Aortic Uptake of 18F-NaF and 18F-FDG and Calcification Predict the Development of Abdominal Aortic Aneurysms and Is Attenuated by Drug Therapy.

BACKGROUND: Abdominal aortic aneurysms expand over time and increase the risk of fatal ruptures. To predict expansion, the isolated assessment of 18F-fluorodeoxyglucose (FDG) and sodium fluoride (NaF) uptake or calcification volume in aneurysms has been investigated with variability in results. We systematically evaluated whether 18F-FDG and 18F-NaF uptake was predictive of abdominal aortic aneurysm expansion. METHODS: Seventy-four male Sprague-Dawley rat abdominal aortic aneurysm models were imaged using positron emission tomography-computed tomography with 18F-FDG and 18F-NaF at 1, 2, 4, 6, and 8 weeks after CaCl2 or saline stimulation. In the 1-week cohort (n=25), the correlation between 18F-FDG or 18F-NaF uptake and pathological markers was investigated. In the time course cohort (n=49), animals received either atorvastatin, losartan, aldactone, or risedronate to assess the effect of these drugs, and the relationship between aortic size and sequential 18F-FDG and 18F-NaF uptake or calcification volume was examined. RESULTS: In the 1-week cohort, the maximum standard unit value of 18F-FDG and 18F-NaF uptake correlated with CD68- (r=0.82; P=0.001) and von Kossa staining-positive areas (r=0.89; P<0.001), respectively. In the time course cohort, 18F-FDG and 18F-NaF uptake changed in a time-dependent manner and drugs attenuated this uptake. Specifically, 18F-FDG showed high uptake at weeks 1 and 2, whereas a high 18F-NaF uptake was noted throughout the study period. Atorvastatin and risedronate showed a decreased and increased aortic size, respectively. The final aortic area correlated well with 18F-FDG and 18F-NaF uptake and calcification volume, especially at 1 and 2 weeks (18F-NaF [1 week]: r=0.61, 18F-FDG [2 weeks]: r=0.51, calcification volume [1 week]: r=0.59; P<0.001). Multiple linear regression analysis showed that the combination of these factors predicted the final aortic size, with 18F-NaF uptake at 1 week being the strongest predictor. CONCLUSIONS: The uptake of 18F-NaF and 18F-FDG and the calcification volume at appropriate times correlated with the development of abdominal aortic aneurysms, with 18F-NaF uptake being the strongest predictor.

Spontaneous coronary artery dissection in patients with prior psychophysical stress: a systematic review of case reports and case series.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an underdiagnosed cause of acute coronary syndrome, particularly in younger women. Due to limited information about SCAD, case reports and case series can provide valuable insights into its features and management. This study aimed to comprehensively evaluate the features of SCAD patients who experienced psychophysical stress before the SCAD event. METHODS: We conducted an electronic search of PubMed, Scopus, and Web of Science from inception until January 7, 2023. We included case reports or series that described patients with SCAD who had experienced psychophysical stress before SCAD. Patients with pregnancy-associated SCAD were excluded from our analysis. RESULTS: In total, we included 93 case reports or series describing 105 patients with SCAD. The average patient age was 44.29 ± 13.05 years and a total of 44 (41.9%) of patients were male. Among the included SCAD patients the most prevalent comorbidities were fibromuscular dysplasia (FMD) and hypertension with the prevalence of 36.4 and 21.9%, respectively. Preceding physical stress was more frequently reported in men than in women; 38 out of 44 (86.4%) men reported physical stress, while 36 out of 61 (59.1%) females reported physical stress (p value = 0.009). On the other hand, the opposite was true for emotional stress (men: 6 (13.6%)), women: 29 (47.6%), p value < 0.001). Coronary angiography was the main diagnostic tool. The most frequently involved artery was the left anterior descending (LAD) (62.9%). In our study, recurrence of SCAD due to either the progression of a previous lesion or new SCAD in another coronary location occurred more frequently in those treated conservatively, however the observed difference was not statistically significant (p value = 0.138). CONCLUSION: While physical stress seems to precede SCAD in most cases, emotional stress is implicated in females more than males.

Spontaneous coronary artery dissection: an unpredictable event.

Spontaneous coronary artery dissection (SCAD) is an under-recognized cause of acute coronary syndrome that predominantly affects women in adulthood and is the leading cause of acute myocardial infarction in pregnancy. The most common clinical presentation is ST-segment elevation myocardial infarction (STEMI) or non-STEMI, followed by cardiogenic shock (∼2%), sudden cardiac death (0.8% in autopsy series), cardiac arrest, ventricular arrhythmias (∼5%), and Takotsubo syndrome. The prevalence of SCAD in the general population is largely uncertain due to underdiagnosis. Oral contraceptives, post-menopausal therapy, and infertility treatments are recognized associated factors. The pathological substrates (fibromuscular dysplasia) and triggers (especially emotional stress) are commonly present in affected women. The few cases with a precise genetic aetiology occur in the context of syndromic and non-syndromic connective tissue diseases. The only true certainty in SCAD is the overwhelming prevalence in women. The first event as well as the recurrence (up to 30%, which varies depending on the definition) is largely unpredictable. The treatment strategy is highly individualized and requires extensive additional study in order to optimize outcomes and prevent major adverse cardiovascular events in affected individuals. We have known about SCAD for nearly a century, but we still do not know how best to prevent, diagnose, and treat it, making SCAD a highly important and unmet clinical need.

Pathologic Disparities Between Peripheral Artery Disease and Coronary Artery Disease.

Atherosclerosis is a systemic disease that involves multiple vascular beds. The pathological characteristics and clinical presentation, however, vary among the different vascular territories. Acute coronary syndrome is a relatively common manifestation of coronary atherosclerotic disease, wherein the thrombosis occurs secondary to disruption (65%-75%) and erosion (25%-35%) of the fibrous caps of atheromatous plaques. The plaques associated with plaque rupture have large necrotic cores and thin and inflamed fibrous caps. However, the pathological manifestations of peripheral artery disease result from thrombosis regardless of the extent of atherosclerosis. Approximately 75% of peripheral arteries with significant stenosis demonstrate presence of thrombi, of which two-thirds have thrombi associated with insignificant atherosclerosis. The presence of obliterative thrombi in peripheral arteries of patients with critical limb ischemia in the absence of coronary artery-like lesions suggests a locally thrombogenic or remotely embolic basis of disease. Extensive calcification of the medial vascular layer is commonly observed. In this review, we have described and compared the pathological basis of coronary and peripheral artery disease in patients with acute coronary syndrome and critical limb ischemia. It is expected that pathogenetic characterization would allow for definition of strategic targets for superior management of peripheral artery disease.

Post-mortem Whole exome sequencing with gene-specific analysis for autopsy-negative sudden unexplained death in the young: a case series.

Annually, thousands of sudden deaths in individuals under 35 years remain unexplained following comprehensive medico-legal autopsy. Previously, post-mortem genetic analysis by Sanger sequencing of four major cardiac channelopathy genes revealed that approximately one-fourth of these autopsy-negative sudden unexplained death in the young (SUDY) cases harbored an underlying mutation. However, there are now over 100 sudden death-predisposing cardiac channelopathy-, cardiomyopathy-, and metabolic disorder-susceptibility genes. Here, we set out to determine whether post-mortem whole exome sequencing (WES) is an efficient strategy to detect ultra-rare, potentially pathogenic variants. We performed post-mortem WES and gene-specific analysis of 117 sudden death-susceptibility genes for 14 consecutively referred Caucasian SUDY victims (average age at death 17.4 ± 8.6 years) to identify putative SUDY-associated mutations. On average, each SUDY case had 12,758 ± 2,016 non-synonymous variants, of which 79 ± 15 localized to these 117 genes. Overall, eight ultra-rare variants (seven missense, one in-frame insertion) absent in three publically available exome databases were identified in six genes (three in TTN, and one each in CACNA1C, JPH2, MYH7, VCL, RYR2) in seven of 14 cases (50 %). Of the seven missense alterations, two (T171M-CACNA1C, I22160T-TTN) were predicted damaging by three independent in silico tools. Although WES and gene-specific surveillance is an efficient means to detect rare genetic variants that might underlie the pathogenic cause of death, accurate interpretation of each variant is challenging. Great restraint and caution must be exercised otherwise families may be informed prematurely and incorrectly that the root cause has been found.

The pathologic basis of recovery.

More patients with end-stage heart failure are now being supported by left ventricular assist devices (LVAD) as a bridge to heart transplant. The LVAD unloads the failing heart and modifies the myocardial structure, with regression of left ventricular hypertrophy. The regression of hypertrophy has been reported histomorphologically in paired samples of myocardial tissues obtained from the same patient at the time of LVAD implantation and the heart excised at transplant. The understanding of the mechanisms of recovery may contribute to strategic development for LVAD weaning and the use of LVAD as a destination therapy.

Sex Disparities in the Management, Outcomes, and Transfer of Patients Hospitalized for Cardiogenic Shock.

Background: Previous studies have shown that women have worse outcomes for cardiogenic shock (CS) than men. Patients who receive care in CS "hubs" have also been shown to have improved outcomes when compared to those treated at "spokes." This study aimed to examine the presence of sex disparities in the outcomes of CS in relation to hospital type. Methods: Hospitalizations of adults with a diagnosis of CS were identified using data from the 2016-2019 Nationwide Readmissions Database. CS "hubs" were defined as any centers receiving at least 1 interhospital transfer with CS, while those without such transfers were classified as "spokes." Data were combined across years and multivariable logistic regression modeling was used to evaluate the association of sex with in-hospital mortality, invasive procedures, and transfer to hubs. Results: There were a total of 618,411 CS hospitalizations (62.2% men) with CS related to acute myocardial infarction comprising 15.3 to 17.3% of women hospitalizations and 17.8 to 20.3% of men hospitalizations. In-hospital mortality was lower at hubs (34.5% for direct admissions, 31.6% for transfers) than at spokes (40.3%, all P < .01). Women underwent fewer invasive procedures (right heart catheterization, percutaneous coronary intervention, mechanical circulatory support) and had higher mortality than men. Female sex was independently associated with decreased transfers to hubs (odds ratio, 0.93; 95% CI, 0.89-0.96) and increased mortality (odds ratio, 1.09; 95% CI, 1.05-1.12). Conclusions: Women with CS were less likely to be treated at a hub or transferred to a hub, had higher in-hospital mortality, and had a lower likelihood of receiving CS-related procedures than men. Further research is needed to understand sex-specific gaps in CS outcomes.

The need to modify patient selection to improve the benefits of implantable cardioverter-defibrillator for primary prevention of sudden death in non-ischaemic dilated cardiomyopathy.

Left ventricular ejection fraction (LVEF) ≤35% is a major determinant for implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death (SD) in patients with non-ischaemic dilated cardiomyopathy (DCM). However, as a risk marker for SD, low LVEF has limited sensibility and specificity. Selecting patients according to the current guidelines shows that most DCM patients do not actually benefit from ICD implantation and may suffer collateral effects and that many patients who are at risk of SD are not identified because a large proportion of SD patients exhibit only mildly depressed LVEF. Identifying patients who are at risk of SD on the sole basis of LVEF appears to be an over-simplification which does not maximize the benefit of ICD therapy. Owing to the complexity of the substrates underlying SD, multiple risk factors used in combination could probably predict the risk of SD better than any individual risk marker. Among non-invasive tests, microvolt T-wave alternans and cardiac magnetic resonance with late gadolinium enhancement may contribute to a better SD risk stratification by their high negative predictive value. Genetics may further contribute because approximately one-third of DCM patients have evidence of familial disease, and mutations in some known disease genes, including LMNA, have been associated with a high risk of SD. In this review, we critically analyse the current indications for ICD implantation and we explore existing knowledge about potentially predicting markers for selecting DCM patients who are at high and low risk of SD.

Risk of Type B Dissection in Marfan Syndrome: The Cornell Aortic Aneurysm Registry.

BACKGROUND: With preventive aortic grafting decreasing the incidence of type A dissections in Marfan syndrome (MFS), most dissections are now type B, for which risk factors remain largely uncertain. OBJECTIVES: We explored the determinants of type B dissection risk in a large, single-center MFS registry. METHODS: Demographic and anthropometric features, cardiovascular disease, and surgical history were compared in patients with MFS with and without type B dissection. RESULTS: Of 336 patients with MFS, 47 (14%) experienced a type B dissection (vs type A in 9%). Patients with type B dissection were more likely to have undergone elective aortic root replacement (ARR) (79 vs 46%; P < 0.001). Of the patients, 55% had type B dissection a mean of 13.3 years after ARR, whereas 45% experienced type B dissection before or in the absence of ARR; 41 patients (87%) were aware of their MFS diagnosis before type B dissection. Among those with predissection imaging, the descending aorta was normal or minimally dilated (<4.0 cm) in 88%. In multivariable analyses, patients with type B dissection were more likely to have undergone ARR and independent mitral valve surgery, to have had a type II dissection, and to have lived longer. CONCLUSIONS: In our contemporary cohort, type B dissections are more common than type A dissections and occur at traditional nonsurgical thresholds. The associations of type B dissection with ARR, independent mitral valve surgery, and type II dissection suggest a more severe phenotype in the setting of prolonged life expectancy.

Sex Differences in Thoracic Aortic Disease and Dissection: JACC Review Topic of the Week.

Despite its higher prevalence among men, women with thoracic aortic aneurysm and dissection (TAAD) have lower rates of treatment and surgical intervention and often have worse outcomes. A growing number of women with TAAD also desire pregnancy, which can be associated with an increased risk of aortic complications. Understanding sex-specific differences in TAAD has the potential to improve care delivery, reduce disparities in treatment, and optimize outcomes for women with TAAD.

Impact of acute TTE-evidenced cardiac dysfunction on in-hospital and outpatient mortality: A multicenter NYC COVID-19 registry study.

BACKGROUND: COVID-19 is associated with cardiac dysfunction. This study tested the relative prognostic role of left (LV), right and bi- (BiV) ventricular dysfunction on mortality in a large multicenter cohort of patients during and after acute COVID-19 hospitalization. METHODS/RESULTS: All hospitalized COVID-19 patients who underwent clinically indicated transthoracic echocardiography within 30 days of admission at four NYC hospitals between March 2020 and January 2021 were studied. Images were re-analyzed by a central core lab blinded to clinical data. Nine hundred patients were studied (28% Hispanic, 16% African-American), and LV, RV and BiV dysfunction were observed in 50%, 38% and 17%, respectively. Within the overall cohort, 194 patients had TTEs prior to COVID-19 diagnosis, among whom LV, RV, BiV dysfunction prevalence increased following acute infection (p<0.001). Cardiac dysfunction was linked to biomarker-evidenced myocardial injury, with higher prevalence of troponin elevation in patients with LV (14%), RV (16%) and BiV (21%) dysfunction compared to those with normal BiV function (8%, all p<0.05). During in- and out-patient follow-up, 290 patients died (32%), among whom 230 died in the hospital and 60 post-discharge. Unadjusted mortality risk was greatest among patients with BiV (41%), followed by RV (39%) and LV dysfunction (37%), compared to patients without dysfunction (27%, all p<0.01). In multivariable analysis, any RV dysfunction, but not LV dysfunction, was independently associated with increased mortality risk (p<0.01). CONCLUSIONS: LV, RV and BiV function declines during acute COVID-19 infection with each contributing to increased in- and out-patient mortality risk. RV dysfunction independently increases mortality risk.

Prevalence and Complications of Aberrant Subclavian Artery in Patients With Heritable and Nonheritable Arteriopathies.

BACKGROUND: An aberrant subclavian artery (ASA) (or lusoria) is the most common congenital anomaly of the aortic arch (0.5%-2.2%; female-to-male ratio 2:1 to 3:1). ASA can become aneurysmal and result in dissection, involving Kommerell's diverticulum when present and the aorta. Data of its significance in genetic arteriopathies are not available. OBJECTIVES: The purpose of this study was to assess the prevalence and complications of ASA in gene-positive and -negative nonatherosclerotic arteriopathies. MATERIALS: The series includes 1,418 consecutive patients with gene-positive (n = 854) and gene-negative arteriopathies (n = 564) diagnosed as part of institutional work-up for nonatherosclerotic syndromic and nonsyndromic arteriopathies. Comprehensive evaluation includes genetic counseling, next-generation sequencing multigene testing, cardiovascular and multidisciplinary assessment, and whole-body computed tomography angiography. RESULTS: ASA was found in 34 of 1,418 cases (2.4%), with a similar prevalence in gene-positive (n = 21 of 854, 2.5%) and gene-negative (n = 13 of 564, 2.3%) arteriopathies. Of the former 21 patients, 14 had Marfan syndrome, 5 had Loeys-Dietz syndrome, 1 had type-IV Ehlers-Danlos syndrome, and 1 had periventricular heterotopia type 1. ASA did not segregate with genetic defects. Dissection occurred in 5 of 21 patients with genetic arteriopathies (23.8%; 2 Marfan syndrome and 3 Loeys-Dietz syndrome), all with associated Kommerell's diverticulum. No dissections occurred in gene-negative patients. At baseline, none of the 5 patients with ASA dissection fulfilled criteria for elective repair according to guidelines. CONCLUSIONS: The risk of complications of ASA is higher in patients with genetic arteriopathies and is difficult to predict. In these diseases, imaging of the supra-aortic trunks should enter baseline investigations. Determination of precise indications for repair can prevent unexpected acute events such as those described.

Impediments to Heart Transplantation in Adults With MELASMT-TL1:m.3243A>G Cardiomyopathy.

BACKGROUND: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results. OBJECTIVES: We analyzed factors preventing HTx in consecutive adult patients with MELASMT-TL1:m.3243A>G cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center. METHODS: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives. RESULTS: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis. CONCLUSIONS: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELASMT-TL1:m.3243A>G patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.

A novel mutation of the glomulin gene in an Italian family with autosomal dominant cutaneous glomuvenous malformations.

Glomuvenous malformations (GVM) are hamartomas characterized histologically by glomus cells, which should be distinguished from glomus tumors. Familial GVM are rare, often present as multiple lesions, and exhibit familial aggregation, with autosomal dominant transmission. GVM are caused by mutations of the glomulin (GLMN) gene on chromosome 1p21-p22. Their development is thought to follow the 'two-hit' hypothesis, with a somatic mutation required in addition to the inherited germline mutation. We describe a novel GLMN mutation in an Italian family with GVM in which some members present with the less commonly observed phenotype of solitary lesions. A second somatic 'hit' mutation in GLMN was not discovered in our family. We further provide histological, immunohistochemical and electron microscopic data exhibiting the classic features of GVM. The diagnosis of GVM is critical because of distinction from venous malformations and blue rubber bleb nevus syndrome, which may demonstrate clinical similarities but require different treatment.

Pregnancy-Related Aortic Complications in Women With Marfan Syndrome.

BACKGROUND: The risk of pregnancy-associated vascular complications in Marfan syndrome (MFS) is uncertain because of ascertainment bias, prepartum lack of knowledge of diagnosis, and insufficient peripartum imaging data. Furthermore, U.S. and European guidelines differ in pregnancy recommendations in MFS. OBJECTIVES: This study describes a single-center experience of 169 MFS women to address these gaps. METHODS: Clinical, imaging, and pregnancy history were compared in never vs ever-pregnant MFS women, and pregnancy-associated vascular complications were described. RESULTS: A total of 74 ever-pregnant women had 112 live births. Elective aortic root replacement occurred at a younger age in never-pregnant women (33 years vs 42 years; P = 0.0026). Although aortic dissection prevalence did not differ between never-pregnant vs ever-pregnant women (23% vs 31%; P = 0.25), it tended to occur at an earlier age in the former group (38 years vs 45 years; P = 0.07). Of observed "sanctioned" pregnancies with prepartum diameters ≤4.5 cm, mean pregnancy-related aortic diameters remained stable. In total, 5 dissections were associated with pregnancy: 2 type A in women unaware of their diagnosis; and 2 type B and 1 isolated coronary artery dissection in women aware of their diagnosis. Dissection rates were 5-fold higher in the pregnancy vs nonpregnancy period. CONCLUSIONS: Pregnancy-related type A dissection only occurred in patients unaware of their diagnosis. Type B dissection remains an unpredictable complication. Although there were baseline differences between the never- and ever-pregnant groups, no difference in dissection risk was observed outside the peripartum period. Those with prepartum aortic diameters between 4.0 and 4.5 cm demonstrated stable aortic dimensions throughout pregnancy. These findings provide a rationale to update existing U.S. guidelines for the management of pregnancy in MFS.

Sex-Based Disparities in Outcomes With Abdominal Aortic Aneurysms.

Although abdominal aortic aneurysms (AAA) are more common in men, women with AAA have increased morbidity and mortality. Additionally, there are discrepancies among professional society guidelines for AAA screening in women. In this retrospective study from the Nationwide Inpatient Sample (NIS) database from 2003 to 2014, we compared rates of AAA repair (rupture and elective) and AAA-related mortality in men vs. women to identify predictors of death among men and women with AAA. We divided the population into 1) AAA rupture 2) elective AAA repair. The main outcomes included temporal trends in AAA rupture, rupture-related death, AAA repair, in-hospital death, and predictors of AAA-related death. There were 570,253 discharge records for AAA admissions between 2003 and 2014, including 22.8% women and 77.2% men. Women had a higher proportion of rupture (18.4% vs 12.6%, p <0.01). A smaller proportion of women underwent endovascular aortic repair (EVAR) compared with men in the ruptured AAA (13.9% vs. 20.3%, p <0.01) and elective repair (55.7% vs. 67.4%, p <0.01) cohorts. Within the ruptured cohort, a higher proportion of women did not receive repair (46.4% vs. 26.1%, p <0.01). On multivariable analysis, female gender was a significant predictor of death with rupture (OR 1.39, 95% CI 1.16 to 1.66) and elective repair (OR 1.74, 95% CI 1.36 to 2.22), with both elective EVAR (OR 2.52, 95% CI 2.06 to 3.09) and elective open aortic repair (OAR; OR 1.50, 95% CI 1.33 to 1.68). Propensity score matching confirmed a higher risk of death in women in both the rupture (OR 1.19, 95% CI 1.09 to 1.30) and elective repair (OR 1.50, 95% CI 1.35 to 1.67) cohorts. In conclusion, AAA poses significant morbidity and mortality, especially in women. Women were more likely to die before repair with AAA rupture and female gender was an independent predictor of mortality in both the rupture and elective repair groups.

A Challenging Case of Extensive Spontaneous Coronary Artery Dissection.

The detection of spontaneous coronary artery dissection (SCAD) causing myocardial infarction is integral in pursuing the appropriate management. Our case posed a diagnostic challenge, with Takotsubo cardiomyopathy and coronary embolism among the potential differential diagnoses upon the initial presentation. Extensive propagation of spontaneous coronary artery dissection subsequently resulted in a significant challenge to management requiring surgical revascularization. (Level of Difficulty: Intermediate.).

Pathologic substrate of gastropathy in Anderson-Fabry disease.

In both classic and late-onset AFD, mutations of the GLA gene cause deficient activity of the alpha-galactosidase enzyme resulting in intracellular accumulation of the undigested substrate. Gastrointestinal symptoms (GI) are common but non-specific and imputed to the AFD, irrespective of the demonstration of substrate accumulation in GI cells. We demonstrate substrate accumulation in gastric epithelial, vascular, and nerve cells of patients with classic AFD and, vice versa, absence of accumulation in late-onset AFD and controls.