Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer's disease.

BACKGROUND: There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer's disease (AD). Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development. METHODS: We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. CSF samples from two well-characterized cohorts (n=178 and n=156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC). RESULTS: All subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders. CONCLUSION: The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration.

Detection of mycobacterial lipoarabinomannan in serum for diagnosis of active tuberculosis.

Urinary detection of Mycobacterium tuberculosis lipoarabinomannan (LAM) for tuberculosis (TB) diagnosis is well characterized, but the utility of serum LAM detection remains unclear. We developed an assay for serum LAM detection using single-molecule array (Simoa), purified M. tuberculosis LAM, and anti-LAM monoclonal antibodies and evaluated performance on diluted/heat-treated serum samples from patients with and without active TB and/or HIV. The Simoa assay had a limit of detection of 0.35 pg/mL and lower limit of quantification of 0.942 pg/mL. Corrected serum LAM concentrations ranged from 0 to 132.0 pg/mL [median 1.71, interquartile range (IQR) 0.94-6.80] in 90 TB+ patients and from 0 to 2.29 pg/mL (median 1.03, IQR 0.47-1.69) in 55 TB- patients. Using a cutoff of 2.3 pg/mL for 100% specificity, assay sensitivity was 37% in all TB+ subjects (33/90; 95% CI 0.27-0.48), 47% in TB+/HIV+ subjects (26/55; 0.34-0.61), and 60% in TB+/HIV+/smear+ subjects (21/35; 0.42-0.76). Mycobacterial LAM is detectable in serum with high specificity and reasonable sensitivity using Simoa.

Effect of acute fatigue of the hip abductors on control of balance in young and older women.

OBJECTIVE: To examine the effects of acute fatigue of the hip abductors on the control of balance in young and older women. DESIGN: Pretest-posttest. SETTING: University research laboratory. PARTICIPANTS: Healthy young women (n=20; age, 23.0+/-1.5y; height, 166.52+/-4.5 cm; mass, 65.33+/-10.5 kg) and community-dwelling older women (n=20; age, 71.65+/-7.2y; height, 162.31+/-3.8 cm; mass, 71.16+/-11.6 kg) without a fall history. INTERVENTION: Measurements of control of single-limb balance before and after fatiguing the hip abductors of the dominant leg. MAIN OUTCOME MEASURE: Performance on 3 clinical assessments of control of balance: the modified Functional Reach Test in the forward, left, and right directions; the Lower-Extremity Reach Test in forward and lateral directions; and the Single-Limb Stance Time Test (SLSTT). RESULTS: Although the younger subjects showed a significantly greater control of balance than the older women in most tests, control of balance after acute fatigue failed to show a significant decline in either age group. The only exception to this was the SLSTT in the younger women in whom a significant 26% decline was noted (P<.05). CONCLUSIONS: Acute fatigue of the hip abductors did not result in a decreased control of balance in healthy young or older women without fall history. Despite considerable changes in movement strategies used to complete the postfatigue tests of balance, quantitative measures of balance did not decrease.

A group M consensus envelope glycoprotein induces antibodies that neutralize subsets of subtype B and C HIV-1 primary viruses.

HIV-1 subtype C is the most common HIV-1 group M subtype in Africa and many parts of Asia. However, to date HIV-1 vaccine candidate immunogens have not induced potent and broadly neutralizing antibodies against subtype C primary isolates. We have used a centralized gene strategy to address HIV-1 diversity and generated a group M consensus envelope gene with shortened consensus variable loops (CON-S) for comparative studies with wild-type (WT) Env immunogens. Our results indicate that the consensus HIV-1 group M CON-S Env elicited cross-subtype neutralizing antibodies of similar or greater breadth and titer than the WT Envs tested, indicating the utility of a centralized gene strategy. Our study also shows the feasibility of iterative improvements in Env immunogenicity by rational design of centralized genes.