Robert DeLaPaz

Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease.

The hippocampal formation is composed of separate anatomical regions interconnected to form a circuit, and investigating abnormal hippocampal function is most revealing at the level of these regions. Until recently, regional analysis of the hippocampal formation could be performed only in animals or in human postmortem tissue. Here, we report a method using functional magnetic resonance imaging that evaluates the hippocampal regions in vivo, and we use this method to study elderly with normal memory, with isolated memory decline, and with probable Alzheimers disease (AD). Although age‐related memory decline occurs commonly, the cause of this decline remains unknown, with disagreement as to whether this decline represents one or more etiologies. Analysis revealed two distinct patterns of regional dysfunction among elderly with isolated memory decline—one pattern similar to that found in elders with AD, involving all hippocampal regions, and a second pattern with dysfunction restricted to only one hippocampal region, the subiculum. These results offer direct evidence of hippocampal dysfunction associated with memory decline in the elderly, and implicate both predementia AD and non‐AD processes as possible underlying causes. Ann Neurol 1999;45:466–472

Incidence of Nephrogenic Systemic Fibrosis at Two Large Medical Centers

PURPOSE To determine the incidence and associated risk factors of nephrogenic systemic fibrosis (NSF) in patients who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS Institutional review board approval was obtained for retrospective review of the medical records from two hospitals to identify all cases of biopsy-confirmed NSF and all patients administered a GBCA from January 1, 1997, to June 30, 2007. Informed patient consent was not required. The incidence of NSF was calculated for patients who received a standard dose of GBCA, patients who received a high dose, and subgroups of patients with renal impairment. RESULTS Fifteen patients developed NSF after gadolinium-enhanced MR imaging. All of them had an estimated glomerular filtration rate (eGFR) lower than 30 mL/min, and 11 had acute renal failure or acute deterioration of chronic renal failure. The incidence of NSF after gadolinium-enhanced MR imaging without screening for renal function was zero of 74,124 patients with the standard dose of GBCA and 15 (0.17%) of 8997 patients with the high dose (P < .001). The NSF incidence associated with a high dose of GBCA increased to 0.4% in patients in a chronic hemodialysis program and to 8.8% in those who had an eGFR lower than 15 mL/min but were not undergoing hemodialysis (P < .001). The NSF incidence in the patients with acute renal failure who received a high dose when their creatinine level was increasing was 19% (11 of 58 patients) when hemodialysis was delayed for longer than 2 days. More patients with NSF had proinflammatory events, and compared with patients without NSF, these patients had lower pH, younger age, lower eGFR, elevated serum phosphorus levels, and a longer delay between GBCA injection and hemodialysis. CONCLUSION For patients with an eGFR lower than 15 mL/min, hemodialysis helped to prevent NSF. For patients with an eGFR lower than 30 mL/min who received a high dose of GBCA, acute renal failure, delayed hemodialysis after contrast agent injection, proinflammatory events, and hyperphosphatemia were associated with increased risk of NSF.

Imaging hippocampal function across the human life span: is memory decline normal or not?

Memory function commonly declines in later life. Whether memory decline represents a disease process or whether it is part of normal aging remains unknown. Here we answer this question by assessing the function of multiple subregions that make up the hippocampal circuit across the human life span. A newly developed MRI approach—designed to detect functional changes in individual hippocampal subregions—was used to assess the hippocampal circuit in 70 subjects between 20 and 88 years of age. Using strict parametric criteria, analysis revealed that function in two hippocampal subregions—the subiculum and the dentate gyrus—decline normally with age. In contrast, function in the entorhinal cortex declines pathologically. Single‐subject analysis revealed that hippocampal dysfunction, found in 60% of elders was selectively correlated with memory decline. These results show that memory decline is caused by different mechanisms and suggests how memory decline should be approached clinically.

Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation

Circuits within the hippocampal formation are active during memory processing. Here we used functional magnetic resonance imaging (fMRI) to examine multiple sites across the long axis of the hippocampal formation while subjects performed different phases of an associative memory task, learning to associate faces with names. Viewing faces and hearing names in isolation resulted in separate hippocampal activation patterns. Pairing faces with names resulted a spatially redistributed activation pattern, rather than a simple summation of the activation patterns resulting from viewing faces and hearing names in isolation. Recalling names when cued with faces reactivated a pattern similar to that found during paired training. Finally, the activation patterns representing faces and names were found to be experience dependent, emerging with repeated exposure. Interpreted in the context of hippocampal anatomy and physiology, these findings reveal hippocampal circuit mechanisms that underlie memory encoding and retrieval.

Radiation Dose from Single-Heartbeat Coronary CT Angiography Performed with a 320–Detector Row Volume Scanner

PURPOSE To determine radiation doses from coronary computed tomographic (CT) angiography performed by using a 320-detector row volume scanner and evaluate how the effective dose depends on scan mode and the calculation method used. MATERIALS AND METHODS Radiation doses from coronary CT angiography performed by using a volume scanner were determined by using metal-oxide-semiconductor field-effect transistor detectors positioned in an anthropomorphic phantom physically and radiographically simulating a male or female human. Organ and effective doses were determined for six scan modes, including both 64-row helical and 280-row volume scans. Effective doses were compared with estimates based on the method most commonly used in clinical literature: multiplying dose-length product (DLP) by a general conversion coefficient (0.017 or 0.014 mSv.mGy(-1).cm(-1)), determined from Monte Carlo simulations of chest CT by using single-section scanners and previous tissue-weighting factors. RESULTS Effective dose was reduced by up to 91% with volume scanning relative to helical scanning, with similar image noise. Effective dose, determined by using International Commission on Radiological Protection publication 103 tissue-weighting factors, was 8.2 mSv, using volume scanning with exposure permitting a wide reconstruction window, 5.8 mSv with optimized exposure and 4.4 mSv for optimized 100-kVp scanning. Estimating effective dose with a chest conversion coefficient resulted in a dose as low as 1.8 mSv, substantially underestimating effective dose for both volume and helical coronary CT angiography. CONCLUSION Volume scanning markedly decreases coronary CT angiography radiation doses compared with those at helical scanning. When conversion coefficients are used to estimate effective dose from DLP, they should be appropriate for the scanner and scan mode used and reflect current tissue-weighting factors. (c) RSNA, 2010.

Exploring the Neural Basis of Cognitive Reserve

There is epidemiologic and imaging evidence for the presence of cognitive reserve, but the neurophysiologic substrate of CR has not been established. In order to test the hypothesis that CR is related to aspects of neural processing, we used fMRI to image 19 healthy young adults while they performed a nonverbal recognition test. There were two task conditions. A low demand condition required encoding and recognition of single items and a titrated demand condition required the subject to encode and then recognize a larger list of items, with the study list size for each subject adjusted prior to scanning such that recognition accuracy was 75%. We hypothesized that individual differences in cognitive reserve are related to changes in neural activity as subjects moved from the low to the titrated demand task. To test this, we examined the correlation between subjects’ fMRI activation and NART scores. This analysis was implemented voxel-wise in a whole brain fMRI dataset. During both the study and test phases of the recognition memory task we noted areas where, across subjects, there were significant positive and negative correlations between change in activation from low to titrated demand and the NART score. These correlations support our hypothesis that neural processing differs across individuals as a function of CR. This differential processing may help explain individual differences in capacity, and may underlie reserve against age-related or other pathologic changes.

Prevalence and determinants of subclinical brain infarction The Northern Manhattan Study

Objective: Risk factors for subclinical brain infarcts (SBI) have not been well studied, especially in Hispanic and black populations who may be at higher risk for vascular disease. We examined the prevalence and determinants of SBI in a multiethnic community cohort. Methods: The Northern Manhattan Study (NOMAS) includes 892 stroke-free participants who underwent brain MRI. Baseline demographic and vascular risk factor data were collected. The presence of SBI was determined from the size, location, and imaging characteristics of the lesion based on fluid attenuated inversion recovery (FLAIR) T1 and T2, and proton density MRI sequences. We calculated the prevalence of SBI and cross-sectional associations with sociodemographic and vascular risk factors, using logistic regression to adjust for relevant covariates. Results: Among 892 subjects (mean age 71.3 years), 158 (17.7%) had SBI (13.5% had 1 lesion, 4.3% had >1 lesion). Of the total 216 infarcts, most were small (<1 cm, 82.4%) and subcortical (82.9%). SBI prevalence increased with age (<65: 9.7%; 65 to 75: 16.4%; >75: 26.1%), was increased among men (21.3% vs 15.2% in women), and was increased among blacks (24.0% vs 18.1% in whites and 15.8% in Hispanics). The presence of SBI was independently associated with older age (per year: OR 1.06, 95% CI 1.04 to 1.09), male sex (OR 1.79, 95% CI 1.22 to 2.61), and hypertension (OR 2.08, 95% CI 1.35 to 3.22) adjusting for age, sex, race-ethnicity, and vascular risk factors. A significant interaction (p = 0.002) between race and age was observed such that younger black subjects had greater odds of having SBI. Conclusions: SBI were detected in nearly 18% of subjects in a multiethnic community-based cohort. Age, male sex, and hypertension were independently associated with SBI. Subclinical cerebral infarcts are more prevalent than symptomatic infarcts and may increase the true public health burden of stroke.

Imaging Physiologic Dysfunction of Individual Hippocampal Subregions in Humans and Genetically Modified Mice

We have developed a variant of functional magnetic resonance imaging (fMRI) designed to be sensitive to static neuronal function. This method is based on resting instead of dynamic changes in oxygen-dependent signal and therefore allows for a spatial resolution that can detect signal from different hippocampal subregions in human subjects as well as in mice. We found that hippocampal signal was significantly diminished in elderly subjects with memory decline compared to age-matched controls, and different subjects showed dysfunction in different subregions. Among healthy elders, signal intensity from the subiculum was correlated selectively with memory performance. This method does not require an activation task; it can be used in anesthetized normal and in genetically modified and cognitively impaired mice. In mice the signal was found to be sufficiently sensitive to detect functional changes in the absence of underlying anatomical changes.

Evaluating the function of hippocampal subregions with high-resolution MRI in Alzheimer's disease and aging

Memory ability declines in older age groups. There is a growing list of physiological processes that target the hippocampal formation in an age‐related fashion, and some might underlie the hippocampal component of memory decline. The hippocampal formation is comprised of separate subregions, and physiological processes differentially target these subregions. The ability to evaluate the functional integrity of individual subregions—performing subregional analysis—is a major clinical goal since it can aid in the diagnosis of memory decline, as well as in elucidating mechanisms of disease and testing potential interventions. Because of its superior spatial resolution, magnetic resonance imaging (MRI) is best suited to accomplish this goal. Despite limited success, most functional MRI (fMRI) protocols have difficulty in performing complete subregional analysis of the hippocampal formation. Here we address sources of difficulty by (1) generating T2* ‐weighted maps of the hippocampal formation with sub‐millimeter resolution; and (2) by adapting an approach used by animal investigators to identify the hippocampal subregions using anatomical landmarks. The protocol is tested in patients with Alzheimers disease and in healthy controls, in an effort to determine whether it can detect neuronal dysfunction. Results showed diminished signal in the hippocampal formation of patients with Alzheimers disease (AD) compared to controls, and multivariate analysis showed that this difference was most prominent in the entorhinal cortex. The protocol can be used to perform subregional analysis of the hippocampal formation. Testing the protocol in other clinical populations is needed to demonstrate its efficacy in evaluating the neuronal integrity of all hippocampal subregions. Microsc. Res. Tech. 51:101–108, 2000.

A Modified Transorbital Baboon Model of Reperfused Stroke

Background and Purpose Although pathophysiological studies of focal cerebral ischemia in nonhuman primates can provide important information not obtainable in rodent models, primate experimentation is limited by considerations of cost, availability, effort, and ethics. A reproducible and quantitative model that minimizes the number of animals necessary to detect differences between treatment groups is therefore crucial. Methods Eight male baboons (weight, 22±2 kg) underwent left transorbital craniectomy followed by 1 hour of temporary ipsilateral internal carotid artery occlusion at the level of the anterior choroidal artery together with bilateral temporary occlusion of both anterior cerebral arteries (A1) proximal to the anterior communicating artery. A tightly controlled nitrous oxide–narcotic anesthetic allowed for intraoperative motor evoked potential confirmation of middle cerebral artery (MCA) territory ischemia. Animals survived to 72 hours or 10 days if successfully self-caring. Outcomes were assessed with a 100-point neurological grading system, and infarct volume was quantified by planimetric analysis of both MRI and triphenyltetrazolium chloride–stained sections. Results Infarction volumes (on T2-weighted images) were 32±7% (mean±SEM) of the ipsilateral hemisphere, and neurological scores averaged 29±9. All animals demonstrated evidence of hemispheric infarction, with damage evident in both cortical and subcortical regions in the MCA vascular territory. Histologically determined infarction volumes differed by <3% and correlated with absolute neurological scores (r =0.9, P =0.003). Conclusions Transorbital temporary occlusion of the entire anterior cerebral circulation with strict control of physiological parameters can reliably produce reperfused MCA territory infarction. The magnitude of the resultant infarct with little interanimal variability diminishes the potential number of animals required to distinguish between 2 treatment regimens. The anatomic distribution of the infarct and associated functional deficits offer comparability to human hemispheric strokes.