CSF Biomarkers in Longitudinal Alzheimer Disease Cohorts: Pre-Analytic Challenges.

BACKGROUND: The sensitivity of amyloid to pre-analytic factors complicates cerebrospinal fluid (CSF) diagnostics for Alzheimer disease. We report reliability and validity evidence for automated immunoassays from frozen and fresh CSF samples in an ongoing, single-site research program. METHODS: CSF samples were obtained from 2 Wisconsin cohorts (1256 measurements; 727 participants). Levels of amyloid beta 1-42 (Aß42), phosphorylated tau 181 (pTau181), and total tau (tTau) were obtained using an Elecsys cobas e 601 platform. Repeatability and fixed effects of storage tube type, extraction method, and freezing were assessed via mixed models. Concordance with amyloid positron emission tomography (PET) was investigated with 238 participants having a temporally proximal PET scan. RESULTS: Repeatability was high with intraclass correlation (ICC) ≥0.9, but tube type strongly affected measurements. Discriminative accuracy for PET amyloid positivity was strong across tube types (area under the curve [AUC]: Aß42, 0.87; pTau181Aß42 , 0.96), although optimal thresholds differed. CONCLUSIONS: Under real-world conditions, the Elecsys platform had high repeatability. However, strong effects of pre-analytic factors suggest caution in drawing longitudinal inferences.

Vitamin B6 and vitamin D deficiency co-occurrence in geriatric memory patients.

INTRODUCTION: Vitamin B6 and D levels are not assessed routinely in geriatric memory patients. This study examined vitamin levels to determine the potential effects on cognition. METHODS: A chart review was conducted of 203 consecutive patients over a 12-month period. Levels of vitamins B1, B6, B12, and D were obtained on the day of clinic to identify deficiencies. A mental status exam (Mini Mental State Examination [MMSE]) was also performed. RESULTS: One hundred sixty-seven patients had one or more vitamin levels obtained on the day of clinical evaluation. Vitamin B6 deficiency was the most common (37.5%), followed by vitamin D deficiency (36.8%). A chi-square test revealed significant co-occurrence of deficiency of vitamins B6 and D (p < 0.001). Vitamin B6 and D deficiencies were associated with lower MMSE scores (p < 0.05). DISCUSSION: Vitamin B6 and D deficiencies are common in geriatric patients. The coexistence of these vitamin deficiencies has a significant association with cognitive performance, indicating the clinical importance of monitoring and supplementation.

Trajectory of clinical symptoms in relation to amyloid chronicity.

Introduction: While it is generally appreciated that amyloid precedes symptomatic Alzheimer's disease (AD) by decades, a greater understanding of this timeline may increase prognostic accuracy, planning, and care of persons who are on the AD continuum. Methods: We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) in n = 123 participants who were all A+ based on [C-11]Pittsburgh compound B positron emission tomography. Results: The average amyloid chronicity at CDR-SB of 2.5 was 20.1 years. The average trajectory of CDR-SB accelerated after 10 years of elevated amyloid and varied greatly between 10 and 30 years. Exploratory analyses suggested that older age and higher volume of white matter hyperintensities shortened the interval between amyloid onset and cognitive impairment. Discussion: The recontextualization of amyloid burden into the time domain will facilitate studies of disease progression, the influence of co-pathology, and factors that hasten or slow cognitive impairment.

The Impact of Risk and Resistance Factors on Quality of Life in Caregivers of Individuals with Dementia.

OBJECTIVES: The present study investigates the effect of caregiver and care recipient risk and resistance factors on caregiver quality of life (QOL). Risk factors are those characteristics that contribute to psychosocial maladjustment of the caregiver and reduce QOL, while resistance factors promote caregiver adjustment and improve QOL. METHODS: One-hundred and three caregiver/care recipient dyads were recruited from a memory assessment clinic in Midwestern United States. Caregivers completed questionnaires estimating perceived social support, spirituality, social problem-solving, and care recipient functional dependence. Care recipients' results from the Mini-Mental State Examination and Animal Naming task were also collected. RESULTS: In the final model, caregiver age, relationship type, social problem-solving, perceived social support, and care recipient functional dependence each accounted for a significant portion of variance in caregiver QOL. The final model accounted for 46.1% of the variance in caregiver QOL. CONCLUSION: Caregiver age, relationship type, social problem-solving, perceived social support, and care recipient functional dependence are important contributors to caregiver QOL. Further research is needed to specify which caregiver and care recipient characteristics are most important to caregiver QOL. CLINICAL IMPLICATIONS: Health professionals should assess caregiver problem-solving skills, social support, and care recipient functional dependence, as these may provide important information about caregiver QOL. Study results also suggest that caregiving has more of a negative impact on caregiver QOL for midlife adult caregivers compared to older adult caregivers, and appears to have a greater negative effect on spouses than on children.

Kenosha County falls prevention study: a randomized, controlled trial of an intermediate-intensity, community-based multifactorial falls intervention.

OBJECTIVES: To decrease the rate of falls in high-risk community-dwelling older adults. DESIGN: Randomized, controlled trial. SETTING: Community-based. PARTICIPANTS: Three hundred forty-nine adults aged 65 and older with two falls in the previous year or one fall in the previous 2 years with injury or balance problems. INTERVENTION: Subjects received two in-home visits from a trained nurse or physical therapist who assessed falls risk factors using an algorithm. The intervention consisted of recommendations to the subject and their primary physician, referrals to physical therapy and other providers, 11 monthly telephone calls, and a balance exercise plan. Control subjects received a home safety assessment. MEASUREMENTS: The primary outcome was rate of falls per year in the community. Secondary outcomes included all-cause hospitalizations and nursing home admissions per year. RESULTS: There was no difference in rate of falls between the intervention and control groups (rate ratio (RR)=0.81, P=.27). Nursing home days were fewer in the intervention group (10.3 vs 20.5 days, P=.04). Intervention subjects with a Mini-Mental State Examination (MMSE) score of 27 or less had a lower rate of falls (RR=0.55; P=.05) and, if they lived with someone, had fewer hospitalizations (RR=0.44, P=.05), nursing home admissions (RR=0.15, P=.003), and nursing home days (7.5 vs 58.2, P=.008). CONCLUSION: This multifactorial intervention did not decrease falls in at-risk community-living adults but did decrease nursing home utilization. There was evidence of efficacy in the subgroup who had an MMSE score of 27 or less and lived with a caregiver, but validation is required.

Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function.

This study investigates the association of vitamin D status with cognitive function and discusses potential mechanisms for such an effect. The relationship of vitamin B12 with cognition was also assessed. A retrospective review of older adults presenting to a university-affiliated clinic providing consultative assessments for memory problems was performed. Charts of all patients (n=80) presenting for initial visits were reviewed to identify those who had serum 25-hydroxyvitamin D (25(OH)D), vitamin B12, and mini-mental state examination score (MMSE) all obtained on their first visit (n=32). Correlation analyses between MMSE and 25(OH)D and vitamin B12 levels were performed. Serum 25(OH)D concentration and MMSE showed a (p=0.006) positive correlation; no (p=0.875) correlation was observed between serum B12 concentration and MMSE. In conclusion, the positive, significant correlation between serum 25(OH)D concentration and MMSE in these patients suggests a potential role for vitamin D in cognitive function of older adults.

A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery.

BACKGROUND: Hemospan (Sangart Inc., San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. METHODS: Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). RESULTS: Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. CONCLUSIONS: In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.

A phase I single blind clinical trial of a new oxygen transport agent (MP4), human hemoglobin modified with maleimide-activated polyethylene glycol.

BACKGROUND AND OBJECTIVES: MP4 (Hemospan), a hemoglobin-based oxygen carrier, has been designed to deliver oxygen to hypoxic tissues without causing vasoconstriction. A phase I clinical trial of MP4 was undertaken to evaluate whether MP4 elicits the clinical side effects associated with previous hemoglobin-based solutions. DESIGN AND METHODS: Twelve volunteers were studied. One cohort (n=4) received 50 mg/kg of MP4, a second (n=4) received 100 mg/kg of MP4, and the third (n=4) received lactated Ringer's solution. Single blind infusions were given at 5 mL/min. Vital signs and symptoms, hematologic parameters, serum chemistry, renal and electrocardiographic measurements were monitored for 15 days after dosing. RESULTS: Five mild adverse events occurred in the controls and 2 each in the 50 mg/kg and 100 mg/kg MP4 groups. None was severe or judged related to MP4 administration by the principal investigator. There were no clinically significant alterations in blood pressure or heart rate, and there were no gastrointestinal symptoms, abdominal or flank pain, loss of appetite or clinically significant alterations of liver or pancreatic enzymes. In one subject (100 mg/kg of MP4), amylase and lipase were slightly above the upper limit of normal 4 hours after dosing, but without associated symptoms or signs. Pharmacokinetic analysis of plasma hemoglobin (assuming no hemolysis) yielded an estimated half-life (T1/2) of 43 hours in the 100 mg/kg MP4 subjects. INTERPRETATION AND CONCLUSIONS: MP4 appears to have a favorable safety profile. Subjects in both study groups survived and did no less well than those in the control group.

Diaspirin-crosslinked hemoglobin reduces blood transfusion in noncardiac surgery: a multicenter, randomized, controlled, double-blinded trial.

UNLABELLED: In this randomized, prospective, double-blinded clinical trial, we sought to investigate whether diaspirin-crosslinked hemoglobin (DCLHb) can reduce the perioperative use of allogeneic blood transfusion. One-hundred-eighty-one elective surgical patients were enrolled at 19 clinical sites from 1996 to 1998. Selection criteria included anticipated transfusion of 2-4 blood units, aortic repair, and major joint or abdomino-pelvic surgery. Once a decision to transfuse had been made, patients received initially up to 3 250-mL infusions of 10% DCLHb (n = 92) or 3 U of packed red blood cells (PRBCs) (n = 89). DCLHb was infused during a 36-h perioperative window. On the day of surgery, 58 of 92 (64%; confidence interval [CI], 54%-74%) DCLHb-treated patients received no allogeneic PRBC transfusions. On Day 1, this number was 44 of 92 (48%; CI, 37%-58%) and decreased further until Day 7, when it was 21 of 92 (23%; CI, 15%-33%). During the 7-day period, 2 (1-4) units of PRBC per patient were used in the DCLHb group compared with 3 (2-4) units in the control patients (P = 0.002; medians and 25th and 75th percentiles). Mortality (4% and 3%, respectively) and incidence of suffering at least one serious adverse event (21% and 15%, respectively) were similar in DCLHb and PRBC groups. The incidence of jaundice, urinary side effects, and pancreatitis were more frequent in DCLHb patients. The study was terminated early because of safety concerns. Whereas the side-effect profile of modified hemoglobin solutions needs to be improved, our data show that hemoglobin solutions can be effective at reducing exposure to allogeneic blood for elective surgery. IMPLICATIONS: In a randomized, double-blinded red blood cell controlled, multicenter trial, diaspirin-crosslinked hemoglobin spared allogeneic transfusion in 23% of patients undergoing elective noncardiac surgery. The observed side-effect profile indicates a need for improvement in hemoglobin development.

Effect of diaspirin crosslinked hemoglobin (DCLHb HemAssist) during high blood loss surgery on selected indices of organ function.

BACKGROUND: The safety of the hemoglobin based oxygen carrier diaspirin crosslinked hemoglobin (DCLHb) has been reported only in the low (50-200 mg/kg) dose range [Przybelski. R.J.; Daily, E.K.; Kisicki, J.C.; Mattia-Goldberg, C.; Bounds, M.J.; Colburn, W.A. Phase I study of the safety and pharmacologic effects of diaspirin crosslinked hemoglobin solution. Crit. Care Med. 1996, 24 (12), 1993-2000, Bloomfield, E.; Rady, M.; Popovich, M.; Esfandiari, S.; Bedocs, N. The use of diaspirin crosslinked hemoglobin (DCLHb 1996, 95, (3A), A220.]. We conducted a randomized prospective open-label trial of DCLHb and packed red blood cells (PRBCs) in high-blood loss surgical patients to show the effect of 750 ml DCLHb (approximately 1000 mg/kg) on selected indices of organ function. METHOD: After institutional approval, 24 patients scheduled to undergo elective orthopedic or abdominal surgery, were randomized to receive either PRBCs or 10% DCLHb within 12 hours after the start of surgery. Patients with renal insufficiency, abnormal liver function, severe coronary artery disease (CAD) and ASA physical status > or = IV were excluded. The anesthetic technique was left to the judgment of the anesthesiologist. Autologous predonation and intraoperative blood conservation techniques were utilized as appropriate. The indications for blood transfusion were individualized on disease state, stage of surgery, and plasma Hb concentration. Laboratory studies were obtained preoperatively and up to 28 days postoperatively. Patients were observed daily for development of jaundice, hematuria, nausea, vomiting, gastrointestinal discomfort, cardiac, respiratory, and infectious complications. Organ effects were assessed with urinalysis, creatinine clearance, electrocardiogram (ECG), and a panel of blood and serum laboratory tests. RESULTS: The dose of DCLHb administered ranged from 680-1500 mg/kg (mean = 999 mg/kg). Estimated blood loss was 27 +/- 13 ml/kg and 31 +/- 15 ml/kg in the control and DCLHb groups, respectively. Fewer PRBCs (1.9 +/- 1.2 vs. 3.4 +/- 2.4 units. P = 0.06) were transfused to DCLHb patients on the operative day although this difference was no longer apparent later on. In the DCLHb group, 4/12 patients avoided any allogeneic PRBC transfusion vs. none in the control group (P = 0.09). Systolic, diastolic and mean blood pressure increased moderately after DCLHb for a period of 24-30 hours. There were no occurrences of cardiac ischemia. myocardial infarction, stroke, or pulmonary edema, by clinical or laboratory parameters up to the 28th postoperative day (POD). Seven of 12 (58%) DCLHb patients had yellow skin discoloration vs. none in the PRBC group (P < 0.01). Two of four non-urologic surgery patients developed asymptomatic postoperative hemoglobinuria after DCLHb. Creatinine clearance was unchanged postoperatively. Because of hemoglobin interference, bilirubin, gamma-glutamyl transferase (GGT), and amylase could not be measured reliably on POD1; on POD2. amylase was transiently elevated to 3 times ULN along with mild elevations of bilirubin, transaminases and BUN. Mean total creatine phoshokinase (CPK) peaked at 8 times the upper limit of normal (ULN) in the DCLHb group, compared with less than twice ULN for controls. Three DCLHb patients had prolonged ileus. Two of these patients had postoperative hyperamylasemia, one of whom developed mild pancreatitis. DCLHb did not affect white blood cell count or coagulation tests. CONCLUSION: Administration of approximately 1000 mg/kg DCLHb was associated with transient arterial hypertension, gastrointestinal side effects, laboratory abnormalities, yellow skin discoloration, and hemoglobinuria. These observations point to opportunities for improvement in future synthetic hemoglobin design.