Harmonizing tau positron emission tomography in Alzheimer's disease: The CenTauR scale and the joint propagation model.

INTRODUCTION: Tau-positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods of analysis. METHODS: Using head-to-head data from five cohorts with tau PET radiotracers designed to target tau deposition in AD, we tested a joint propagation model (JPM) to harmonize quantification (units termed "CenTauR" [CTR]). JPM is a statistical model that simultaneously models the relationships between head-to-head and anchor point data. JPM was compared to a linear regression approach analogous to the one used in the amyloid PET Centiloid scale. RESULTS: A strong linear relationship was observed between CTR values across brain regions. Using the JPM approach, CTR estimates were similar to, but more accurate than, those derived using the linear regression approach. DISCUSSION: Preliminary findings using the JPM support the development and adoption of a universal scale for tau-PET quantification. HIGHLIGHTS: Tested a novel joint propagation model (JPM) to harmonize quantification of tau PET. Units of common scale are termed "CenTauRs". Tested a Centiloid-like linear regression approach. Using five cohorts with head-to-head tau PET, JPM outperformed linearregressionbased approach. Strong linear relationship was observed between CenTauRs values across brain regions.

Classifications in adult pes cavus - A scoping review.

AIMS: The adult cavus foot represents a challenging clinical problem, with varied aetiology and complex, 3-dimensional deformities. Thus far, the cavus foot has eluded a unified classification. The aim of this paper was to appraise the literature to identify classification systems which guide the operative management of neurological cavus feet in adults. METHODS: As the aim of this paper was broad, a scoping review was conducted. The review was conducted in line with published frameworks. Our principal research question was 'what classification systems that guide surgical management currently exist for neurological cavus feet in adults'. We searched CINAHL, Embase, OVID, Proquest, Pubmed, Scopus and Web of Science databases using MESH and non-MESH terms. Two authors independently reviewed abstracts / papers and a data extraction sheet was used to collect the relevant data. RESULTS: A total of 1140 articles were initially screened, identifying 125 articles for which a full text review was performed. Only three articles met all our inclusion criteria. All these articles reported an anatomical classification with suggestions for treatment based on the classification. All were considered to comprise Level V evidence, and none reported outcomes of treatment based on the classification. CONCLUSIONS: There is currently a paucity of robust classifications to guide treatment in neurological cavus feet in adults. The few classifications systems that exist are varied and do not as yet have sufficient evidence to support their widespread use. Further work is required, aimed at identifying specific features of cavus feet that would guide operative treatment.

Forefoot Morphotypes in Cavovarus Feet: A Novel Assessment of Deformity.

BACKGROUND: The cavovarus foot is a complex 3-dimensional deformity. Although a multitude of techniques are described for its surgical management, few of these are evidence based or guided by classification systems. Surgical management involves realignment of the hindfoot and soft tissue balancing, followed by forefoot balancing. Our aim was to analyze the pattern of residual forefoot deformities once the hindfoot is corrected, to guide forefoot correction. METHODS: We included 20 cavovarus feet from 16 adult patients with Charcot-Marie-Tooth who underwent weightbearing CT (mean age 43.4 years, range: 22-78 years, 14 males). Patients included had flexible deformities, with no previous surgery. Using specialized software (Bonelogic 2.1, Disior) a 3-dimensional, virtual model was created. Using morphologic data captured from normal feet in patients without pathology as a guide, the talonavicular joint of the cavovarus foot was digitally reduced to a "normal" position to simulate the correction that would be achieved during surgical correction. Models of the corrected position were exported and geometrically analyzed using Blender 3.64 to identify anatomical trends. RESULTS: We identified 4 types of cavovarus forefoot morphotypes. Type 0 was defined as a balanced forefoot (2 cases, 10%). Type 1 was defined as a forefoot where the first metatarsal was relatively plantarflexed to the rest of the foot, with no significant residual adduction after talonavicular joint correction (12 cases, 60%). Type 2 was defined as a forefoot where the second and first metatarsals were progressively plantarflexed, with no significant adduction (4 cases, 20%). Type 3 was defined as a forefoot where the metatarsals were adducted after talonavicular derotation (2 cases, 10%). CONCLUSION: In this relatively small cohort, we identified 4 forefoot morphotypes in cavovarus feet that might help surgeons to recognize and anticipate the residual forefoot deformities after hindfoot correction. Different treatment strategies may be required for different morphotypes to achieve balanced correction. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Comparing a pre-defined versus deep learning approach for extracting brain atrophy patterns to predict cognitive decline due to Alzheimer's disease in patients with mild cognitive symptoms.

BACKGROUND: Predicting future Alzheimer's disease (AD)-related cognitive decline among individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) is an important task for healthcare. Structural brain imaging as measured by magnetic resonance imaging (MRI) could potentially contribute when making such predictions. It is unclear if the predictive performance of MRI can be improved using entire brain images in deep learning (DL) models compared to using pre-defined brain regions. METHODS: A cohort of 332 individuals with SCD/MCI were included from the Swedish BioFINDER-1 study. The goal was to predict longitudinal SCD/MCI-to-AD dementia progression and change in Mini-Mental State Examination (MMSE) over four years. Four models were evaluated using different predictors: (1) clinical data only, including demographics, cognitive tests and APOE ε4 status, (2) clinical data plus hippocampal volume, (3) clinical data plus all regional MRI gray matter volumes (N = 68) extracted using FreeSurfer software, (4) a DL model trained using multi-task learning with MRI images, Jacobian determinant images and baseline cognition as input. A double cross-validation scheme, with five test folds and for each of those ten validation folds, was used. External evaluation was performed on part of the ADNI dataset, including 108 patients. Mann-Whitney U-test was used to determine statistically significant differences in performance, with p-values less than 0.05 considered significant. RESULTS: In the BioFINDER cohort, 109 patients (33%) progressed to AD dementia. The performance of the clinical data model for prediction of progression to AD dementia was area under the curve (AUC) = 0.85 and four-year cognitive decline was R2 = 0.14. The performance was improved for both outcomes when adding hippocampal volume (AUC = 0.86, R2 = 0.16). Adding FreeSurfer brain regions improved prediction of four-year cognitive decline but not progression to AD (AUC = 0.83, R2 = 0.17), while the DL model worsened the performance for both outcomes (AUC = 0.84, R2 = 0.08). A sensitivity analysis showed that the Jacobian determinant image was more informative than the MRI image, but that performance was maximized when both were included. In the external evaluation cohort from ADNI, 23 patients (21%) progressed to AD dementia. The results for predicted progression to AD dementia were similar to the results for the BioFINDER test data, while the performance for the cognitive decline was deteriorated. CONCLUSIONS: The DL model did not significantly improve the prediction of clinical disease progression in AD, compared to regression models with a single pre-defined brain region.

A blood-based biomarker workflow for optimal tau-PET referral in memory clinic settings.

Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer's disease. Plasma Aß42/Aß40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; "saved scans") and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; "positive predictive value"). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value.

Talar neck rotation angle in adults with clubfoot deformity: Observed values and intra- and inter-observer reliability using weightbearing CT.

INTRODUCTION: Adults presenting with symptomatic clubfoot represent a challenging cohort of patients. An appreciation of the location and degree of deformities is essential for management. Talar anatomy is often abnormal with varus within the talar neck, however, there are few reproducible methods which quantify talar neck deformity in adults. We describe a technique of assessing talar neck deformity, and report on observed values and intra- / inter-observer reliability. METHODS: This was a single-centre, retrospective study including 96 feet from 56 adult patients with clubfeet (82 feet had clubfoot deformity, 14 were normal). Mean age was 34.3 ± 16.9 years and 31 (55.3%) were male. Weight-bearing CT scans captured as part of routine clinical care were analysed. Image reformats were oriented parallel to the long axis of the talus in the sagittal plane. In the corresponding axial plane two lines were drawn (on separate slices): 1) a line perpendicular to the intermalleolar axis, 2) a line connecting the midpoints of the talar head and narrowest part of the talar neck. The talar neck rotation angle (TNR angle) was the angle formed between these lines. Intraclass correlation coefficients (ICC) were performed for intra- and inter-observer reliability. RESULTS: Mean TNR angle in clubfeet was 27.6 ± 12.2 degrees (95%CI = 25.0 to 30.2 degrees). Mean TNR angle in normal feet was 18.7 ± 5.1 degrees (95%CI = 16.0 to 21.4 degrees) (p < 0.001). The ICC for clubfeet was 0.944 (95%CI = 0.913 to 0.964) for intra-observer agreement, and 0.896 (95%CI = 0.837 to 0.932) for inter-observer agreement. CONCLUSION: This measurement technique demonstrated excellent intra- and inter-observer agreement. It also demonstrated that compared to normal feet, clubfeet had about 9 degrees of increased varus angulation of the talar neck. This technique and data may be used for future research into clubfoot deformity and in planning treatment. LEVEL OF CLINICAL EVIDENCE: 3.

Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology: a post hoc analysis of the "ADAMANT" randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial.

BACKGROUND: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available. METHODS: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI. STATISTICAL METHODS: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. RESULTS: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = -0.99 points, 95% CI [-2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [-0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = -0.15 log pg/mL, CI [-0.27, -0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = -0.10, CI [-0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18-0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus). CONCLUSIONS: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. FUNDING: AXON Neuroscience SE.

Comparing a pre-defined versus deep learning approach for extracting brain atrophy patterns to predict cognitive decline due to Alzheimer's disease in patients with mild cognitive symptoms.

Background: Predicting future Alzheimer's disease (AD)-related cognitive decline among individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI) is an important task for healthcare. Structural brain imaging as measured by magnetic resonance imaging (MRI) could potentially contribute when making such predictions. It is unclear if the predictive performance of MRI can be improved using entire brain images in deep learning (DL) models compared to using pre-defined brain regions. Methods: A cohort of 332 individuals with SCD/MCI were included from the Swedish BioFINDER-1 study. The goal was to predict longitudinal SCD/MCI-to-AD dementia progression and change in Mini-Mental State Examination (MMSE) over four years. Four models were evaluated using different predictors: 1) clinical data only, including demographics, cognitive tests and APOE e4 status, 2) clinical data plus hippocampal volume, 3) clinical data plus all regional MRI gray matter volumes (N=68) extracted using FreeSurfer software, 4) a DL model trained using multi-task learning with MRI images, Jacobian determinant images and baseline cognition as input. Models were developed on 80% of subjects (N=267) and tested on the remaining 20% (N=65). Mann-Whitney U-test was used to determine statistically significant differences in performance, with p-values less than 0.05 considered significant. Results: In the test set, 21 patients (32.3%) progressed to AD dementia. The performance of the clinical data model for prediction of progression to AD dementia was area under the curve (AUC)=0.87 and four-year cognitive decline was R2=0.17. The performance was significantly improved for both outcomes when adding hippocampal volume (AUC=0.91, R2=0.26, p-values <0.05) or FreeSurfer brain regions (AUC=0.90, R2=0.27, p-values <0.05). Conversely, the DL model did not show any significant difference from the clinical data model (AUC=0.86, R2=0.13). A sensitivity analysis showed that the Jacobian determinant image was more informative than the MRI image, but that performance was maximized when both were included. Conclusions: The DL model did not significantly improve the prediction of clinical disease progression in AD, compared to regression models with a single pre-defined brain region.

Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia.

Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant frontotemporal dementia. This retrospective analysis drew its population from two clinical samples recruited from memory clinics at university hospitals in the USA and The Netherlands. Individuals with sporadic behavioural variant frontotemporal dementia were enrolled between 2000 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. The study population consisted of 186 individuals with sporadic behavioural variant frontotemporal dementia (113 males and 73 females), mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus [60.2 years (8.54)] versus individuals who did not [57.76 (8.05)], 95% confidence interval > 0.41, P = 0.02. Education was not associated with age at onset (ß = -0.05, P = 0.75). The presence of a right paracingulate sulcus was associated with an 83% increased risk of death per year after age at onset (hazard ratio 1.83, confidence interval [1.09-3.07], P < 0.02), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus (P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant frontotemporal dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant frontotemporal dementia that may be important in the design of trials for future therapeutic approaches.

Outcomes of Tenosynovial Giant Cell Tumor of the Foot and Ankle.

BACKGROUND: Tenosynovial giant cell tumor (TGCT) is a benign proliferative disease affecting synovial membranes. There are 2 forms, localized (L-TGCT) and diffuse (D-TGCT), which although histologically similar behave differently. It is locally invasive and is treated in most cases by operative excision. The aim of this study was to assess current practice, how the patients' presentation affected their outcome, as well as review the recurrence rates and complications. METHODS: A retrospective analysis of 123 cases was performed in patients treated between 2003 and 2019 with TGCT of the foot and/or ankle. Data were collected on age at presentation, radiologic pattern of disease, location of disease, treatment provided, and recurrence rates. The minimum follow-up was 2 years with a mean of 7.7 years. RESULTS: There were 61.7% female patients with a mean age of 39 (range, 11-76) years. L-TGCT accounted for 85 (69.1%) cases and D-TGCT for 38 (30.9%). The most prevalent preoperative symptoms were a palpable mass (78/123) and pain (65/123). Radiologically confirmed recurrence in the operative group was noted in 14.5% (16/110) cases. This comprised 4% (3/75) of operatively treated L-TGCT and 37% (13/35) of operatively treated D-TGCT. Patients with pain on presentation and those with erosive changes on presenting magnetic resonance imaging (MRI) were more likely to have persistent postoperative pain (P < .001 for both). Where patients had both preoperative pain and erosive changes, 57.1% had postoperative pain. Thirteen cases were managed nonoperatively where symptoms were minimal, with 1 case requiring surgery at a later date. CONCLUSION: Outcomes of TGCT management are dependent on the disease type, extent of preoperative erosive changes, and presence of preoperative pain. These data are useful for counseling patients regarding the outcomes of surgical intervention and help guide the timing of intervention. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

A two-step workflow based on plasma p-tau217 to screen for amyloid ß positivity with further confirmatory testing only in uncertain cases.

Cost-effective strategies for identifying amyloid-ß (Aß) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aß immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aß-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aß-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aß42/Aß40 testing, whereas step 1 alone determined Aß-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aß-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings.

First Metatarsal Rotation After Scarf Osteotomy for Hallux Valgus.

BACKGROUND: Recurrence after surgical correction of hallux valgus may be related to coronal rotation of the first metatarsal. The scarf osteotomy is a commonly used procedure for correcting hallux valgus but has limited ability to correct rotation. Using weight-bearing computed tomography (WBCT), we aimed to measure the coronal rotation of the first metatarsal before and after a scarf osteotomy, and correlate these to clinical outcome scores. METHODS: We retrospectively analyzed 16 feet (15 patients) who had a WBCT before and after scarf osteotomy for hallux valgus correction. On both scans, hallux valgus angle (HVA), intermetatarsal angle (IMA), and anteroposterior/lateral talus-first metatarsal angle were measured using digitally reconstructed radiographs. Metatarsal pronation angle (MPA), alpha angle, sesamoid rotation angle, and sesamoid position were measured on standardized coronal WBCT slices. Preoperative and postoperative (12 mo) clinical outcome scores (Manchester Oxford Foot Questionnaire and Visual Analogue Scores) were captured. RESULTS: Mean HVA was 28.6 ± 10.1° preoperatively and 12.1 ± 7.7° postoperatively (P < .001). Mean IMA was 13.7 ± 3.8° preoperatively and 7.5 ± 3.0° postoperatively (P < .001). Before and after surgery, there were no significant differences in MPA (11.4 ± 7.7 and 11.4 ± 9.9°, respectively; P = .75) or alpha angle (10.9 ± 8.0 and 10.7 ± 13.1°, respectively; P = .83). There were significant improvements in sesamoid rotation angle (SRA) (26.4 ± 10.2 and 15.7 ± 10.2°, respectively; P = .03) and sesamoid position (1.4 ± 1.0 and 0.6 ± 0.6, respectively; P = .04) after a scarf osteotomy. There were significant improvements in all outcome scores after surgery. Poorer outcome scores correlated with greater postoperative MPA and alpha angles (r = .76 (P = .02) and .67 (P = .03), respectively). CONCLUSION: A scarf osteotomy does not correct first metatarsal coronal rotation, and worse outcomes are linked to greater postoperative metatarsal rotation. Rotation of the metatarsal needs to be measured and considered when planning hallux valgus surgery. Further work was needed to compare postoperative outcomes with rotational osteotomies and modified Lapidus procedures when addressing rotation.Level of Evidence: 4.

Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia.

Background: Frontotemporal dementia is the second most common form of early onset dementia (< 65 years). Despite this there are few known disease modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia. Sulcation of the anterior cingulate is denoted by the presence of a paracingulate sulcus, a tertiary sulcus developing, where present during the third gestational trimester and remaining stable throughout life. This study aims to examine the impact of right paracingulate sulcal presence on the expression and prognosis of behavioural variant Frontotemporal Dementia. Methods: This retrospective analysis drew it's population from two clinical samples recruited from memory clinics at University Hospitals in The United States of America and The Netherlands. Individuals with sporadic behavioural variant Frontotemporal Dementia were enrolled between 2004 and 2022 and followed up for an average of 7.71 years. T1-MRI data were evaluated for hemispheric paracingulate sulcal presence in accordance with an established protocol by two blinded raters. Outcome measures included age at onset, survival, cortical thickness, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating determined clinical disease progression. Results: The study population consisted of 186 individuals with sporadic behavioural variant Frontotemporal Dementia, (113 males and 73 females) mean age 63.28 years (SD 8.32). The mean age at onset was 2.44 years later in individuals possessing a right paracingulate sulcus (60.2 years (SD 8.54)) versus individuals who did not (57.76 (8.05)), 95% CI >0.41, P = 0.02. Education was not associated with age at onset (ß = -0.05, P =0.75). Presence of a right paracingulate sulcus was associated with a 119% increased risk of death per year after age at onset (HR 2.19, CI [1.21 - 3.96], P <0.01), whilst the mean age at death was similar for individuals with a present and absent right paracingulate sulcus ( P = 0.7). Right paracingulate sulcal presence was not associated with baseline cortical thickness. Conclusion: Right paracingulate sulcal presence is associated with disease expression and survival in sporadic behavioural variant Frontotemporal Dementia. Findings provide evidence of neurodevelopmental brain reserve in behavioural variant Frontotemporal Dementia which may be important in the design of trials for future therapeutic approaches.

Assessing the coronal plane deformity in Charcot Marie Tooth Cavovarus feet using automated 3D measurements.

BACKGROUND: This study assesses the coronal-plane deformities in cavovarus feet secondary to Charcot-Marie-Tooth disease (CMT) using Weightbearing-CT (WBCT) and semi-automated 3D-segmentation software. METHODS: WBCTs from 30 CMT-cavovarus feet were matched to 30 controls and analysed using semi-automatic 3D-segmentation (Bonelogic, DISIOR). The software used automated cross-section sampling with subsequent straight-line representation of weighted centre points to calculate 3D axes of bones in the hindfoot, midfoot and forefoot. Coronal relationships of these axes were analysed. Supination/pronation of the bones in relation to the ground and within each joint were measured and reported. RESULTS: The most significant deformity in CMT-cavovarus feet occurred at the talonavicular joint (TNJ) with 23 degrees more supination than normal feet (6.4 ± 14.5 versus 29.4 ± 7.0 degrees, p < 0.001). This was countered by relative pronation at the naviculo-cuneiform joints (NCJ) of 7.0 degrees (-36.0 ± 6.6 versus -43.0 ± 5.3 degrees, p < 0.001). Combined hindfoot varus and TNJ supination resulted in an additive supination effect not compensated by NCJ pronation. The cuneiforms in CMT-cavovarus feet were therefore supinated by 19.8 degrees to the ground relative to normal feet (36.0 ± 12.1 versus 16.2 ± 6.8 degrees, p < 0.001). The forefoot-arch and 1st metatarsal-ground angles demonstrated similar supination to the cuneiforms suggesting no further significant rotation occurred distally. CONCLUSION: Our results demonstrate coronal plane deformity occurs at multiple levels in CMT-cavovarus feet. Majority of the supination arises at the TNJ, and this is partially countered by pronation distally, mainly at the NCJ. An understanding of the location of coronal deformities may help when planning surgical correction. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Associations Between CSF Markers of Inflammation, White Matter Lesions, and Cognitive Decline in Individuals Without Dementia.

BACKGROUND AND OBJECTIVES: Small vessel disease (SVD) and neuroinflammation both occur in Alzheimer disease (AD) and other neurodegenerative diseases. It is unclear whether these processes are related or independent mechanisms in AD, especially in the early stages of disease. We therefore investigated the association between white matter lesions (WML; the most common manifestation of SVD) and CSF biomarkers of neuroinflammation and their effects on cognition in a population without dementia. METHODS: Individuals without dementia from the Swedish BioFINDER study were included. The CSF was analyzed for proinflammatory markers (interleukin [IL]-6 and IL-8), cytokines (IL-7, IL-15, and IL-16), chemokines (interferon γ-induced protein 10, monocyte chemoattractant protein 1), markers of vascular injury (soluble intercellular adhesion molecule 1, soluble vascular adhesion molecule 1), and markers of angiogenesis (placental growth factor [PlGF], soluble fms-related tyrosine kinase 1 [sFlt-1], vascular endothelial growth factors [VEGF-A and VEFG-D]), and amyloid ß (Aß)42 Aß40, and p-tau217. WML volumes were determined at baseline and longitudinally over 6 years. Cognition was measured at baseline and follow-up over 8 years. Linear regression models were used to test associations. RESULTS: A total of 495 cognitively unimpaired (CU) elderly individuals and 247 patients with mild cognitive impairment (MCI) were included. There was significant worsening in cognition over time, measured by Mini-Mental State Examination, Clinical Dementia Rating, and modified preclinical Alzheimer composite score in CU individuals and patients with MCI, with more rapid worsening in MCI for all cognitive tests. At baseline, higher levels of PlGF (ß = 0.156, p < 0.001), lower levels of sFlt-1 (ß = -0.086, p = 0.003), and higher levels of IL-8 (ß = 0.07, p = 0.030) were associated with more WML in CU individuals. In those with MCI, higher levels of PlGF (ß = 0.172, p = 0.001), IL-16 (ß = 0.125, p = 0.001), IL-8 (ß = 0.096, p = 0.013), IL-6 (ß = 0.088, p = 0.023), VEGF-A (ß = 0.068, p = 0.028), and VEGF-D (ß = 0.082, p = 0.028) were associated with more WML. PlGF was the only biomarker that was associated with WML independent of Aß status and cognitive impairment. Longitudinal analyses of cognition showed independent effects of CSF inflammatory markers and WML on longitudinal cognition, especially in people without cognitive impairment at baseline. DISCUSSION: Most neuroinflammatory CSF biomarkers were associated with WML in individuals without dementia. Our findings especially highlight a role for PlGF, which was associated with WML independent of Aß status and cognitive impairment.

Plasma amyloid-ß42/40 and apolipoprotein E for amyloid PET pre-screening in secondary prevention trials of Alzheimer's disease.

The extent to which newly developed blood-based biomarkers could reduce screening costs in secondary prevention trials of Alzheimer's disease is mostly unexplored. We collected plasma amyloid-ß42/40, apolipoprotein E ε4 status and amyloid PET at baseline in 181 cognitively unimpaired participants [the age of 72.9 (5.3) years; 61.9% female; education of 11.9 (3.4) years] from the Swedish BioFINDER-1 study. We tested whether a model predicting amyloid PET status from plasma amyloid-ß42/40, apolipoprotein E status and age (combined) reduced cost of recruiting amyloid PET + cognitively unimpaired participants into a theoretical trial. We found that the percentage of cognitively unimpaired participants with an amyloid PET + scan rose from 29% in an unscreened population to 64% [(49, 79); P < 0.0001] when using the biomarker model to screen for high risk for amyloid PET + status. In simulations, plasma screening also resulted in a 54% reduction of the total number of amyloid PET scans required and reduced total recruitment costs by 43% [(31, 56), P < 0.001] compared to no pre-screening when assuming a 16× PET-to-plasma cost ratio. Total savings remained significant when the PET-to-plasma cost ratio was assumed to be 8× or 4×. This suggests that a simple plasma biomarker model could lower recruitment costs in Alzheimer's trials requiring amyloid PET positivity for inclusion.

Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study.

INTRODUCTION: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases. METHODS: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aß42, Aß40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit). RESULTS: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aß42 alone (R2 ≥ 0.31) or together with NfL (R2  = 0.25), while p-tau/Aß42 (R2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aß42 (AUC ≥ 0.87) and p-tau/Aß42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively. DISCUSSION: P-tau/Aß42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.

Robustness of CSF Aß42/40 and Aß42/P-tau181 measured using fully automated immunoassays to detect AD-related outcomes.

INTRODUCTION: This study investigated the comparability of cerebrospinal fluid (CSF) cutoffs for Elecsys immunoassays for amyloid beta (Aß)42/Aß40 or Aß42/phosphorylated tau (p-tau)181 and the effects of measurement variability when predicting Alzheimer's disease (AD)-related outcomes (i.e., Aß-positron emission tomography [PET] visual read and AD neuropathology). METHODS: We studied 750 participants (BioFINDER study, Alzheimer's Disease Neuroimaging Initiative [ADNI], and University of California San Francisco [UCSF]). Youden's index was used to identify cutoffs and to calculate accuracy (Aß-PET visual read as outcome). Using longitudinal variability in Aß-negative controls, we identified a gray zone around cut-points where the risk of an inconsistent predicted outcome was >5%. RESULTS: For Aß42/Aß40, cutoffs across cohorts were <0.059 (BioFINDER), <0.057 (ADNI), and <0.058 (UCSF). For Aß42/p-tau181, cutoffs were <41.90 (BioFINDER), <39.20 (ADNI), and <46.02 (UCSF). Accuracy was ≈90% for both Aß42/Aß40 and Aß42/p-tau181 using these cutoffs. Using Aß-PET as an outcome, 8.7% of participants fell within a gray zone interval for Aß42/Aß40, compared to 4.5% for Aß42/p-tau181. Similar findings were observed using a measure of overall AD neuropathologic change (7.7% vs. 3.3%). In a subset with CSF and plasma Aß42/40, the number of individuals within the gray zone was ≈1.5 to 3 times greater when using plasma Aß42/40. DISCUSSION: CSF Aß42/p-tau181 was more robust to the effects of measurement variability, suggesting that it may be the preferred Elecsys-based measure in clinical practice and trials.

An accurate fully automated panel of plasma biomarkers for Alzheimer's disease.

INTRODUCTION: There is a great need for fully automated plasma assays that can measure amyloid beta (Aß) pathology and predict future Alzheimer's disease (AD) dementia. METHODS: Two cohorts (n = 920) were examined: Panel A+ (n = 32 cognitively unimpaired [CU], n = 106 mild cognitive impairment [MCI], and n = 89 AD) and BioFINDER-1 (n = 461 CU, n = 232 MCI). Plasma Aß42/Aß40, phosphorylated tau (p-tau)181, two p-tau217 variants, ApoE4 protein, neurofilament light, and GFAP were measured using Elecsys prototype immunoassays. RESULTS: The best biomarker for discriminating Aß-positive versus Aß-negative participants was Aß42/Aß40 (are under the curve [AUC] 0.83-0.87). Combining Aß42/Aß40, p-tau181, and ApoE4 improved the AUCs significantly (0.90 to 0.93; P< 0.01). Adding additional biomarkers had marginal effects (ΔAUC ≤0.01). In BioFINDER, p-tau181, p-tau217, and ApoE4 predicted AD dementia within 6 years in CU (AUC 0.88) and p-tau181, p-tau217, and Aß42/Aß40 in MCI (AUC 0.87). DISCUSSION: The high accuracies for Aß pathology and future AD dementia using fully automated instruments are promising for implementing plasma biomarkers in clinical trials and clinical routine.

Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients.

INTRODUCTION: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. METHODS: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aß)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. DISCUSSION: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia.