Faculty Bibliography

Background: Recent reports have linked reproductive behavior with severity and age of onset of Alzheimer's Disease (AD) in women but not men, suggesting a gender disparity in disease process which is affected by reproductive functions. We attempted to shed further light on this interaction by examining the relationship of a known genetic risk factor for AD, the presence of the ApoE4 allele, with study participants' reproductive histories. Methods: 467 participants in ongoing outpatient AD studies were retrospectively evaluated for apoE status and number of children. SPSS (version 19.0, Chicago, IL) was used for data analyses. Participants' diagnoses were not factored into the analyses. All participants were past reproductive age and belonged to the same generational group. Results: In a logistic regression analysis predicting the probability of having none vs. 1 or more children with covariates of marital status, year of birth, education, and race, there was a significant interaction between gender and ApoE status (P=0.035). The male ApoE4 carrier group included significantly less individuals with children (n = 31 58%) compared to male ApoE4 non carriers (n = 69, 70%), (X2 (2)=4.3 P=0.04 odds ratio, OR=2.4 95% C.I.: 1.0-5.7) after accounting for covariates. Conversely, there was no relationship between ApoE4 status and whether or not a subject had children in the female group (n = 132 or 63% of the ApoE4 non carrier women, and n = 74 or 70% of the ApoE4 carrier women, n.s.). Conclusions: ApoE4 a known genetic risk factor for AD, negatively affects fertility in men than women. Thus it is more likely to be transmitted to future generations through the maternal line than the paternal line. These findings lend further evidence to a connection between reproductive function and the development and transmission of AD

Background: Biomarkers such as amyloid beta (e.g. Ab42) and hyperphosphorylated tau (e.g. pTau181) in cerebral spinal fluid (CSF) and hippocampal volume loss measured by magnetic resonance imaging (MRI) are useful for identifying cognitively normal elderly likely to have "preclinical" Alzheimer's disease (AD), but such methods are invasive and/or expensive. We investigated whether cognitive tasks dependent on brain regions affected in early AD can serve as proxies of AD biomarkers. Research indicates that the hippocampal formation (Hipp), particularly CA3/dentate gyrus (CA3/DG) and the entorhinal cortex (EC) are affected in preclinical AD. Therefore, we hypothesized that performance on a CA3/DG-dependent spatial pattern separation task (PST) and a Hipp/ EC-dependent discrimination and generalization task (DGT) would be impaired in cognitively normal individuals with biomarker evidence for AD. Methods: We collected initial data on our tasks from 31 cognitively normal NYU Alzheimer's Disease Center/Center for Brain Health participants who had MRI and who also provided CSF for longitudinal studies. In the PST, participants discriminated between two identical dots, one in a previously viewed location and one in a new location. In the DGT, participants learned to discriminate pairs of stimuli determined by shapes or colors in a discrimination phase, then had to generalize the "preferred" shapes and colors to novel stimuli in a generalization phase. Results: Linear regression analyses (with age and years of education as covariates) were used to determine whether task performance correlates with bilateral Hipp volume (used as a surrogate for CA3/DG and controlled for total intracranial volume) and CSF biomarkers. Performance on the PST correlates with bilateral Hipp volume (n = 31; R 2 = 0.151, P = 0.004) and CSF Ab42/pTau181 ratio (n = 26; R 2 = 0.182, P = 0.026). Performance on generalization correlates with Ab42 (R 2 = 0.182, P = 0.026) and marginally with Ab42/pTau181 ratio (R 2 = 0.119, P = 0.079). Performance on discrimination correlates with Ab42/ pTau181 ratio only (R 2 = 0.159, P = 0.039). A standard memory test (NYU Paragraph Recall) shows no significant correlations. Conclusions: These preliminary results are consistent with our hypothesis that cognitive tasks dependent on brain regions affected by early AD pathology may provide a non-invasive and cost-effective method to identify and track change in clinically normal individuals at high risk for progressing to theMCI and dementia stages of AD

Background: The regulation of CSF Abeta42 is poorly understood. Recent studies show Abeta42 levels affected by sleep, stress, diet, depression, ApoE genotype, white matter lesions (WML), and Abeta plaques. The purpose of this study was to examine the heterogeneity of Abeta42 as related to ApoE genotype when interacting with known AD risk factors in healthy, cognitively normal subjects. Methods: In cross-section, we examined the Abeta42, T-Tau and P-tau levels as predicted by ApoE4 status in its interaction with depressive symptoms (HAM-D), MRI white-matter hyperintensity volume (WMH V), and memory (Wechsler Logical-Memory). We studied 41 ApoE4+ and 71 ApoE4- subjects (mean age 62.0 6 11.9). All participants were non-depressed (HAM-D-10), cognitively normal (CDR = 0) and free of MRI brain pathology. Results: ApoE4+ subjects compared to the ApoE4- had lower levels of Abeta42 (442 6 27 vs. 603 6 22 ng/L; P <0.01), higher levels of T-Tau (289617 vs. 229613 ng/L; P <0.01), higher p-Tau (2861.6 vs. 17 6 21.9ng/L; P <0.01) and higher WMHv (3.77 6 0.41 vs. 2.67 6 0.32 cm 3, P<0.05). Predicting CSF Abeta42 levels, controlling for age, we observed three significant 2-way interactions: ApoE genotype X mood, ApoE genotype X memory, ApoE genotype X WMH V (F-values range = 4.03-12.35, P<0.05). No interactions were seen for T-tau or P-Tau. Among ApoE4-, mood symptoms, and to a lesser extent worse memory, had a negative correlation with Abeta42 (r = .-44, n = 71, P <0.01 and r = -.22, n = 71, P = 0.07). Among ApoE4+ there was a negative correlation between Abeta42 and WMH V (r = -0.45, n = 26, P<0.05). Conclusions: This is the first study to report the effect of multiple risk factor interactions on CSFAbeta42 levels in cognitively normal subjects with different ApoE4 alleles. Our results indicate that the relationship between risk factors and CSF Abeta42 is dependent on the presence/absence of ApoE4. E4 carriers show reduced CSF Abeta42, and lower Abeta42 was associated with more MRI-WML whereas a more typical clinical AD-type phenotype (poor memory, minor depressive symptoms), was associated with decreased CSF Abeta42 levels in the ApoE4-non-carriers. These data suggest that Apoe4 carriers and noncarriers may offer divergent trajectories of brain and symptom changes. A better knowledge of the presymptomatic early stages of AD and the interactions with the ApoE4 allele may help us understand the variability of our CSF biomarker measures

Background: Due to well-known markedly increased susceptibility contrast at ultra-high-field MR, this work is using 7T MR susceptibiltyweighted imaging (SWI) to better identify the histopathologic correlate of amyloid plaques containing iron and otherwise invisible subhippocampal structures of human post-mortem brain in patients with Alzheimer's disease. Methods: Post-mortem brain specimens of the frontal lobe and hippocampus were obtained from 8 patients (mean age 71.266.2 years) with clinically diagnosed AD and 6 age-matched healthy controls (72.4 66.6 years) without AD. Coronal 1w3 cm thick brain slices were preserved and fixed in 2% agar or formalin for this study. Imaging was performed on a 7.0T MR. A 24- element phased array head coil was used. High resolution 3D SWI was obtained with isotropic voxel size 150w320I=m. For imaging optimization to better visualize amyloid plaques, we varied TR, TE, bandwidth and flip angle from 30-100ms, 12-36ms, 60-140Hz/pixel and 10-40-; respectively. Results: Compared to controls, 7T SWI revealed a largely increased number of hypointense foci inADbrain samples along the cortical mantle of the frontal and entorhinal cortex due to enhanced susceptibility effects and superb signal. Figure 1 shows amyloid plaques identified with histologic slice (A) and in post-processed SWI image of the frontal cortex of an AD patient (B) as compared to a healthy control (C). The average phase value in the cortex region of AD data (2296 6 72) is significantly higher than that of control data (2032 6 64), which indicates higher iron amount in AD samples. In addition, 7T SWI also provides high resolution images for subregional hippocampal structures including CA1 CA2 CA3 subiculum, and dentate gyrus with significant atrophy of these structures in AD patients. Conclusions: Our findings suggest that SWI with optimization at ultra-high-field strength MR (i.e. 7T) has exhibited the capability to detect diminutive susceptibility contrast associated with iron deposition and otherwise invisible fine hippocampal structures with near histopathologic resolution. Therefore, SWI has great potential for direct detection and quantification of amyloid plaques in live human brain, and may become feasible in vivo in the near future

BACKGROUND: It has been shown that amyloid ss (Abeta), a product of proteolytic cleavage of the amyloid beta precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type-specific amount. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Abeta load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Abeta load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Abeta was mainly N-terminally truncated. Increased intraneuronal accumulation of Abeta(17-40/42) in children and adults suggests a life-long enhancement of APP processing with alpha-secretase in autistic subjects. Abeta accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced alpha-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Abeta(1-40/42) detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Abeta and an extracellular deposition of full-length Abeta in nonfibrillar plaques. CONCLUSIONS/SIGNIFICANCE: The higher prevalence of excessive Abeta accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Abeta accumulation and diffuse plaque formation.

Background: In hypertension (HTN), cerebral blood flow (CBF) regulation limits are changed and the blood pressure (BP) threshold at which CBF is safely maintained is higher. This shift may increase the brain's vulnerability to hypoperfusion at lower BP. Despite growing recognition of the link between hypoperfusion and neurodegeneration little is known about whether blood pressure reductions can induce deficient perfusion and promote expression of cerebrospinal fluid (CSF) biomarkers of amyloid and neurofibrillary pathology. We investigated the relationship between longitudinal changes in mean arterial pressure (MAP) and CSF biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without HTN. Methods: Longitudinal assessments of blood pressure (MAP), CSF ptau181 (phosphorylated tau), total tau, amyloid beta 1-42 (Abeta42), cognition and whole brain volume were conducted on average 2.060.6 years apart in a group of 77 cognitively healthy elderly (age 63.469.4, range 44-86 years; education 16.962.1, range 10-22 years; 60% women). MAP was calculated as: 1/3 systolic blood pressure + 2/3 of diastolic blood pressure. Results: At baseline HTN was found in 23 individuals (30%). When longitudinal change (y) in p-tau181 was predicted with theyMAP, HTN, and the HTNxyMAP interaction, both the total model (F 3,73=3.9, p=.01), and the interaction term (p=.01) were significant. These data indicate that the relationship between yMAP and yp-tau181 was strongly dependent on the presence or absence of HTN. Only in the HTN group was a decrease in MAP from baseline to follow-up related to an increase in p-tau181 (r=-0.5 p=.01). In addition, only among subjects with HTN, was a reduction in MAP related to the worsening of verbal episodic memory (r=0.46 p=.03). Finally in the entire group the increase in p-tau181 was associated with reduction in the verbal episodic memory score (beta=-.223, p=.048). No relationship was observed between changes in MAP and whole brain volume. Conclusions: In subjects with HTN, MAP reduction is associated with increased CSF p-tau181 and deterioration of episodic memory, possibly resulting from suboptimal perfusion and subsequent accumulation of neurofibrillary tangles. Prior experimental work has demonstrated a relationship between perfusion, energetic reductions and tauopathy

Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Abeta) Abeta42/Abeta40, t-tau/Abeta42 and p-tau(231)/Abeta42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Abeta42/Abeta40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage

Having a parent affected with late-onset Alzheimer's disease (LOAD) is a major risk factor for developing the disease among cognitively normal (NL) individuals. This magnetic resonance imaging (MRI) study examines whether NL with a LOAD-affected parent show preclinical brain atrophy, and whether there are parent-of-origin effects. Voxel-based morphometry (VBM) on Statistical parametric mapping (SPM8) was used to examine volumetric T1-MRI scans of 60 late-middle-aged NL subjects, divided into 3 size-matched, demographically balanced groups of 20 subjects each, including NL with a maternal (FHm), paternal (FHp), or negative family history (FH-) of LOAD. There were no group differences for clinical and neuropsychological measures, and ApoE status. On VBM, FHm showed reduced gray matter volumes (GMV) in frontal, parietal, and temporal cortices and precuneus as compared with FH-, and in precuneus compared with FHp (p < 0.05, family-wise error [FWE]-corrected). Results remained significant controlling for age, gender, education, ApoE, and total intracranial volume. No differences were observed between FHp and FH- in any regions. NL FHm showed reduced GMV in LOAD-affected brain regions compared with FH- and FHp, indicating higher risk for Alzheimer's disease. Our findings support the use of regional brain atrophy as a preclinical biomarker for LOAD among at-risk individuals

Often viewed as a potential tool for preclinical diagnosis in early asymptomatic stages of Alzheimer's disease (AD), the term 'endophenotype' has acquired a recent popularity in the field. In this review, we analyze the construct of endophenotype-originally designed to discover genes, and examine the literature on potential endophenotypes for the late-onset form of AD (LOAD). We focus on the [18F]-fluoro-2-deoxyglucose (FDG) PET technique, which shows a characteristic pattern of hypometabolism in AD-related regions in asymptomatic carriers of the ApoE E4 allele and in children of AD mothers. We discuss the pathophysiological significance and the positive predictive accuracy of an FDG-endophenotype for LOAD in asymptomatic subjects, and discuss several applications of this endophenotype in the identification of both promoting and protective factors. Finally, we suggest that the term 'endophenotype' should be reserved to the study of risk factors, and not to the preclinical diagnosis of LOAD