Citations

AbstractBackgroundResting state electroencephalography (rsEEG) is a neurophysiologic Alzheimer disease (AD) and alpha‐synucleinopathy (dementia with Lewy body (DLB) and Parkinson disease (PDD)) biomarker [1]–[5]. Background slowing (increased low frequency power, dominant rhythm (DR) slowing) is frequent in AD and DLB, more so in DLB. We sought to identify distinguishing rsEEG signatures between DLB and AD.MethodParticipants included dementia patients [AD (n=26), DLB (n=12), PD (PDD; n=5)] and controls (HC; n=56). 20‐channel rsEEG was collected in eyes‐closed/eyes‐open conditions (5‐min each). Power spectral densities and coherences were measured using established methods [6]. Individual rsEEG power (delta, 1‐3 Hz; theta, 3‐7 Hz; alpha, 8‐13 Hz), theta/alpha ratio (TAR), dominant rhythm (DR), and DR frequency domain prominence were measured and averaged across groups, and effect sizes were determined and compared using Hedges g.ResultAD, DLB, and PDD groups exhibited increased low frequency (delta‐theta, 1‐5 Hz) power and TAR compared to controls (p<4x10‐4), with higher effect sizes in the DLB and PDD groups compared to AD. DR frequency was also decreased in all patient groups (DLB>PDD>AD) compared to controls (p=3x10‐9, p=3x10‐5, p=4x10‐4).AD alpha power and DR frequency domain prominence were reduced compared to controls and PDD/DLB groups (p<0.003). Both AD patients and controls had comparable posterior power distribution predominance of DR, while DLB power of DR was more anteriorly distributed. Compared to controls, delta coherence was higher in AD, but lower in DLB. Delta power was positively correlated with cognitive fluctuation (CAF) in DLB (r(8)=+0.67, p=0.03), while negatively correlated with MMSE in AD (r(24)=‐0.64, p=10‐5).ConclusionDLB and AD had both common and distinct rsEEG signatures. Both had DR slowing and background slowing that was more severe in DLB than AD. Distinctive DLB findings included reduced posterior DR spatial dominance and decreased delta coherence. Conversely, distinct AD features were increased delta coherence, decreased alpha power, and decreased DR frequency prominence. Finally, the DLB and PDD groups had a similar magnitude of DR slowing, consistent with posteriorly dominant functional impairment in synucleinopathy reflected by corresponding regional rsEEG slowing, although future longitudinal prospective sequential rsEEG analyses are necessary to confirm these findings.

AbstractBackgroundAdvancing age is an important risk factor for dementia and cancer. An inverse association between these conditions has been described, yet caution from potential biases/confounders is warranted. Dementia and cancer may represent a spectrum of opposing dysregulated degenerative (apoptosis) and growth (proliferative) pathways respectively (Driver, 2014). Risk or resiliency factors affecting these pathways may influence cognitive outcomes in the oldest‐old. We sought to investigate demographics, clinical characteristics, and the impact of medical comorbidity on possible risk‐resiliency factors for neurodegeneration in nondemented and demented oldest‐old who died and underwent autopsy.MethodMedical records of 161 decedents (female n=134) from the Mayo Clinic 95+ year‐old cohort (age range 95‐106 years‐old) were reviewed. Groups consisting of nondemented (n=72) and demented (n=89) decedents were stratified and compared according to demographics and clinical variables, including history of cancer. Autopsy and neuropathologic evaluation was also conducted.ResultAge at death, sex, race, and education showed no differences between nondemented and demented decedents. History of cancer was higher in nondemented (57%) compared to demented decedents (30%) (p=0.002). APOE ε4 allele presence did not differ amongst groups, while APOE ε2 allele was more common in the nondemented group (p=0.026). History of coronary artery disease was higher in the nondemented (p=0.033). No differences were observed in other vascular risk factors, alcohol use, or depression. Smoking history approached significance and was higher in nondemented compared to demented (p=0.068). MMSE scores were higher in the nondemented group (p<0.001). Neuropathology findings included a lower Braak tangle staging in nondemented (median=III) compared to demented (median=V) groups (p<0.001) and less frequent diffuse plaques observed in the nondemented (67%) compared with those demented (93%) (p<0.001).ConclusionDementia is less frequent among cancer survivors in the 95+ oldest‐old. Disease‐related mechanisms associated with malignancy and surviving it may be protective against neurodegeneration in the oldest old.

AbstractBackgroundDiagnostic criteria emphasize the use of real‐time quaking‐induced conversion (RT‐QuIC) assays in cerebrospinal fluid (CSF) to identify patients with rapidly progressive dementia (RPD) due to for Creutzfeldt‐Jakob disease (CJD; CDC Diagnostic Criteria; Oct‐2018). Yet, this test is often performed in specialized centers, leading to delays in return of results. There is a need to leverage clinical features and the results of readily available tests to distinguish patients with CJD from those with other causes (‘CJD mimics’), including patients with potentially treatment‐responsive RPD.MethodPatients with definite (pathology‐confirmed) or probable CJD (clinical features with positive RT‐QuIC) were identified through retrospective review of Mayo Clinic Enterprise (n=91) and Washington University in St. Louis records (n=14; Jan‐2014 to Dec‐2020). Demographic, clinical details and results of common investigations (e.g., neuroimaging, CSF analyses and electroencephalogram) were compared between CJD cases and ‘mimics’ who met clinical criteria for probable CJD but did not have CJD.ResultCJD mimics were diagnosed with autoimmune encephalitis (n=8), neurosarcoidosis (n=1), FTLD/MND (n=1) and unknown dementia (n=1), comprising 11/155 (7%) patients enrolled with RPD at study sites. Median [range] ages‐at‐presentation (65.6 [21.9‐81.5] vs 62.4 [32.8‐76.4] years; p=0.09), % females (51% vs 46%; p>0.99) and symptoms/signs were similar between groups, with the exception of motor complaints (e.g., spasms, focal weakness), which were more common in mimics (11/11 vs 55/105; p<0.01). Electroencephalogram findings did not differ between groups. MRI findings compatible with CJD (i.e., restricted diffusion within deep nuclei/cortical ribbon) predominated in cases (80/105 vs 4/11; p<0.01), while elevations in CSF leukocytes (>5 cells/hpf: 6/11 vs 5/103; p<0.01) and protein >45 mg/dL (10/11 vs 43/103; p<0.01) were more common in mimics. Total‐tau levels >1150 pg/mL (76/84 vs 2/10; p<0.01) and ‘positive’ 14‐3‐3 (67/98 vs 3/10; p=0.03) were frequent in cases. Autoantibodies associated with autoimmune encephalitis were detected in 5/10 mimics but 0/87 cases (p<0.01). Immunosuppressant therapies were provided to 10 mimics and 24 cases, with response limited to mimics.ConclusionsAutoimmune encephalitis, neurosarcoidosis and select neurodegenerative diseases may mimic CJD at presentation. Findings from brain MRI and commonly available CSF tests may facilitate early recognition of mimics, providing an opportunity for early treatment.

AbstractBackgroundPatients with prion disease commonly present with visual, sensorimotor or gait complaints that may prompt surgical interventions for related disorders (e.g., cataracts, carpal tunnel syndrome and joint disease). To prevent iatrogenic transmission of prion disease, surgical instruments used on patients with possible prion disease must be decontaminated or decommissioned. This is only done when the diagnosis of possible prion disease is recognized by the healthcare team. We considered the frequency with which patients with definite or probable prion disease underwent surgeries within one year of the symptomatic onset of prion disease diagnosed.MethodThe Mayo Clinic’s Advanced Cohort Explorer was used to identify patients with prion disease diagnostic codes assessed since 1/1/2014 (n=296). Patients with prion disease enrolled in prospective studies of rapidly progressive dementia beginning 2/14/2015 at Washington University School of Medicine (St. Louis, MO) were also included (n=14). Charts were independently reviewed by two team members, and demographic and clinical details extracted.Result108 patients with probable or definite prion disease were identified, including 62 (57%) with autopsy‐ or genetically‐proven prion disease (57 sporadic, 4 familial, 1 fatal familial insomnia). The majority of patients experienced a rapidly progressive course (mean symptom‐duration 10.0±9.7 months). Twenty‐nine patients (26.9%) underwent 36 surgeries or invasive procedures using durable instruments, including 3 high‐risk procedures directly involving the central nervous system, and 13 intermediate‐ (e.g., joint replacement) and 20 low‐risk procedures (e.g., endoscopy). Surgeries were performed a median of 10.2 months before death (range: 0.8‐62.3), with 16 (44%) performed after symptom onset. Surgical operators were unaware of the diagnosis of possible prion disease in all but one case (diagnostic brain biopsy).ConclusionSurgeries were common in patients with prion disease in this series and were commonly performed by operators who were unaware of the diagnosis. Coordinated approaches to screening and reporting may be needed to reduce the risk of iatrogenic spread of prion disease.

Purpose To examine and analyze Medicare reimbursement rates from 2000 to 2020 for orthopaedic foot and ankle procedures. Methods The 20 most used orthopaedic foot and ankle surgical procedures were gathered from the Centers for Medicare & Medicaid Services website using the Medicare Provider Utilization and Payment Data Public Use File 2017. The reimbursement data for each code were gathered from The Physician Fee Schedule Look‐Up Tool from Centers for Medicare & Medicaid Services. The reimbursement values were adjusted for inflation to 2020 U.S. dollars using the consumer price index. Results The average inflation‐adjusted reimbursement for included procedures decreased by 30% from 2000 to 2020. The greatest mean decreases were observed for “correction of hallux valgus” (–47%) and “partial excision of foot bone” (–41%). The procedures with the smallest mean decreases were observed in “treatment of “Amputation of toe” (–19%) and “closed treatment of metatarsal fracture” (–7%). Conclusions From 2000 to 2020, Inflation‐adjusted Medicare reimbursement for foot and ankle surgery decreased by 30%. Level of Evidence IV; economic analysis.

Background: Sequencing Mendelian arrhythmia genes in individuals without an indication for arrhythmia genetic testing can identify carriers of pathogenic or likely pathogenic (P/LP) variants. However, the extent to which these variants are associated with clinically meaningful phenotypes before or after return of variant results is unclear. In addition, the majority of discovered variants are currently classified as variants of uncertain significance, limiting clinical actionability. Methods: The eMERGE-III study (Electronic Medical Records and Genomics Phase III) is a multicenter prospective cohort that included 21 846 participants without previous indication for cardiac genetic testing. Participants were sequenced for 109 Mendelian disease genes, including 10 linked to arrhythmia syndromes. Variant carriers were assessed with electronic health record–derived phenotypes and follow-up clinical examination. Selected variants of uncertain significance (n=50) were characterized in vitro with automated electrophysiology experiments in HEK293 cells. Results: As previously reported, 3.0% of participants had P/LP variants in the 109 genes. Herein, we report 120 participants (0.6%) with P/LP arrhythmia variants. Compared with noncarriers, arrhythmia P/LP carriers had a significantly higher burden of arrhythmia phenotypes in their electronic health records. Fifty-four participants had variant results returned. Nineteen of these 54 participants had inherited arrhythmia syndrome diagnoses (primarily long-QT syndrome), and 12 of these 19 diagnoses were made only after variant results were returned (0.05%). After in vitro functional evaluation of 50 variants of uncertain significance, we reclassified 11 variants: 3 to likely benign and 8 to P/LP. Conclusions: Genome sequencing in a large population without indication for arrhythmia genetic testing identified phenotype-positive carriers of variants in congenital arrhythmia syndrome disease genes. As the genomes of large numbers of people are sequenced, the disease risk from rare variants in arrhythmia genes can be assessed by integrating genomic screening, electronic health record phenotypes, and in vitro functional studies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier; NCT03394859.

This Phase Ib study combined programmed death-ligand 1 inhibitor, atezolizumab, with other immunomodulatory agents in locally advanced and metastatic solid tumors. Arms B-D evaluated atezolizumab plus interferon-α, with/without vascular endothelial growth factor inhibitor, bevacizumab, in renal cell carcinoma (RCC) and other solid tumors. Arm B predominantly recruited patients with previously treated RCC or melanoma to receive atezolizumab plus interferon α-2b. Arm C investigated atezolizumab plus polyethylene glycol (PEG)-interferon α-2a in previously treated RCC. Arm D evaluated atezolizumab plus PEG-interferon α-2a and bevacizumab. Primary objectives were safety and tolerability; secondary objectives included clinical activity. Combination therapy was well tolerated, with safety profiles consistent with known risks of individual agents. The most frequent treatment-related toxicities were fatigue, chills, and pyrexia. The objective response rate (ORR) in arm B was 20.0% overall and 17.8% in patients with previously treated checkpoint inhibitor–naive RCC (n = 45). No responses were reported in arm C. The highest ORR in arm D was 46.7% in patients with treatment-naive RCC (n = 15). Data showed preliminary clinical activity and acceptable tolerability of atezolizumab plus interferon α-2b in patients with previously treated checkpoint inhibitor–naive RCC and of atezolizumab plus PEG-interferon α-2a and bevacizumab in patients with treatment-naive RCC.