post-SARS-CoV-2 volumes differed significantly from the baseline. Fourteen RRMS patients with a total of 113 longitudinal magnetic resonance images were retrospectively analyzed. We found no acceleration of brain atrophy after infection with SARS-CoV-2 for global gray matter volume (p= 0.17). However, on the regional level, parahippocampal gyri showed a tendency toward volume reduction (p= 0.0076), suggesting accelerated atrophy during or after infection. Our results illustrate the opportunity of using longitudinal MRIs from existing MS registries to study brain changes associated with SARS-CoV-2 infections. We would like to address the global MS community with a call for action to use the available cohorts, reproduce the proposed analysis, and pool the results.

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&lt;0.01), in contrast to increases in both white matter and grey matter in Alzheimer’s disease (P&lt;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&lt;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.

KDM6A expression is associated with a sex‐disease interaction in activated microglia

AbstractBackgroundThere is increasing evidence indicating sex‐specific patterns in disease manifestation and sex differences in the rates of cognitive decline and brain atrophy. Women are protected, relative to men, at the prodromal phases but later exhibit steeper cognitive decline and higher brain atrophy rates1. Sex‐related differences in AD‐associated genes are starting to emerge. The X‐linked gene, KDM6A, avoids X‐inactivation and the resulting elevation in expression confers resilience in women2. KDM6A is also dysregulated in disease associated microglia (DAM) in the 5XFAD mouse model3. We sought to identify if activated microglia was the effector cell type for the KDM6A resilience effect in the brain using single‐nucleus RNA‐seq (snRNA‐seq).MethodsUsing snRNA‐seq data from the parietal cortex of 56 pathologically confirmed control, sporadic AD (sAD), and autosomal dominant AD (ADAD) samples from the Knight ADRC and DIAN cohorts4, we applied a linear mixed model to confirm the female specific upregulation of KDM6A in the major brain cell types and their alternative transcriptional states. We then applied a sex‐AD interaction linear mixed model to identify the cell types and expression states that potentially contribute to disease resilience through KDM6A expression.Results KDM6A is expressed in all major brain cell types, with the highest expression in oligodendrocytes, followed by endocytes, microglia, astrocytes, OPCs, and neurons (http://ngi.pub/SNARE/). All cell types showed increased KDM6A expression in females compared to males (oligo P=4.22×10‐15, microglia P=1.07×10‐41, astro P=1.30×10‐13, OPC P=2.55×10‐5, neuron P=7.55×10‐8). We identified a sex‐AD interaction in KDM6A expression within activated microglia (sAD P=9.12×10‐3; ADAD P=2.28×10‐3; Fig. 1), but no evidence in the overall DAM signature. Female sAD and ADAD samples showed higher expression compared to controls, while male sAD and ADAD samples had less expression than controls. Furthermore, we observed sex differences in KDM6A expression within transcriptional states of oligodendrocytes, OPCs, astrocytes and neurons. We are validating these results in additional generated data and publicly available data sets.ConclusionThese results suggest that the role of KDM6A in AD resilience could be mediated through activated microglia, but current data cannot rule out additional cell types as effectors in KDM6A resilience.

Alzheimer‐like biomarker heterogeneity in a preclinical elderly birth cohort: Insight46

AbstractBackgroundTwo main complexities of Alzheimer’s Disease (AD) arise from pathological changes (such as amyloid accumulation) occurring a decade or more before symptom onset, and AD being a highly heterogeneous disease with various clinical subtypes. Subtype and Stage Inference (SuStaIn), a data‐driven modelling technique, has been previously applied to ADNI to better understand AD. Here we apply SuStaIn to Insight46, a sub‐study of the British 1946 Birth Cohort to detect different trajectories of preclinical neurodegeneration.MethodSuStaIn was applied to cross‐sectional MRI, amyloid PET, plasma biomarkers, and cognition (Preclinical Alzheimer Cognitive Composite [PACC]) from 466 study members (Table 1). 376 Amyloid‐negative individuals (computed as Lane et al. 2019) were designated as controls. SuStaIn subtypes were also estimated in ADNI (N=789; Tables 1 and 2) for comparison. T‐tests and Chi‐squared tests were used to assess subtype differences in baseline APOE, amyloid status, white matter hyperintensity volume (WMHV), and rates of change in whole brain, ventricular and hippocampal volume calculated using the boundary shift integral.ResultFigure 1 shows three subtypes uncovered by SuStaIn: ‘Typical’, ‘Subcortical’ and ‘Cortical’. The ‘Typical’ subtype appears to reflect a typical AD progression pattern, with early involvement of Aβ40/42 ratio and Neurofilament light (NFL), followed by the PACC and finally, plasma tau. MRI volumetric changes appear later. Both ‘Subcortical’ and ‘Cortical’ subtypes are characterised by earlier abnormality in MRI volumes.Figure 2 shows that subjects assigned to the ‘Cortical’ subtype had significantly higher WMHV than the other two subtypes (p‐value &lt; 0.002). No other significant differences in baseline characteristics were found.Figure 3 shows ‘Typical’ subtype has significantly higher rates of ventricular expansion and whole brain atrophy compared with ‘Subcortical’ subtype (p‐values = 0.001).ConclusionThis study reveals three different subtypes (‘Typical’, ‘Subcortical’ and ‘Cortical’) of presumed neurodegeneration in an elderly, preclinical cohort; these are consistent with those found in AD patient cohorts, e.g. ADNI, meaning that these methods may have utility in population based cohorts. These results suggest that SuStaIn may be helpful in determining different subtypes of neurodegeneration at a very early stage with implications for recruitment to, and powering of, clinical trials.

Associations of sNfL with clinico-radiological measures in a large MS population.

Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice. Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay. Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable. Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking.

HLA-DRB1*1501 influences long-term disability progression and tissue damage on MRI in relapse-onset multiple sclerosis

Background: Whether genetic factors influence the long-term course of multiple sclerosis (MS) is unresolved. Objective: To determine the influence of HLA-DRB1*1501 on long-term disease course in a homogeneous cohort of clinically isolated syndrome (CIS) patients. Methods: One hundred seven patients underwent clinical and MRI assessment at the time of CIS and after 1, 3, 5 and 15 years. HLA-DRB1*1501 status was determined using Sanger sequencing and tagging of the rs3135388 polymorphism. Linear/Poisson mixed-effects models were used to investigate rates of change in EDSS and MRI measures based on HLA-DRB1*1501 status. Results: HLA-DRB1*1501 -positive (n = 52) patients showed a faster rate of disability worsening compared with the HLA-DRB1*1501 -negative (n = 55) patients (annualised change in EDSS 0.14/year vs. 0.08/year, p < 0.025), and a greater annualised change in T2 lesion volume (adjusted difference 0.45 mL/year, p < 0.025), a higher number of gadolinium-enhancing lesions, and a faster rate of brain (adjusted difference −0.12%/year, p < 0.05) and spinal cord atrophy (adjusted difference −0.22 mm2/year, p < 0.05). Interpretation: These findings provide evidence that the HLA-DRB1*1501 allele plays a role in MS severity, as measured by long-term disability worsening and a greater extent of inflammatory disease activity and tissue loss. HLA-DRB1*1501 may provide useful information when considering prognosis and treatment decisions in early relapse-onset MS.

RBIO-07. HIGHER CSF IL-10 CORRELATE WITH BRAIN ATROPHY AFTER WHOLE BRAIN RADIATION THERAPY IN PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

Abstract Whole brain radiation therapy (WBRT) to primary central nervous system lymphoma (PCNSL) correlate with brain atrophy and leukoencephalopathy on serial computed tomography or MRI scans, negatively impacting cognitive function and quality of life. We retrospectively evaluated 53 patients with histologically proven PCNSL who underwent cerebrospinal fluid (CSF) examination including β2-MG, sIL2R, CXCL13, and IL-10 preoperatively. All patients were newly diagnosed and followed up every 3 months from the day they were discharged from the hospital. Follow up period is at least 1 year from last day of chemotherapy. Clinical data included patient demographics, radiological and characteristics; whole brain volume (mm2) calculated from BainLabTM automatically, Global Cortical Atrophy (GCA) for global brain atrophy, Medial Temporal Atrophy (MTA) for temporal atrophy, and Fazekas scale for white matter lesions. The unpaired t test and multivariable liner regression were used to examine the clinical, CSF and radiological characteristics of patients. The mean age at symptom onset was 65.2 years (47-85 years). Thirty three of 53 (62%) patients underwent WBRT with chemotherapy (WBRT group). In all patients, multivariable analysis revealed WBRT correlate with brain volume reduction (p=0.0005) and progression of temporal lobe atrophy (p=0.0056). In addition, Age correlated with increasing white matter lesions at 1 year after chemotherapy (p=0.0422). In WBRT group, multivariable analysis indicated that high CSF IL-10 level accelerated brain volume reduction (p=0.0122) and temporal lobe atrophy (p=0.0343) at 6 months after chemotherapy. However, there were no significant factor for influencing brain atrophy at 1 year. Higher IL-10 ( &amp;gt; 100mg/ml) level demonstrated higher brain atrophy rate (p=0.0366) and severe temporal atrophy at 1 year (p=0.0214). In elderly patients with high preoperative CSF IL-10 levels, cerebral atrophy and toxic leukoencephalopathy may progress in short period of time after WBRT. We should consider treatment strategy that avoid WBRT, such as R-MPV chemotherapy, for PCNSL patients.

An investigation of the effect of brain atrophy on brain injury in multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system (CNS) that affects the brain and spinal cord. It is estimated that the average prevalence of MS is 35.9 cases per 100,000 and a total of 2.8 million people worldwide have MS. Brain atrophy is usually seen in the early stages of MS, and its progress is faster than healthy people. The present study was a numerical study that uses the Fluid–structure interaction (FSI) model to investigate the effect of brain atrophy on brain injury in MS. Firstly, a healthy model was constructed from MRI images and validated by experimental data. Then three models with different degrees of brain atrophy, which showed the rate of brain atrophy in different years in MS patients, were developed to model the brain atrophy in MS. The models were subjected to two different types of impact conditions. Type I, which only produced a translational motion and the HIC value of 744, was applied to each model. Type II produced both translational and rotational motion. In this type of impact, the experimental kinematics, with peaks of 450 g for the translational acceleration and 26.2 krad/s2 for the rotational acceleration, were applied to the nodes that located in the center of gravity of the head models and the results were extracted from each one. According to the results of impact type I, the pressure of the frontal lobe of the brain is 149,647 Pa in the health model and 137,690 Pa in the model with severe atrophy.

Longitudinal Brain Atrophy Rates in Presymptomatic Carriers of Genetic Frontotemporal Dementia.

It is important to identify at what age brain atrophy rates in genetic frontotemporal dementia (FTD) start to accelerate and deviate from normal aging effects to find the optimal starting point for treatment. We investigated longitudinal brain atrophy rates in the presymptomatic stage of genetic FTD using normative brain volumetry software. Presymptomatic GRN, MAPT, and C9orf72 pathogenic variant carriers underwent longitudinal volumetric T1-weighted magnetic resonance imaging of the brain as part of a prospective cohort study. Images were automatically analyzed with Quantib® ND, which consisted of volume measurements (CSF and sum of gray and white matter) of lobes, cerebellum, and hippocampus. All volumes were compared with reference centile curves based on a large population-derived sample of nondemented individuals (n = 4,951). Mixed-effects models were fitted to analyze atrophy rates of the different gene groups as a function of age. Thirty-four GRN, 8 MAPT, and 14 C9orf72 pathogenic variant carriers were included (mean age = 52.1, standard deviation = 7.2; 66% female). The mean follow-up duration of the study was 64 ± 33 months (median = 52; range 13-108). GRN pathogenic variant carriers showed a faster decline than the reference centile curves for all brain areas, though relative volumes remained between the 5th and 75th percentiles between the ages of 45 and 70 years. In MAPT pathogenic variant carriers, frontal lobe volume was already at the 5th percentile at age 45 years and showed a further decline between the ages 50 and 60 years. Temporal lobe volume started in the 50th percentile at age 45 years but showed fastest decline over time compared with other brain structures. Frontal, temporal, parietal, and cerebellar volume already started below the 5th percentile compared with the reference centile curves at age 45 years for C9orf72 pathogenic variant carriers, but there was minimal decline over time until the age of 60 years. We 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. These techniques could help in identifying the optimal time window for starting treatment and monitoring treatment response.

Herpes simplex virus and rates of cognitive decline or whole brain atrophy in the Dominantly Inherited Alzheimer Network.

To investigate whether herpes simplex virus type 1 (HSV-1) infection was associated with rates of cognitive decline or whole brain atrophy among individuals from the Dominantly Inherited Alzheimer Network (DIAN). Among two subsets of the DIAN cohort (age range 19.6-66.6 years; median follow-up 3.0 years) we examined (i) rate of cognitive decline (N = 164) using change in mini-mental state examination (MMSE) score, (ii) rate of whole brain atrophy (N = 149), derived from serial MR imaging, calculated using the boundary shift integral (BSI) method. HSV-1 antibodies were assayed in baseline sera collected from 2009-2015. Linear mixed-effects models were used to compare outcomes by HSV-1 seropositivity and high HSV-1 IgG titres/IgM status. There was no association between baseline HSV-1 seropositivity and rates of cognitive decline or whole brain atrophy. Having high HSV-1 IgG titres/IgM was associated with a slightly greater decline in MMSE points per year (difference in slope - 0.365, 95% CI: -0.958 to -0.072), but not with rate of whole brain atrophy. Symptomatic mutation carriers declined fastest on both MMSE and BSI measures, however, this was not influenced by HSV-1. Among asymptomatic mutation carriers, rates of decline on MMSE and BSI were slightly greater among those who were HSV-1 seronegative. Among mutation-negative individuals, no differences were seen by HSV-1. Stratifying by APOE4 status yielded inconsistent results. We found no evidence for a major role of HSV-1, measured by serum antibodies, in cognitive decline or whole brain atrophy among individuals at high risk of early-onset AD.

Editors' Note: Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials.

In a post hoc blinded analysis of 2 placebo-controlled, phase 3 trials, Dr. Leppert and colleagues investigated the association of plasma neurofilament light (pNfL) levels with disability progression, cognitive decline, and brain atrophy in 1,452 patients with secondary progressive multiple sclerosis (SPMS; EXPAND trial of siponimod) and 378 patients with primary progressive multiple sclerosis (PPMS; INFORMS trial of fingolimod). They found that higher pNfL levels were independently associated with higher risks of confirmed 3- and 6-month disability progression, earlier wheelchair dependence, cognitive decline (in SPMS), and higher rates of 24-month brain atrophy. pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo, and the authors concluded that pNfL may be a meaningful outcome measure in PMS studies. In response, Dr. Barro raises concerns about whether the pNfL quantification in the 2 trials were performed with the same batches of reagents, given the potential for batch-to-batch variability, and questions the use of a fixed threshold for high vs low pNfL levels in the analyses instead of age-adjusted thresholds, given the association of older age with both higher pNfL levels and disability progression. Responding to these comments, the authors agree that batch-to-batch variability may be an important assay confounder, but note that the coefficient of variation was less than 15% for each of the 3 native serum control samples with high, medium, and low pNfL used in the study. They argue that whereas the assay used in their study did not allow direct application of the age-adjusted cutoffs, age was included as a covariable in all statistical models, so the higher risk of progression in patients with a higher baseline pNfL in their study cannot be attributed to age differences. They also agree that z scores or percentiles would be preferable to fixed cutoffs. This exchange indicates the difficulties of standardization of assays for pNfL measurement. Although pNfL measurements now permeate the literature on numerous neurologic conditions, harmonization of study methods continues to be a challenge. In a post hoc blinded analysis of 2 placebo-controlled, phase 3 trials, Dr. Leppert and colleagues investigated the association of plasma neurofilament light (pNfL) levels with disability progression, cognitive decline, and brain atrophy in 1,452 patients with secondary progressive multiple sclerosis (SPMS; EXPAND trial of siponimod) and 378 patients with primary progressive multiple sclerosis (PPMS; INFORMS trial of fingolimod). They found that higher pNfL levels were independently associated with higher risks of confirmed 3- and 6-month disability progression, earlier wheelchair dependence, cognitive decline (in SPMS), and higher rates of 24-month brain atrophy. pNfL levels were lower in patients treated with siponimod or fingolimod vs placebo, and the authors concluded that pNfL may be a meaningful outcome measure in PMS studies. In response, Dr. Barro raises concerns about whether the pNfL quantification in the 2 trials were performed with the same batches of reagents, given the potential for batch-to-batch variability, and questions the use of a fixed threshold for high vs low pNfL levels in the analyses instead of age-adjusted thresholds, given the association of older age with both higher pNfL levels and disability progression. Responding to these comments, the authors agree that batch-to-batch variability may be an important assay confounder, but note that the coefficient of variation was less than 15% for each of the 3 native serum control samples with high, medium, and low pNfL used in the study. They argue that whereas the assay used in their study did not allow direct application of the age-adjusted cutoffs, age was included as a covariable in all statistical models, so the higher risk of progression in patients with a higher baseline pNfL in their study cannot be attributed to age differences. They also agree that z scores or percentiles would be preferable to fixed cutoffs. This exchange indicates the difficulties of standardization of assays for pNfL measurement. Although pNfL measurements now permeate the literature on numerous neurologic conditions, harmonization of study methods continues to be a challenge.

Brain Atrophy Is Substantially Accelerated in Neurological Wilson's Disease: A Longitudinal Study.

Although brain atrophy is common in neurological Wilson's disease, longitudinal studies are lacking. The objective of this study was to measure longitudinal brain atrophy rate and to relate it to the change in neurological impairment in Wilson's disease. We included patients with brain imaging done at diagnosis and at least 12months later. The atrophy rate was measured as percentage change in ventricular volume, whereas the change in neurological impairment was scored on the Unified Wilson's Disease Rating Scale. Of 57 patients, 36 had neurological presentation, 17 had hepatic presentation, and 4 were presymptomatic. The annualized atrophy rate was significantly greater in patients with the neurological presentation than in other patients (P=0.001). In the neurological presentation, the atrophy rate correlated with the change in impairment (rho=0.39, P=0.018) and was significantly greater in those with worsening after diagnosis than in those without worsening (P < 0.001). Brain atrophy rate appears as a promising marker of neurodegeneration in Wilson's disease. © 2022 International Parkinson and Movement Disorder Society.

Life course, genetic, and neuropathological associations with brain age in the 1946 British Birth Cohort: a population-based study

A neuroimaging-based biomarker termed the brain age is thought to reflect variability in the brain's ageing process and predict longevity. Using Insight 46, a unique narrow-age birth cohort, we aimed to examine potential drivers and correlates of brain age. Participants, born in a single week in 1946 in mainland Britain, have had 24 prospective waves of data collection to date, including MRI and amyloid PET imaging at approximately 70 years old. Using MRI data from a previously defined selection of this cohort, we derived brain-predicted age from an established machine-learning model (trained on 2001 healthy adults aged 18-90 years); subtracting this from chronological age (at time of assessment) gave the brain-predicted age difference (brain-PAD). We tested associations with data from early life, midlife, and late life, as well as rates of MRI-derived brain atrophy. Between May 28, 2015, and Jan 10, 2018, 502 individuals were assessed as part of Insight 46. We included 456 participants (225 female), with a mean chronological age of 70·7 years (SD 0·7; range 69·2 to 71·9). The mean brain-predicted age was 67·9 years (8·2, 46·3 to 94·3). Female sex was associated with a 5·4-year (95% CI 4·1 to 6·8) younger brain-PAD than male sex. An increase in brain-PAD was associated with increased cardiovascular risk at age 36 years (β=2·3 [95% CI 1·5 to 3·0]) and 69 years (β=2·6 [1·9 to 3·3]); increased cerebrovascular disease burden (1·9 [1·3 to 2·6]); lower cognitive performance (-1·3 [-2·4 to -0·2]); and increased serum neurofilament light concentration (1·2 [0·6 to 1·9]). Higher brain-PAD was associated with future hippocampal atrophy over the subsequent 2 years (0·003 mL/year [0·000 to 0·006] per 5-year increment in brain-PAD). Early-life factors did not relate to brain-PAD. Combining 12 metrics in a hierarchical partitioning model explained 33% of the variance in brain-PAD. Brain-PAD was associated with cardiovascular risk, and imaging and biochemical markers of neurodegeneration. These findings support brain-PAD as an integrative summary metric of brain health, reflecting multiple contributions to pathological brain ageing, and which might have prognostic utility. Alzheimer's Research UK, Medical Research Council Dementia Platforms UK, Selfridges Group Foundation, Wolfson Foundation, Wellcome Trust, Brain Research UK, Alzheimer's Association.

The Role of Amyloid, Tau, and APOE Genotype on the Relationship Between Informant-Reported Sleep Disturbance and Alzheimer's Disease Risks.

The association between sleep and Alzheimer's disease (AD) biomarkers are well-established, but little is known about how they interact to change the course of AD. To determine the potential interaction between sleep disturbance and Aβ, tau, and APOE4 on brain atrophy and cognitive decline. Sample included 351 participants (mean age 72.01 ± 6.67, 50.4%female) who were followed for approximately 5 years as part of the Alzheimer's Disease Neuroimaging Initiative. Informant-reported sleep disturbance (IRSD) was measured using the Neuropsychiatric Inventory (NPI). Changes in magnetic resonance imaging (MRI)-measured AD signature brain regions and cognitive performance and IRSD's interaction with cerebrospinal fluid amyloid-β (Aβ42) and p-Tau depositions and APOE4 status were examined using the linear mixed models. Baseline IRSD was not significantly associated with the rate of atrophy after adjusting for covariates (age, sex, education, total NPI severity score, and sleep medications). However, there was a significant interaction between IRSD and AD biomarkers on faster atrophy rates in multiple brain regions, including the cortical and middle temporal volumes. Post-hoc analyses indicated that Aβ and p-Tau/Aβ predicted a faster decline in these regions/domains in IRSD, compared with biomarker-negative individuals with IRSD (ps≤0.001). There was a significant IRSD*APOE4 interaction for brain atrophy rate (ps≤0.02) but not for cognition. IRSD may increase the future risk of AD by contributing to faster brain atrophy and cognitive decline when combined with the presence of AD biomarkers and APOE4. Early intervention for sleep disturbance could help reduce the risk of developing AD.

Retinal inner nuclear layer thinning is decreased and associates with the clinical outcome in ocrelizumab-treated primary progressive multiple sclerosis

BackgroundOcrelizumab was found to decrease brain atrophy rate in primary progressive multiple sclerosis (PPMS), but no data are currently available on the effect of ocrelizumab on retinal layer thicknesses in the PPMS population.ObjectiveTo assess retinal layer changes in ocrelizumab-treated PPMS and test their possible application as biomarkers of therapy response.Methods36 PPMS patients, treated with ocrelizumab for at least 6 months, and 39 sex- and age-matched healthy controls (HC) were included in a blind, longitudinal study. Spectrum-domain optical coherence tomography (SD-OCT) was performed at study entry (T0) and after 6 (T6) and 12 months (T12). At month 24 (T24), patients were divided into responders (no evidence of 1-year confirmed disability progression, 1y-CDP) and non-responders (evidence of 1y-CDP).ResultsAt T24, 23/36 (64%) patients were considered responders and 13/36 (36%) non-responders. At T0, peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell–inner plexiform layer (GCIPL) and inner retinal layer (IRL) volume were significantly lower in PPMS compared to HC (p = 0.001 for all comparisons). At T6 and T12, non-responders significantly differed in the inner nuclear layer (INL) thinning rate compared to responders (p = 0.005 at both time-points).ConclusionsOcrelizumab significantly slows down INL thinning rate in PPMS responders. The longitudinal analysis of retina layer changes by means of OCT may be a promising prognostic test, and merits further investigations.

Association of Brain Atrophy With Disease Progression Independent of Relapse Activity in Patients With Relapsing Multiple Sclerosis

The mechanisms driving neurodegeneration and brain atrophy in relapsing multiple sclerosis (RMS) are not completely understood. To determine whether disability progression independent of relapse activity (PIRA) in patients with RMS is associated with accelerated brain tissue loss. In this observational, longitudinal cohort study with median (IQR) follow-up of 3.2 years (2.0-4.9), data were acquired from January 2012 to September 2019 in a consortium of tertiary university and nonuniversity referral hospitals. Patients were included if they had regular clinical follow-up and at least 2 brain magnetic resonance imaging (MRI) scans suitable for volumetric analysis. Data were analyzed between January 2020 and March 2021. According to the clinical evolution during the entire observation, patients were classified as those presenting (1) relapse activity only, (2) PIRA episodes only, (3) mixed activity, or (4) clinical stability. Mean difference in annual percentage change (MD-APC) in brain volume/cortical thickness between groups, calculated after propensity score matching. Brain atrophy rates, and their association with the variables of interest, were explored with linear mixed-effect models. Included were 1904 brain MRI scans from 516 patients with RMS (67.4% female; mean [SD] age, 41.4 [11.1] years; median [IQR] Expanded Disability Status Scale score, 2.0 [1.5-3.0]). Scans with insufficient quality were excluded (n = 19). Radiological inflammatory activity was associated with increased atrophy rates in several brain compartments, while an increased annualized relapse rate was linked to accelerated deep gray matter (GM) volume loss. When compared with clinically stable patients, patients with PIRA had an increased rate of brain volume loss (MD-APC, -0.36; 95% CI, -0.60 to -0.12; P = .02), mainly driven by GM loss in the cerebral cortex. Patients who were relapsing presented increased whole brain atrophy (MD-APC, -0.18; 95% CI, -0.34 to -0.02; P = .04) with respect to clinically stable patients, with accelerated GM loss in both cerebral cortex and deep GM. No differences in brain atrophy rates were measured between patients with PIRA and those presenting relapse activity. Our study shows that patients with RMS and PIRA exhibit accelerated brain atrophy, especially in the cerebral cortex. These results point to the need to recognize the insidious manifestations of PIRA in clinical practice and to further evaluate treatment strategies for patients with PIRA in clinical trials.

Investigating Heterogeneity and Neuroanatomic Correlates of Longitudinal Clinical Decline in Atypical Alzheimer Disease.

The aims of this work were to compare rates of longitudinal change in neurologic and neuropsychological test performance between the logopenic progressive aphasia (LPA) and posterior cortical atrophy (PCA) variants of atypical Alzheimer disease (AD) and to use unbiased principal component analysis to assess heterogeneity in patterns of change and relationships to demographics and concurrent brain atrophy. Patients with PCA or LPA who were positive for amyloid and tau AD biomarkers and had undergone serial neurologic and neuropsychological assessments and structural MRI were identified. Rates of change in 13 clinical measures were compared between groups in a case-control design, and principal component analysis was used to assess patterns of clinical change unbiased by clinical phenotype. Components were correlated with rates of regional brain atrophy with tensor-based morphometry. Twenty-eight patients with PCA and 27 patients with LPA were identified. Those with LPA showed worse baseline performance and faster rates of decline in naming, repetition, and working memory, as well as faster rates of decline in verbal episodic memory, compared to those with PCA. Conversely, patients with PCA showed worse baseline performance in tests of visuospatial and perceptual function and on the Clinical Dementia Rating Scale and faster rates of decline in visuoperceptual function compared to those with LPA. Principal component analysis showed that patterns of clinical decline were highly heterogeneous across the cohort, with 10 principal components required to explain >90% of the variance. The first principal component reflected overall severity, with higher scores in LPA than PCA reflecting faster decline in LPA, and was related to left temporoparietal atrophy. The second and third principal components were not related to clinical phenotype but showed some relationship to regional atrophy. No relationships were identified between the principal components and age, sex, disease duration, amyloid PET findings, or apolipoprotein genotype. Longitudinal patterns of clinical decline differ between LPA and PCA but are heterogeneous and related to different patterns of topographic spread. PCA is associated with a more slowly progressive course than LPA.