Citations

Abstract Background Little is known about the risk factors associated with complications after free flap scalp reconstruction. The purpose of this study was to identify patient, scalp defect, and flap characteristics associated with increased risk of surgical complications. Methods A retrospective study was performed of free-flap scalp reconstruction in oncologic patients at Memorial Sloan Kettering Cancer Center from 2002 to 2017. Data collection included patient, defect, flap, and complication characteristics. Complications were classified into major, defined as complications requiring surgical intervention, and minor, defined as complications requiring conservative treatment. Risk factors and outcome variables were compared using chi-square with Fisher's exact test. Results A total of 63 free flaps to the scalp in 58 patients were performed; average follow-up was 3.5 years. Most flaps were muscle-only or musculocutaneous. One-third of patients with free flaps experienced complications (n = 21, 15 major and 6 minor). Examining risk factors for complications, patients with cardiovascular disease were nearly three times more likely to have suffered a major complication than patients without cardiovascular disease (36.7 vs. 12.1%, p = 0.04). This was the only significant risk factor noted. Perioperative radiotherapy, prior scalp surgery, flap type, and recipient vessel selection were found to be nonsignificant risk factors. Conclusion Cardiovascular disease may be a significant marker of risk for major complications in patients undergoing free-flap reconstruction of the scalp. This information should be used to help guide perioperative counseling and decision making in this challenging patient population.

Abstract Background Glial fibrillary acidic protein (GFAP) is a promising candidate blood‐based biomarker for Alzheimer's disease (AD) diagnosis and prognostication. The timing of its disease‐associated changes, its clinical correlates, and biofluid‐type dependency will influence its clinical utility. Methods We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (Aβ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished Aβ‐positive from Aβ‐negative ADAD participants and showed a stronger relationship with Aβ load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion Our findings support a role for plasma GFAP as a clinical biomarker of Aβ‐related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer's disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not.

Abstract Background Deep brain stimulator (DBS)–related infection is a recognized complication that may significantly alter the course of DBS therapy. We describe the Mayo Clinic Rochester experience with DBS-related infections. Methods This was a retrospective study of all adults (≥18 years old) who underwent DBS-related procedures between 2000 and 2020 at the Mayo Clinic Rochester. Results There were 1087 patients who underwent 1896 procedures. Infection occurred in 57/1112 (5%) primary DBS implantations and 16/784 (2%) revision surgeries. The median time to infection (interquartile range) was 2.1 (0.9–6.9) months. The odds of infection were higher with longer operative length (P = .002), higher body mass index (BMI; P = .006), male sex (P = .041), and diabetes mellitus (P = .002). The association between infection and higher BMI (P = .002), male sex (P = .016), and diabetes mellitus (P = .003) remained significant in a subgroup analysis of primary implantations but not revision surgeries. Infection was superficial in 17 (23%) and deep in 56 (77%) cases. Commonly identified pathogens were Staphylococcus aureus (65%), coagulase-negative staphylococci (43%), and Cutibacterium acnes (45%). Three device management approaches were identified: 39 (53%) had complete device explantation, 20 (27%) had surgical intervention with device retention, and 14 (19%) had medical management alone. Treatment failure occurred in 16 (23%) patients. Time-to-event analysis showed fewer treatment failures with complete device explantation (P = .015). Only 1 individual had complications with brain abscess at failure. Conclusions Primary DBS implantations had higher rates of infection compared with revision surgeries. Complete device explantation was favored for deep infections. However, device salvage was commonly attempted and is a reasonable approach in select cases given the low rate of complications.

Background Covert cerebrovascular disease (CCD) has been shown to be associated with dementia in population‐based studies with magnetic resonance imaging (MRI) screening, but dementia risk associated with incidentally discovered CCD is not known. Methods and Results Individuals aged ≥50 years enrolled in the Kaiser Permanente Southern California health system receiving head computed tomography (CT) or MRI for nonstroke indications from 2009 to 2019, without prior ischemic stroke/transient ischemic attack, dementia/Alzheimer disease, or visit reason/scan indication suggestive of cognitive decline or stroke were included. Natural language processing identified incidentally discovered covert brain infarction (id‐CBI) and white matter disease (id‐WMD) on the neuroimage report; white matter disease was characterized as mild, moderate, severe, or undetermined. We estimated risk of dementia associated with id‐CBI and id‐WMD. Among 241 050 qualified individuals, natural language processing identified 69 931 (29.0%) with id‐WMD and 11 328 (4.7%) with id‐CBI. Dementia incidence rates (per 1000 person‐years) were 23.5 (95% CI, 22.9–24.0) for patients with id‐WMD, 29.4 (95% CI, 27.9–31.0) with id‐CBI, and 6.0 (95% CI, 5.8–6.2) without id‐CCD. The association of id‐WMD with future dementia was stronger in younger (aged <70 years) versus older (aged ≥70 years) patients and for CT‐ versus MRI‐discovered lesions. For patients with versus without id‐WMD on CT, the adjusted HR was 2.87 (95% CI, 2.58–3.19) for younger and 1.87 (95% CI, 1.79–1.95) for older patients. For patients with versus without id‐WMD on MRI, the adjusted HR for dementia risk was 2.28 (95% CI, 1.99–2.62) for younger and 1.48 (95% CI, 1.32–1.66) for older patients. The adjusted HR for id‐CBI was 2.02 (95% CI, 1.70–2.41) for younger and 1.22 (95% CI, 1.15–1.30) for older patients for either modality. Dementia risk was strongly correlated with id‐WMD severity; adjusted HRs compared with patients who were negative for id‐WMD by MRI ranged from 1.41 (95% CI, 1.25–1.60) for those with mild disease on MRI to 4.11 (95% CI, 3.58–4.72) for those with severe disease on CT. Conclusions Incidentally discovered CCD is common and associated with a high risk of dementia, representing an opportunity for prevention. The association is strengthened when discovered at younger age, by increasing id‐WMD severity, and when id‐WMD is detected by CT scan rather than MRI.

Background: There are limited data about the stage D heart failure (advanced HF) in adults with congenital heart disease. Our study objectives were (1) to determine the incidence of new-onset advanced HF in patients and the relationship between advanced HF and all-cause mortality and (2) to determine the relationship between therapies for advanced HF and all-cause mortality. Methods: Retrospective cohort study of adults with congenital heart disease at Mayo Clinic (2003–2019). We defined advanced HF using the European Society of Cardiology diagnostic criteria for advanced HF. Therapies received by the patients with advanced HF were classified into 3 mutually exclusive groups (treatment pathways): (1) conventional cardiac intervention, (2) transplant listing, and (3) palliative care. Results: Of 5309 patients without advanced HF at baseline assessment, 432 (8%) developed advanced HF during follow-up (1.1%/y), and the incidence of advanced HF was higher in patients with severe or complex congenital heart disease. Onset of advanced HF was associated with 6-fold increase in the risk of mortality. Conventional cardiac intervention was associated with significantly higher risk of mortality as compared to transplant listing. The longer the interval from the initial onset of advanced HF to transplant evaluation, the lower the odds of being listed for transplant. Conclusions: Based on these data, we postulate that early identification of patients with advanced HF, and a timely referral for transplant evaluation (instead of conventional cardiac intervention) may offer the best chance of survival for these critically ill patients. Further studies are required to validate this postulation.

AbstractBackgroundWhite matter (WM) injury visible on MRI is a common finding in Alzheimer’s disease (AD) and is often attributed to small vessel ischemic changes secondary to increased systemic vascular risk. Increased WM injury has been associated with the progression of Autosomal Dominant AD (ADAD), though ADAD pathogenic variant carriers are relatively young and may not have elevated vascular risk factors. We hypothesized that WM injury in ADAD may reflect worsening of cerebral amyloid angiopathy (CAA) and neurodegeneration. Here we examine this hypothesis using cross‐sectional and longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN).MethodMRI data from ADAD pathogenic variant carriers (n=223) and non‐carriers (n=136) were used in the present study (Table 1). We extracted FreeSurfer‐based WM lesion (WML) volume from T1‐weighted images (hypointensities). Cortical microbleed (CMB) burden was assessed visually on susceptibility weighted/T2*‐weighted gradient echo images by experienced radiologists (blineded to the mutation status) at the Mayo Clinic in Rochester. Linear regression models compared WML volume at baseline in people with and without CMB. Linear mixed effect models assessed the relationships between longitudinal WML and both CMBs and FreeSurfer‐based total gray matter (GM) volume. Models were corrected for age and estimated years to symptom onset (EYO).ResultGreater baseline WML volume was seen in ADAD carriers vs. non‐carriers, particularly close to the age of estimated symptom onset. Baseline WML volume was greater in carriers with CMBs compared to those without (t=2.9, p=0.003, Figure 1). Longitudinal increase in WML amongst ADAD pathogenic variant carriers with CMBs was estimated to be 214 mm3/year greater than that amongst carriers without CMBs (t=4.1, p<0.001, Figure 2). Independent of this CMB effect, decreasing GM volume was strongly associated with increasing longitudinal WML volume (t=‐6.2, p<0.001, Figure 3). Similar analyses in the non‐carrier group yielded no significant findings.ConclusionConsistent with prior reports, WML volume was increased in ADAD pathogenic variant carriers. However, the results here suggest WML in ADAD may not solely be due to small vessel ischemic changes, but rather may be a result of worsening CAA and more rapid neurodegeneration.

AbstractBackgroundGiven the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development.MethodWe assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium‐Down Syndrome (ABC‐DS) and 265 mutation‐carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated‐years‐to‐symptom‐onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC‐DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40.ResultThe relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ ‐23 but was not elevated in DS until EYO ≥ ‐15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5).ConclusionThese results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5‐10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.

AbstractBackgroundMayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform optimized for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). Study aims were to determine 1) convergent validity of MTD through correlations with in‐person neuropsychological measures and 2) criterion validity of MTD by qualitatively comparing the ability of Mayo Test Drive and in‐person administered neuropsychological measures to differentiate biomarker‐defined groups, independent of clinical diagnosis.MethodsMayo Clinic Study of Aging participants (N = 282) completed a brief remote cognitive assessment (mean age = 74, SD = 12; 262 CU and 20 MCI per consensus conference diagnosis; see Table 1). A subset of participants had brain amyloid and/or brain tau PET scans available within 3 years; overlapping groups were formed for 1) those on the Alzheimer’s disease (AD) continuum (A+, n = 31) or not (A‐, n = 57) and for 2) those with biological AD (A+T+, n = 19) or without any AD biomarkers (A‐T‐, n = 47). Primary outcome variables were SLS sum of trials, AVLT sum of trials, SYM Correct Trials response time, Digit Symbol Coding, MTD composite and Mayo‐PACC (AVLT sum of trials, Trails B, animals). Bivariate correlations were performed across all participants. Linear model ANOVAs were used to investigate biomarker subgroup differences; Hedge’s g effect sizes are reported.ResultsConvergent validity was supported through significant correlation (p’s < .001) of SLS and AVLT (r = .63), SYM and Coding (r = ‐.64), and MTD composite with Mayo‐PACC (r = .67); see Table 2. MTD subtests showed expected relationships with age and education (p’s < .05; Table 3). All MTD performances were significantly lower for A+ and A+T+ participants relative to A‐ or A‐T‐ (p’s<.001; Table 4). All MTD outcome measures showed a similar or greater group difference effect size relative to traditional in‐person administered neuropsychological measures for separating A+ vs. A‐ and A+T+ vs. A‐T‐ groups. See Figure 1 and Table 4.ConclusionsMTD subtests show evidence of convergent validity through strong correlations with traditional in‐person cognitive measures. Preliminary analyses suggest MTD has promise for differentiating PET biomarker groups.

AbstractBackgroundRemote assessment tools offer significant promise for aiding early detection of cognitive impairment. Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for remote self‐administered assessment that includes a computer adaptive word list memory test (Stricker Learning Span; SLS) and a measure of processing speed (Symbols Test). We examined the diagnostic accuracy of the SLS and a MTD composite (SLS max span, SLS trials 1–5 total correct, SLS delay correct, [Symbols correct item response time*‐1]) for amnestic mild cognitive impairment (aMCI). We also explored diagnostic accuracy for a broader group that included individuals with possible MCI (pMCI; see Figure 1).MethodsParticipants were recruited from the Mayo Clinic Study of Aging for this ancillary remote study. 226 were cognitively unimpaired (CU; concordant CU diagnosis by 3 independent raters). Fifty‐six participants had possible MCI (at least 1 of 3 raters indicated MCI) and 16 had a consensus diagnosis of aMCI. Primary outcome variables were SLS sum of trials, AVLT sum of trials, Symbols correct items response time, and MTD composite. Mean difference analyses used linear model ANOVAs (alpha = .05). Receiver operating characteristic (ROC) curves were applied; we derived optimal cutoff scores based on the Youden index method.ResultsBoth aMCI and possible MCI groups showed significantly lower performance than the CU group on SLS (Hedge’s g aMCI = ‐1.72, pMCI = ‐1.04), Symbols (Hedge’s g aMCI = 1.38, pMCI = 0.64), and MTD composite (Hedge’s g aMCI = ‐1.89, pMCI = ‐1.09); see Tables 1 and 2 (all p‘s<.01 even when additionally covarying age, education, sex). Total area under the curve was high for differentiating of CU vs. aMCI (MTD Composite = 0.91, SLS = 0.91) and acceptable for CU vs. pMCI (MTD Composite = 0.77, SLS = 0.77); see Table 2. Consistent with our flexible platform, a variety of device types were used to complete remote testing (32% smartphone, 12% tablet, 56% PC).ConclusionsMTD and the SLS show high diagnostic accuracy for aMCI. MTD is a flexible, brief, and easy‐to‐use remote cognitive assessment tool with great potential for scalable use in future studies seeking to maximize inclusion of individuals with aMCI in clinical trials or for cognitive screening in clinical settings.

AbstractBackgroundRates of cognitive and biomarker change in Autosomal Dominant Alzheimer disease (ADAD) vary substantially across individuals. Prior cross‐sectional work suggests that the location of the pathogenic variant within PSEN1, specifically whether the underlying variant affects transmembrane (TM) or cytoplasmic (CY) domains in PSEN1, may be a key determinant in these differential rates of progression. Here we use longitudinal data from the Dominantly Inherited Alzheimer Network observational study (DIAN‐Obs) to examine whether variants affecting TM versus CY domains in PSEN1 have differential rates of change in key cognitive and neurodegenerative markers, and whether these differences are relevant to ADAD clinical trials.MethodsUsing longitudinal clinical, cognitive, and MRI data from PSEN1 pathogenic variant carriers [TM group N=76 and CY group N=44; Table 1], we assessed rates of change in Mini‐Mental State Exam (MMSE), Clinical Dementia Rating® Sum of Boxes (CDR®‐SOB), and hippocampal volume (HV) using linear mixed effects models accounting for disease stage (estimated years to symptom onset [EYO]). We further assessed how PSEN1 mutation location (TM versus CY) impacts sample size and detectable effect size in a potential ADAD clinical trial (modeled as a 4‐year trial with annual assessments; 80% power; α = 0.05).ResultsPSEN1 TM and PSEN1 CY groups did not differ on baseline age, EYO, or CDR®. The PSEN1 TM group had significantly greater rates of change on MMSE (B[SE] = ‐0.42[0.1], p=0.002), CDR®‐SOB (B[SE] = 0.23[0.1], p=0.001), and HV atrophy (B[SE] = ‐58.93[14.3], p=0.0006 compared to the PSEN1 CY group (Fig.1). Consistent with these differential rates of change, power analyses indicated the required sample size to detect a 30% treatment effect on MMSE or HV would be reduced by 59.6% for MMSE and 91.0% for HV for a trial population comprised of PSEN1 TM versus CY carriers (Fig.2).ConclusionsIndividuals who had a variant affecting the transmembrane domains of PSEN1 had greater rates of cognitive decline and neurodegeneration compared to those with variants affecting cytoplasmic domains. In addition to having implications for ADAD pathophysiology, these results suggest that incorporating information regarding the location of PSEN1 variants may be beneficial in analyzing and designing stratification approaches for ADAD trials.