Greater abnormalities of brain cerebrospinal fluid volumes in younger than in older patients with Alzheimer's disease

OBJECTIVE: This study used a semiautomated analysis technique to quantify differences in regional brain cerebrospinal fluid volumes observed with computed tomography between healthy adults and patients with Alzheimer's disease (AD). DESIGN: Cross-sectional, between-subject design, using an age-regression model. SETTING: Palo Alto (Calif) Department of Veterans Affairs Medical Center. PATIENTS AND OTHER PARTICIPANTS: The 117 patients with probable or definite AD were recruited from the Geriatric Psychiatry Research Unit and National Institute of Mental Health Clinical Research Center of the Palo Alto Department of Veterans Affairs Medical Center. The 114 healthy volunteers were recruited from the local community. MAIN OUTCOME MEASURES: Cerebrospinal fluid volumes estimated from computed tomographic scans and neuropsychological test scores. RESULTS: The computed tomographic estimates of ventricular and sulcal cerebrospinal fluid volumes increased significantly in all sampled brain regions in normal aging and were vastly larger in AD than in normal aging. Furthermore, younger patients with AD had significantly greater cerebrospinal fluid volume enlargement than did older patients with AD compared with healthy controls of their age. When the AD group was divided on the basis of reported age at symptom onset, patients in the early-onset group (onset before age 65 years) were quantitatively more abnormal than and showed a different pattern of abnormality from the patients in the late-onset group. This onset difference was also evident in neuropsychological test performance. CONCLUSIONS: This cross-sectional study revealed a number of converging findings that suggested greater abnormality in the early-onset than in the late-onset group of patients with AD. The possibility remains, however, that the two onset groups represent different stages along a continuum of pathologic changes.     

Structural brain correlates of verbal and nonverbal fluency measures in Alzheimer's disease.

This study examined the relationships between regional brain volumes and semantic, phonological, and nonverbal fluency in 32 participants with Alzheimer's disease (AD). Object but not animal semantic fluency correlated with frontal and temporal gray matter volumes. Phonological fluency was not significantly associated with any brain volume examined. Nonverbal fluency was selectively associated with bilateral frontal gray matter volumes. Hippocampal volumes, although markedly reduced in these patients, were not related to any of the fluency measures. Results lend evidence to the importance of the frontal lobes in the directed generation of nonverbal and verbal exemplars by AD patients. Furthermore, both left and right-hemisphere regions contribute to the generation of verbal and nonverbal exemplars. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Longitudinal MRI and cognitive change in healthy elderly.

Cross-sectional studies of normal aging indicate an association between memory and hippocampal volume, and between executive functioning and subcortical-frontal circuits. Much less is known, however, about the relationship between longitudinal MRI changes and cognitive decline. The authors hypothesized that longitudinal change in memory would be best predicted by change in hippocampal volumes, whereas change in executive functioning would be best predicted by cortical atrophy and progression of MRI markers of cerebrovascular disease. For this study, 50 healthy elderly subjects underwent structural MRI and cognitive testing at baseline and again at follow-up, with a mean follow-up interval of 45 months. Volumetric MRI measures were hippocampus, cortical gray matter, white matter signal hyperintensity (WMSH), and lacunae. Neuropsychological measures were psychometrically robust composite scores of episodic memory (MEM) and executive functioning (EXEC). Hierarchical multiple regression indicated that a decrease in hippocampus was associated with a decline in MEM, whereas decreased cortical gray matter and increased WMSH were independently associated with a decline in EXEC. Results suggest that in normal aging, cognitive functioning declines as cortical gray matter and hippocampus decrease, and WMSH increases. The association between WMSH and EXEC further highlights the cognitive sequealae associated with cerebrovascular disease in normal elderly. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lack of an association between delayed memory and hippocampal and temporal lobe size in patients with schizophrenia and healthy controls

The purpose of the present study was to investigate putative neural substrates of long-term (delayed) memory in schizophrenia and young healthy controls. Ten "low" and 10 "high" memory patients were selected from a large sample of DSM-III-R diagnosed schizophrenia spectrum patients, based on composite verbal and nonverbal delayed recall memory scores. Ten "low" and 9 "high" memory individuals were also selected from a larger sample of young healthy controls. Magnetic resonance imaging scans were acquired on a 1.5-T GE Signa scanner using a SPGR sequence (repetition time = 24 msec, echo time = 5 msec). Hippocampal volumes were computed from manual tracings (intraclass correlation = .96), and temporal lobe and whole brain tissue volumes were obtained using a semiautomated technique. In both the patient sample and controls, there was no significant relationship between delayed memory ability and hippocampal, temporal lobe, or whole brain volume. The integration of results from this study, and from studies on normal aging and Alzheimer's disease, supports a model suggesting that hippocampal size may be an indicator of long-term memory ability, but only when hippocampal measures reflect aging and degenerative hippocampal atrophy. If the hippocampal measures reflect individual differences in hippocampal size prior to the onset of hippocampal atrophy, then hippocampal size does not appear to predict long-term memory ability.     

Differential Associations Between Entorhinal and Hippocampal Volumes and Memory Performance in Older Adults.

Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r=.79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r=.57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cortical and hippocampal volume deficits in temporal lobe epilepsy

PURPOSE: To use quantitative magnetic resonance imaging (MRI) methods to examine the extent of volume abnormalities in the hippocampus and in extrahippocampal brain regions in localization-related epilepsy of temporal lobe origin (TLE). METHODS: Hippocampal, temporal lobe, and extratemporal lobe volumes were examined with 3-mm spin-echo coronal MRI scans in patients with unilateral TLE who were candidates for temporal lobe resection. Measures were adjusted for normal variation due to intracranial volume and age based on 72 healthy male controls. Group differences between 14 male TLE [7 left TLE (LTLE), 7 right TLE (RTLE)] patients and a subset of 49 age range-matched controls were examined with analysis of variance (ANOVA). RESULTS: As compared with controls, patients with TLE had smaller temporal lobe and frontoparietal region gray matter volumes, bilaterally, smaller temporal lobe white matter volumes bilaterally, and larger ventricular volumes. In contrast to these bilateral tissue volume deficits, hippocampal volume deficits in TLE were ipsilateral to the epileptogenic temporal lobe. CONCLUSIONS: Extrahippocampal volume abnormalities were bilateral and occurred in both temporal and extra-temporal cortical regions in TLE, whereas hippocampal deficits were related to the side of the epileptogenic focus. These data suggest that brain abnormalities in TLE are not limited to the epileptogenic region.     

Neuroanatomical and cognitive mediators of age-related differences in episodic memory.

Aging is associated with declines in episodic memory. In this study, the authors used a path analysis framework to explore the mediating role of differences in brain structure, executive functions, and processing speed in age-related differences in episodic memory. Measures of regional brain volume (prefrontal gray and white matter, caudate, hippocampus, visual cortex), executive functions (working memory, inhibitory control, task switching, temporal processing), processing speed, and episodic memory were obtained in a sample of young and older adults. As expected, age was linked to reduction in regional brain volumes and cognitive performance. Moreover, neural and cognitive factors completely mediated age differences in episodic memory. Whereas hippocampal shrinkage directly affected episodic memory, prefrontal volumetric reductions influenced episodic memory via limitations in working memory and inhibitory control. Age-related slowing predicted reduced efficiency in temporal processing, working memory, and inhibitory control. Lastly, poorer temporal processing directly affected episodic memory. No direct effects of age on episodic memory remained once these factors were taken into account. These analyses highlight the value of a multivariate approach with the understanding of complex relationships in cognitive and brain aging. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dysfunctional uterine bleeding

Alzheimer's disease (AD) is characterized by progressive dementia and distinct neuropathology at autopsy. In order to test the relationship between dementia severity and loss of brain volumes, we prospectively documented the neurological/medical health of 26 male and 26 female controls and AD cases, and evaluated a subset of controls and AD cases using the Mini Mental State Examination (MMSE). At autopsy, Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria confirmed diagnoses in 33 AD cases and 19 controls, and using unbiased stereology we quantified total volumes of cortical gray matter, subcortical grey matter including white matter, and forebrain. For ages of death between 50 to 100 years, controls showed minor cortical atrophy in the absence of cognitive decline. Cortical atrophy in AD cases was 20 to 25% greater than that in controls; AD patients dying at older ages showed less severe cortical atrophy than those dying at younger ages. Across all AD cases there was a strong correlation between cognitive performance on the Mini Mental State Examination and cortical volume loss. These findings confirm fundamental differences in the temporal patterns of cortical volume loss in aging and AD, and support cortical degeneration as the primary basis for cognitive decline in AD.     

Deficits in gray matter volume are present in schizophrenia but not bipolar disorder

Studies using magnetic resonance (MR) imaging have provided strong evidence that patients with schizophrenia as a group have structural brain abnormalities, including enlarged ventricles and sulci as well as smaller cortical gray matter volumes. This study was undertaken to investigate whether the brain abnormalities found in schizophrenia could be distinguished from those seen in bipolar disorder. The MR scans of 23 patients with schizophrenia were compared to those of 17 healthy community volunteers and 14 patients with bipolar disorder. Images were processed using computer-based image processing techniques to generate quantitative measures of cerebrospinal fluid (CSF), gray matter and white matter volumes. Compared to the community volunteers, the schizophrenia group had larger total CSF volumes while the bipolar group had larger ventricles. Smaller cortical gray matter volumes were found in the schizophrenia group, but not in the bipolar group. The schizophrenia group had regional deficits in gray matter volumes in comparison with both the community volunteers and the bipolar group. These findings suggest that the brain tissue abnormalities found in schizophrenia and bipolar disorder may be distinguishable using MR imaging.     

Hippocampal volume is associated with memory but not monmemory cognitive performance in patients with mild cognitive impairment

Mild cognitive impairment (MCI) appears to be a transitional stage in the development of Alzheimer's disease (AD). Patients with MCI show impaired memory performance and hippocampal atrophy relative to normal elderly controls. Prior studies indicate that the degree of hippocampal atrophy in MCI patients predicts conversion to AD. In contrast to patients with MCI who have deficits primarily in memory, AD patients have clinically evident impairments in both memory and nonmemory cognitive domains. One explanation for the observation that a smaller hippocampal volume predicts conversion to AD might be that hippocampal atrophy is associated with early impairment in nonmemory cognitive areas as well as memory. A link between hippocampal volume and nonmemory function could occur if hippocampal atrophy was correlated with AD pathology in other brain regions. We therefore sought to determine the relationship of hippocampal volume with performance on memory and nonmemory tasks in patients with MCI. Although we found a significant correlation between hippocampal volume and memory performance, we did not find a significant correlation between hippocampal volume and nonmemory performance. We conclude that the relationship between hippocampal volume and risk of AD is likely tied to reduced memory performance and not associated with impairment in nonmemory cognitive domains.     

Introduction of a normal retinoblastoma (Rb) gene into Rb-deficient lymphoblastoid cells delays tumorigenicity in immunodefective mice

BACKGROUND: We report on structural brain changes during a 5-year period in healthy control and alcoholic men. METHODS: Alcoholic patients (n = 16), from an initial group of 58 who underwent brain magnetic resonance imaging scanning while in treatment, were rescanned with the same acquisition sequence approximately 5 years later. Control subjects (n = 28) spanning the same age range also were scanned twice at a comparable interval. Changes in brain volume were corrected for error due to differences in head placement between scans and expressed as slopes (cubic centimeters per year), percentage of change over baseline for the control subjects, and standardized change for the alcoholic patients. The alcoholic patients varied considerably in the percentage of time that symptoms of alcohol dependence were present and in the amount of alcohol consumed during follow-up. RESULTS: The cortical gray matter diminished in volume over time in the control subjects, most prominently in the prefrontal cortex, while the lateral and third ventricles enlarged. The alcoholic patients showed similar age-related changes with a greater rate of gray matter volume loss than the control subjects in the anterior superior temporal lobe. The amount of alcohol consumed during follow-up predicted the rate of cortical gray matter volume loss, as well as sulcal expansion. The rate of ventricular enlargement in alcoholic patients who maintained virtual sobriety was comparable to that in the control subjects. CONCLUSIONS: During a 5-year period, brain volume shrinkage is exaggerated in the prefrontal cortex in normal aging with additional loss in the anterior superior temporal cortex in alcoholism. The association of cortical gray matter volume reduction with alcohol consumption over time suggests that continued alcohol abuse results in progressive brain tissue volume shrinkage.     

Neuroanatomical and cognitive mediators of age-related differences in perceptual priming and learning.

Our objectives were to assess age differences in perceptual repetition priming and perceptual skill learning and to determine whether they are mediated by cognitive resources and regional cerebral volume differences. Fragmented picture identification paradigm allows the study of both priming and learning within the same task. The authors presented this task to 169 adults (ages 18–80), assessed working memory and fluid intelligence, and measured brain volumes of regions that were deemed relevant to those cognitive skills. The data were analyzed within a hierarchical path modeling framework. In addition to finding age-related decrease in both perceptual priming and learning, the authors observed several dissociations with regards to their neural and cognitive mediators. Larger visual cortex volume was associated with greater repetition priming, but not perceptual skill learning, and neither process depended upon hippocampal volume. In contrast, the volumes of the prefrontal gray and white matter were differentially related to both processes via direct and indirect effects of cognitive resources. The results indicate that age-related differences in perceptual priming and skill learning have dissociable cognitive and neural correlates. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Regional cerebral volume loss associated with verbal learning and memory in dementia of the Alzheimer type.

Twenty-seven research participants with dementia of the Alzheimer type were studied with the California Verbal Learning Test (D. C. Delis, J. H. Kramer, E. Kaplan, & B. A. Ober, 1987) and standardized volume measures of the mesial temporal cortical gray matter, neocortical gray matter, thalamus, and caudate nuclei, from magnetic resonance imaging. A pattern of atrophic brain changes in the mesial temporal lobes (MTL) and the thalamus, with relatively less severe atrophy in the neocortical gray matter, was associated with poorer learning of the word list. Similar patterns of brain atrophy were observed for measures of delayed recall and recognition hits. However, for delayed recall, neither contribution was statistically significant, and for recognition hits, MTL was only at the trend level for significance. These results provide evidence that the verbal memory deficit of Alzheimer's disease (AD) is associated not only with the mesial temporal limbic cortex, thought to be the site of earliest and most severe pathology in AD, but also with damage in the thalamus. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Association of memory and cognition in Alzheimer's disease with volumetric estimates of temporal lobe structures.

The hypothesis that explicit memory impairment in Alzheimer's disease (AD) depends in part on hippocampal formation atrophy was tested in 47 persons with AD. Volumes of the hippocampal formation, parahippocampal gyrus, and temporal neocortex (excluding the hippocampal formation, amygdala, and parahippocampal gyrus) were estimated by reconstruction of magnetic resonance images. Tests of explicit memory, language, and constructional praxis were administered. Psychometric-volumetric associations were evaluated in regression analyses controlling for age, gender, education, and intracranial volume. Hippocampal formation volume was associated with a delayed-recall measure but not with immediate recall: temporal neocortical volume was correlated with performance on measures of language and constructional praxis. The results suggest that patterns of mnemonic and cognitive impairment in AD are due in part to differences in the distribution of pathology in the temporal lobe. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Volumetric MRI measurements in bipolars compared with schizophrenics and healthy controls

Twenty-six patients with RDC bipolar disorder were compared with a previously reported group of 48 RDC schizophrenics and 34 healthy controls, using volumetric MRI measurements of cerebral, cortical and sulcal volumes. The bipolar group appeared no different from the controls, and both of these groups had significantly larger cerebral and cortical volumes than the schizophrenics. Our previous report of a significantly reduced cortical volume in the schizophrenic group, with a corresponding increase in the volume of sulcal fluid is, therefore, not a generalized feature of psychotic illness but may be more specific to schizophrenia.     

Exploratory factor analysis of MRI brain structure measures in schizophrenia

Much of the literature shows various regional structural brain abnormalities in schizophrenia, but the complexity and variability of brain makes it difficult to determine how these regions are related. Statistical methods which estimate factors underlying patterns of covariance have not been widely used, but could be useful for analyzing such complex data. We applied exploratory and confirmatory factor analysis procedures to specific cortical and subcortical regional brain volume measures from MRI data in 60 normal and 44 schizophrenic subjects. Basal ganglia, heteromodal cortical gray, and medial temporal lobe factors were present in both the normal and the schizophrenia groups. The factor structure observed in the normal group showed a high degree of bilateral symmetry which is present but disrupted in the schizophrenia group. In the bilateral data, the disruption is most pronounced with medial and lateral temporal lobe structures including entorhinal cortex and anterior and posterior superior temporal gyri. There was a significant correlation between the basal ganglia factor and the heteromodal cortical gray factor in the normal group that was not present in the schizophrenia group. In the unilateral data, left posterior superior temporal gyrus did not load onto any factor in the schizophrenia group. Confirmatory factor analyses showed significant differences between the two groups in factor structure. A number of specific brain regions are affected in schizophrenia, and structural relationships between groups of regions also are abnormal. The results suggest that heteromodal dorsolateral prefrontal and superior temporal cortical gray regions are structurally related, whereas inferior parietal cortical gray is less so. These results should be viewed as preliminary as the ratio of parameters to subjects was relatively low, and replication is needed. However, the results demonstrate the potential utility of latent structure methods such as factor analysis in study of complex relationships in neuropsychiatric data.     

MRI correlates of cognitive impairment in childhood-onset multiple sclerosis.

Objective: Brain MRI measures were correlated with neuropsychological function in 35 pediatric-onset multiple sclerosis (MS) patients and 33 age- and sex-matched healthy controls. Method: Mean age of MS patients was 16.3 ± 2.3 years with average disease duration of 4.3 ± 3.1 years. Cortical gray matter, thalamic, and global brain volumes were calculated for all participants using a scaling factor computed using normalization of atrophy method to normalize total and regional brain volumes for head size. T1- and T2-weighted lesion volumes were calculated for MS patients. Results: Cognitive impairment (CI) was identified in 29% of the MS cohort. Cognitive deficits predominantly involved attention and processing speed, expressive language, and visuomotor integration. Relative to controls, the MS group showed significantly lower thalamic volume (p p p p     

A cross-sectional study of hormone treatment and hippocampal volume in postmenopausal women: Evidence for a limited window of opportunity.

The influence of hormone treatment on brain and cognition in postmenopausal women has been a controversial topic. Contradictory patterns of results have prompted speculation that a critical period, or limited window of opportunity, exists for hormone treatment to protect against neurocognitive. In this cross-sectional study of 102 postmenopausal women, we examined whether hippocampal, amygdala, or caudate nucleus volumes and spatial memory performance were related to the interval between menopause and the initiation of hormone treatment. Consistent with a critical period hypothesis, we found that shorter intervals between menopause and the initiation of hormone treatment were associated with larger hippocampal volumes compared with longer intervals between menopause and treatment initiation. Initiation of hormone treatment at the time of menopause was also associated with larger hippocampal volumes when compared with peers who had never used hormone treatment. Furthermore, these effects were independent from potentially confounding factors such as age, years of education, the duration of hormone treatment, current or past use of hormone therapy, the type of therapy, and age at menopause. Larger hippocampal volumes in women who initiated hormone treatment at the time of menopause failed to translate to improved spatial memory performance. There was no relationship between timing of hormone initiation, spatial memory performance, and amygdala or caudate nucleus volume. Our results provide support for a limited window of opportunity for hormone treatment to influence hippocampal volume, yet the degree to which these effects translate to improved memory performance is uncertain. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cortical gray matter atrophy in healthy aging cannot be explained by undetected incipient cognitive disorders: A comment on Burgmans et al. (2009).

Burgmans, van Boxtel, Vuurman, et al. (2009) published an interesting study titled “The Prevalence of Cortical Gray Matter Atrophy May Be Overestimated in the Healthy Aging Brain” on how subclinical cognitive disorders may affect correlations between age and cortical volume. Correlations between cortical gray matter volume and age were found in 30 elderly with cognitive decline after 6 years, but not in 28 elderly without cognitive decline. This study is important, and demonstrates that preclinical cognitive disorders may affect cortical brain volumes before being detectable by neuropsychological tests. However, we are not convinced by the conclusions: “… gray matter atrophy… is to a lesser extent associated with the healthy aging process, but more likely with brain processes underlying significant cognitive decline” (p. 547) and “… cortical gray matter atrophy in the aging brain may be overestimated in a large number of studies on healthy aging” (p. 547). We analyzed the cross-sectional MR data (n = 1,037) as well as longitudinal data from a sample of very well-screened elderly followed by cognitive testing for 2 years. In the cross-sectional data, the correlations between age and brain volumes were generally not much reduced when the upper age limit was lowered. This would not be expected if age-related incipient cognitive disorders caused the correlations given that the incidence of cognitive decline increased with age. Longitudinally, 1-year atrophy was identified in all tested regions. It is likely that cortical brain atrophy is manifested in cognitively normal elderly without subclinical cognitive disorders. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Use and misuse of syringes in anaesthesia

OBJECTIVE: To assess whether the cerebral gray and white matter volume deficits described in patients with anorexia nervosa (AN) are fully reversible with weight rehabilitation. DESIGN: A prospective cohort study using magnetic resonance imaging to examine the brains of female adolescents after weight recovery from AN. SETTING: An adolescent eating disorder program located in a tertiary care children's hospital. PARTICIPANTS: Of 13 patients who underwent a previous magnetic resonance imaging study at a low weight, 6 patients were weight recovered and underwent rescanning. All brain measures were corrected for the effects of intracranial volume and age, based on a regression analysis of a group of 34 healthy female control subjects. Scans from the patients with AN were also compared with scans from an age-matched subset of 16 healthy female controls. MAIN OUTCOME MEASURES: White matter volumes, gray matter volumes, and cerebrospinal fluid volumes in the weight-recovered AN group. RESULTS: Quantitative analysis showed that white matter and ventricular cerebrospinal fluid volumes changed significantly (P = .03 for both) on weight recovery from AN. The weight-recovered patients had significant gray matter volume deficits (P = .01) and elevated cerebrospinal fluid volumes (P = .005) compared with those of the age-matched controls. They no longer had significant (P = .30) white matter volume deficits. CONCLUSION: The finding of persistent gray matter volume deficits in patients who have recovered their weight after AN suggests an irreversible component to the structural brain changes associated with AN, in addition to a component that resolves on weight recovery.