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Preservation of Brain Nerve Growth Factor in Mild Cognitive Impairment and Alzheimer Disease

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Preservation of Brain Nerve Growth Factor in Mild Cognitive Impairment and Alzheimer Disease ORIGINAL CONTRIBUTION Preservation of Brain Nerve Growth Factor in Mild Cognitive Impairment and Alzheimer Disease Elliott J. Mufson, PhD; Milos D. Ikonomovic, MD; Scot D. Styren, PhD; Scott E. Counts, PhD; Joanne Wuu, MA; Sue Leurgans, PhD; David A. Bennett, MD; Elizabeth. J. Cochran, MD; Steven T. DeKosky, MD Background: The status of nerve growth factor (NGF) Setting and Patients: Subjects were from the Rush levels during the prodromal phase of Alzheimer disease Religious Orders Study and the University of Pittsburgh (AD), characterized by mild cognitive impairment (MCI), Alzheimer’s Disease Research Center (Pittsburgh, Pa). remains unknown. Results: We found no changes in cortical or hippocam- Objective: To investigate whether cortical and/or hip- pal NGF levels across groups; in MCI, levels did not cor- pocampal NGF levels are altered in subjects with MCI relate with an increase in choline acetyltransferase ac- or different levels of AD severity. tivity in these regions. Design and Main Outcome Measures: An NGF Conclusion: Brain NGF levels appear sufficient to sup- enzyme-linked immunosorbent assay determined pro- port the cholinergic plasticity changes seen in MCI and tein levels in the hippocampus and 5 cortical areas in remain stable throughout the disease course. people clinically diagnosed as having no cognitive im- pairment, MCI, mild AD, or severe AD. Arch Neurol. 2003;60:1143-1148 T HAS BEEN hypothesized that cho- METHODS linergic basal forebrain (CBF) cortical and hippocampal pro- We evaluated 54 individuals (Table 1) who jection neurons degenerate in participated in a longitudinal study of aging and Alzheimer disease (AD) because AD among the Catholic clergy, the Religious Iof the loss of neurotrophic support from Orders Study (ROS).15,17-20 Subjects were cat- their target sites, which produce nerve egorized as having NCI, MCI, or mild AD. growth factor (NGF).1 This protein has Twelve subjects with severe AD were selected well-known survival effects on CBF from the University of Pittsburgh Alzheimer’s neurons.2,3 Studies have reported un- Disease Research Center (Pittsburgh, Pa). At changed,4-7 decreased,8 or increased8-13 their last evaluation (performed within 12 NGF levels in the cortex and hippocam- months of death), they had a mean Mini- pus in patients with end-stage AD. De- Mental State Examination score of 8.3 (signifi- cantly lower than all 3 ROS groups; PϽ.001). spite these inconsistencies and the initia- These subjects were similar to the 3 ROS groups From the Department of tion of a clinical trial to test the effect of in age at death, sex, level of education, APOE Neurological Sciences and Rush NGF gene therapy as a treatment for mild ⑀4 status, and postmortem delay (Table 1). The 14 Alzheimer’s Disease Center, AD, there are scant data concerning al- human investigations committees of Rush Pres- Rush Presbyterian–St Luke’s terations in NGF levels in the cortex and byterian–St Luke’s Medical Center (Chicago, Medical Center, Chicago, Ill hippocampus throughout the course of Ill) and the University of Pittsburgh approved (Drs Mufson, Counts, Leurgans, AD. Interestingly, choline acetyltransfer- this study. Bennett, and Cochran and ase (ChAT) activity is increased in the fron- Ms Wuu); Departments of tal cortex and hippocampus in people with CLINICAL EVALUATION Neurology and Psychiatry and mild cognitive impairment (MCI).15,16 To the Alzheimer’s Disease determine whether NGF levels exhibit a Details of the clinical evaluation in the ROS and Research Center, University of University of Pittsburgh cases have been pub- Pittsburgh School of Medicine, similar plasticity response, we evaluated lished elsewhere.15,17-21 Our MCI population was Pittsburgh, Pa (Drs Ikonomovic these levels in the hippocampus and 5 cor- defined as subjects rated as impaired on neu- and DeKosky); and Aventis tical areas in people clinically diagnosed ropsychological testing but not having demen- Pharmaceuticals, Bridgewater, as having no cognitive impairment (NCI), tia.17-20 The University of Pittsburgh patients NJ (Dr Styren). MCI, mild AD, or severe AD. were diagnosed as having AD following a stan- (REPRINTED) ARCH NEUROL / VOL 60, AUG 2003 WWW.ARCHNEUROL.COM 1143 ©2003 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Demographic and Clinical Characteristics ROS Cases NCI MCI Mild AD Total Severe AD Cases* (n = 24) (n = 18) (n = 12) (N = 54) (n = 12) P Value† Age at death, y Mean ± SD 81.6 ± 7.3 84.5 ± 5.7 86.0 ± 7.1 83.6 ± 6.9 79.6 ± 8.0 .15‡ Range 66-92 75-97 70-95 66-97 66-90 M, % 58 44 67 56 25 .47§ Level of education, y Mean ± SD 18.3 ± 4.3 17.7 ± 3.4 15.1 ± 4.2 17.4 ± 4.0 NA .09‡ Range 8-25 8-22 6-19 6-25 APOE ⑀4 allele, % 20 28 42 26 92 .43§ Postmortem interval, h Mean ± SD 8.1 ± 6.8 6.9 ± 5.5 6.2 ± 3.2 7.3 ± 5.7 5.9 ± 3.3 .63‡ Range 2.8-29.0 0.2-23.0 3-12 0.2-29.0 2.5-12.0 MMSE score Mean ± SD 27.9 ± 1.6 26.1 ± 2.5 18.2 ± 6.1 25.1 ± 5.1 8.1 ± 5.3࿣ Ͻ0.001‡ Range 25-30 20-30 5-25 5-30 3-17 ROS ADϽMCI or NCI¶ Abbreviations: AD, Alzheimer disease; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; NA, not applicable; NCI, no cognitive impairment; ROS, Religious Orders Study. *Subjects with severe AD were from the University of Pittsburgh Alzheimer’s Disease Research Center (Pittsburgh, Pa). †Comparison among the 3 ROS groups. ‡One-way analysis of variance. §Fisher exact test. ࿣Four subjects had missing MMSE scores. The MMSE scores of the other 8 cases were significantly lower than for each of the 3 ROS groups (PϽ.001). ¶Tukey test for multiple comparisons. dardized Alzheimer’s Disease Research Center evaluation at a hibitors. An aliquot was then removed for total protein deter- consensus conference using criteria from the National Insti- mination (BCA Protein Assay Kit; Pierce Biotechnology, Inc, tute of Neurological and Communicative Disorders and Stroke– Rockford, Ill). The remaining tissue lysate was centrifuged at Alzheimer’s Disease and Related Disorders Association 17000g for 60 minutes, and NGF was measured in the resulting (NINCDS-ADRDA)22 and Diagnostic and Statistical Manual of supernatant using a sandwich enzyme immunoassay. All tissue Mental Disorders, Revised Third Edition23 (now the Diagnostic samples were run in triplicate. The capture antibody was mono- and Statistical Manual of Mental Disorders, Fourth Edition, Text clonal antibody anti-␤ (2.5 Svedberg flotation units [Sf]; 7 Sf) Revision). NGF, whereas the detection antibody was monoclonal anti- body anti-␤ (2.5 Sf; 7 Sf) NGF-␤-Gal, a ␤-galactosidase– TISSUE PREPARATION AND conjugated form of the capture antibody (both from Roche Di- NEUROPATHOLOGIC DESIGNATION agnostics, Mannheim, Germany). Detailed assay description and the sensitivity and specificity of human NGF antibodies have been Brain tissue collection and processing were virtually identical published previously.8,28,29 The amount of NGF present in tis- for ROS and University of Pittsburgh subjects.15,17-19,21 Cases were sue samples was determined by monitoring the color change of excluded from these studies if brain abnormalities were sub- a substrate solution (chlorophenol red galactopyranoside; Sigma stantial. Tissue was snap frozen in liquid nitrogen and frozen Chemical, St Louis, Mo) at 570 nm using a plate reader (Dyna- at −80°C until analysis. All cases were assigned a neuropatho- tech, Vienna, Va) and comparing the results with human NGF logic diagnosis based on Braak and Braak staging scores24 and standards (Roche Diagnostics) run in parallel with the same plate. National Institute on Aging (NIA)–Reagan criteria25 and geno- To control for any nonspecific binding of NGF in the tissue ly- typed for apolipoprotein E (APOE) using restriction isotyping sates, tissue samples were spiked with a known amount of NGF of genomic DNA isolated from plasma, performed by polymer- standard, and the percentage of NGF recovered corrected the read- ase chain reaction amplification.18,21,26 Designations of normal ing value. Samples from all 4 diagnostic groups were run in par- (with respect to AD or other dementia processes), possible or allel. To ensure reproducibility of the assay, randomly chosen probable AD, and definite AD were based on criteria from the samples were run using multiple plates, yielding comparable val- Consortium to Establish a Registry for Alzheimer’s Disease27 ues for the same sample. The NGF measurements were ex- and NINCDS-ADRDA.22 pressed as picograms of NGF per milligrams of protein. Semiquantitative counts of diffuse and neuritic plaques were performed on Bielschowsky silver-stained paraffin-embedded STATISTICAL ANALYSES cortical sections and scanned at original magnification ϫ10 to determine the area of greatest plaque density. A grid reticule Demographic and clinical characteristics of diagnostic groups was placed over the area; at original magnification ϫ20, only were compared using analysis of variance for continuous vari- plaques identified within the grid boundaries were counted. The ables and the Fisher exact test for categorical variables; pair- grid was moved across and up and down the field using fidu- wise comparisons were performed using the Tukey test. To as- ciary landmarks to prevent counting objects twice. sess NGF levels across diagnostic groups, we used the nonparametric Kruskal-Wallis test. Distribution of neuropatho- NGF ASSAY logic lesions according to NIA-Reagan criteria and Braak and Braak staging was compared using the Fisher exact test. Cor- Homogenate samples were prepared using brain tissue sonica- relations were performed using the Spearman rank correla- tion in phosphate buffer saline (pH, 7.2) containing protease in- tion.
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