QUANTIFICATION OF NORMAL BRAIN AGING USING FULLY DEFORMABLE REGISTRATION

Over the next twenty-five years, the proportion of the population over age 65 will increase 76%; therefore understanding both the normal and pathological processes involved in the aging of the human brain is of the highest public health priority. We report here the use of a computational method that provides estimates of the “brain age” of individuals that is based solely on a high resolution Magnetic Resonance Image (MRI) of the brain of the individual, and is blinded to his or her true chronological age. The method proceeds in two phases: first, a statistical learning algorithm is used to determine the numerical MRI-based features that predict true age on a training set of 198 healthy elderly individuals; second, these features are used to predict the true age of previously-unseen individuals. In cross-validation experiments, the brain age estimates differed from true age by a mean absolute error of 5.35 years in an elderly cohort, reflecting the broad heterogeneity in structural integrity of the elderly brain. The “brain age” of female subjects was significantly lower than that of male subjects who had the same true age (3.0 years younger for 50-year-olds and 1.6 years younger for 79 year olds), reflecting the longer life expectancy of females. Across the elderly age spectrum, the “brain age” of individuals with Alzheimer's Disease (AD) was significantly higher than that of cognitively-healthy elderly subjects with equivalent true age; however, this was not the case for the subjects with mild cognitive impairment (MCI), a possible AD prodrome

Developmental pathway for potent V1V2-directed HIV-neutralizing antibodies.

CAPRISA, 2014.Antibodies capable of neutralizing HIV-1 often target variable regions 1 and 2 (V1V2) of the HIV-1 envelope, but the mechanism of their elicitation has been unclear. Here we define the developmental pathway by which such antibodies are generated and acquire the requisite molecular characteristics for neutralization. Twelve somatically related neutralizing antibodies (CAP256-VRC26.01-12) were isolated from donor CAP256 (from the Centre for the AIDS Programme of Research in South Africa (CAPRISA)); each antibody contained the protruding tyrosine-sulphated, anionic antigen-binding loop (complementarity-determining region (CDR) H3) characteristic of this category of antibodies. Their unmutated ancestor emerged between weeks 30-38 post-infection with a 35-residue CDR H3, and neutralized the virus that superinfected this individual 15 weeks after initial infection. Improved neutralization breadth and potency occurred by week 59 with modest affinity maturation, and was preceded by extensive diversification of the virus population. HIV-1 V1V2-directed neutralizing antibodies can thus develop relatively rapidly through initial selection of B cells with a long CDR H3, and limited subsequent somatic hypermutation. These data provide important insights relevant to HIV-1 vaccine development

A novel Alzheimer disease locus located near the gene encoding tau protein

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted

Human cholinergic basal forebrain: Chemoanatomy and neurologic dysfunction

The human cholinergic basal forebrain (CBF) is comprised of magnocellular hyperchromic neurons within the septal/diagonal band complex and nucleus basalis (NB) of Meynert. CBF neurons provide the major cholinergic innervation to the hippocampus, amygdala and neocortex. They play a role in cognition and attentional behaviors, and are dysfunctional in Alzheimer\u27s disease (AD). The human CBF displays a continuum of large cells that contain various cholinergic markers, nerve growth factor (NGF) and its cognate receptors, calbindin, glutamate receptors, and the estrogen receptors, ERα and ERβ. Admixed with these cholinergic neuronal phenotypes are smaller interneurons containing the m2 muscarinic acetylcholine receptor (mAChRs), NADPH-diaphorase, GABA, calcium binding proteins and several inhibitory neuropeptides including galanin (GAL), which is over expressed in AD. Studies using human autopsy material indicate an age-related dissociation of calbindin and the glutamate receptor GluR2 within CBF neurons, suggesting that these molecules act synergistically to induce excitotoxic cell death during aging, and possibly during AD. Choline acetyltrasnferease (ChAT) activity and CBF neuron number is preserved in the cholinergic basocortical system and up regulated in the septohippocampal system during prodromal as compared with end stage AD. In contrast, the number of CBF neurons containing NGF receptors is reduced early in the disease process suggesting a phenotypic silence and not a frank loss of neurons. In end stage AD, there is a selective reduction in trkA mRNA but not p75NTR in single CBF cells suggesting a neurotrophic defect throughout the progression of AD. These observations indicate the complexity of the chemoanatomy of the human CBF and suggest that multiple factors play different roles in its dysfunction in aging and AD. © 2003 Published by Elsevier B.V

Chronic traumatic encephalopathy: clinical‐biomarker correlations and current concepts in pathogenesis

Background\ud Chronic traumatic encephalopathy (CTE) is a recently revived term used to describe a neurodegenerative process that occurs as a long term complication of repetitive mild traumatic brain injury (TBI). Corsellis provided one of the classic descriptions of CTE in boxers under the name “dementia pugilistica” (DP). Much recent attention has been drawn to the apparent association of CTE with contact sports (football, soccer, hockey) and with frequent battlefield exposure to blast waves generated by improvised explosive devices (IEDs). Recently, a promising serum biomarker has been identified by measurement of serum levels of the neuronal microtubule associated protein tau. New positron emission tomography (PET) ligands (e.g., [18 F] T807) that identify brain tauopathy have been successfully deployed for the in vitro and in vivo detection of presumptive tauopathy in the brains of subjects with clinically probable CTE.\ud \ud Methods\ud Major academic and lay publications on DP/CTE were reviewed beginning with the 1928 paper describing the initial use of the term CTE by Martland.\ud \ud Results\ud The major current concepts in the neurological, psychiatric, neuropsychological, neuroimaging, and body fluid biomarker science of DP/CTE have been summarized. Newer achievements, such as serum tau and [18 F] T807 tauopathy imaging, are also introduced and their significance has been explained.\ud \ud Conclusion\ud Recent advances in the science of DP/CTE hold promise for elucidating a long sought accurate determination of the true prevalence of CTE. This information holds potentially important public health implications for estimating the risk of contact sports in inflicting permanent and/or progressive brain damage on children, adolescents, and adults

Chronic traumatic encephalopathy: clinical‐biomarker correlations and current concepts in pathogenesis

Background\ud Chronic traumatic encephalopathy (CTE) is a recently revived term used to describe a neurodegenerative process that occurs as a long term complication of repetitive mild traumatic brain injury (TBI). Corsellis provided one of the classic descriptions of CTE in boxers under the name “dementia pugilistica” (DP). Much recent attention has been drawn to the apparent association of CTE with contact sports (football, soccer, hockey) and with frequent battlefield exposure to blast waves generated by improvised explosive devices (IEDs). Recently, a promising serum biomarker has been identified by measurement of serum levels of the neuronal microtubule associated protein tau. New positron emission tomography (PET) ligands (e.g., [18 F] T807) that identify brain tauopathy have been successfully deployed for the in vitro and in vivo detection of presumptive tauopathy in the brains of subjects with clinically probable CTE.\ud \ud Methods\ud Major academic and lay publications on DP/CTE were reviewed beginning with the 1928 paper describing the initial use of the term CTE by Martland.\ud \ud Results\ud The major current concepts in the neurological, psychiatric, neuropsychological, neuroimaging, and body fluid biomarker science of DP/CTE have been summarized. Newer achievements, such as serum tau and [18 F] T807 tauopathy imaging, are also introduced and their significance has been explained.\ud \ud Conclusion\ud Recent advances in the science of DP/CTE hold promise for elucidating a long sought accurate determination of the true prevalence of CTE. This information holds potentially important public health implications for estimating the risk of contact sports in inflicting permanent and/or progressive brain damage on children, adolescents, and adults

α7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease

Background: Dysfunction of basocortical cholinergic projection neurons of the nucleus basalis (NB) correlates with cognitive deficits in Alzheimer disease (AD). Nucleus basalis neurons receive cholinergic inputs and express nicotinic acetylcholine receptors (nAChRs) and muscarinic AChRs (mAChRs), which may regulate NB neuron activity in AD. Although alterations in these AChRs occur in the AD cortex, there is little information detailing whether defects in nAChR and mAChR gene expression occur in cholinergic NB neurons during disease progression. Objective: To determine whether nAChR and mAChR gene expression is altered in cholinergic NB neurons during the progression of AD. Design: Individual NB neurons from subjects diagnosed ante mortem as having no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild to moderate AD were analyzed by single-cell AChR expression profiling via custom-designed microarrays. Setting: Academic research. Participants: Participants were members of the Rush Religious Orders Study cohort. Main Outcome Measures: Real-time quantitative polymerase chain reaction was performed to validate microarray findings. Results: Cholinergic NB neurons displayed a statistically significant up-regulation of α7 nAChR messenger RNA expression in subjects with mild to moderate AD compared with those with NCI and MCI (P\u3c.001). No differences were found for other nAChR and mAChR subtypes across the cohort. Expression levels of α7 nAChRs were inversely associated with Global Cognitive Score and with Mini-Mental State Examination performance. Conclusions: Up-regulation of α7 nAChRs may signal a compensatory response to maintain basocortical cholinergic activity during AD progression. Alternatively, putative competitive interactions of this receptor with β-amyloid may provide a pathogenic mechanism for NB dysfunction. Increasing NB α7 nAChR expression may serve as a marker for the progression of AD. ©2007 American Medical Association. All rights reserved

Mild cognitive impairment: Pathology and mechanisms

Mild cognitive impairment (MCI) is rapidly becoming one of the most common clinical manifestations affecting the elderly. The pathologic and molecular substrate of people diagnosed with MCI is not well established. Since MCI is a human specific disorder and neither the clinical nor the neuropathological course appears to follow a direct linear path, it is imperative to characterize neuropathology changes in the brains of people who came to autopsy with a well-characterized clinical diagnosis of MCI. Herein, we discuss findings derived from clinical pathologic studies of autopsy cases who died with a clinical diagnosis of MCI. The heterogeneity of clinical MCI imparts significant challenges to any review of this subject. The pathologic substrate of MCI is equally complex and must take into account not only conventional plaque and tangle pathology but also a wide range of cellular, biochemical and molecular deficits, many of which relate to cognitive decline as well as compensatory responses to the progressive disease process. The multifaceted nature of the neuronal disconnection syndrome associated with MCI suggests that there is no single event which precipitates this prodromal stage of AD. In fact, it can be argued that neuronal degeneration initiated at different levels of the central nervous system drives cognitive decline as a final common pathway at this stage of the dementing disease process. © 2011 Springer-Verlag

Cortical α7 nicotinic acetylcholine receptor and β-amyloid levels in early Alzheimer disease

Objective: To examine α7 nicotinic acetylcholine receptor (nAChR) binding and β-amyloid (Aβ) peptide load in superior frontal cortex (SFC) across clinical and neuropathological stages of Alzheimer disease (AD). Design: Quantitative measures of α7 nAChR by [3H] methyllycaconitine binding and Aβ concentration by enzyme-linked immunosorbent assay in SFC were compared across subjects with antemortem clinical classification of no cognitive impairment, mild cognitive impairment, or mild to moderate AD, and with postmortem neuropathological diagnoses. Setting: Academic medical center. Subjects: Twenty-nine elderly retired clergy. Main Outcome Measures: Quantitative measures of α7 nAChR binding and Aβ peptide concentration in SFC. Results: Higher concentrations of total Aβ peptide in SFC were associated with clinical diagnosis of mild to moderate AD (P = .02), lower Mini-Mental State Examination scores (P = .003), presence of cortical Aβ plaques (P = .02), and likelihood of AD diagnosis by the National Institute on Aging-Reagan criteria (P = .002). Increased α7 nAChR binding was associated with National Institute on Aging-Reagan diagnosis (P = .02) and, albeit weakly, the presence of cortical Aβ plaques (P = .08). There was no correlation between the 2 biochemical measures. Conclusions: These observations suggest that during the clinical progression from normal cognition to neurodegenerative disease state, total Aβ peptide concentration increases while α7 nAChRs remain relatively stable in SFC. Regardless of subjects\u27 clinical status, however, elevated α7 nAChR binding is associated with increased Aβ plaque pathology, supporting the hypothesis that cellular expression of these receptors may be upregulated selectively in Aβ plaque-burdened brain areas. ©2009 American Medical Association. All rights reserved