Faculty Bibliography

Cognitive function and peripheral glucose regulation both decrease with age. There is a consistent and growing literature reporting memory and other cognitive problems among individuals with diabetes mellitus as well as those with pre-diabetes. There are two papers in the literature documenting, relative to matched controls, hippocampal volume reductions among both diabetics and insulin resistant individuals. The mechanism(s) for the cognitive and brain problems associated with impairments in peripheral glucose regulation remain unknown. In this paper, I present a selective review of the literature that builds a case for a theoretical model that could be used to investigate how abnormalities in peripheral glucose regulation may give rise to brain impairments in general, and affect hippocampal integrity in particular

The goal of this article is to review the role of structural neuroimaging in the diagnosis of Alzheimer's disease (AD). We present relevant neuroanatomy, highlight progress in the domain of AD imaging, and review the clinical characteristics of the prodromal phase of AD. We describe the history of the diagnostic issue by examining at cross-section and longitudinally the differences between patients who have AD and normal controls. We also present how subsequent works applied these characteristic traits to the early detection of the prodromal disease and to prediction of future decline. The article delineates the differences between subjects who have mild cognitive impairment and AD, which illustrate the spreading of the pathology with disease progression. The last section describes problems encountered in the differential diagnosis

The origin and clinical significance of subjective memory complaints among middle aged and older individuals is not well understood. Associations with objective memory impairments, personality traits or mood disturbances have been reported. Elevated cortisol levels occur in aging and depression and causal links to cognitive or emotional problems have been suggested. The goal of this study was to investigate the associations between basal and feedback indices of cortisol regulation and subjective memory impairment in a sample of healthy middle aged and older subjects (mean age 61.8 years) with (n=27) and without (n=19) subjective memory complaints. Participants with memory complaints had both higher basal cortisol levels and higher cortisol levels after dexamethasone. There was a significant group by gender interaction for basal cortisol levels, where women without memory complaints showed significantly lower cortisol levels, whereas no such difference was found for the men. All effects were not due to slight differences in depression scores. Differences in personality traits or in stress susceptibility might underlie the present findings. Future studies of memory complaints should take a comprehensive approach including relevant endocrine parameters

Much of the effort to understand the brain substrate of theory of mind and empathy has involved the study of individuals with deficits in that domain, such as those on the autism spectrum. Studying individuals with presumed superior abilities in picking up social signals may yield important additional information. We predicted that psychic readers may have superior abilities and tested this by contrasting a group of 22 professional psychic readers with matched controls on a measure of theory of mind ('Reading the Mind in the Eyes' test) and a multidimensional measure of empathy [Interpersonal Reactivity Index (IRI)]. Although psychic readers were not superior in reading the language of the eyes, they were shown to have more cognitive empathy, as measured with the 'Fantasy' subscale of the IRI. We discuss the merits of research involving 'experts' in social cognition and propose other possible groups of 'master mindreaders.'

BACKGROUND: To facilitate image analysis, most recent 2-[18F]fluoro-2-deoxy-d-glucose PET (FDG-PET) studies of glucose metabolism (MRglc) have used automated voxel-based analysis (VBA) procedures but paradoxically none reports hippocampus MRglc reductions in mild cognitive impairment (MCI) or Alzheimer disease (AD). Only a few studies, those using regions of interest (ROIs), report hippocampal reductions. The authors created an automated and anatomically valid mask technique to sample the hippocampus on PET (HipMask). METHODS: Hippocampal ROIs drawn on the MRI of 48 subjects (20 healthy elderly [NL], 16 MCI, and 12 AD) were used to develop the HipMask. The HipMask technique was applied in an FDG-PET study of NL (n = 11), MCI (n = 13), and AD (n = 12), and compared to both MRI-guided ROIs and VBA methods. RESULTS: HipMask and ROI hippocampal sampling produced significant and equivalent MRglc reductions for contrasts between MCI and AD relative to NL. The VBA showed typical cortical effects but failed to show hippocampal MRglc reductions in either clinical group. Hippocampal MRglc was the only discriminator of NL vs MCI (78% accuracy) and added to the cortical MRglc in classifying NL vs AD and MCI vs AD. CONCLUSIONS: The new HipMask technique provides accurate and rapid assessment of the hippocampus on PET without the use of regions of interest. Hippocampal glucose metabolism reductions are found in both mild cognitive impairment and Alzheimer disease and contribute to their diagnostic classification. These results suggest re-examination of prior voxel-based analysis 2-[18F]fluoro-2-deoxy-d-glucose PET studies that failed to report hippocampal effects

Chronically elevated cortisol levels have been associated with elevated blood pressure, brain atrophy, and cognitive impairments. In this cross-sectional exploratory study, we assessed whether hypertension was related to hypothalamo-pituitary-adrenal axis hyperactivity and whether this may in part explain prefrontal brain atrophy and cognitive impairments in this population. We studied 27 patients with hypertension and 27 normotensive control subjects. Glucocorticoid feedback was assessed using the combined dexamethasone-CRH test. All participants completed a neuropsychological battery and received brain magnetic resonance imaging for volumetric measurement of frontal and medial temporal lobe regions. Hypertension was significantly associated with impaired glucocorticoid feedback control after statistically controlling for age, gender, and body mass index (P = 0.01). Hypertensive patients also showed a trend toward reductions in frontal lobe volume (P = 0.09) and had significantly lower scores in one of two tests of executive function (P = 0.03). Significant correlations were observed between hypothalamo-pituitary-adrenal hyperactivity and frontal lobe atrophy. Our data indicate that impaired glucocorticoid feedback control may partly account for the prefrontal volume reductions present in patients with hypertension. Future studies assessing the impact of hypertension on the brain should include cortisol assessments

OBJECTIVE: To establish the progression of brain atrophy rates in patients with a known date of onset of Alzheimer disease (AD). METHODS: Each of 18 subjects had two high-resolution T1-weighted three-dimensional MRI examinations. The two MRIs were coregistered and the annual rate of brain tissue atrophy was derived both for the entire brain and regionally for the left and right medial temporal lobe (MTL). Time since onset (TSO) of AD, defined as the interval between the date of onset and the midpoint of MRI dates, ranged from -2.9 to 4.2 years. RESULTS: In patients with AD, TSO was a correlate of the atrophy rate for both the left MTL (R2 = 0.58, p = 0.001) and right MTL (R2 = 0.30, p = 0.03). When serial measurements were applied to a control group of 21 cognitively normal elderly subjects, MTL atrophy rate classified the group membership (AD vs normal cognition) with an accuracy of 92.3%. CONCLUSION: Increased annual atrophy rate in the medial temporal lobe is a potential diagnostic marker of the progression of Alzheimer disease

The demographics of aging identify an immediate need for the early diagnosis and development of dementia prevention strategies. Recent neuropathological studies have pointed to the early involvement of the hippocampus and entorhinal cortex in the progression of Alzheimer's disease in the brain. In particular, these studies have implicated tau-related pathology as an important cause of neuronal death. In addition, there is a large body of evidence showing that beta-amyloid, which has a predilection for the neocortex, is also involved early in the course of the disease and may also have toxic effects on cells. In vivo cerebrospinal fluid studies have shown that markers for these brain changes have a diagnostic value for Alzheimer's disease and that some measures also provide diagnostic specificity for Alzheimer's disease. Structural and metabolic imaging studies demonstrate brain changes in impaired and at-risk individuals. While currently available magnetic resonance and positron emission tomography techniques are not by themselves specific for the pathologic features of Alzheimer's disease, there are patterns of change that have been useful for the early diagnosis. As such, both prediction and longitudinal imaging studies demonstrate a capacity to recognize abnormalities that relate to future Alzheimer's disease and most recently to future mild cognitive impairment. This review highlights cross-sectional, prediction, and longitudinal magnetic resonance and positron emission tomography imaging studies and attempts to put into perspective their utility for the early diagnosis of Alzheimer's disease, and for their utility to provide diagnostic specificity. It is concluded that there is considerable promise for an early and specific diagnosis for Alzheimer's disease by combining information from imaging and biomarker modalities