Citations

SUMMARY Neurodegenerative diseases are often accompanied by systemic comorbidities, including changes in bone health, but the molecular relationship between neurodegeneration, skeletal decline, and cellular senescence remains poorly understood. In this study, we investigated sex-specific changes in circulating bone- and senescence-related proteins across the spectrum of Alzheimer’s disease(AD), Lewbody dementia(LB) and Parkinson’s disease(PD). Plasma proteomic profiling was performed on samples from 408 participants deeply phenotyped for neurodegenerative diseases, followed by differential protein and pathway analyses. This study reveals sex-dependent alterations in bone and senescence-related circulating proteins in AD-related, PD and LB-related neurodegenerative diseases, providing insights into the complex relationship between neurodegeneration and bone health. Several candidate proteins were also associated with established plasma neurodegeneration biomarkers, particularly pTau181. Pathway analyses revealed shared mitochondrial and metabolic dysfunction across neurodegenerative diseases, with disease-specific features including vesicle trafficking disruption in AD and inflammatory-senescence pathways in LB, plus sex-divergent patterns in inflammatory signaling and bone-related pathways.

Abstract Background Monoclonal antibodies targeting amyloid‐β (Aβ), including aducanumab, have been tested to treat Alzheimer's disease (AD). However, limited data exist on neuropathology following treatment and the effects of amyloid‐related imaging abnormalities (ARIA). We report on such data from five aducanumab‐treated study participants with AD of whom two experienced ARIA. Methods Aducanumab‐treated study participants who came to autopsy ( n = 5) were matched to AD controls ( n = 12) based on the presence/type of autosomal dominant AD mutation, APOE genotype, age at cognitive symptom onset, and sex. We assessed cognitive measures, 18 F‐florbetapir PET centiloid, ARIA risk factors, and AD neuropathologic change. Using multiplex immunofluorescence, brain regions affected along Thal Aβ phases were stained for Aβ isoforms and phosphorylated tau, as well as for ARIA‐associated markers, including Perls’ Prussian blue to detect ferric iron, fibrinogen‐α for blood brain barrier integrity, membrane attack complex (C5b‐C9) for complement activation, and activated microglia (IBA1, CD68). Results Study participants included four males and one female, all carrying at least one APOE ε4 allele. Two participants carried a PSEN1 NM_000021.4:c.817G>A , p.Glu273Lys mutation. Cumulative aducanumab dosage ranged between 5–241 mg/kg, with death occurring 5–41 months after the last infusion. Amyloid burden on PET declined in all participants (range 15‐100 centiloids). Two participants experienced ARIA. Compared to AD controls, Aβ aa1‐8 and Aβ 42 were selectively reduced in cortical layer I of aducanumab‐treated study participants ( p <0.05) but not in the total cortex, as shown for the middle frontal cortex in Figure 1. No differences were observed in phosphorylated tau burden. Prussian blue‐stained hemosiderin was present in both treated and untreated AD cases. However, in participants with ARIA, hemosiderin accumulated in superficial cortical layers near CAA‐laden meningeal and penetrating vessels, which also exhibited extensive complement and microglial activation (Figure 2). Conclusions Aβ clearance and ARIA‐related findings were localized predominantly in superficial cortical layers, suggesting that aducanumab biodistribution is more pronounced in these regions rather than deeper cortical layers.

Abstract Neurofibrillary tangles are dynamic neuropathologic hallmarks of Alzheimer’s disease with a hypothesized lifespan morphologically-defined by three maturity levels: pretangles, mature tangles, and ghost tangles. To better understand the progression of tangle pathophysiology, we characterized tangle maturity level predilection of 15 tau antibodies recognizing a broad range of linear, phosphorylation, conformational, and truncation epitopes in the hippocampus of 24 postmortem brains. We developed the tangle maturity scoring system to semi-quantitatively evaluate each tangle maturity level. Based on proportions of tangle maturity levels, we classified antibodies as “early” (mostly pretangles and mature tangles), “middling” (mature tangles with pretangles and ghost tangles), and “advanced” (mostly ghost tangles and mature tangles) tangle maturity markers. To summarize tangle maturity predilection, we developed the tangle maturity scale to integrate individual tangle maturity scores. Correlations showed stronger relationships between tangle maturity scale and subsector thickness for more advanced tangle maturity markers in CA1 and subiculum, whereas Braak tangle stage remained consistently correlated throughout markers of the tangle lifespan. To aid in scoring hippocampi, we used machine learning to recognize tangle maturity levels, which performed comparably to a domain expert and showed similar relationships by Spearman correlation. Pattern recognition software was used to assess tangle and neuritic tau burden separately, which generally correlated with Braak stage and neuronal counts. However, tangle-derived tau burden more consistently correlated with hippocampal subsector thickness. In conclusion, we developed manual and automated scoring systems to evaluate tangle maturity levels, demonstrating early 4R, phosphorylated, and oligomeric tau accumulation preceding more advanced 3R and truncated tau. Our study provides supportive evidence of disease-relevant ordering of tau posttranslational modifications in the brain, which may have implications for theragnostic development. These findings underscore the promise of computerized quantitative analyses (i.e., pathomics) for high-throughput feature extraction from whole-slide images to enhance our understanding of microscopically observed morphologic changes.

Background: Snapping scapula syndrome (SSS) is a rare condition that is oftentimes debilitating. For patients whose symptoms are resistant to nonoperative treatment, arthroscopic surgery may offer relief. Because of the rarity of SSS, reports of clinical outcomes after arthroscopic SSS surgery are primarily limited to small case series and short-term follow-up studies. Purpose: To report minimum 5-year clinical and sport-specific outcomes after arthroscopic bursectomy and partial scapulectomy for SSS and to identify demographic and clinical factors at baseline associated with clinical outcomes at minimum 5-year follow-up. Study Design: Case series; Level of evidence, 4. Methods: Patients who underwent arthroscopic bursectomy and partial scapulectomy for SSS between October 2005 and February 2016 with a minimum of 5 years of postoperative follow-up were enrolled in this single-center study. Clinical outcome scores, including the 12-Item Short Form Health Survey (SF-12), American Shoulder and Elbow Surgeons (ASES) Shoulder Score, shortened version of the Disabilities of the Arm, Shoulder and Hand (QuickDASH) score, Single Assessment Numeric Evaluation (SANE), and visual analog scale (VAS) score for pain, were collected at a minimum 5-year follow-up. Additionally, it was determined which patients reached the minimal clinically important difference. Bivariate analysis was used to determine whether baseline demographic and clinical factors had any association with the outcome scores. Results: Of 81 patients eligible for inclusion in the study, follow-up was obtained for 66 patients (age 33.6 ± 13.3 years; 31 female). At a mean follow-up of 8.9 ± 2.5 years (range, 5.0-15.4 years), all of the outcome scores significantly improved compared with baseline. These included the ASES (from 56.7 ± 14.5 at baseline to 87.2 ± 13.9 at follow-up; P < .001), QuickDASH (from 38.7 ± 17.6 to 13.1 ± 14.6; P < .001), SANE (from 52.4 ± 21.2 to 82.7 ± 19.9; P < .001), SF-12 Physical Component Summary (from 39.7 ± 8.3 to 50.3 ± 8.2; P < .001), SF-12 Mental Component Summary (from 48.2 ± 11.7 to 52.0 ± 9.0; P = 0.014) and VAS pain (from 5.2 ± 2.1 to 1.4 ± 2.0; P < .001). The minimal clinically important difference in the ASES score was reached by 77.6% of the patients. Median postoperative satisfaction was 8 out of 10. It was found that 90.5% of the patients returned to sport, with 73.8% of the patients able to return to their preinjury level. At the time of final follow-up, 8 (12.1%) patients had undergone revision surgery for recurrent SSS symptoms. Older age at surgery ( P = .044), lower preoperative SF-12 Mental Component Summary score ( P = .008), lower preoperative ASES score ( P = .019), and increased preoperative VAS pain score ( P = .016) were significantly associated with not achieving a Patient Acceptable Symptom State on the ASES score. Conclusion: Patients undergoing arthroscopic bursectomy and partial scapulectomy for SSS experienced clinically significant improvements in functional scores, pain, and quality of life, which were sustained at a minimum of 5 years and a mean follow-up of 8.9 years postoperatively. Higher patient age, inferior mental health status, increased shoulder pain, and lower ASES scores at baseline were significantly associated with worse postoperative outcomes.

Advanced Care at Home is a Mayo Clinic hospital-at-home (HaH) program that provides hospital-level care for patients. The study examines patient- and community-level factors that influence health outcomes. The authors performed a retrospective study using patient data from July 2020 to December 2022. The study includes 3 Mayo Clinic centers and community-level data from the Agency for Healthcare Research and Quality. The authors conducted binary logistic regression analyses to examine the relationship among the independent variables (patient- and community-level characteristics) and dependent variables (30-day readmission, mortality, and escalation of care back to the brick-and-mortar hospital). The study examined 1433 patients; 53% were men, 90.58% were White, and 68.2% were married. The mortality rate was 2.8%, 30-day readmission was 11.4%, and escalation back to brick-and-mortar hospitals was 8.7%. At the patient level, older age and male gender were significant predictors of 30-day mortality ( P -value <0.05), older age was a significant predictor of 30-day readmission ( P -value <0.05), and severity of illness was a significant predictor for readmission, mortality, and escalation back to the brick-and-mortar hospital ( P -value <0.01). Patients with COVID-19 were less likely to experience readmission, mortality, or escalations ( P -value <0.05). At the community level, the Gini Index and internet access were significant predictors of mortality ( P -value <0.05). Race and ethnicity did not significantly predict adverse outcomes ( P -value >0.05). This study showed promise in equitable treatment of diverse patient populations. The authors discuss and address health equity issues to approximate the vision of inclusive HaH delivery.

AbstractBackgroundHospital‐at‐home (HaH) is a growing model of care that has been shown to improve patient outcomes, satisfaction, and cost‐effectiveness. However, selecting appropriate patients for HaH is challenging, often requiring burdensome manual screening by clinicians. To facilitate HaH enrollment, electronic health record (EHR) tools such as best practice advisories (BPAs) can be used to alert providers of potential HaH candidates.ObjectiveTo describe the development and implementation of a BPA for identifying HaH eligible patients in Mayo Clinic's Advanced Care at Home (ACH) program, and to evaluate the provider response and the patient characteristics that triggered the BPA.Design, Setting, and ParticipantsWe conducted a retrospective multicenter study of hospitalized patients who triggered the BPA notification for ACH eligibility between March and December 2021 at Mayo Clinic in Jacksonville, FL and Mayo Clinic Health System in Eau Claire, WI. We extracted demographic and diagnosis data from the patients as well as characteristics of the providers who received the BPA notification.InterventionThe BPA was developed based on the ACH inclusion and exclusion criteria, which were derived from clinical guidelines, literature review, and expert consensus. The BPA was integrated into the EHR and displayed a pop‐up message to the provider when a patient met the criteria for ACH eligibility. The provider could choose to refer the patient to ACH, dismiss the notification, or defer the decision.Main Outcomes and MeasuresThe main outcomes were the number and proportion of BPA notifications that resulted in a referral to ACH, and the number and proportion of referrals that were accepted by the ACH clinical team and transferred to ACH. We also analyzed the factors associated with the provider's decision to refer or not refer the patient to ACH, such as the provider's role, location, and specialty.ResultsDuring the study period, 8962 notifications were triggered for 2847 patients. Providers opted to refer 711 (11.4%) of the total notifications linked to 324 unique patients. After review by the ACH clinical team, 31 of the 324 referrals (9.6%) met clinical and social criteria and were transferred to ACH. In multivariable analysis, Wisconsin nurses, physician assistants, and in‐training personnel had lower odds of referring the patients to ACH when compared to attending physicians.

AbstractBackgroundThere is a gap in knowledge concerning which tangle maturity levels (Moloney, Alzheimers Dement, 2021) are associated with antemortem measures (tau‐PET, MRI, cognitive testing). We hypothesized antemortem measures would be more strongly correlated with markers recognizing middling to advanced tangle maturity. We additionally sought to assess the strength of the relationship with tangle and neuritic pathology recognized by tangle maturity markers.MethodPosterior hippocampi from n = 30 cases with antemortem measures ≤3 years prior to death were cut (5µm) and immunostained with tau antibodies to evaluate early (AT8), middling (PHF‐1), or advanced (2E9) tangle maturity. GENIE (pattern recognition software) separated tangle from neuritic burden (Figure). Hippocampus, parahippocampus, and fusiform were analyzed to correlate digital pathology with flortaucipir tau‐PET standard uptake value ratio (SUVr, cerebellar crus normalization), MRI volume/thickness, and cognitive measures which included Auditory Verbal Learning Test (AVLT) delayed recall, Mini‐Mental State Exam (MMSE), and Clinical Dementia Rating (CDR).ResultThe strongest relationships observed with flortaucipir were with PHF‐1 and 2E9 burden (Table). AT8 tangle and neuritic burden correlations with flortaucipir were relatively similar in the hippocampus but were stronger with neuritic pathology in parahippocampus and fusiform. PHF‐1 tangle and neuritic burden correlations were relatively similar with flortaucipir. 2E9 correlations were stronger with neuritic pathology in hippocampus. MRI measures were more strongly correlated with PHF‐1 and 2E9 burden. AT8 tangle and neuritic burden were correlated with fusiform thickness. The correlations between MRI measures and 2E9 tangle and neuritic burden were similar. Correlations between cognitive measures were similar between tangle maturity markers. AVLT delayed recall correlated with all tangle maturity markers, but neuritic burden was stronger for AT8 and 2E9 in hippocampus compared to tangle burden. MMSE correlated with neuritic burden for all tangle maturity markers. CDR remained statistically non‐significant.ConclusionInterpretation of the strength of the relationship between tau burden and antemortem measures differed across tangle maturity markers. Neuroimaging measures may be more sensitive to middle/advanced maturity markers with limited differences between tangle and neuritic pathology. These findings may be biologically relevant and imply either a limited recognition of tangles depending on antibody epitope, and/or may represent the clinicoradiologic impact of increasing neuritic burden.

AbstractBackgroundIncreasing evidence suggests that transactive response DNA‐binding protein 43 (TDP‐43) pathology in Alzheimer’s Disease (AD), or AD‐TDP, can be diffuse or limbic‐predominant. Understanding whether diffuse AD‐TDP has genetic, clinical, and pathological features that differ from limbic AD‐TDP could have clinical and research implications. We aimed to better characterize the clinicopathologic features of diffuse AD‐TDP and differentiate it from limbic‐predominant AD‐TDP pathology.MethodThree hundred sixty‐three participants were prospectively recruited and followed in the Mayo Clinic Study of Aging, Alzheimer’s Disease Research Center, and Neurodegenerative Research Group and died between May 1999 and August 2021. All underwent genetic, clinical, neuropsychologic, and neuropathologic evaluations. At postmortem evaluation, they showed Alzheimer’s disease neuropathologic changes and TDP‐43‐immunoreactive inclusions. The distribution of TDP‐43 pathology was assessed using the Josephs 6‐stage scheme. Participants with TDP‐43 stages 1‐3 were classified as Limbic, while those with stages 4‐6 were classified as Diffuse. Neuropathologically defined frontotemporal lobar degeneration cases were excluded. Multivariable logistic regression was used to identify clinicopathological features that predicted diffuse TDP‐43 pathology at postmortem. We hypothesized that the Diffuse group would show impairment in cognitive domains beyond episodic memory and more hippocampal sclerosis.ResultsThe cohort was 61% female and old at onset (median:76 years [IQR:70‐82]) and death (median:88 years [IQR:82‐92]). Fifty‐four percent (n = 197) were classified as Limbic and 46% (n = 166) as Diffuse. A “clinical” multivariate logistic regression fit to 85 participants with all clinical variables of interest showed that later age at onset (OR:1.09, 95%CI:1.01‐1.19;P = 0.03), longer disease duration (OR:1.17, 95%CI:1.02‐1.36;P = 0.03) and higher Neuropsychiatric Inventory scores (OR:1.14, 95%CI:1.01‐1.28;P = 0.03) all independently increased the odds of being Diffuse, while higher Trails Making Test‐B (OR:0.99, 95%CI:0.98‐0.99;P = 0.02) and Block Design Test scores (OR:0.91, 95%CI:0.85‐0.99;P = 0.023) independently decreased the odds of being Diffuse. A “pathology” multivariate logistic regression fit to 233 cases with all neuropathological data revealed that widespread amyloid‐β pathology corresponding to Thal phases 3‐5 all significantly decreased the odds of diffuse pathology by 80‐90%, while hippocampal sclerosis increased it sixfold (OR:6.18, 95% CI:2.93‐13.03;P<0.001).ConclusionsDiffuse AD‐TDP shows clinicopathological features that differ from Limbic AD‐TDP, which could have public health implications relating to treatment and research on AD and dementia.

OBJECTIVE The Woven EndoBridge (WEB) device is an intrasaccular flow disruptor designed for wide-necked bifurcation aneurysms. These aneurysms may require the use of a concomitant stent. The objective of this study was to determine the clinical and radiological outcomes of patients undergoing stent-assisted WEB treatment. In addition, the authors also sought to determine the predictors of a concomitant stent in aneurysms treated with the WEB device. METHODS The data for this study were taken from the WorldWideWEB Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups based on treatment: stent-assisted WEB and WEB device alone. The authors compared clinical and radiological outcomes of both groups. Univariable and multivariable binary logistic regression analyses were performed to determine factors that predispose to stent use. RESULTS The study included 691 intracranial aneurysms (31 with stents and 660 without stents) treated with the WEB device. The adequate occlusion status did not differ between the two groups at the latest follow-up (83.3% vs 85.6%, p = 0.915). Patients who underwent stenting had more thromboembolic (32.3% vs 6.5%, p < 0.001) and procedural (16.1% vs 3.0%, p < 0.001) complications. Aneurysms treated with a concomitant stent had wider necks, greater heights, and lower dome-to-neck ratios. Increasing neck size was the only significant predictor for stent use. CONCLUSIONS This study demonstrates that there is no difference in the degree of aneurysm occlusion between the two groups; however, complications were more frequent in the stent group. In addition, a wider aneurysm neck predisposes to stent assistance in WEB-treated aneurysms.

To understand why US patients refused participation in hospital-at-home (H@H) during the coronavirus disease 2019 Public Health Emergency, eligible adult patients seen at 2 Mayo Clinic sites, Mayo Clinic Health System—Northwest Wisconsin region (NWWI) and Mayo Clinic Florida (MCF), from August 2021 through March 2022, were invited to participate in a convergent-parallel study. Quantitative associations between H@H participation status and patient baseline data at hospital admission were investigated. H@H patients were more likely to have a Mayo Clinic patient portal at baseline ( P-value: .014), indicating a familiarity with telehealth. Patients who refused were more likely to be from NWWI ( P-value < .001) and have a higher Epic Deterioration Index score ( P-value: .004). The groups also had different quarters (in terms of fiscal calendar) of admission ( P-value: .040). Analyzing qualitative interviews (n = 13) about refusal reasons, 2 themes portraying the quantitative associations emerged: lack of clarity about H@H and perceived domestic challenges. To improve access to H@H and increase patient recruitment, improved education about the dynamics of H@H, for both hospital staff and patients, and inclusive strategies for navigating domestic barriers and diagnostic challenges are needed.