Atrophy Measures Research Articles

42 Cognitive and Neuroanatomic Correlates of Olfactory Function in Cognitively Unimpaired and Impaired Older Adults

Objective:Olfactory function declines during normal aging; however, accelerated olfactory decline is observed in neurodegenerative diseases, such as Alzheimer’s disease (AD). Moreover, olfactory deficits in pre-clinical AD are associated with future cognitive decline. Odor identification and memory deficits have been consistently reported in early stage AD indicating its potential sensitivity to AD pathophysiology in olfactory and limbic structures, yet few studies of olfaction have incorporated structural measures in a well-characterized cohort of older adults. In the current study we examined the association between odor identification impairment, cognition, and medial temporal lobe (MTL) sub-regions in cognitively unimpaired and impaired older adults.Participants and Methods:We enrolled 140 participants (age=72.25±6.54, 56% female, years of education=16.30±2.63, 82% Caucasian, 15% Black/AA, 3% Multiracial) from the Penn Alzheimer’s Disease Research Center Clinical Cohort. Participants completed the Sniffin’ Sticks Odor Identification Test (SS-OIT), cognitive testing (NACC UDS2 or UDS3 and additional cognitive tests), and MRI scans (3T Siemens MAGNETOM Prisma MRI scanner). For the SS-OIT, participants were presented with 16 odorants using felt-tipped pen dispensers and asked to identify each odor from four multiple-choice options. Scores range from 0 to 16. Additionally, cognitive domains were created by averaging z-scores from tests within each domain: attention, memory, language, executive function, and visuospatial. This cohort was divided into participants with unimpaired cognition (n=96) and impaired cognition (MCI, dementia; n=44) using established normative data and consensus diagnosis. Linear regressions were performed to examine the association between SS-OIT score, each cognitive domain, and MTL measurements for unimpaired and impaired groups. For all analyses, we controlled for age, race, sex, education, smoking status, and hypertension and additionally for MOCA score and intracranial volume with MTL measurements.Results:In the unimpaired group, SS-OIT significantly associated with language (p<.05). In the impaired group, SS-OIT significantly associated with language and memory (p<.05). In the unimpaired group, SS-OIT significantly associated with right anterior hippocampal volume (p<.05). In the impaired group, significant associations were found between SS-OIT and right anterior hippocampal volume (p<.05) and left hippocampal mean thickness (p<.05). Additionally, SS-OIT significantly associated with left and right entorhinal cortex volume (p<.05) and mean thickness (p<.05).Conclusions:This study reveals that lower odor identification performance is related to lower performance on measures of cognition and atrophy in MTL sub-regions in unimpaired and impaired older adults. Our findings support prior results demonstrating relationships between olfactory function, cognition, and MTL sub-regions. Specifically, olfactory function and episodic memory have been shown to follow similar patterns of decline in the course of AD, potentially reflecting AD pathology in shared regions of the MTL subserving episodic memory and olfactory function. Our findings demonstrate that reductions in both cortical thickness and grey matter volume of MTL regions are linked to olfactory deficits in individuals at risk for Alzheimer’s dementia. Future steps will include the analysis of longitudinal cognitive and imaging indices and the incorporation of fluid biomarker data.

Interactions of optic radiation lesions with retinal and brain atrophy in early multiple sclerosis.

Retrograde trans-synaptic neuroaxonal degeneration is considered a key pathological factor of subclinical retinal neuroaxonal damage in multiple sclerosis (MS). We aim to evaluate the longitudinal association of optic radiation (OR) lesion activity with retinal neuroaxonal damage and its role in correlations between retinal and brain atrophy in people with clinically isolated syndrome and early MS (pweMS). Eighty-five pweMS were retrospectively screened from a prospective cohort (Berlin CIS cohort). Participants underwent 3T magnetic resonance imaging (MRI) for OR lesion volume and brain atrophy measurements and optical coherence tomography (OCT) for retinal layer thickness measurements. All pweMS were followed with serial OCT and MRI over a median follow-up of 2.9 (interquartile range: 2.6-3.4) years. Eyes with a history of optic neuritis prior to study enrollment were excluded. Linear mixed models were used to analyze the association of retinal layer thinning with changes in OR lesion volume and brain atrophy. Macular ganglion cell-inner plexiform layer (GCIPL) thinning was more pronounced in pweMS with OR lesion volume increase during follow-up compared to those without (Difference: -0.82 μm [95% CI:-1.49 to -0.15], p = 0.018). Furthermore, GCIPL thinning correlated with both OR lesion volume increase (β [95% CI] = -0.27 [-0.50 to -0.03], p = 0.028) and brain atrophy (β [95% CI] = 0.47 [0.25 to 0.70], p < 0.001). Correlations of GCIPL changes with brain atrophy did not differ between pweMS with or without OR lesion increase ( = 5.92e-7 , p = 0.762). Faster GCIPL thinning rate is associated with increased OR lesion load. Our results support the value of GCIPL as a sensitive biomarker reflecting both posterior visual pathway pathology and global brain neurodegeneration.

Validation of brain parenchyma sonography as a marker of neurodegeneration in multiple sclerosis

BackgroundMultiple sclerosis (MS) is widely known to cause brain atrophy due to neurodegeneration. Neuroimaging investigations revealed a direct link between brain atrophy detected by MRI and impairment. Transcranial sonography is a safe, feasible and cost-effective imaging technique. In this study, we aimed to validate B-mode transcranial sonography (TCS) as a marker of neurodegeneration in MS. This study is the first study directed to set cut-off point for brain parenchyma measurement in Egyptian population. An observational, case–control study, conducted on 125 subjects; divided into 2 groups: first group, 71 healthy volunteers and patients’ group (54 patients) with relapsing–remitting multiple sclerosis (RRMS). All studied subjects were assessed using B-mode TCS. Transcranial sonography findings were categorized into: first, assessment of brain atrophy parameters by measuring diameter (cm) of third ventricle and both frontal horns of lateral ventricles. Then, the echogenicity of thalamus and brainstem structures (substantia nigra (SN), red nucleus) planimetric surface area (cm2) were assessed along with their abnormal echogenicity (cm2), while brainstem raphe was assessed semi-quantitatively for its echogenicity (intact or interrupted).ResultsQuantitative measures of brain atrophy: in normal control group the third ventricle diameter mean was 0.2 cm (± 0.08), right and left frontal horn diameter were 0.3 cm (± 0.13) and 0.28 cm (± 0.1), respectively, brain atrophy parameters could differentiate between MS patients and normal control group as a statistically significant (p< 0.001) larger ventricular diameter was found in MS patients. On the other hand, assessment of brain stem structures and thalamus showed no statistical significance between MS patients and normal control except in surface area of both red nuclei.ConclusionsBrain parenchymal sonography may be used as a tool in assessment of neurodegeneration in MS patients.

Increased Resolution of Structural MRI at 3T Improves Estimation of Regional Cortical Degeneration in Individual Dementia Patients Using Surface Thickness Maps.

Objective measurement of regional cortical atrophy in individual patients would be a highly desirable adjunct for diagnosis of degenerative dementias. We hypothesized that increasing the resolution of magnetic resonance scans would improve the sensitivity of cortical atrophy detection for individual patients. 46 participants including 8 semantic-variant primary progressive aphasia (svPPA), seven posterior cortical atrophy (PCA), and 31 cognitively unimpaired participants underwent clinical assessment and 3.0T brain scans. SvPPA and PCA were chosen because there is overwhelming prior knowledge of the expected atrophy pattern. Two sets of T1-weighted images with 0.8 mm3 (HighRes) and conventional 1.0 mm3 (ConvRes) resolution were acquired. The cortical ribbon was segmented using FreeSurfer software to obtain surface-based thickness maps. Inter-sequence performance was assessed in terms of cortical thickness and sub-cortical volume reproducibility, signal-to-noise and contrast-to-noise ratios. For clinical cases, diagnostic effect size (Cohen's d) and lesion distribution (z-score and t-value maps) were compared between HighRes and ConvRes scans. The HighRes scans produced higher image quality scores at 90 seconds extra scan time. The effect size of cortical thickness differences between patients and cognitively unimpaired participants was 15-20% larger for HighRes scans. HighRes scans showed more robust patterns of atrophy in expected regions in each and every individual patient. HighRes T1-weighted scans showed superior precision for identifying the severity of cortical atrophy in individual patients, offering a proof-of-concept for clinical translation. Studying svPPA and PCA, two syndromes with well-defined focal atrophy patterns, offers a method to clinically validate and contrast automated algorithms.

Towards a more precise rating of neurological disability in multiple sclerosis: A new automatic and linear quantification of limbs function.

The Expanded Disability Status Scale (EDSS) is the gold standard for evaluating clinical disability in multiple sclerosis (MS) in daily practice. However, more precise clinical assessment tools are needed. We assessed a new, automated rating of the neurological examination obtained with a mobile application (Quantified Neurological Examination - QNE). Consecutive MS patients were assessed for EDSS score and QNE application that calculates, from the description of the examination, a global score and subscores (qFSS) corresponding to the EDSS functional system scores (FSS). Brain MRI was analysed to obtain automatic measures of brain atrophy. We performed 200 examinations and included 78 patients in the MRI analysis. The global QNE score was strongly correlated with the EDSS. qFSS was statistically different according to the corresponding FSS for each function, except for the visual FSS. EDSS was predominantly correlated to the pyramidal function of the lower limbs. QNE score and qFSS had at least equivalent correlation to MRI measures than EDSS, particularly regarding the gray matter and cortical volumes. We propose an automated method to rate neurological disability in MS. While QNE strongly correlates with EDSS, it may allow a more precise way to monitor the evolution of disability.

Cortical and Subcortical Brain Atrophy Assessment Using Simple Measures on NCCT Compared with MRI in Acute Stroke.

Brain atrophy is an important surrogate for brain reserve, the capacity of the brain to cope with acquired injuries such as acute stroke. It is unclear how well atrophy measurements on MR imaging can be reproduced using NCCT imaging. We aimed to compare pragmatic atrophy measures on NCCT with MR imaging in patients with acute ischemic stroke. This is a post hoc analysis, including baseline NCCT and 24-hour follow-up MR imaging data from the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial. Cortical atrophy was measured using the global cortical atrophy scale, and subcortical atrophy was measured using the intercaudate distance-to-inner-table width (CC/IT) ratio. Agreement and correlation between these measures on NCCT and MR imaging were calculated using the Gwet agreement coefficient 1 and Pearson correlation coefficients, respectively. Among 1105 participants in the ESCAPE-NA1 trial, interpretable NCCT and 24-hour MR imaging were available in 558 (50.5%) patients (mean age, 67.2 [SD, 13.7] years; 282 women). Cortical atrophy assessments performed on NCCT underestimated atrophy severity compared with MR imaging (eg, patients with global cortical atrophy of ≥1 assessed on NCCT = 133/558 [23.8%] and on MR imaging = 247/558 [44.3%]; a 20.5% difference). Overall, cortical (ie, global cortical atrophy) atrophy assessments on NCCT had substantial or better agreement with MR imaging (Gwet agreement coefficient 1 of > 0.784; P < .001). Subcortical atrophy measures (CC/IT ratio) showed strong correlations between NCCT and MR imaging (Pearson correlation = 0.746, P < .001). Brain atrophy can be evaluated using simple measures in emergently acquired NCCT. Subcortical atrophy assessments on NCCT show strong correlations with MR imaging. Although cortical atrophy assessments on NCCT are strongly correlated with MR imaging ratings, there is a general underestimation of atrophy severity on NCCT.

Brain Atrophy as an Outcome of Disease-Modifying Therapy for Remitting-Relapsing Multiple Sclerosis.

Currently, clinical trials of DMTs strive to determine their effect on neuroinflammation and neurodegeneration. We aimed to determine the impact of currently used DMTs on brain atrophy and disability in RRMS. The main goal of this review is to evaluate the neuroprotective potential of MS therapy and assess its impact on disability. We performed a systematic analysis of clinical trials that used brain atrophy as an outcome or performed post hoc analysis of volumetric MRI parameters to assess the neuroprotective potential of applied therapies. Trials between 2008 and 2019 that included published results of brain parenchymal fraction (BPF) change and brain volume loss (BVL) in the period from baseline to week 96 or longer were considered. Twelve from 146 clinical trials met the inclusion criteria and were incorporated into the analysis. DMTs that presented a large reduction in BVL also exhibited robust effects on clinical disability worsening, e.g., alemtuzumab with a 42% risk reduction in 6-month confirmed disability accumulation (p = 0.0084), ocrelizumab with a 40% risk reduction in 6-month confirmed disability progression (p = 0.003), and other DMTs (cladribine and teriflunomide) with moderate influence on brain atrophy were also associated with a marked impact on disability worsening. Dimethyl fumarate (DEFINE) and fingolimod (FREEDOMS I) initially exhibited significant effect on BVL; however, this effect was not confirmed in further clinical trials: CONFIRM and FREEDOMS II, respectively. Peg-IFN-β1a shows a modest effect on BVL and disability worsening. Our results show that BVL in one of the components of clinical disability worsening, together with other variables (lesion volume and annualized relapse rate). Standardization of atrophy measurement technique as well as harmonization of disability worsening and progression criteria in further clinical trials are of utmost importance as they enable a reliable comparison of neuroprotective potential of DMTs.

Treatment Effect on Brain Atrophy Correlates with Treatment Effect on Cognition in Multiple Sclerosis.

The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)-derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS). We collected all published randomized clinical trials in MS lasting at least 2 years and including as end points: active MRI lesions (defined as new/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition. Fourteen trials including more than 8,813 patients with MS were included in the meta-regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (R2 = 0.79, p < 0.001), but was not correlated with the treatment effect on active MRI lesions (R2 = 0.16, p = 0.14). Results reported here suggest that brain atrophy, a well-established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. ANN NEUROL 2023.

Gradeability and Reproducibility of Geographic Atrophy Measurement in GATHER-1, a Phase II/III Randomized Interventional Trial

To validate GATHER-1 inclusion criteria and the study's primary anatomic end point by assessing the reproducibility of geographic atrophy (GA) measurements and factors that affect reproducibility. Post hoc analysis of phase II/III clinical trial. All 286 participants included in the GATHER-1 study. For each subject, blue-light fundus autofluorescence (FAF), color fundus photographs, fluorescein angiograms, and OCT scans were obtained on the study eye and fellow eye. Geographic atrophy area and other lesion characteristics were independently graded by 2 experienced primary readers. If the 2 readers differed on gradeability, GA area (> 10%) or other lesion characteristics, the image was graded by an arbitrator whose measurement or characterization was the final grade. The main outcome measures were gradeability and reproducibility of FAF imaging data. Imaging data included lesion area, confluence of GA with peripapillary atrophy (PPA), whether GA involved the foveal centerpoint, and type of hyperautofluorescence pattern. A total of 2004 images (1002 visits, 286 participants) were analyzed. Gradeability (90.5%) and interreader gradeability concordance (90.2%) were high across all visits. Study eye images were more gradable compared with fellow-eye images. A greater proportion of smaller lesions required arbitration, but interreader reproducibility was consistently high for all images. There was no difference in gradeability, gradeability concordance, or lesion-area concordance for images with PPA-confluent GA compared with those with nonconfluent PPA. Foveal centerpoint-involving lesions had lower gradeability and lesion-area concordance. Images with diffuse patterns of hyperautofluorescence had better gradeability and gradeability concordance than those with nondiffuse patterns but had no difference in lesion-area or lesion-area concordance. There is high gradeability and excellent reproducibility measures across all images. These data support the validity of conclusions from GATHER-1 and the chosen inclusion criteria and end point. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Reliability of brain atrophy measurements in multiple sclerosis using MRI: an assessment of six freely available software packages for cross-sectional analyses.

Volume measurement using MRI is important to assess brain atrophy in multiple sclerosis (MS). However, differences between scanners, acquisition protocols, and analysis software introduce unwanted variability of volumes. To quantify theses effects, we compared within-scanner repeatability and between-scanner reproducibility of three different MR scanners for six brain segmentation methods. Twenty-one people with MS underwent scanning and rescanning on three 3T MR scanners (GE MR750, Philips Ingenuity, Toshiba Vantage Titan) to obtain 3D T1-weighted images. FreeSurfer, FSL, SAMSEG, FastSurfer, CAT-12, and SynthSeg were used to quantify brain, white matterand (deep) gray matter volumes both from lesion-filled and non-lesion-filled 3D T1-weighted images. We used intra-class correlation coefficient (ICC) to quantify agreement; repeated-measures ANOVA to analyze systematic differences; and variance component analysis to quantify the standard error of measurement (SEM) and smallest detectable change (SDC). For all six software, both between-scanner agreement (ICCs ranging 0.4-1) and within-scanner agreement (ICC range: 0.6-1) were typically good, and good to excellent (ICC > 0.7) for large structures. No clear differences were found between filled and non-filled images. However, gray and white matter volumes did differ systematically between scanners for all software (p < 0.05). Variance component analysis yielded within-scanner SDC ranging from 1.02% (SAMSEG, whole-brain) to 14.55% (FreeSurfer, CSF); and between-scanner SDC ranging from 4.83% (SynthSeg, thalamus) to 29.25% (CAT12, thalamus). Volume measurements of brain, GM and WM showed high repeatability, and high reproducibility despite substantial differences between scanners. Smallest detectable change was high, especially between different scanners, which hampers the clinical implementation of atrophy measurements.

Patterns of brain atrophy in recently-diagnosed relapsing-remitting multiple sclerosis.

Recurrent neuroinflammation in relapsing-remitting MS (RRMS) is thought to lead to neurodegeneration, resulting in progressive disability. Repeated magnetic resonance imaging (MRI) of the brain provides non-invasive measures of atrophy over time, a key marker of neurodegeneration. This study investigates regional neurodegeneration of the brain in recently-diagnosed RRMS using volumetry and voxel-based morphometry (VBM). RRMS patients (N = 354) underwent 3T structural MRI <6 months after diagnosis and 1-year follow-up, as part of the Scottish multicentre 'FutureMS' study. MRI data were processed using FreeSurfer to derive volumetrics, and FSL for VBM (grey matter (GM) only), to establish regional patterns of change in GM and normal-appearing white matter (NAWM) over time throughout the brain. Volumetric analyses showed a decrease over time (q<0.05) in bilateral cortical GM and NAWM, cerebellar GM, brainstem, amygdala, basal ganglia, hippocampus, accumbens, thalamus and ventral diencephalon. Additionally, NAWM and GM volume decreased respectively in the following cortical regions, frontal: 14 out of 26 regions and 16/26; temporal: 18/18 and 15/18; parietal: 14/14 and 11/14; occipital: 7/8 and 8/8. Left GM and NAWM asymmetry was observed in the frontal lobe. GM VBM analysis showed three major clusters of decrease over time: 1) temporal and subcortical areas, 2) cerebellum, 3) anterior cingulum and supplementary motor cortex; and four smaller clusters within the occipital lobe. Widespread GM and NAWM atrophy was observed in this large recently-diagnosed RRMS cohort, particularly in the brainstem, cerebellar GM, and subcortical and occipital-temporal regions; indicative of neurodegeneration across tissue types, and in accord with limited previous studies in early disease. Volumetric and VBM results emphasise different features of longitudinal lobar and loco-regional change, however identify consistent atrophy patterns across individuals. Atrophy measures targeted to specific brain regions may provide improved markers of neurodegeneration, and potential future imaging stratifiers and endpoints for clinical decision making and therapeutic trials.

Greater cognitive reserve is related to lower cortical excitability in healthy cognitive aging, but not in early clinical Alzheimer's disease.

To investigate the relationship between cortico-motor excitability and cognitive reserve (CR) in cognitively unimpaired older adults (CU) and in older adults with mild cognitive impairment or mild dementia due to Alzheimer's disease (AD). Data were collected and analyzed from 15 CU and 24 amyloid-positive AD participants aged 50-90 years. A cognitive reserve questionnaire score (CRQ) assessed education, occupation, leisure activities, physical activities, and social engagement. Cortical excitability was quantified as the average amplitude of motor evoked potentials (MEP amplitude) elicited with single-pulse transcranial magnetic stimulation delivered to primary motor cortex. A linear model compared MEP amplitudes between groups. A linear model tested for an effect of CRQ on MEP amplitude across all participants. Finally, separate linear models tested for an effect of CRQ on MEP amplitude within each group. Exploratory analyses tested for effect modification of demographics, cognitive scores, atrophy measures, and CSF measures within each group using nested regression analysis. There was no between-group difference in MEP amplitude after accounting for covariates. The primary model showed a significant interaction term of group*CRQ (R2adj = 0.18, p = 0.013), but no main effect of CRQ. Within the CU group, higher CRQ was significantly associated with lower MEP amplitude (R2adj = 0.45, p = 0.004). There was no association in the AD group. Lower cortico-motor excitability is related to greater CRQ in CU, but not in AD. Lower MEP amplitudes may reflect greater neural efficiency in cognitively unimpaired older adults. The lack of association seen in AD participants may reflect disruption of the protective effects of CR. Future work is needed to better understand the neurophysiologic mechanisms leading to the protective effects of CR in older adults with and without neurodegenerative disorders.

Short-term brain atrophy evolution after initiation of immunotherapy in a real-world multiple sclerosis cohort.

In multiple sclerosis (MS), brain atrophy measurements have emerged as an important biomarker reflecting neurodegeneration and disability progression. However, due to several potential confounders, investigation of brain atrophy in clinical routine and even in controlled clinical studies can be challenging. The aim of this study was to investigate the short-term dynamics of brain atrophy development after initiation of disease-modifying therapy (DMT) in a "real-world setting." In this retrospective study, we included MS patients starting DMT (natalizumab, fingolimod, dimethyl fumarate, or interferon-ß1a) or without DMT, availability of a baseline MRI, and two annual follow-up scans on the same MRI system. Two-timepoint percentage brain volume changes (PBVCs) were calculated. Fifty-five MS patients (12 patients starting DMT with natalizumab, 7 fingolimod, 14 dimethyl fumarate, 11 interferon-ß1a, and 11 patients without DMT) were included. We found the highest PBVCs in the first 12 months after initiation of natalizumab treatment. Furthermore, the PBVCs in our study were very much comparable to the results observed by other groups, as well as for fingolimod, dimethyl fumarate, and interferon-ß1a. We found PBVCs that are comparable to the results of previous studies, suggesting that brain atrophy, assessed on 3D MRI data sets acquired on the same 3T MRI, provides a robust MS biomarker.

LASSI-L detects early cognitive changes in pre-motor manifest Huntington's disease: a replication and validation study.

Cognitive decline is an important early sign in pre-motor manifest Huntington's disease (preHD) and is characterized by deficits across multiple domains including executive function, psychomotor processing speed, and memory retrieval. Prior work suggested that the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L)-a verbal learning task that simultaneously targets these domains - could capture early cognitive changes in preHD. The current study aimed to replicate, validate and further analyze the LASSI-L in preHD using larger datasets. LASSI-L was administered to 50 participants (25 preHD and 25 Healthy Controls) matched for age, education, and sex in a longitudinal study of disease progression and compared to performance on MMSE, Trail A & B, SCWT, SDMT, Semantic Fluency (Animals), and CVLT-II. Performance was then compared to a separate age-education matched-cohort of 25 preHD participants. Receiver operating curve (ROC) and practice effects (12 month interval) were investigated. Group comparisons were repeated using a preHD subgroup restricted to participants predicted to be far from diagnosis (Far subgroup), based on CAG-Age-Product scaled (CAPs) score. Construct validity was assessed through correlations with previously established measures of subcortical atrophy. PreHD performance on all sections of the LASSI-L was significantly different from controls. The proactive semantic interference section (PSI) was sensitive (p = 0.0001, d = 1.548), similar across preHD datasets (p = 1.0), reliable on test-retest over 12 months (spearman rho = 0.88; p = <0.00001) and associated with an excellent area under ROC (AUROC) of 0.855. In the preHD Far subgroup comparison, PSI was the only cognitive assessment to survive FDR < 0.05 (p = 0.03). The number of intrusions on PSI was negatively correlated with caudate volume. The LASSI-L is a sensitive, reliable, efficient tool for detecting cognitive decline in preHD. By using a unique verbal learning test paradigm that simultaneously targets executive function, processing speed and memory retrieval, the LASSI-L outperforms many other established tests and captures early signs of cognitive impairment. With further longitudinal validation, the LASSI-L could prove to be a useful biomarker for clinical research in preHD.

Current Status of Oral Disease-Modifying Treatment Effects on Cognitive Outcomes in Multiple Sclerosis: A Scoping Review.

Cognitive impairment represents one of the most hidden and disabling clinical aspects of multiple sclerosis (MS). In this regard, the major challenges are represented by the need for a comprehensive and standardised cognitive evaluation of each patient, both at disease onset and during follow-up, and by the lack of clear-cut data on the effects of treatments. In the present review, we summarize the current evidence on the effects of the available oral disease-modifying treatments (DMTs) on cognitive outcome measures. In this systematised review, we extract all the studies that reported longitudinally acquired cognitive outcome data on oral DMTs in MS patients. We found 29 studies that evaluated at least one oral DMT, including observational studies, randomised controlled trials, and their extension studies. Most of the studies (n = 20) evaluated sphingosine-1-phosphate (S1P) modulators, while we found seven studies on dimethyl fumarate, six on teriflunomide, and one on cladribine. The most frequently used cognitive outcome measures were SDMT and PASAT. Most of the studies reported substantial stability or mild improvement in cognitive outcomes in a short-time follow-up (duration of most studies ≤2 years). A few studies also reported MRI measures of brain atrophy. Cognitive outcomes were evaluated only in a minority of prospective studies on oral DMTs in MS patients with variable findings. More solid and numerous data are present for the S1P modulators. A standardised cognitive evaluation remains a yet unmet need to better clarify the possible positive effect of oral DMTs on cognition.

Learning from pseudo-labels: deep networks improve consistency in longitudinal brain volume estimation.

Brain atrophy is a critical biomarker of disease progression and treatment response in neurodegenerative diseases such as multiple sclerosis (MS). Confounding factors such as inconsistent imaging acquisitions hamper the accurate measurement of brain atrophy in the clinic. This study aims to develop and validate a robust deep learning model to overcome these challenges; and to evaluate its impact on the measurement of disease progression. Voxel-wise pseudo-atrophy labels were generated using SIENA, a widely adopted tool for the measurement of brain atrophy in MS. Deformation maps were produced for 195 pairs of longitudinal 3D T1 scans from patients with MS. A 3D U-Net, namely DeepBVC, was specifically developed overcome common variances in resolution, signal-to-noise ratio and contrast ratio between baseline and follow up scans. The performance of DeepBVC was compared against SIENA using McLaren test-retest dataset and 233 in-house MS subjects with MRI from multiple time points. Clinical evaluation included disability assessment with the Expanded Disability Status Scale (EDSS) and traditional imaging metrics such as lesion burden. For 3 subjects in test-retest experiments, the median percent brain volume change (PBVC) for DeepBVC and SIENA was 0.105 vs. 0.198% (subject 1), 0.061 vs. 0.084% (subject 2), 0.104 vs. 0.408% (subject 3). For testing consistency across multiple time points in individual MS subjects, the mean (± standard deviation) PBVC difference of DeepBVC and SIENA were 0.028% (± 0.145%) and 0.031% (±0.154%), respectively. The linear correlation with baseline T2 lesion volume were r = -0.288 (p < 0.05) and r = -0.249 (p < 0.05) for DeepBVC and SIENA, respectively. There was no significant correlation of disability progression with PBVC as estimated by either method (p = 0.86, p = 0.84). DeepBVC is a deep learning powered brain volume change estimation method for assessing brain atrophy used T1-weighted images. Compared to SIENA, DeepBVC demonstrates superior performance in reproducibility and in the context of common clinical scan variances such as imaging contrast, voxel resolution, random bias field, and signal-to-noise ratio. Enhanced measurement robustness, automation, and processing speed of DeepBVC indicate its potential for utilisation in both research and clinical environments for monitoring disease progression and, potentially, evaluating treatment effectiveness.

Associations of CSF PDGFRβ With Aging, Blood-Brain Barrier Damage, Neuroinflammation, and Alzheimer Disease Pathologic Changes.

Injured pericytes in the neurovascular unit release platelet-derived growth factor β (PDGFRβ) into the CSF. However, it is not clear how pericyte injury contributes to Alzheimer disease (AD)-related changes and blood-brain barrier (BBB) damage. We aimed to test whether CSF PDGFRβ was associated with different AD-associated and age-associated pathologic changes leading to dementia. PDGFRβ was measured in the CSF of 771 participants with cognitively unimpaired (CU, n = 408), mild cognitive impairment (MCI, n = 175), and dementia (n = 188) from the Swedish BioFINDER-2 cohort. We then checked association with β-amyloid (Aβ)-PET and tau-PET standardized uptake value ratio, APOE ε4 genotype and MRI measurements of cortical thickness, white matter lesions (WMLs), and cerebral blood flow. We also analyzed the role of CSF PDGFRβ in the relationship between aging, BBB dysfunction (measured by CSF/plasma albumin ratio, QAlb), and neuroinflammation (i.e., CSF levels of YKL-40 and glial fibrillary acidic protein [GFAP], preferentially expressed in reactive astrocytes). The cohort had a mean age of 67 years (CU = 62.8, MCI = 69.9, dementia = 70.4), and 50.1% were male (CU = 46.6%, MCI = 53.7%, dementia = 54.3%). Higher CSF PDGFRβ concentrations were related to higher age (b = 19.1, β = 0.5, 95% CI 16-22.2, p < 0.001), increased CSF neuroinflammatory markers of glial activation YKL-40 (b = 3.4, β = 0.5, 95% CI 2.8-3.9, p < 0.001), GFAP (b = 27.4, β = 0.4, 95% CI 20.9-33.9, p < 0.001), and worse BBB integrity measured by QAlb (b = 37.4, β = 0.2, 95% CI 24.9-49.9, p < 0.001). Age was also associated with worse BBB integrity, and this was partly mediated by PDGFRβ and neuroinflammatory markers (16%-33% of total effect). However, PDGFRβ showed no associations with APOE ε4 genotype, PET imaging of Aβ and tau pathology, or MRI measures of brain atrophy and WMLs (p > 0.05). In summary, pericyte damage, reflected by CSF PDGFRβ, may be involved in age-related BBB disruption together with neuroinflammation, but is not related to Alzheimer-related pathologic changes.

Poster 363: Post-Operative Protein Supplementation following Orthopaedic Surgery: A Systematic Review

Objectives: Decreased mechanical loading after orthopaedic surgery predisposes patients to develop muscle atrophy. The purpose of the study was to assess whether oral protein supplementation can help decrease postoperative muscle atrophy and/or improve patient outcomes following orthopaedic surgery. Methods: A systematic review of the literature was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The review was registered with the Prospective Register of Systematic Reviews (PROSPERO). A search of the PROSPERO registration did not identify similar prior systematic reviews or meta-analyses. Databases were searched during April 2021 and included: MEDLINE (Pubmed), Embase, Scopus, and Web of Science. Each search contained a combination of the following terms: “orthopaedic procedures” AND “protein” OR “amino acid” AND “dietary supplements” OR “supplementation” OR “supplement.” Orthopaedic procedures were listed individually using the PubMed index of orthopaedic procedures, as well as using the mesh function to extract articles with orthopaedic procedures listed as keywords. Eligibility Criteria The principal inclusion criteria consisted of randomized controlled trials evaluating protein or amino acid regimens as a measure to counteract muscle atrophy following orthopaedic surgery. Articles that evaluated other forms of dietary supplementation or non-orthopaedic procedures were excluded. Control groups included either placebo or a natural history control (i.e. routine post-operative protocol). The scope of surgery was intentionally left broad, to allow for a comparison of protein supplementation effectiveness across different surgical interventions. Each study’s reference list was manually reviewed for additional articles to prevent unintentional exclusion of studies. Two reviewers independently assessed all articles identified by the search strategy and applied the eligibility criteria. Data Extraction The content extracted from each article included: (1) demographic data, (2) protein supplement regimen used, (3) outcomes, (4) complications, and (5) length of follow up. Primary outcomes included functional or physiologic measures of muscle atrophy or strength. Secondary outcomes included patient satisfaction and time to return to sport or work. Data Analysis Quality assessment of studies was performed using Modified Coleman Methodology Scoring (MCMS). Heterogeneity of study design was noted including differences in protocols, measurement techniques, and outcomes measured, which prevented an adequate statistical comparison for meta-analysis. Results: Fourteen studies including 611 patients (224 male, 387 female) were analyzed (Figure 1). Four surgical cohorts were identified: Anterior cruciate ligament reconstruction (ACLR), total hip arthroplasty (THA), hip fractures (THA, revision THA, hip resurfacing), and total knee arthroplasty (TKA). The ACLR, THA, and hip fracture cohorts were each composed of 3 studies, while there were 5 studies in the TKA cohort. Average length of follow-up was 9 weeks for ACLR, 7 weeks for THA, 10 weeks for hip fracture, and 7 weeks for TKA. Protein supplementation included various combinations of essential amino acids in tablet form or whey protein powder. Placebo supplements were most commonly an isocaloric carbohydrate tablet or powder. Protein supplementation was reported to have beneficial effects across all types of identified surgeries. The primary benefit was decreased muscle atrophy measured by muscle cross sectional area. The most significant difference in muscle atrophy was observed in the final week of follow-up for the majority of studies (average follow up was 8 weeks). Multiple studies also demonstrated improved functional measures, including increased muscle function measured by isokinetic muscle strength. Of note, most participants were involved in some form of formal physical therapy for varying durations after surgery, but this was not standardized across all studies. There were no significant increases in side effects reported comparing protein supplementation cohorts to controls. Of the included investigations, only 2 studies (both for hip fracture) had participants follow a standardized diet. Average MCMS scores for each surgical cohort were as follows: ACLR 55 (fair), TKA 55 (fair), THA 46 (poor), hip fracture 44 (poor). Conclusions: In conclusion, protein supplementation appears to have beneficial effects on mitigating muscle atrophy in the postoperative period following ACLR, THA, TKA, and surgical treatment of hip fracture. This response often correlates with improved functional measures and quicker achievement of rehabilitation benchmarks. Further research is needed to establish standardized supplementation regimens and guidelines for improving clinical outcomes in the postoperative period.

Biomarkers for predicting disease course in Sanfilippo syndrome: An urgent unmet need in childhood-onset dementia.

Sanfilippo syndrome (MPS III) is an autosomal recessive inherited disorder causing dementia in children, following an essentially normal early developmental period. First symptoms typically include delayed language development, hyperactivity and/or insomnia from 2 years of age, followed by unremitting and overt loss of previously acquired skills. There are no approved treatments, and the median age of death is 18 years. Treatments under clinical trial demonstrate therapeutic benefit when applied pre-symptomatically in children diagnosed early through known familial inheritance risk. Newborn screening for Sanfilippo syndrome would enable pre-symptomatic diagnosis and optimal therapeutic benefit, however, many fold more patients with Sanfilippo syndrome are expected to be identified in the population than present with childhood dementia. Therefore, the capacity to stratify which Sanfilippo infants will need treatment in toddlerhood is necessary. While diagnostic methods have been developed, and continue to be refined, currently there are no tools or laboratory-based biomarkers available to provide pre-symptomatic prognosis. There is also a lack of progression and neurocognitive response-to-treatment biomarkers; disease stage and rate of progression are currently determined by age at symptom onset, loss of cerebral grey matter volume by magnetic resonance imaging and developmental quotient score for age. Robust blood-based biomarkers are an urgent unmet need. In this review, we discuss the development of biomarker assays for Sanfilippo based on the neuropathological pathways known to change leading into symptom onset and progression, and their performance as biomarkers in other neurodegenerative diseases. We propose that neural-derived exosomes extracted from blood may provide an ideal liquid biopsy to detect reductions in synaptic protein availability, and mitochondrial function. Furthermore, given the prominent role of neuroinflammation in symptom expression, glial fibrillary acidic protein detection in plasma/serum, alongside measurement of active brain atrophy by neurofilament light chain, warrant increased investigation for prognostic, progression and neurocognitive response-to-treatment biomarker potential in Sanfilippo syndrome and potentially other childhood dementias.

Parcellation of Brain Magnetic Resonance Images using Improved Atlases Selection Model

Introduction: Multiple atlas-based parcellation model has been demonstrated to perform better than single atlas-based parcellation model in terms of accuracy of the parcellation of human brain Magnetic Resonance Images (MRI). The weakness of the existing multiple atlas-based parcellation models is that the level of accuracy is limited if used for the ageing brain due to the presence of age-related changes such as atrophy. Aim: The aim of this study is to develop a novel multiple atlases selection model that ensures improved accuracy for the parcellation of the ageing brain by combining Cost function with the Similarity metric and Atrophy measure for atlases selection. This model is called COSA. Materials and Methods: A dataset with ten brain MRIs and ten atlases was used. A brain MRI was used one at a time as the target image while the remaining images constituted the source images. Using each target image, consensus atlases were obtained for COSA from the combination of a cost function, similarity index, and atrophy measure. These atlases were consequently used to parcellate the target image. Performance was assessed using Dice Coefficient and COSA was compared with existing atlases selection models. The existing atlases selection models investigated were Normalized Mutual Information (NMI), Mutual Information (MI), Correlation Ratio (CR), Normalized Correlation Ratio (NCR), and Least Square Error (LSE). Results: Mean of Dice Coefficient were: COSA = 0.7495196, NMI = 0.7479508, MI = 0.7473333, Jaccard Index = 0.7392522, CR = 0.7358384, NC = 0.7358043, Atrophy Measure = 0.7300867, LSE = 0.7299367, Single Atlas =0.6830223. Conclusion: Results show that COSA performs better than the existing multiple Atlas-based models.