Clinical Impairment Research Articles

An exploratory study of longitudinal trajectory of language, swallowing and cognition post endovascular clot retrieval.

Endovascular clot retrieval (ECR) is known to reduce global disability at 3 months post stroke however limited research exists regarding the trajectory of specific clinical impairments including language, swallowing and cognitive deficits between onset and 3 months. To assess language, swallowing, and cognitive performance following ECR and explore whether impairment severity is correlated with modified Thrombolysis in Cerebral Infarction score (mTICI), stroke severity or quality of life (QoL). Assessment was completed within 7 days (T1), 1 month (T2) and 3 months (T3) post-stroke. Performance was measured with the Functional Oral Intake Scale (FOIS), Repeatable Battery for Assessment of Neuropsychological Status (RBANS), Trail Making Test (TMT A and B) and Brixton Spatial Awareness Test. The Western Aphasia Battery (WAB) was used for left hemisphere stroke. QoL was measured with the Stroke and Aphasia Quality of Life Scale. Twenty-five participants (median 72 years; 64% male) were prospectively recruited following ECR. High reperfusion success (68% mTICI 3) and low stroke severity post ECR (median 24h NIHSS = 3, IQR 7-18) were noted. At T1, 10 participants presented with aphasia, eight required a modified diet and 20 had impaired cognition. At T3 all had recovered to a normal oral diet, 39% had persistent cognitive impairment and 45% of patients with left hemisphere stroke remained aphasic. Performance on the WAB, FOIS, RBANS and TMT changed significantly over time (all p<0.05). The severity score at T1 for all measures, excluding TMT B and Brixton, was significantly correlated with 24h NIHSS. WAB scores at T3 were correlated with QoL (r = 0.618; p = 0.043). This exploratory study found the longitudinal performance of language, swallowing and cognition significantly improved over time and severity in the first-week post-ECR was correlated with 24h NIHSS rather than the degree of reperfusion. What is already known on the subject Randomised control trials have demonstrated the benefit of ECR in patients with ischemic stroke using global measures of disability and function. Limited research exists regarding the trajectory of specific clinical impairments including language, swallowing and cognitive deficits. There is also a reliance on screening assessments and a lack of consideration of the influence of co-occurring impairments. What this paper adds to existing knowledge This prospective study is amongst the first to explore the longitudinal trajectory of language, swallowing and cognitive impairment using a standardised assessment battery. Twenty-four-hour NIHSS was significantly correlated with language, swallowing, global cognition and some measures of executive function. Language performance post ECR was correlated with domain-specific cognitive assessment of attention, immediate memory and delayed memory, which differed from swallowing performance post ECR that correlated with measures of executive function. What are the potential or actual clinical implications of this work? It is important for speech-language pathologists and the wider medical team to monitor language, swallowing and cognitive performance post ECR regardless of treatment success. Stroke severity at 24h post-ECR influences the severity of language, swallowing and cognitive impairments.

Het syndroom van Poland: een casusbespreking

Poland syndrome: a case report Poland syndrome (PS) is a rare congenital disorder characterized by the absence of the pectoralis major or minor muscle. This syndrome can be associated with a wide variety of other abnormalities. This case concerns a 5-year-old boy with thoracic asymmetry without other clinical abnormalities or functional impairment. An ultrasound confirmed the absence of the pectoralis minor muscle. The additional pediatric examination, abdominal ultrasound and chest X-ray were normal. The characteristics, diagnosis and treatments of PS are discussed based on a literature review.

Apparent diffusion coefficient values of the white matter in magnetic resonance imaging of the neonatal brain may help predict outcome in congenital cytomegalovirus infection

BackgroundWhite matter change is a well-known abnormality in congenital cytomegalovirus (cCMV) infection, but grading remains challenging and clinical relevance unclear.ObjectiveTo investigate if quantitative measurement of white matter apparent diffusion coefficient (ADC) values in magnetic resonance imaging (MRI) of the neonatal brain can predict outcome in cCMV.Materials and methodsA retrospective, single-center observational study, including patients with cCMV who had a neonatal brain MRI with diffusion-weighted imaging, was performed between 2007 and 2020. Regions of interest were systematically placed in the white matter on the ADC maps. Two pediatric radiologists independently scored additional brain abnormalities. Outcome measures were neonatal hearing and cognitive and motor development. Statistical analysis included simple and penalized elastic net regression.ResultsNeonatal brain MRI was evaluated in 255 patients (median age 21 days, 25–75 percentiles: 14–28 days, 121 male). Gyral abnormalities were noted in nine patients (3.5%), ventriculomegaly in 24 (9.4%), and subependymal cysts in 58 (22.7%). General white matter ADC was significantly higher in patients with neonatal hearing loss and cognitive and motor impairment (P< 0.05). For neonatal hearing loss, simple logistic regression using only general white matter was the best prediction model, with a receiver operating characteristic area under the curve (AUC)=0.76. For cognitive impairment, interacting elastic net regression, including other brain abnormalities and frontoparietal white matter ADC, performed best, with AUC=0.89. For motor impairment, interacting elastic net regression, including other brain abnormalities and deep anterior frontal white matter performed best, with AUC=0.73.ConclusionNeonatal white matter ADC was significantly higher in patients with clinical impairments. Quantitative ADC measurement may be a useful tool for predicting clinical outcome in cCMV.Graphical

Balance Impairment in the Burn Population: A Burn Model System National Database Study.

Balance is an important component of daily function and impairments can lead to injury and quality-of-life limitations. Balance is not well studied in the burn population. This study examines the frequency of long-term balance impairments and associated factors after a burn injury. The Burn Model System National Database was analyzed. Trouble with balance was self-reported at discharge, 6, 12, 24, and 60 months after injury. Regression analyses examined the associations between demographic and clinical characteristics and balance impairments at 12 months. Of 572 participants, balance impairments were most reported at discharge (40.3%), continuing over 60 months (26.8-36.0%). Those reporting balance impairments (n = 153) were more likely to be older, unemployed, have Medicaid or Medicare, receive inpatient rehabilitation, receive outpatient physical or occupational therapy, have vision problems, have leg or feet burns and swelling, and have foot numbness compared to those without (p ≤ 0.001). Regression analysis demonstrated a 4% increased odds of balance impairment for every increase in year of age (p < 0.001), 71% lower odds if employed at time of injury (p < 0.001), and 140% higher odds if receiving outpatient physical or occupational therapy at 12 months (p = 0.008). Common reports of balance impairments highlight the need for routine screenings to identify burn survivors that may benefit from targeted interventions.

Disparities in structural brain imaging in older adults from rural communities in Southern Nevada.

Identifying the associations between rural-living or neighborhood disadvantage and neurobiology may clarify rural-urban disparities in older adults with cognitive impairment related to Alzheimer's disease. We examined rural-urban differences and neighborhood disadvantages in brain cortical thickness (CT) measures among 71 rural and 87 urban-dwelling older adults. Analysis of covariance was used to test each FreeSurfer-derived CT measures' associations with rural-urban living, clinical impairment status, and their interactions. Post-hoc linear regressions were used to test the association between CT measures and neighborhood disadvantage index. Rural-dwelling older adults had thinner cortices in temporal and inferior frontal regions compared to urban participants, especially among clinically normal participants, where the thinner temporal cortex further correlated with higher neighborhood disadvantage. Conversely, rural participants had thicker cortices in superior frontal, parietal and occipital regions. Our results suggest a complex interplay between community contexts and neurobiology. For memory-related regions, rural-living and neighborhood disadvantage might be negatively associated with subjects' brain structures.

A multidisciplinary non-invasive approach to monitor response to intravenous immunoglobulin treatment in neurodegenerative Langerhans cell histiocytosis: a real-world study.

Early detection and treatment of neurodegenerative Langerhans cell histiocytosis (ND-LCH) have been suggested to prevent neurodegenerative progression. The aim of the study is to validate a standardized multidisciplinary diagnostic work-up to monitor the intravenous immunoglobulins (IVIG) treatment response and the natural course of the disease in untreated patients. Patients with abnormal somatosensory evoked potentials (SEPs) received monthly 0.5 g/kg IVIG. The diagnostic protocol included structural 3T MRI, neurological examination, brainstem auditory evoked potentials (BAEPs) and SEPs. Twenty-two patients were followed for 5.2 years (median) from the first MRI evidence of ND-LCH. Eleven patients received IVIG for 1.7 years (median). At treatment start neurological examination was abnormal in 10 patients, of whom two had severe clinical impairment and four had abnormal BAEPs. At last follow-up, 1/11 remained stable and 7/11 improved, while worsening of neurological or neurophysiological findings, or both, occurred in 3/11. Risk factors for worsening were a severe clinical or MRI ND-LCH at treatment initiation and prolonged exposure to LCH. Of the 11 untreated patients, none improved and three worsened. Using a standardized diagnostic protocol, we demonstrated that IVIG treatment can lead to clinical stabilization or improvement in all pauci-symptomatic patients with an MRI grading of less than 4.

The Cortical Silent Period and Its Association with Fatigue in Multiple Sclerosis: The Need for Standardized Data Collection.

The cortical silent period (CSP), assessed with transcranial magnetic stimulation (TMS), provides insights into motor cortex excitability. Alterations in the CSP have been observed in multiple sclerosis (MS), although a comparison of the sometimes contradictory results is difficult due to methodological differences. The aim of this study is to provide a more profound neurophysiological understanding of fatigue's pathophysiology and its relationship to the CSP. Twenty-three patients with MS, along with a matched control group, underwent comprehensive CSP measurements at four intensities (125, 150, 175, and 200% resting motor threshold), while their fatigue levels were assessed using the Fatigue Scale for Motor and Cognitive Functions (FSMC) and its motor and cognitive subscore. MS patients exhibited a significantly increased CSP duration compared to controls (p = 0.02), but CSP duration was not associated with the total FSMC, or the motor or cognitive subscore. Our data suggest a systematic difference in MS patients compared to healthy controls in the CSP but no association with fatigue when measured with the FSMC. Based on these results, and considering the heterogeneous literature in the field, our study highlights the need for a more standardized approach to neurophysiological data collection and validation. This standardization is crucial for exploring the link between TMS and clinical impairments in diseases like MS.

ENHANCE proof-of-concept three-arm randomized trial: effects of reaching training of the hemiparetic upper limb restricted to the spasticity-free elbow range

Post-stroke motor recovery processes remain unknown. Timescales and patterns of upper-limb (UL) recovery suggest a major impact of biological factors, with modest contributions from rehabilitation. We assessed a novel impairment-based training motivated by motor control theory where reaching occurs within the spasticity-free elbow range. Patients with subacute stroke (≤ 6 month; n = 46) and elbow flexor spasticity were randomly allocated to a 10-day UL training protocol, either personalized by restricting reaching to the spasticity-free elbow range defined by the tonic stretch reflex threshold (TSRT) or non-personalized (non-restricted) and with/without anodal transcranial direct current stimulation. Outcomes assessed before, after, and 1 month post-intervention were elbow flexor TSRT angle and reach-to-grasp arm kinematics (primary) and stretch reflex velocity sensitivity, clinical impairment, and activity (secondary). Results were analyzed for 3 groups as well as those of the effects of impairment-based training. Clinical measures improved in both groups. Spasticity-free range training resulted in faster and smoother reaches, smaller (i.e., better) arm-plane path length, and closer-to-normal shoulder/elbow movement patterns. Non-personalized training improved clinical scores without improving arm kinematics, suggesting that clinical measures do not account for movement quality. Impairment-based training within a spasticity-free elbow range is promising since it may improve clinical scores together with arm movement quality.Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT02725853; Initial registration date: 01/04/2016.

RACIAL/ETHNIC DIFFERENCES IN SUBJECTIVE COGNITIVE DECLINE (SCD) AND SCD-INDUCED OUTCOMES

Abstract Alzheimer’s disease and related dementias (ADRD) prevalence will double by 2060, with significant racial/ethnic (R/E) differences in rates. Understanding R/E differences in risk factors of subjective cognitive decline (SCD)—a precursor to ADRD—is critical for timely premorbid interventions to modify ADRD onset. We used 2015 CDC Behavioral Risk Factor Surveillance System data from non-Hispanic White (NHW), Black (NHB), and Hispanic individuals aged ≥45 years (n=142,657) to examine R/E differences in SCD Status and five SCD-induced functional limitations and healthcare outcomes (e.g., health provider communication). We used generalized linear modeling to assess the contributions of predisposing (e.g., age), enabling (e.g., insurance), and health need (e.g., chronic disease) factors to explaining R/E differences. NHWs were generally older and healthier, with higher educational attainment than NHBs and Hispanics. NHBs (13.5%) were slightly more likely to endorse SCD (11.5% overall). NHBs and Hispanics endorsing SCD were significantly more likely than NHWs to report SCD-induced functional limitations. R/E differences were minimally attenuated after adjusting for the above-mentioned factors. We found no R/E differences in getting access to help, or in communicating with healthcare providers. NHBs and Hispanics (vs. NHWs) endorsing SCD are more likely to also endorse functional limitations despite reporting equivalent access to help and communication with healthcare providers. Clinical cognitive impairment depends on functional status and as such NHBs and Hispanics are potentially more vulnerable to cognitive disease (e.g., ADRD) onset. More research is required to understand gaps in care and how interventions can help mitigate this differential risk.

COGNITIVE DECLINE AND FALLS ARE INDEPENDENT RISK FACTORS FOR SWALLOWING DYSFUNCTION IN OLDER PEOPLE

Abstract Aging, oropharyngeal lesion, neuromuscular and progressive neurological disease such as dementia are well-known risk factors of dysphagia. The aim of this study is to evaluate the significant risk factors of swallowing dysfunction in clinical practice. 100 subjects aged 65 or older who received Comprehensive Geriatric Assessment (CGA) were enrolled at EDA Hospital, Taiwan, form January 2022 to February 2023 (IRB: EMRP-110-108). Exclusion criteria: unable to communicate 、advanced disease or totally dependent. CGA was performed by well-trained nurses and geriatrician. Swallowing dysfunction was identified by abnormal swallow exam or related complaints. Cognitive impairment was defined as Short Portable Mental State Questionnaire (SPMSQ) &amp;lt; 8 (SPMSQ &amp;lt; 6 in those without education) or with diagnosed dementia. Binary logistic regression was constructed to assess the independent associated factors of dysphagia. Basic demographic analysis showed that patients with dysphagia were older, had poor ADL, higher number of geriatric syndromes and chronic comorbidities. Multivariate analysis revealed that cognitive decline (OR: 82.74, p=0.035) and falls (OR: 45.17, p=0.011) are still independent associated factors of swallow dysfunction after adjustment for age, sex, BMI, socioeconomics, other geriatric syndromes, chronic comorbidities including stoke and Parkinson disease. Dementia was known as one of the risk factors of dysphagia. Another small follow-up study demonstrated that falls risk is predictive of dysphagia in Parkinson’s disease. Through this study, participants will be able to identify the high-risk group of dysphagia. Prevention such as pneumococcus vaccination, oral hygiene, and speech therapy can be applied on those who have a fall history and clinical cognitive impairment.

Musculoskeletal, Functional and Performance Impairment in Female Overhead Athletes with a Previous Shoulder Injury.

Shoulder injuries are substantial problems in overhead athletes, and more studies are necessary to deepen the knowledge on this type of injury. The objective of this study was to compare the overall function and performance of female overhead athletes with and without a previous history of shoulder injuries. In this cross-sectional study, female overhead athletes with and without a previous shoulder injury were included. Muscular impairment, the stability of the shoulder, strength, scapular dyskinesia, functionality and sports performance were evaluated. A total of 50 females were included. There were significant differences in strength (p = 0.046) and stability (p = 0.039) between groups, with a poorer score in the group with a history of shoulder injury. Regarding scapular dyskinesia, significant differences were also observed between groups (p = 0.048), with higher levels of dyskinesia in the group with previous shoulder injury. Also, muscular impairment showed significant differences between groups for the three muscles evaluated (p < 0.005). Additionally, the group without a previous shoulder injury presented with a significantly greater score in functionality (p = 0.046) and sports performance (p = 0.004). In conclusion, previous shoulder injuries are an important factor to take into account in female overhead athletes. Players with a history of shoulder injury present clinical impairments during the game, leading to poorer functional status and performance in sport.

The impact of electronic versus paper-based data capture on data collection logistics and on missing scores in thyroid cancer patients

PurposeThe purpose of this study was to investigate the impact of the type of data capture on the time and help needed for collecting patient-reported outcomes as well as on the proportion of missing scores.MethodsIn a multinational prospective study, thyroid cancer patients from 17 countries completed a validated questionnaire measuring quality of life. Electronic data capture was compared to the paper-based approach using multivariate logistic regression.ResultsA total of 437 patients were included, of whom 13% used electronic data capture. The relation between data capture and time needed was modified by the emotional functioning of the patients. Those with clinical impairments in that respect needed more time to complete the questionnaire when they used electronic data capture compared to paper and pencil (ORadj 24.0; p = 0.006). This was not the case when patients had sub-threshold emotional problems (ORadj 1.9; p = 0.48). The odds of having the researcher reading the questions out (instead of the patient doing this themselves) (ORadj 0.1; p = 0.01) and of needing any help (ORadj 0.1; p = 0.01) were lower when electronic data capture was used. The proportion of missing scores was equivalent in both groups (ORadj 0.4, p = 0.42).ConclusionsThe advantages of electronic data capture, such as real-time assessment and fewer data entry errors, may come at the price of more time required for data collection when the patients have mental health problems. As this is not uncommon in thyroid cancer, researchers need to choose the type of data capture wisely for their particular research question.

Should Tinnitus Patients with Subclinical Hearing Impairment Be Offered Hearing Aids? A Comparison of Tinnitus Mitigation Following 3 Months Hearing Aid Use in Individuals with and without Clinical Hearing Impairment.

There is a consensus among tinnitus experts to not recommend hearing aids for tinnitus patients with subclinical hearing impairment. However, this notion is arbitrary, as no previous study has compared the treatment effect of hearing aids on tinnitus distress in patients with and without clinical hearing impairment. In this article, we investigate whether tinnitus patients with clinical and subclinical hearing impairment differ in terms of tinnitus mitigation after hearing aid fitting. Twenty-seven tinnitus patients with either clinical (n = 13) or subclinical (n = 14) hearing impairment were fitted with hearing aids. All participants filled out the tinnitus functional index (TFI) before hearing aid fitting and after 3 months of hearing aid use. Clinically meaningful reductions in tinnitus distress (-13 TFI points or more) were seen in both groups, and the difference in tinnitus mitigation between tinnitus patients with clinical (mean TFI reduction = 17.0 points) and subclinical hearing impairment (mean TFI reduction = 16.9 points) was not statistically significant (p = 0.991). Group differences on the suspected confounding factors of age, sex, time since tinnitus debut, tinnitus distress (TFI score) at baseline, and treatment adherence were statistically insignificant. In light of this, we argue that clinical hearing impairment is not required to achieve meaningful tinnitus mitigation with hearing aids, and that hearing aids could be recommended for tinnitus patients with subclinical hearing impairment.

Diagnostic and Monitoring Value of β-2 Transferrin and Transferrin for Intracranial Infection After Neurosurgery.

After neurosurgery, intracranial infection is a common complication with high rates of clinical impairment and death. Traditional diagnostic approaches are time-consuming. Early and correct diagnosis improves infection control, treatment success, and survival. Novel markers are used to diagnose and classify post-neurosurgical meningitis (PNM) to overcome the difficulties of diagnosing postoperative intracranial infections and avoid the drawbacks of existing diagnostic measures. The objective was to investigate the diagnostic value of β-2 transferrin (β-2TF) and transferrin (TF) in the cerebrospinal fluid (CSF) for the identification of intracranial infection after neurosurgery. Owing to their symptoms and laboratory results, 168 patients with suspected intracranial infection after neurosurgery were divided into 3 groups: post-neurosurgical bacterial meningitis (PNBM; n = 61), post-neurosurgical aseptic meningitis (PNAM; n = 45), and non-PNM (n = 62). We measured lactate (LA), β-2TF, and TF levels in the CSF. CSF LA levels were significantly higher in the PNM, PNBM, and PNAM groups compared with the non-PNM group ( P < .05). The CSF β-2TF level in PNM, PNBM, and PNAM were statistically higher than those in non-PNMs ( P < .05). CSF TF levels in the PNBM group were statistically higher than those in the PNAM and non-PNM groups ( P < .05). The PNBM and non-PNM receiver operating curve (ROC) analysis indicates that the cutoff values for the combination (LA, β-2TF, TF) was 0.349, and the area under the curve (AUC) was 0.945 ( P < .0001), with 92.86% sensitivity and 92.98% specificity. The PNAM and non-PNM ROC analysis indicates that the cutoff values for the combination (LA, β-2TF, TF) was 0.346, and the AUC was 0.962 ( P < .0001), with 89.29% sensitivity and 90.24% specificity. The PNM and non-PNM ROC analysis indicates that the cutoff values for the combination (LA, β-2TF, TF) was 0.609, and the AUC was 0.941 ( P < .0001), with 96.36% sensitivity and 82.83% specificity. A Glasgow Coma Scale score ≤8, LA, β-2TF/TF ratio, length of hospital stay, intensive care unit admission, poor surgical wound, and craniotomy were associated with poor outcomes ( P < .05). LA and β-2TF were independent risk factors for intracranial infection. Postoperative cerebral infections can be identified using CSF β-2TF as a particular marker protein. CSF TF helps distinguish PNBM from PNAM. Combining CSF LA with them improves diagnostic speed, sensitivity, and accuracy. LA and β-2TF were independent risk factors for cerebral infection.

Postural control deficits due to bilateral pyramidal tract lesions exemplified by hereditary spastic paraplegia (HSP) originate from increased feedback time delay and reduced long-term error corrections.

Pyramidal tract lesions determine the clinical syndrome of Hereditary Spastic Paraplegia (HSP). The clinical impairments of HSP are typically exemplified by their deficits in mobility, leading to falls and injuries. The first aim of this study was to identify the cause for postural abnormalities caused by pyramidal tract lesions in HSP. The second aim was to specify the effect of treadmill training for postural abnormalities. We examined nine HSP patients before and after treadmill training, as well as nine healthy control subjects during perturbed and unperturbed stance. We found that HSP was associated with larger sway amplitudes and velocities. Body excursions following platform tilts were larger, and upper body excursions showed a phase lead. Model-based analysis detected a greater time delay and a reduced long-term error correction of postural reactions in the center of mass. HSP patients performed significantly better in clinical assessments after treadmill training. In addition, treadmill training reduced sway amplitudes and body excursions, most likely by increasing positional and velocity error correction gain as a compensatory mechanism, while the time delay and long-term error correction gain remained largely unaffected. Moreover, the upper body's phase lead was reduced. We conclude that HSP leads to very specific postural impairments. While postural control generally benefits from treadmill training, the effect seems to mainly rely on compensatory mechanisms, whereas the original deficits are not affected significantly.

Whole Genome Deconvolution Unveils Alzheimer’s Resilient Epigenetic Signature.

AbstractBackgroundThe pathological hallmarks of Alzheimer’s disease (AD) are amyloid beta plaques and neurofibrillary tangles that usually progressively affect characteristic brain regions as individuals advance from latent to prodromal to severe AD dementia (ADD). An uncommon exception to coupled progression of disease burden and clinical impairment are resilient individuals who harbor a high pathological load sufficient to cause ADD yet remain cognitively normal. We hypothesize that determining the biological mechanisms of such underlying resilience to AD (RAD) will provide unique insights into therapeutic opportunities.MethodHere, we combined epigenetic sequencing data and an innovative computational algorithm to identify gene regulatory mechanisms and putative mediators distinguishing RAD from normal control and ADD at an unprecedented scale. We developed and validated a novel machine learning method, Cellformer, for deconvoluting bulk ATAC‐seq into cell type‐specific expression across the whole genome, leading to extensive regional and cellular chromatin profiling of RAD.ResultCellformer successfully deconvoluted in silico bulk ATAC‐seq data across cross‐validation iterations, achieving strong performances with a mean Spearman coefficient of 0.82 between deconvoluted and ground truth expressions, outperforming other approaches. Validation was performed using external single nucleus datasets and showed a significant correlation above 0.75 (P‐value&lt;0.05) between deconvoluted cell type‐specific ATAC‐seq and single‐ATAC‐seq expressions for each cell type. Applied on 191 samples from normal control, RAD and ADD’s 3 brain regions, CellFormer predicted cell type‐specific expression of more than 41954 open chromatin regions (OCR), preserving regional and phenotypic variations. Downstream analysis of the derived RAD‐specific epigenetic features pinpointed the hippocampus, a region critical for learning and memory, as the major player in the resilience, modulating synaptic and neuronal process in a cell‐type specific manner.ConclusionCellformer opens new perspectives to advance bulk analysis and understand biological mechanisms using cost effective bulk sequencing. Through this study, we showed that cell type‐resolved data nominated potential epigenetic and transcriptional mediators underlying RAD that may illuminate therapeutic opportunities to limit the cognitive impact of this highly prevalent yet stubbornly incurable disease. Cellformer will be made publicly available to advance analysis of high‐throughput bulk ATAC‐seq in future investigations.

Identification of Necessary Plasma Biomarkers for Prediction of Alzheimer’s Disease Neuropathologic Change

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) such as phosphorylated tau protein 181 (p‐tau 181), neurofilament light chain (NfL), amyloid‐β 42/40 ratio (Aβ42/40), and glial fibrillary acidic protein (GFAP) have shown high performance in the discrimination of those with clinical mild cognitive impairment (MCI) or dementia from cognitively unimpaired individuals, but few population‐based autopsy studies have evaluated the neuropathological correlates of plasma biomarkers.MethodWe utilized a population‐based prospective study of 350 participants with autopsy and antemortem plasma biomarker data. Plasma biomarkers Aβ42/40 ratio, p‐tau181, GFAP, and NfL were measured using Quanterix Simoa assays. We predicted AD neuropathological change (ADNC), Braak staging, and neuritic plaque score using these plasma biomarkers and investigated the added utility of cognitive and demographic information. We utilized a variable selection procedure in cross‐validated (CV) logistic regression models by minimizing the Bayesian Information Criterion to identify the best set of predictors for a given outcome among plasma biomarkers, demographic variables, and neuropsychological tests included in the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo‐PACC).ResultADNC was best predicted with plasma GFAP, NfL, p‐tau181 biomarkers along with APOE ε4 carrier status and Mayo‐PACC cognitive score (CV AUC = 0.821). Braak staging was best predicted using plasma GFAP, p‐tau181, and cognitive scores (CV AUC = 0.788). Neuritic plaque score was best predicted using plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL biomarkers (CV AUC = 0.778). Inclusion of plasma biomarkers demonstrated significantly better prediction of Braak staging (p&lt;0.01) and neuritic plaque score (p&lt;0.01), but not ADNC (p = 0.13), when compared to models that included only cognitive and demographic information. Univariate models consistently underperformed in comparison to multivariate models.ConclusionPlasma biomarkers can provide valuable predictive information about the presence of AD pathology, which can facilitate earlier recognition and diagnosis of AD. Incorporation of demographic and cognitive variables along with plasma variables in multivariable models will improve prediction accuracy of AD pathology, specifically Braak staging and ADNC.

Amyloid and Tau PET Positivity in Progressive Apraxia of Speech and Agrammatic Aphasia

AbstractBackgroundThe spectrum of what is referred to as nonfluent/agrammatic primary progressive aphasia includes patients with isolated apraxia of speech (PPAOS), progressive agrammatic aphasia (PAA), or a combination thereof (AOS‐PAA). When AOS is present, there is typically an underlying 4R tauopathy (corticobasal degeneration; progressive supranuclear palsy); isolated PAA is more often associated with a 3R tauopathy (Pick’s disease). While pathological studies confirm the clinical syndrome is the sequela of these proteinopathies, beta‐amyloid (Aβ) deposition has also been observed. Given the growing number of treatment options, it is important to better understand the incidence of Alzheimer’s disease (AD) in PPAOS‐PAA spectrum disorders.Methods65 patients recruited by the Neurodegenerative Research Group at Mayo Clinic underwent Aβ‐PET imaging using Pittsburgh Compound B (PiB) and tau‐PET imaging with [18F]flortaucipir at the same visit (PPAOS = 23; PAA = 6; AOS‐PAA = 36). A global PiB SUVR (standardized uptake value ratio)≥1.48 and temporal lobe tau meta‐ROI SUVR≥1.25 were deemed Aβ and tau positive, respectively. The incidence of Aβ and tau positivity and clinical‐demographic profiles were compared among groups.ResultsThere was no difference in age, sex, APOE status, tau/Aβ positivity or PET SUVRs across clinical groups (Table 1). Patients differed on indices of aphasia and AOS severity, in concordance with group membership; there was no difference on a memory measure. Eight patients (12%) were both Aβ and tau positive (indicative of the presence of AD), with an additional 20 patients (31%) positive on only one biomarker (Table 1). Of the eight Aβ and tau positive patients, seven had AOS (six prosodic predominant AOS). Aβ more than tau SUVRs increased with age and were related to each other (Figure 1).ConclusionsAβ and tau positivity is not uncommon in AOS and/or PAA patients, particularly in older patients. Enrollment criteria for Aβ or tau targeted pharmacological trials should consider concordance of biological variables and clinical presentations, rather than simply biological biomarkers. Alternatively, if such patients are enrolled, the outcome measures should reflect the clinical impairments, as it is not yet known if or how concomitant AD influences the clinical presentation.

Development and Validation of the 17-Point Brazilian Portuguese Translated Version of the Modified Japanese Orthopedic Association Score (mJOA-BR17).

Cervical spondylotic myelopathy (CSM) is the most common degenerative dysfunction of the spinal cord in the cervical spine in patients older than 55 years. The Japanese Orthopedic Association developed a scoring system to quantify clinical impairment of CSM patients, allocate them according to the degree of impairment, and suggest best timing for surgery. The original version evaluates the upper limb motor function through the ability of feeding with chopsticks, which are not intrinsic in western populations. To compare severity and treatment improvement of any diseases, it is preferable to have modified and translated versions of questionnaires and scores closest to the original ones. The authors present a prospective cohort study to validate the 17-point Brazilian Portuguese translated version of the modified Japanese Orthopedic Association (mJOA-BR17) survey. Patients with CSM (n = 36) were allocated to the disease group, while age- and sex-matched healthy volunteers (n = 34) were recruited for the control group. Comparison of statistical analysis of mJOA-BR17 domains for each group was established. After the translation and adaptation of mJOA-BR17, the validation was made through application to the 2 groups. There were statistical differences between groups in total mJOA-BR17 score (CSM, 14.14 ± 2.92; control, 16.68 ± 0.59: P < 0.001), lower limbs motor function (CSM, 3.25 ± 1.02; control, 3.91 ± 0.29: P < 0.001), upper limbs sensory function (CSM, 1.17 ± 0.81; control, 1.86 ± 0.36: P < 0.001), lower limbs sensory function (CSM, 1.62 ± 0.64; control, 2.0 ± 0.0: P < 0.001), and bladder function (CSM, 2.69 ± 0.52; control, 2.97 ± 0.17: P = 0.005). The receiver operating characteristic curve was 0.81, indicating usefulness of the mJOA-BR17 score to identify patients with CSM from healthy controls. The mJOA-BR17 demonstrated similarity, applicability, and good understanding in comparison to the English-modified version of 17-point JOA score for CSM, becoming a valuable tool to quantify and differentiate CSM patients from healthy individuals.

The impact of genetic risk for schizophrenia on eating disorder clinical presentations

A growing body of literature recognizes associations between eating disorders (EDs) and schizophrenia and suggests that familial liability to schizophrenia in individuals with anorexia nervosa (AN) reveals distinct patterns of clinical outcomes. To further investigate the influence of schizophrenia genetic liability among individuals with EDs, we evaluated the associations between schizophrenia polygenic risk scores (PRS) and clinical presentations of individuals with EDs including their overall health condition and ED-related symptoms. Using data from two previous studies of the genetics of EDs comprising 3,573 Anorexia Nervosa Genetics Initiative (ANGI) cases and 696 Binge Eating Genetics Initiative (BEGIN) cases born after 1973 and linked to the Swedish National Patient Register, we examined the association of schizophrenia PRS on ED clinical features, psychiatric comorbidities, and somatic and mental health burden. Among ANGI cases, higher schizophrenia PRS was statistically significantly associated with higher risk of major depressive disorder (MDD) measured by hazard ratio (HR) with 95% confidence interval (CI) (HR [95% CI]: 1.07 [1.02, 1.13]) and substance abuse disorder (SUD) (HR [95% CI]: 1.14 [1.03, 1.25]) after applying multiple testing correction. Additionally, higher schizophrenia PRS was associated with decreased clinical impairment assessment scores (−0.56, 95% CI: [−1.04, −0.08]) at the conventional significance level (p < 0.05). Further, in BEGIN cases, higher schizophrenia PRS was statistically significantly associated with earlier age at first ED symptom (−0.35 year, 95% CI: [−0.64, −0.06]), higher ED symptom scores (0.16, 95% CI: [0.04, 0.29]), higher risk of MDD (HR [95% CI]: 1.18 [1.04, 1.34]) and SUD (HR [95% CI]: 1.36 [1.07, 1.73]). Similar, but attenuated, patterns held in the subgroup of exclusively AN vs other eating disorder (OED) cases. These results suggest a similar pattern of influence of schizophrenia PRS for AN and OED cases in terms of psychiatric comorbidities, but a different pattern in terms of ED-related clinical features. The disparity of the effect of schizophrenia PRS on AN vs OED merits further investigation.