Elecsys Cerebrospinal Fluid Assays Accurately Distinguish Alzheimer's Disease from Frontotemporal Lobar Degeneration.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD) are heterogeneous in their clinical presentation and underlying pathology, but they often have overlapping features. Diagnostic accuracy is critical for guiding patient management. Cerebrospinal fluid (CSF) diagnostic assays for the differentiation of AD and FTLD may increase diagnostic accuracy. OBJECTIVES: In this study, we aimed to understand the potential role of CSF biomarkers and biomarker ratios, measured using Elecsys® CSF immunoassays (Roche Diagnostics International Ltd, Rotkreuz, Switzerland), in the differential diagnosis of AD and FTLD. DESIGN: This study was conducted at a single center in Munich, Germany between July 2019 and July 2020. Patient CSF samples were retrospectively collected from the study center biobank. PARTICIPANTS: A total of 130 patients with cognitive impairment were included in the study; 86 patients were diagnosed with AD and 44 with FTLD (behavioral variant frontotemporal dementia, semantic variant of primary progressive aphasia, and non-fluent variant of primary progressive aphasia), based on core clinical criteria and a non-CSF biomarker, a typical pattern of regional hypometabolism on [18F] fluorodeoxyglucose positron emission tomography. MEASUREMENTS: Patient CSF biomarker concentrations were measured using Elecsys CSF immunoassays. Receiver operating characteristic analyses were conducted to determine areas under the curve (AUCs) for CSF biomarker performance. Sensitivity and specificity analyses were conducted to evaluate the performance of established cut-offs (Aß42 ≤1000 pg/mL, pTau181/Aß42 ratio >0.024, and tTau/Aß42 ratio >0.28) and optimized cut-offs based on Youden's index. RESULTS: AUC-based performance was similarly good for the pTau181/Aß42 ratio (AUC=0.841; 95% CI: 0.759-0.923), pTau181/Aß40 ratio (AUC=0.837; 95% CI: 0.754-0.919), Aß42/Aß40 ratio (AUC=0.829; 95% CI: 0.746-0.912), tTau/Aß42 ratio (AUC=0.822; 95% CI: 0.736-0.908), pTau181/Aß42/Aß40 ratio (AUC=0.817; 95% CI: 0.734-0.901), and Aß42 (AUC=0.812; 95% CI: 0.722-0.902). Performance was slightly lower for the tTau/Aß42/Aß40 ratio (AUC=0.799; 95% CI: 0.713-0.885), pTau181 alone (AUC=0.793; 95% CI: 0.707-0.880), tTau/Aß40 ratio (AUC=0.751; 95% CI: 0.657-0.844), and tTau alone (AUC=0.706; 95% CI: 0.613-0.799). The highest qualitative performance was observed with the pTau181/Aß42 ratio with an established cut-off value of >0.024 and optimized cut-off value of >0.022: sensitivity and specificity values were 0.892 and 0.773, respectively. CONCLUSIONS: Elecsys CSF immunoassays demonstrate good diagnostic accuracy in differentiating patients with AD from those with FTLD. These immunoassays have the potential to support clinical decision making, i.e. in diagnosing patients with FTLD by excluding patients with amyloid positivity, which is indicative of underlying AD.

Restored hypoglycemic counterregulation is stable in successful pancreas transplant recipients for up to 19 years after transplantation.

BACKGROUND: Pancreas transplantation has been shown to fully restore glucagon response and partially restore epinephrine response to hypoglycemia during the first few years after transplantation in patients with type 1 diabetes. However, prior studies have not examined hypoglycemic counterregulation in any pancreas transplant recipient of more than 6 years' duration. METHODS: To determine whether restoration of hypoglycemic counterregulation is maintained over a prolonged period after transplantation, we studied counterregulatory responses and symptom recognition in two groups of pancreas transplant recipients using a stepped hypoglycemic, hyperinsulinemic clamp. Group 1 consisted of 11 successful transplant recipients of 11 to 19 years' duration (mean+/-SE, 13.9+/-0.7 years). Group 2A consisted of seven successful pancreas transplant recipients of 5 to 11 years' duration (mean+/-SE, 8.7+/-0.9 years) who had been studied approximately 5 years earlier using the same stepped, hypoglycemic clamp technique. RESULTS: Both groups had significant rises in plasma glucagon during the hypoglycemic clamp similar to that seen in short-term recipients and normal controls. Both groups also had significant increases in plasma epinephrine responses similar to that seen in short-term transplant recipients but less than that of normal control subjects. The mean symptom scores of group 1 were significantly less than those of the control group at glucose levels of 60 and 50 mg/dL but not at 40 mg/dL. The mean symptom scores of group 2A were not significantly different than that of control subjects. CONCLUSION: These results indicate that the restoration of hypoglycemic counterregulation by pancreas transplantation remains stable in successful pancreas transplant recipients for up to 19 years after transplantation.

Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis.

Patients with chronic pancreatitis who undergo total pancreas resection inevitably become diabetic unless their islets are autotransplanted to prevent diabetes. We studied patients who underwent this procedure to assess its long-term efficacy in providing stable glucose regulation. Six patients were followed for up to 13 (6.2 +/- 1.7) years after intrahepatic islet autotransplantation. From 290,000 to 678,000 islets were transplanted and no patients received drugs to control glucose levels postoperatively. Islet function was assessed by measurements of fasting plasma glucose (FPG), intravenous glucose disappearance rate (KG), HbA1c, insulin responses to intravenous glucose and to arginine, and insulin secretory reserve. Patients were studied two to four times each to obtain longitudinal data. Five of six patients remained free of insulin treatment and maintained FPG <126 mg/dl and HbA1c levels <6.5%. As a group, they maintained stable insulin secretory reserve, but insulin responses to glucose tended to decrease over time in three patients. KG values correlated significantly with the number of islets originally transplanted. These data indicate that intrahepatic autoislet transplantation can successfully maintain stable beta-cell function and normal levels of blood glucose and HbA1c for up to 13 years after total pancreatectomy as treatment for chronic painful pancreatitis. This usually overlooked procedure of intrahepatic islet transplantation designed to prevent diabetes in patients undergoing pancreatectomy for chronic pancreatitis should be considered more often.

Normoglycemia and preserved insulin secretory reserve in diabetic patients 10-18 years after pancreas transplantation.

Pancreas transplantation is a controversial form of therapy for type I diabetes. A major obstacle to acceptance of this procedure for many physicians is the lack of demonstrable long-term success. We performed these studies to assess the hypothesis that successful pancreas transplantation is efficacious in normalizing endogenous insulin secretion and glycemia in the long term (1-2 decades). Sixteen patients with a history of diabetic complications who had undergone a transplant 10-18 years earlier involving either a whole or a segment of pancreas were recruited for measurements of fasting plasma glucose, HbA1c, intravenous glucose tolerance, and insulin secretory reserve. All patients were taking immunosuppressive drugs, but none was using insulin or other hypoglycemic agents. All recipients had normal levels of fasting blood glucose, intravenous glucose tolerance, and HbA1c, and 15 of 16 stated that their quality of life had improved after transplantation. They had intact acute insulin responses to intravenous pulses of glucose and to arginine and insulin secretory reserve. Glucose potentiation of arginine-induced insulin secretion, the measure of insulin secretory reserve, correlated significantly (r = 0.095, P < 0.001) with the acute insulin response to intravenous glucose, rendering the latter a much simpler and valid measure of functional beta-cell mass. We conclude that successful pancreas transplants are efficacious for periods as long as 1-2 decades in returning euglycemia to type 1 diabetic patients by restoring endogenous insulin secretion and insulin secretory reserve. Thus, concern about long-term deterioration, as distinct from rejection, should not be a major obstacle when deciding whether to recommend pancreas transplantation.