Clinical Rating Scale Research Articles

Magnetic resonance-guided focused ultrasound in the treatment of refractory essential tremor: a systematic review and meta-analysis.

Magnetic resonance-guided focused ultrasound (MRgFUS) is an emerging treatment for medication-refractory essential tremor (ET). The objective of this study was to evaluate long-term (up to 5 years) safety and efficacy of unilateral MRgFUS in the treatment of ET. The authors performed a systematic search through 4 databases to find relevant clinical studies. Binary outcomes were analyzed and reported as odds ratios and 95% confidence intervals, while continuous outcomes were analyzed and reported as standardized mean differences (SMDs) and 95% confidence intervals. Furthermore, a univariable meta-regression was performed to evaluate the association between various covariates and the outcomes including the mean difference in the Clinical Rating Scale for Tremor (CRST) score and hand tremor scores. Sensitivity analysis was performed to address any heterogeneity. A total of 43 studies comprising 1818 patients with ET who underwent MRgFUS were identified. Of the 1539 patients with data on sex, 1095 (71.2%) were male. The mean follow-up duration ranged from 3 months to 8.4 years among the studies. The mean total CRST score significantly decreased at 3, 6, and 12 months post-MRgFUS (SMD -4.5, p = 0.0069; SMD -4.9, p = 0.0045; and SMD -2.95, p = 0.0039, respectively). The mean hand tremor scores significantly mitigated at 3, 6, 12, 24, and 36 months post-MRgFUS (SMD -3.99, p = 0.05; SMD -4.5, p = 0.05; SMD -1.99, p < 0.0001; SMD - 2.07, p = 0.0002; and SMD -2.1, p < 0.0001, respectively). Furthermore, the mean Quality of Life in Essential Tremor Questionnaire scores were improved at 3 months (SMD -2.8, p = 0.0025), 6 months (SMD -4.1, p = 0.04), 12 months (SMD -1.57, p = 0.0004), 2 years (SMD -1.64, p = 0.0003), and 3 years (SMD -1.14, p = 0.08). Our meta-regression findings showed that sex (p = 0.03), unlike age, handedness, symptom duration, and peak energy levels at 3 months, was associated with a significantly higher mean difference in tremor severity. This meta-analysis provides strong evidence supporting the efficacy and safety of unilateral MRgFUS for the treatment of ET in terms of tremor severity and quality of life with acceptable adverse events.

Predicting tremor improvement after MRgFUS thalamotomy in essential tremor from preoperative spontaneous brain activity: A machine learning approach

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) thalamotomy is an emerging technique for medication-refractory essential tremor (ET), but with variable outcomes. This study used pattern regression analysis to identify brain signatures predictive of tremor improvements. Fifty-four ET patients (mean age = 63.06 years, standard deviation (SD) = 10.55 years, 38 males) underwent unilateral MRgFUS thalamotomy and were scanned for resting-state functional magnetic resonance imaging (rs-fMRI). Seventy-four healthy controls (mean age = 58.09 years, SD = 10.30 years, 38 males) were recruited for comparison. Tremor responses at 12 months posttreatment were evaluated by the Clinical Rating Scale for Tremor. The fractional amplitude of low-frequency fluctuations (fALFF) was calculated from rs-fMRI data. Two-sample t-test was used to generate a disease-specific mask, within which Multivariate Kernel Ridge Regression analyses were conducted. Predicted and actual clinical scores were compared using Pearson’s correlation coefficient (r) and normalized mean squared error (Norm. MSE). Permutation test and leave-one-out strategy were applied for results validation. KRR identified fALFF patterns that significantly predicted the hand tremor improvement (r = 0.23, P = 0.025; Norm. MSE = 0.05, P = 0.026) and the postural tremor improvement (r = 0.28, P = 0.025; Norm. MSE = 0.06, P = 0.023), but not action tremor improvement. Lobule VI of right cerebellum (Cerebelum_6_R), right superior occipital gyrus (Occipital_Sup_R) and lobule X of vermis (Vermis_10) contributed most for hand tremor prediction (normalized weights (NW): 2.77%, 2.40%, 2.34%) while Vermis_10, left supplementary motor area (Supp_Motor_Area_L) and right hippocampus (Hippocampus_R) for postural tremor prediction (NW: 2.69%, 2.12%, 2.05%). The low contributing NW of the individual brain regions suggested that the fALFF pattern as a whole is an overall predicting feature. Preoperative fALFF pattern predicts tremor benefits induced by MRgFUS thalamotomy. ClinicalTrials.gov number: NCT04570046.

2248 Clinical relevance of Donanemab treatment

Abstract Objective To assess in Alzheimer’s disease (ad), the treatment impact of donanemab, an amyloid plaque-reducing monoclonal antibody, on readily interpretable item-measures and constructs that matter to patients, care-partners, and clinicians. Background Positive outcomes were reported from TRAILBLAZER-ALZ2, a randomised, double-blind, placebo-controlled, 18-month, phase 3 study evaluating donanemab as an investigational treatment for mild cognitive impairment (MCI) or mild dementia due to ad. In 1736 participants, donanemab significantly slowed the rate of clinical decline (by 22–36%) as measured by the integrated ad Rating Scale (iADRS) and the Clinical Dementia Rating Scale—Sum-of-Boxes (CDR-SB); both measures of cognition and function as indications of global clinical severity. In these subsequent post-hoc exploratory analyses, the impact of donanemab treatment on individual iADRS cognition and function items, CDR domains, and risks of advancing to greater disease severity were assessed. Methods Mixed model repeated measures and Cox proportional hazard modelling methodology assessed treatment effects on iADRS items and CDR domains. Results Donanemab treatment was associated with significant beneficial effects on: 1) iADRS cognitive items related to episodic memory and executive function, and instrumental activities of daily living items related to communication and others (e.g. being left alone, making a meal, using household appliances); 2) all CDR-SB cognitive and functional domains (i.e. memory, orientation, judgement/problem solving, community affairs, home/hobbies, and personal care); and 3) lowering risk of progression to a more advanced clinical stage of disease. Conclusions These analyses explored the impact of donanemab treatment on constructs that matter to and are considered more readily interpretable by patients, care-partners, and clinicians. These results provide further support that treating those with MCI or mild dementia due to ad with donanemab can meaningfully reduce risk of progression to more severe clinical stages (e.g. moderate stage dementia), and potentially allow greater independence for a longer period of time.

The Different Associations of White Matter Hyperintensities With Severity of Dementia and Cognitive Impairment According to the Distance From the Lateral Ventricular Surface in Patients With Alzheimer's Disease.

White matter hyperintensities (WMH) are common among the elderly. Although WMH play a key role in lowering the threshold for the clinical expression of dementia in Alzheimer's disease (AD)-related pathology, the clinical significance of their location is not fully understood. This study aimed to investigate the association between WMH and cognitive function according to the location of WMH in AD. Subjects underwent clinical evaluations including volumetric brain magnetic resonance imaging study and neuropsychological tests using the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet. WMH were calculated using automated quantification method. According to the distance from the lateral ventricular surface, WMH within 3 mm, WMH within 3-13 mm, and WMH over 13 mm were classified as juxtaventricular WMH (JVWMH), periventricular WMH (PVWMH), and deep WMH (DWMH), respectively. Total WMH volume was associated with poor performance in categorical verbal fluency test (β=-0.197, p=0.035). JVWMH volume was associated with poor performances on categorical verbal fluency test (β=-0.201, p=0.032) and forward digit span test (β= -0.250, p=0.012). PVWMH volume was associated with poor performances on categorical verbal fluency test (β=-0.185, p=0.042) and word list memory test (β=-0.165, p=0.042), whereas DWMH volume showed no association with cognitive tests. PVWMH volume were also related to Clinical Dementia Rating Scale Sum of Boxes score (β=0.180, p=0.026). WMH appear to exhibit different associations with the severity of dementia and cognitive impairment according to the distance from ventricle surface in AD.

Evaluation of Ultrasound Changes With the Use of Microneedling Versus Fractional CO2 Laser in Atrophic Acne Scars.

Atrophic acne scarring, a common sequela of acne, can be treated by different interventions, including microneedling and laser resurfacing. We sought to evaluate the comparative efficacy of microneedling versus fractional CO2 laser in treating atrophic acne facial scars using imaging with high and ultra-high frequency ultrasound. Participants received 2 sessions, separated by 1 month, of microneedling on the left side of the face and fractional CO2 laser on the right. Color Doppler ultrasound evaluations (24 and 70 MHz) were conducted at baseline and 3 months after treatment. Each patient completed questionnaires on satisfaction, pain, and adverse effects. Nine subjects were enrolled. The frequency order of scar types was boxcar, ice-pick, and rolling. At 3 months, using the acne scar clinical evaluation scale, a decrease in scar scores of both methods was observed for total scars (P = 0.0005), ice-pick scars (P = 0.0128), and rolling scars (P = 0.0007). Twenty-two scars analyzed by ultrasound demonstrated a trend to decrease in size; however, no significant changes were observed for either microneedling or CO2 laser treatments. Moreover, there were no significant differences between these methods. Both treatments were rated as good or very good by patient assessments. There was a low frequency of pain and hyperpigmentation reported with both modalities, albeit somewhat higher with microneedling. Both microneedling and CO2 laser improved atrophic acne scars. Ultrasound did not show significant differences between these modalities.

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms.

Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Safety and Efficacy of Staged, Bilateral Focused Ultrasound Thalamotomy in Essential Tremor

Unilateral magnetic resonance-guided focused ultrasound ablation of ventralis intermedius nucleus of the thalamus for essential tremor reduces tremor on 1 side, but untreated contralateral or midline symptoms remain limiting for some patients. Historically, bilateral lesioning produced unacceptable risks and was supplanted by deep brain stimulation; increasing acceptance of unilateral focused ultrasound lesioning has led to interest in a bilateral option. To evaluate the safety and efficacy of staged, bilateral focused ultrasound thalamotomy. This prospective, open-label, multicenter trial treated patients with essential tremor from July 2020 to October 2021, with a 12-month follow-up, at 7 US academic medical centers. Of 62 enrolled patients who had undergone unilateral focused ultrasound thalamotomy at least 9 months prior to enrollment, 11 were excluded and 51 were treated. Eligibility criteria included patient age (22 years and older), medication refractory, tremor severity (Clinical Rating Scale for Tremor [CRST] part A score ≥2 for postural or kinetic tremor), and functional disability (CRST part C score ≥2 in any category). A focused ultrasound system interfaced with magnetic resonance imaging allowed real-time alignment of thermography maps with anatomy. Subthreshold sonications allowed target interrogation for efficacy and off-target effects before creating an ablation. Tremor/motor score (CRST parts A and B) at 3 months for the treated side after treatment was the primary outcome measure, and secondary assessments for efficacy and safety continued to 12 months. The mean (SD) population age was 73 (13.9) years, and 44 participants (86.3%) were male. The mean (SD) tremor/motor score improved from 17.4 (5.4; 95% CI, 15.9-18.9) to 6.4 (5.3; 95% CI, 4.9 to 7.9) at 3 months (66% improvement in CRST parts A and B scores; 95% CI, 59.8-72.2; P < .001). There was significant improvement in mean (SD) postural tremor (from 2.5 [0.8]; 95% CI, 2.3 to 2.7 to 0.6 [0.9]; 95% CI, 0.3 to 0.8; P < .001) and mean (SD) disability score (from 10.3 [4.7]; 95% CI, 9.0-11.6 to 2.2 [2.8]; 95% CI, 1.4-2.9; P < .001). Twelve participants developed mild (study-defined) ataxia, which persisted in 6 participants at 12 months. Adverse events (159 of 188 [85%] mild, 25 of 188 [13%] moderate, and 1 severe urinary tract infection) reported most commonly included numbness/tingling (n = 17 total; n = 8 at 12 months), dysarthria (n = 15 total; n = 7 at 12 months), ataxia (n = 12 total; n = 6 at 12 months), unsteadiness/imbalance (n = 10 total; n = 0 at 12 months), and taste disturbance (n = 7 total; n = 3 at 12 months). Speech difficulty, including phonation, articulation, and dysphagia, were generally mild (rated as not clinically significant, no participants with worsening in all 3 measures) and transient. Staged, bilateral focused ultrasound thalamotomy significantly reduced tremor severity and functional disability scores. Adverse events for speech, swallowing, and ataxia were mostly mild and transient. ClinicalTrials.gov Identifier NCT04112381.

Osteopontin: A novel marker of pre-symptomatic sporadic Alzheimer's disease.

We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains. Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aβ) and tau positivity. Survival analyses investigated the link between OPN and rate of conversion to AD. In PREVENT-AD, CSF OPN was positively correlated with synaptic biomarkers. In PREVENT-AD and ADNI, OPN was elevated in CSF Aβ42/40(+)/total tau(+) and CSF Aβ42/40(+)/phosphorylated tau181(+) individuals. In ADNI, OPN was increased in Aβ(+) positron emission tomography (PET) and tau(+) PET individuals, and associated with an accelerated rate of conversion to AD. OPN was elevated in autopsy-confirmed AD brains. Strong associations between CSF OPN and key markers of AD pathophysiology suggest a significant role for OPN in tau neurobiology, particularly in the early stages of the disease. In the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease cohort, we discovered that cerebrospinal fluid (CSF) osteopontin (OPN) levels can indicate early synaptic dysfunction, tau deposition, and neuronal loss in cognitively unimpaired elderly with a parental history. CSF OPN is elevated in amyloid beta(+) positron emission tomography (PET) and tau(+) PET individuals. Elevated CSF OPN is associated with an accelerated rate of conversion to Alzheimer's disease (AD). Elevated CSF OPN is associated with an accelerated rate of cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive subscale 13, Montreal Cognitive Assessment, Mini-Mental State Examination, and Clinical Dementia Rating Scale Sum of Boxes. OPN mRNA and protein levels are significantly upregulated in the frontal cortex of autopsy-confirmed AD brains.

Multiomics of parkinsonism cynomolgus monkeys highlights significance of metabolites in interaction between host and microbiota

The gut microbiota has been demonstrated to play a significant role in the pathogenesis of Parkinson’s disease (PD). However, conflicting findings regarding specific microbial species have been reported, possibly due to confounding factors within human populations. Herein, our current study investigated the interaction between the gut microbiota and host in a non-human primate (NHP) PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a multi-omic approach and a self-controlled design. Our transcriptomic sequencing of peripheral blood leukocytes (PBL) identified key genes involved in pro-inflammatory cytokine dysregulation, mitochondrial function regulation, neuroprotection activation, and neurogenesis associated with PD, such as IL1B, ATP1A3, and SLC5A3. The metabolomic profiles in serum and feces consistently exhibited significant alterations, particularly those closely associated with inflammation, mitochondrial dysfunctions and neurodegeneration in PD, such as TUDCA, ethylmalonic acid, and L-homophenylalanine. Furthermore, fecal metagenome analysis revealed gut dysbiosis associated with PD, characterized by a significant decrease in alpha diversity and altered commensals, particularly species such as Streptococcus, Butyrivibrio, and Clostridium. Additionally, significant correlations were observed between PD-associated microbes and metabolites, such as sphingomyelin and phospholipids. Importantly, PDPC significantly reduced in both PD monkey feces and serum, exhibiting strong correlation with PD-associated genes and microbes, such as SLC5A3 and Butyrivibrio species. Moreover, such multi-omic differential biomarkers were linked to the clinical rating scales of PD monkeys. Our findings provided novel insights into understanding the potential role of key metabolites in the host-microbiota interaction involved in PD pathogenesis.

Towards New Methodology for Cross-Validation of Clinical Evaluation Scales and Functional MRI in Psychiatry.

Objective biomarkers have been a critical challenge for the field of psychiatry, where diagnostic, prognostic, and theranostic assessments are still based on subjective narratives. Psychopathology operates with idiographic knowledge and subjective evaluations incorporated into clinical assessment inventories, but is considered to be a medical discipline and, as such, uses medical intervention methods (e.g., pharmacological, ECT; rTMS; tDCS) and, therefore, is supposed to operate with the language and methods of nomothetic networks. The idiographic assessments are provisionally "quantified" into "structured clinical scales" to in some way resemble nomothetic measures. Instead of fostering data merging and integration, this approach further encapsulates the clinical psychiatric methods, as all other biological tests (molecular, neuroimaging) are performed separately, only after the clinical assessment has provided diagnosis. Translational cross-validation of clinical assessment instruments and fMRI is an attempt to address the gap. The aim of this approach is to investigate whether there exist common and specific neural circuits, which underpin differential item responses to clinical self-rating scales during fMRI sessions in patients suffering from the two main spectra of mental disorders: schizophrenia and major depression. The current status of this research program and future implications to promote the development of psychiatry as a medical discipline are discussed.

An Algorithm for Automated Measurement of Kinetic Tremor Magnitude Using Digital Spiral Drawings

Introduction: Essential tremor is a common movement disorder. Numerous validated clinical rating scales exist to quantify essential tremor severity by employing rater-dependent visual observation but have limitations, including the need for trained human raters and the lack of precision and sensitivity compared to technology-based objective measures. Other continuous objective methods to quantify tremor amplitude have been developed, but frequently provide unitless measures (e.g., tremor power), limiting real-world interpretability. We propose a novel algorithm to measure kinetic tremor amplitude using digital spiral drawings, applying the V3 framework (sensor verification, analytical validation, and clinical validation) to establish reliability and clinical utility. Methods: Archimedes spiral drawings were recorded on a digitizing tablet from participants (n = 7) enrolled in a randomized placebo control double-blinded crossover pilot trial evaluating the efficacy of oral cannabinoids in reducing essential tremor. We developed an algorithm to calculate the mean and maximum tremor amplitude derived from the spiral tracings. We compared the digitally measured tremor amplitudes to manual measurement to evaluate sensor reliability, determined the test-retest reliability of the digital output across two short-interval repeated measures, and compared the digital measure to kinetic tremor severity graded using The Essential Tremor Rating Assessment Scale (TETRAS) score for spiral drawings. Results: This algorithm for automated assessment of kinetic tremor amplitude from digital spiral tracings demonstrated a high correlation with manual spot measures of tremor amplitude, excellent test-retest reliability, and a high correlation with human ratings of the TETRAS score for spiral drawing severity when the tremor severity was rated “slight tremor” or worse. Discussion: This digital measure provides a simple and clinically relevant evaluation of kinetic tremor amplitude that shows promise as a potential future endpoint for use in clinical trials of essential tremor.

Impact of Different Diagnostic Measures on Drug Class Association with Dementia Progression Risk: A Longitudinal Prospective Cohort Study.

The Clinical Dementia Rating Scale Sum of Boxes (CDRSOB) score is known to be highly indicative of cognitive-functional status and is regularly employed for clinical and research purposes. Our aim is to determine whether CDRSOB is consistent with clinical diagnosis in evaluating drug class associations with risk of progression to mild cognitive impairment (MCI) and dementia. We employed weighted Cox regression analysis on longitudinal NACC data, to identify drug classes associated with disease progression risk, using clinical diagnosis and CDRSOB as the outcome. Aspirin (antiplatelet/NSAID), angiotensin II inhibitors (antihypertensive), and Parkinson's disease medications were significantly associated with reduced risk of progression to MCI/dementia and Alzheimer's disease medications were associated with increased MCI-to-Dementia progression risk with both clinical diagnosis and CDRSOB as the outcome. However, certain drug classes/subcategories, like anxiolytics, antiadrenergics, calcium (Ca2+) channel blockers, and diuretics (antihypertensives) were associated with reduced risk of disease progression, and SSRIs (antidepressant) were associated with increased progression risk only with CDRSOB. Additionally, metformin (antidiabetic medication) was associated with reduced MCI-to-Dementia progression risk only with clinical diagnosis as the outcome. Although the magnitude and direction of the effect were primarily similar for both diagnostic outcomes, we demonstrate that choice of diagnostic measure can influence the significance of risk/protection attributed to drug classes and consequently the conclusion of findings. A consensus must be reached within the research community with respect to the most accurate diagnostic outcome to identify risk and improve reproducibility.

Loneliness and Resting-State Functional Brain Connectivity Among Older Adults: A Proportional Correlation.

Loneliness reportedly increases the risk of dementia, especially Alzheimer's disease (AD). The authors' previous study demonstrated associations between loneliness and structural abnormalities observed in early-stage AD. The present study examined associations between the brain's functional characteristics and loneliness among older adults with concerns about cognitive decline. This single-center study included 43 participants (13 with amnestic mild cognitive impairment and 30 with normal cognition). Participants were assessed with the revised University of California Los Angeles (UCLA) Loneliness Scale and underwent resting-state functional MRI. Functional images were preprocessed with the CONN toolbox. The selected seeds were within brain regions reportedly associated with loneliness. One-sample general linear model analysis was performed to examine regressions of UCLA Loneliness Scale scores and functional connectivity between the seeds and regions of interest. The revised UCLA Loneliness Scale scores were positively correlated with functional connectivity between the right hippocampus and left lateral parietal lobe and were negatively correlated with functional connectivity between the left amygdala and left frontal operculum and between the left amygdala and right supramarginal gyrus. Analyses were adjusted for age, sex, and education and scores on the Mini-Mental State Examination and Clinical Dementia Rating scale. Loneliness was associated with abnormal function of the hippocampus, parts of the parietal lobe and frontal cortex, and the amygdala. These findings may suggest a possible correlation between loneliness and neurological changes associated with dementia.

Development of a machine learning algorithm to predict the residual cognitive reserve index.

Elucidating the mechanisms by which late-life neurodegeneration causes cognitive decline requires understanding why some individuals are more resilient than others to the effects of brain change on cognition (cognitive reserve). Currently, there is no way of measuring cognitive reserve that is valid (e.g. capable of moderating brain-cognition associations), widely accessible (e.g. does not require neuroimaging and large sample sizes), and able to provide insight into resilience-promoting mechanisms. To address these limitations, this study sought to determine whether a machine learning approach to combining standard clinical variables could (i) predict a residual-based cognitive reserve criterion standard and (ii) prospectively moderate brain-cognition associations. In a training sample combining data from the University of California (UC) Davis and the Alzheimer's Disease Neuroimaging Initiative-2 (ADNI-2) cohort (N = 1665), we operationalized cognitive reserve using an MRI-based residual approach. An eXtreme Gradient Boosting machine learning algorithm was trained to predict this residual reserve index (RRI) using three models: Minimal (basic clinical data, such as age, education, anthropometrics, and blood pressure), Extended (Minimal model plus cognitive screening, word reading, and depression measures), and Full [Extended model plus Clinical Dementia Rating (CDR) and Everyday Cognition (ECog) scale]. External validation was performed in an independent sample of ADNI 1/3/GO participants (N = 1640), which examined whether the effects of brain change on cognitive change were moderated by the machine learning models' cognitive reserve estimates. The three machine learning models differed in their accuracy and validity. The Minimal model did not correlate strongly with the criterion standard (r = 0.23) and did not moderate the effects of brain change on cognitive change. In contrast, the Extended and Full models were modestly correlated with the criterion standard (r = 0.49 and 0.54, respectively) and prospectively moderated longitudinal brain-cognition associations, outperforming other cognitive reserve proxies (education, word reading). The primary difference between the Minimal model-which did not perform well as a measure of cognitive reserve-and the Extended and Full models-which demonstrated good accuracy and validity-is the lack of cognitive performance and informant-report data in the Minimal model. This suggests that basic clinical variables like anthropometrics, vital signs, and demographics are not sufficient for estimating cognitive reserve. Rather, the most accurate and valid estimates of cognitive reserve were obtained when cognitive performance data-ideally augmented by informant-reported functioning-was used. These results indicate that a dynamic and accessible proxy for cognitive reserve can be generated for individuals without neuroimaging data and gives some insight into factors that may promote resilience.

Prestroke Cognitive Impairment: Frequency and Association With Premorbid Neuropsychiatric, Functional, and Neuroimaging Features.

Some patients with stroke have prestroke cognitive impairment (pre-SCI), but its etiology is not clear. The aim of this cross-sectional study was to assess the frequency of pre-SCI and its association with premorbid neuropsychiatric, functional, and neuroimaging features. Patients hospitalized in stroke unit with an informant who could complete IQCODE (Informant Questionnaire for Cognitive Decline in the Elderly) were included. Pre-SCI was diagnosed if the IQCODE score was >3.3. Prestroke assessment also included NPI-Q (Neuropsychiatric Inventory Questionnaire), the basic Activities of Daily Living and Instrumental Activities of Daily Living scales, and the Clinical Dementia Rating scale. A multivariate logistic regression model was used to evaluate the association of pre-SCI with age, sex, education, arterial hypertension, atrial fibrillation, white matter lesions, cerebral microbleeds, and pathological medial temporal lobe atrophy. IQCODE was available in 474 of 520 patients (91.2%; 45% women; mean age 75.5±13.3 years). Pre-SCI had a prevalence of 32.5% and was associated with prestroke NPI-Q (pre-SCI absent versus present, 1.7±2.3 versus 5.5±4.9; P<0.001), Activities of Daily Living scale (0.3±0.8 versus 1.8±1.9; P<0.001), Instrumental Activities of Daily Living scale (0.6±1.3 versus 3.8±4.0; P<0.001), and Clinical Dementia Rating scale score (0.7±1.7 versus 7.2±6.2; P<0.001). In the 271 patients with a magnetic resonance imaging available, the multivariate logistic regression showed that age (odds ratio [OR], 1.05 [95% CI, 1.62-9.73]), white matter lesions (OR, 1.26 [95% CI, 1.003-1.58]), and a pathological medial temporal lobe atrophy score (OR, 3.97 [95% CI, 1.62-9.73]) were independently associated with pre-SCI. In the 218 patients with ischemic stroke, white matter lesions (OR, 1.34 [95% CI, 1.04-1.72]) and medial temporal lobe atrophy (OR, 3.56 [95% CI, 1.38-9.19]), but not age, were associated with pre-SCI. One-third of patients admitted to a stroke unit have pre-SCI that is associated with preexisting neuropsychiatric symptoms and functional performance. White matter lesions and medial temporal lobe atrophy are associated with pre-SCI, suggesting that both small vessel disease and neurodegeneration might be involved in its etiology.

Heterogeneity of Treatment Effects in Internet- and Mobile-Based Interventions for Depression

While the effects of internet- and mobile-based interventions (IMIs) for depression have been extensively studied, no systematic evidence is available regarding the heterogeneity of treatment effects (HTEs), indicating to what extent patient-by-treatment interactions exist and personalized treatment models might be necessary. To investigate the HTEs in IMIs for depression as well as their efficacy and effectiveness. A systematic search in Embase, MEDLINE, Central, and PsycINFO for randomized clinical trials and supplementary reference searches was conducted on October 13, 2019, and updated March 25, 2022. The search string included various terms related to digital psychotherapy, depression, and randomized clinical trials. Titles, abstracts, and full texts were reviewed by 2 independent researchers. Studies of all populations with at least 1 intervention group receiving an IMI for depression and at least 1 control group were eligible, if they assessed depression severity as a primary outcome and followed a randomized clinical trial (RCT) design. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Risk of bias was evaluated using the Cochrane Risk of Bias Tool. HTE was investigated using logarithmic variance ratios (lnVR) and effect sizes using Hedges g. Three-level bayesian meta-regressions were conducted. Heterogeneity of treatment effects was the primary outcome of this study; magnitudes of treatment effect sizes were the secondary outcome. Depression severity was measured by different self-report and clinician-rated scales in the included RCTs. The systematic review of 102 trials included 19 758 participants (mean [SD] age, 39.9 [10.58] years) with moderate depression severity (mean [SD] in Patient Health Questionnaire-9 score, 12.81 [2.93]). No evidence for HTE in IMIs was found (lnVR = -0.02; 95% credible interval [CrI], -0.07 to 0.03). However, HTE was higher in more severe depression levels (β̂ = 0.04; 95% CrI, 0.01 to 0.07). The effect size of IMI was medium (g = -0.56; 95% CrI, -0.46 to -0.66). An interaction effect between guidance and baseline severity was found (β̂ = -0.24, 95% CrI, -0.03 to -0.46). In this systematic review and meta-analysis of RCTs, no evidence for increased patient-by-treatment interaction in IMIs among patients with subthreshold to mild depression was found. Guidance did not increase effect sizes in this subgroup. However, the association of baseline severity with HTE and its interaction with guidance indicates a more sensitive, guided, digital precision approach would benefit individuals with more severe symptoms. Future research in this population is needed to explore personalization strategies and fully exploit the potential of IMI.

Assessment of Severity of Substance use for Outcomes Research and Treatment (ASSORT): A substance use severity scale developed and validated across six tertiary care centers in India.

Assessment of the severity of substance use disorders (SUDs) in a culture-sensitive manner can help gauge the current condition of the substance user and assess change with time. The present study aimed to develop a scale for the assessment of the severity of SUDs in the Indian clinical context. Based upon the review of literature on previously available instruments and a consultative meeting of experts, a clinician-rated scale was developed that finally comprised 41 items. A briefer 5-item scale with current and lifetime versions was also developed. The scales were applied to patients with SUDs at six different clinical sites. The instrument was applied to 720 patients (98.2% males, mean age: 34.6 years). The Cronbach's alpha of the full scale was 0.852. The inter-rater reliability Pearson correlation coefficient of the full-scale was r = 0.821 (P < 0.001), and the intra-class correlation coefficient single measure was 0.800 (95% confidence interval: 0.724-0.956). A four-factor solution was suggested to be the most tenable. The mean application duration of the full scale was 13.4 minutes, and that of the briefer version was 2 minutes. This validated scale could be a potentially useful assessment measure for the severity of SUDs in the Indian context. The utility lies in the simplicity of administration and scoring and the balance between brevity and thorough assessment.

Clinically feasible automated MRI volumetry of the brain as a prognostic marker in subjective and mild cognitive impairment.

The number of patients suffering from cognitive decline and dementia increases, and new possible treatments are being developed. Thus, the need for time efficient and cost-effective methods to facilitate an early diagnosis and prediction of future cognitive decline in patients with early cognitive symptoms is becoming increasingly important. The aim of this study was to evaluate whether an MRI based software, NeuroQuant® (NQ), producing volumetry of the hippocampus and whole brain volume (WBV) could predict: (1) conversion from subjective cognitive decline (SCD) at baseline to mild cognitive impairment (MCI) or dementia at follow-up, and from MCI at baseline to dementia at follow-up and (2) progression of cognitive and functional decline defined as an annual increase in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score. MRI was performed in 156 patients with SCD or MCI from the memory clinic at Oslo University Hospital (OUH) that had been assessed with NQ and had a clinical follow-up examination. Logistic and linear regression analyses were performed with hippocampus volume and WBV as independent variables, and conversion or progression as dependent variables, adjusting for demographic and other relevant covariates including Mini-Mental State Examination-Norwegian Revised Version score (MMSE-NR) and Apolipoprotein E ɛ4 (APOE ɛ4) carrier status. Hippocampus volume, but not WBV, was associated with conversion to MCI or dementia, but neither were associated with conversion when adjusting for MMSE-NR. Both hippocampus volume and WBV were associated with progression as measured by the annual change in CDR-SB score in both unadjusted and adjusted analyses. The results indicate that automated regional MRI volumetry of the hippocampus and WBV can be useful in predicting further cognitive decline in patients with early cognitive symptoms.

Dementia severity at incident diagnosis in a population representative sample of older Americans.

We provide the first analysis of distribution of dementia severity at incident diagnosis for a population representative sample of older Americans. Using data from the Aging, Demographics, and Memory Study (ADAMS), the Health Retirement Study (HRS), and traditional Medicare claims, we estimated the Clinical Dementia Rating Scale for ADAMS respondents and applied parameter estimates to predict dementia severity for HRS respondents with claims-based incident dementia diagnosis. Seventy percent of older adults received a dementia diagnosis of mild cognitive impairment or mild dementia (early stages). Fewer individuals were diagnosed at early stages in years 2000 to 2008 (65%) compared to years 2009 to 2016 (76%). About 72% of non-Hispanic white persons were diagnosed at early stages, compared to 63% non-Hispanic black and 59% Hispanic persons. More males than females were diagnosed at early stages (75%vs 67%). These data linkages allow population surveillance of early and equitable dementia detection in the older US population to assess clinical and policy levers to improve detection. For the US population 70 and older, 30% were diagnosed with dementia at a moderate or severe stage.Fewer were diagnosed at early stages in years 2000 to 2008 compared to 2009 to 2016 (65%vs 76%).A total of 72% of white persons were diagnosed at early stages, compared to 63% black and 59% Hispanic persons.More males than females were diagnosed at early stages (75%vs 67%).High wealth and education level were associated with diagnosis at early stages disease.

Neuropathological Lesions and Cognitive Abilities in Black and White Older Adults in Brazil

Race differences in dementia prevalence and incidence have previously been reported, with higher dementia burden in Black decedents. However, previous neuropathological studies were conducted mostly in convenience samples with White participants; conducting clinicopathological studies across populations is crucial for understanding the underlying dementia causes in individuals from different racial backgrounds. To compare the frequencies of neuropathological lesions and cognitive abilities between Black and White Brazilian adults in an autopsy study. This cross-sectional study used samples from the Biobank for Aging Studies, a population-based autopsy study conducted in Sao Paulo, Brazil. Participants were older adults whose family members consented to the brain donations; Asian participants and those with missing data were excluded. Samples were collected from 2004 to 2023. Neuropathologists were masked to cognitive outcomes. Race as reported by the deceased's family member. The frequencies of neurodegenerative and cerebrovascular lesions were evaluated in 13 selected cerebral areas. Cognitive and functional abilities were examined with the Clinical Dementia Rating Scale. The mean (SD) age of the 1815 participants was 74.0 (12.5) years, 903 (50%) were women, 617 (34%) were Black, and 637 (35%) had cognitive impairment. Small vessel disease (SVD) and siderocalcinosis were more frequent in Black compared with White participants (SVD: odds ratio [OR], 1.74; 95% CI, 1.29-2.35; P < .001; siderocalcinosis: OR, 1.70; 95% CI, 1.23-2.34; P = .001), while neuritic plaques were more frequent in White compared with Black participants (OR, 0.61; 95% CI, 0.44-0.83; P = .002). Likewise, Alzheimer disease neuropathological diagnosis was more frequent in White participants than Black participants (198 [39%] vs 77 [33%]), while vascular dementia was more common among Black participants than White participants (76 [32%] vs 121 [24%]). Race was not associated with cognitive abilities, nor did it modify the association between neuropathology and cognition. In this cross-sectional study of Brazilian older adults, Alzheimer disease pathology was more frequent in White participants while vascular pathology was more frequent in Black participants. Further neuropathological studies in diverse samples are needed to understand race disparities in dementia burden.