Volumes of medial temporal lobe structures in patients with Alzheimer's disease and mild cognitive impairment (and in healthy controls).

BACKGROUND: The clinical diagnosis of Alzheimer's disease (AD) can be difficult to make in early stages of disease. Structural neuroimaging offers a potential tool in the clinical diagnosis of AD with mild cognitive impairment. Postmortem studies indicate that early neuropathology in AD occurs in medial temporal lobe limbic structures. Magnetic resonance imaging (MRI) studies that assessed these volumes in mildly impaired AD patients remain inconclusive. METHODS: Using MRI, we measured volumes of left and right hippocampus, amygdala, and anterior and posterior parahippocampal gyrus (PHG) in 13 AD patients with mild cognitive impairment, defined as > or = 20 on the Mini-Mental State Exam, and in 21 healthy age- and sex-matched controls. RESULTS: The AD patients had smaller medial temporal lobe volumes, except for the right anterior PHG. Discriminant function analysis using MRI volumes produced 94% correct group classification. CONCLUSIONS: These results show that in mildly impaired AD patients atrophy is present in medial temporal lobe structures; that MRI volumes of the anterior PHG, which contains entorhinal cortex, are reduced, but the amygdala and hippocampal volumes show greater reduction; and that discriminant function analysis using all volumes as predictors can correctly classify a high proportion of individuals.

High brain myo-inositol levels in the predementia phase of Alzheimer's disease in adults with Down's syndrome: a 1H MRS study.

OBJECTIVE: An extra portion of chromosome 21 in Down's syndrome leads to a dementia in later life that is phenotypically similar to Alzheimer's disease. Down's syndrome therefore represents a model for studying preclinical stages of Alzheimer's disease. Markers that have been investigated in symptomatic Alzheimer's disease are myoinositol and N-acetyl-aspartate. The authors investigated whether abnormal brain levels of myo-inositol and other metabolites occur in the preclinical stages of Alzheimer's disease associated with Down's syndrome. METHOD: The authors used 1H magnetic resonance spectroscopy (MRS) with external standards to measure absolute brain metabolite concentrations in 19 nondemented adults with Down's syndrome and 17 age- and sex-matched healthy comparison subjects. RESULTS: Concentrations of myoinositol and choline-containing compounds were significantly higher in the occipital and parietal regions of the adults with Down's syndrome than in the comparison subjects. Within the Down's syndrome group, older subjects (42-62 years, N = 11) had higher myo-inositol levels than younger subjects (28-39 years, N = 8). Older subjects in both groups had lower N-acetylaspartate levels than the respective younger subjects, although this old-young difference was not greater in the Down's syndrome group. CONCLUSIONS: The approximately 50% higher level of myo-inositol in Down's syndrome suggests a gene dose effect of the extra chromosome 21, where the human osmoregulatory sodium/myo-inositol cotransporter gene is located. The even higher myoinositol level in older adults with Down's syndrome extends to the predementia phase earlier findings of high myoinositol levels in symptomatic Alzheimer's disease.

Increasing required neural response to expose abnormal brain function in mild versus moderate or severe Alzheimer's disease: PET study using parametric visual stimulation.

OBJECTIVE: The authors examined the interaction of Alzheimer's disease severity and visual stimulus complexity in relation to regional brain function. METHOD: Each subject had five positron emission tomography [15]H2O scans while wearing goggles containing a grid of red lights embedded into each lens. Regional cerebral blood flow (CBF) was measured at 0 Hz and while lights were flashed alternately into the two eyes at 1, 4, 7, and 14 Hz. Changes in regional CBF from the 0-Hz baseline were measured at each frequency in 19 healthy subjects (mean age = 65 years, SD = 11), 10 patients with mild Alzheimer's disease (mean age = 69, SD = 5; Mini-Mental State score > or = 20), and 11 patients with moderate to severe Alzheimer's disease (mean age = 73, SD = 12; Mini-Mental State score < or = 19). RESULTS: As pattern-flash frequency increased, CBF responses in the comparison group included biphasic rising then falling in the striate cortex, linear increase in visual association areas, linear decrease in many anterior areas, and a peak at 1 Hz in V5/MT. Despite equivalent resting CBF and CBF responses to low frequencies among all groups, the groups with Alzheimer's disease had significantly smaller CBF responses than the comparison group at the frequency producing the largest response in the comparison group in many brain regions. Also, patients with moderate/severe dementia had smaller responses at frequencies producing intermediate responses in comparison subjects. CONCLUSIONS: Functional failure was demonstrated in patients with mild dementia when large neural responses were required and in patients with moderate/severe dementia when large and intermediate responses were required.

Brain metabolite concentration and dementia severity in Alzheimer's disease: a (1)H MRS study.

OBJECTIVE: (1)H-MRS studies have shown abnormalities in brain levels of myo-inositol (mI) and N-acetyl aspartate (NAA) in AD, but the relation of these abnormalities with dementia severity was not examined. The authors sought to determine whether altered brain levels of mI and other metabolites occur in mild AD and whether they change as dementia severity worsens. METHODS: The authors used (1)H-MRS with external standards to measure absolute brain concentrations of mI, NAA, total creatine (Cr), and choline (Cho)-containing compounds in 21 subjects with AD and 17 age- and sex-matched controls in occipital and left and right parietal regions. RESULTS: Concentrations of NAA were significantly decreased, whereas mI and Cr concentrations were significantly increased in all three brain regions in subjects with AD compared with controls. Higher concentrations of mI and Cr occurred even in mild AD. A discriminant analysis of the (1)H-MRS data combined with CSF volume measurements distinguished subjects with AD, ranging from mild to severe dementia, from controls with 100% correct classification. NAA concentration, though not other metabolites, was positively correlated with Mini-Mental State Examination score. CONCLUSION: The measurements with (1)H-MRS of absolute metabolite concentrations in the neocortex showed abnormal concentrations of brain metabolites in AD; these metabolite concentrations do not necessarily correlate with disease severity. Although changes in myo-inositol and creatine occur in the early stages of AD, abnormalities of N-acetyl aspartate do not occur in mild AD but progressively change with dementia severity. Further, subjects with mild AD can be differentiated from controls with (1)H-MRS.

Muscarinic versus nicotinic modulation of a visual task. a pet study using drug probes.

Little is known about acetylcholine (ACh) modulation of central visual processing in humans. Receptor densities in visual brain regions are differentially distributed suggesting that receptor subtypes have different functions. Using PET, we have previously described the brain regions activated by a simple pattern-flash stimulus in healthy elderly subjects. To evaluate muscarinic and nicotinic contributions to ACh modulation of visual processing, we scanned elderly subjects watching the pattern-flash stimulus during no drug, during physostigmine augmentation, and during scopolamine antagonism of physostigmine's action. These manipulations of ACh significantly altered regional cerebral blood flow (rCBF) in brain regions activated by the task. The pattern of rCBF values across drug conditions suggested that muscarinic and nicotinic effects were dissociated. Muscarinic action predominated in striate cortex (Brodmann Area, BA 17) and lateral visual association areas (BA 18, 19), while nicotinic action predominated in the thalamus and inferior parietal regions (BA 39/40). Both muscarinic and nicotinic actions increased rCBF in some regions while decreasing it in others. A parsimonious reconciliation of these results with functional anatomy suggests that muscarinic action modulates visual attribute processing, while nicotinic action modulates arousal and selective attention to the visual task.

Cortical regions involved in visual texture perception: a fMRI study.

To determine visual areas of the human brain involved in elementary form processing, functional magnetic resonance imaging (fMRI) was used to measure regional responses to two types of achromatic textures. Healthy young adults were presented with 'random' textures which lacked spatial organization of the black and white pixels that make up the image, and 'correlated' textures in which the pixels were ordered to produce extended contours and rectangular blocks at multiple spatial scales. Relative to a fixation condition, random texture stimulation resulted in increased signal intensity primarily in the striate cortex, with slight involvement of the cuneus and middle occipital, lingual and fusiform gyri. Correlated texture stimulation also resulted in activation of these areas, yet the regional extent of this activation was significantly greater than that produced by random textures. Unlike random stimulation, correlated stimulation additionally resulted in middle temporal activation. Direct comparison of the two stimulation conditions revealed significant differences most consistently in the anterior fusiform gyrus, but also in striate, middle occipital, lingual and posterior temporal regions in subjects with robust activation patterns. While both random and correlated stimulation produced activation in similar areas of the occipital lobe, the increase in regional activation during the correlated condition suggests increased recruitment of neuronal populations occurs in response to textures containing visually salient features. This increased recruitment occurs within striate, extrastriate and temporal regions of the brain, also suggesting the presence of receptive field mechanisms in the ventral visual pathway that are sensitive to features produced by higher-order spatial correlations.

Attention-related modulation of activity in primary and secondary auditory cortex.

We investigated the effects of auditory attention on brain activity using functional magnetic resonance imaging. Subjects listened to three word lists, three times each, and were instructed to count the number of times they heard a target word during two of these presentations. For the third, they listened to the words without counting. All subjects showed significant areas of activation in auditory cortex during the listening conditions compared to rest. There was significantly more activation and a larger area of activation, particularly in association cortex, in the left temporal lobe during counting of targets compared to the no-target conditions, with a similar trend in the right hemisphere. These results provide evidence of an attention-related enhancement of both activation magnitude and extent in auditory cortex.

Structural and functional neuroimaging findings in substance-related disorders.

Intoxication with alcohol results in depressed global glucose metabolism that continues into the stages of withdrawal and abstinence. The decrease in metabolism, however, is not equal across the brain, with certain regions more affected than others. Such a pattern of disturbance suggests that the effect of alcohol on the brain cannot simply be a nonspecific depressant effect secondary to decreased blood flow or glucose transport into the cells but may be related to the dysfunction of the various neurotransmitter systems. Different authors have suggested the dysfunction to be related to the GABAergic, cholinergic, and dopaminergic systems. Long-term alcoholism is associated with atrophy of several brain regions. The frontal lobes and limbic structures seem to be most vulnerable. The data are encouraging with regard to the normalization in brain metabolism and in size of vulnerable brain regions with continued abstinence. In addition to findings of improvement in cognitive functioning and many health parameters, these findings arm clinicians with further data on the benefits of abstinence in the struggle to aid patients in maintaining their sobriety. Several areas remain to be addressed. In particular, clinicians are in need of data, neuroimaging and otherwise, that serve as prognostic indicators, thus allowing patients at higher risk for relapse to be identified and provided with more intensive treatment. A similar need exists for indicators of diagnostic heterogeneity that would guide the development of more highly tailored treatment regimens for identified subgroups of patients. Currently, we have rudimentary knowledge of the gender differences of the effects of alcohol and cocaine on the brain.

Neuropsychiatric sequelae of ischaemic cerebrovascular disease: clinical and neuroanatomic correlates and implications for the concept of dementia.

Neuropsychiatric disturbances along the continuum of cognitive disturbances in ischaemic cerebrovascular disease are reviewed and their neuroanatomic correspondences are explored. Depression, apathy, disinhibition, and delusions are common in ischaemic, cerebrovascular disease. Delirium, hallucinations, confabulations, akinesia, pathological affect, anxiety, and catastrophic reaction are less common, while manic syndromes appear rarely. Many of these neuropsychiatric syndromes remain poorly delineated. The presence of neuropsychiatric disturbance may not be correlated with the degree of cognitive disturbance. The implications of this finding for the concept of dementia are explored. The authors conclude that neuropsychiatric disturbances should be considered essential features of dementia.

Frequency variation of a pattern-flash visual stimulus during PET differentially activates brain from striate through frontal cortex.

We evaluate regional cerebral blood flow (rCBF) in 19 healthy elderly subjects, mean age 64 +/- 11 (SD, years), during a passive visual stimulus in which pattern-flash frequency was parametrically manipulated. Using goggles with a grid of red lights imbedded into each lens, we performed five positron emission tomography (PET) H2(15)O water scans on each subject at alternating (left to right eye) flash frequencies of 0, 1, 4, 7, and 14 Hz. We found a biphasic rising and falling rCBF response in the striate cortex (7 Hz peak) and left anterior cingulate (4 Hz peak), 1 Hz activation in left middle temporal gyrus (V5), monotonically increasing rCBF in posterior areas (lateral and inferior visual association areas, Brodmann 18 and 19), and monotonically decreasing rCBF in anterior areas (frontal, cingulate, and superior temporal) predominantly in right hemisphere. We suggest the striate rCBF changes at all frequencies primarily reflect lateral geniculate input, the middle temporal activation at 1 Hz reflects perception of apparent motion, and the posterior extrastriate rCBF monotonic increase represents a neural response to increasing luminance intensity and form and color complexity that occur as pattern-flash frequency increases. The anterior monotonic rCBF decrease may represent active cross-modal functional suppression of brain areas irrelevant for processing the passive visual stimulus. Pattern-flash rCBF responses were highly reproducible (no series effect), more so in posterior than in anterior brain regions. The reproducibility and systematically changing rCBF responses to this passive stimulus suggest that it could be successfully used as a disease probe to evaluate neural function and drug effects in cognitively impaired patients.

Interactive effects of age and hypertension on volumes of brain structures.

BACKGROUND AND PURPOSE: Advanced age and hypertension have each been associated with changes in brain morphology and cognitive function. To investigate the interaction of age and hypertension with structural brain changes and neuropsychological performance in otherwise healthy patients with essential hypertension, we compared young-old (ages 56 to 69 years) and old-old (ages 70 to 84 years) hypertensive patients (n = 27) with 20 age-matched normotensive healthy control subjects, using quantitative volumetric MRI and a battery of neuropsychological tests. METHODS: Quantitative regions of interest and segmentation analyses were applied to MRI scans of brain to measure volumes of different brain structures and of cerebrospinal fluid (CSF). Severity of white matter hyperintensities (WMHs) was qualitatively rated in the MRI scans. A battery of neuropsychological tests was administered to each subject. RESULTS: The combined hypertensive group (young-old and old-old) had smaller volumes of thalamic nuclei and larger volumes of CSF in the cerebellum and temporal lobes and showed poorer performance in memory and language tests than did the control subjects. Main effects for age were significant in multiple brain regions of interest. The old-old hypertensive patients and age-matched control subjects demonstrated volume reductions in brain structures and increases in ventricular and peripheral CSF volumes compared with the younger subjects. There was a significant group x age-group interaction in temporal and occipital CSF, not related to WMH, with the old-old hypertensive patients having significantly larger CSF volumes in these regions than the young-old hypertensives and both healthy control groups. CONCLUSIONS: Hypertension exacerbates the morphological changes accompanying advanced age. Temporal and occipital regions appear most vulnerable to brain atrophy due to the interactive effects of age and hypertension.

Striate cortex in humans demonstrates the relationship between activation and variations in visual form.

Electrophysiologic and functional imaging studies have shown that the visual cortex produces differential responses to the presence or absence of structure within visual textures. To further define and characterize regions involved in the analysis of form, functional magnetic resonance imaging (fMRI) was used to detect changes in activation during the viewing of four levels of isodipole textures. The texture levels systematically differed in the density of visual features such as extended contours and blocks of solid color present within the images. A linear relationship between activation level and density of structure was observed in the striate cortex of human subjects. This finding suggests that a special subpopulation of striate cortical neurons participates in the ability to extract and process structural continuity within visual stimuli.