Frontal-hippocampal double dissociation between normal aging and Alzheimer's disease

Controversy persists regarding whether Alzheimer's disease (AD) is a distinct entity or instead exists on a continuum with nondemented aging. To explore this issue, volumetric analyses of callosal and hippocampal regions were performed on 150 participants aged 18-93 years. Group-level analyses revealed that nondemented age-related differences were greater in anterior than posterior callosal regions and were not augmented by early-stage AD. In contrast, early-stage AD was associated with substantial reduction in hippocampal volume. Examination of the 100 older adults using regression analyses demonstrated age-associated differences in callosal volume that were similar in demented and nondemented individuals. Early-stage AD was again characterized by a marked reduction in hippocampal volume while age alone induced only mild differences in hippocampal volume. As a final analysis, the formal double dissociation was confirmed by comparing the effects of age directly against the effects of dementia. These results suggest a multiple-component model of aging. One process, associated with AD, manifests early and prominently in the medial temporal lobe. A separate process, ubiquitous in aging, affects brain white matter with an anterior-to-posterior gradient and may underlie the executive difficulties common in aging.     

Cortical change in Alzheimer's disease detected with a disease-specific population-based brain atlas

We report the first detailed population-based maps of cortical gray matter loss in Alzheimer's disease (AD), revealing prominent features of early structural change. New computational approaches were used to: (i) distinguish variations in gray matter distribution from variations in gyral patterns; (ii) encode these variations in a brain atlas (n = 46); (iii) create detailed maps localizing gray matter differences across groups. High resolution 3D magnetic resonance imaging (MRI) volumes were acquired from 26 subjects with mild to moderate AD (age 75.8+/-1.7 years, MMSE score 20.0+/-0.9) and 20 normal elderly controls (72.4+/-1.3 years) matched for age, sex, handedness and educational level. Image data were aligned into a standardized coordinate space specifically developed for an elderly population. Eighty-four anatomical models per brain, based on parametric surface meshes, were created for all 46 subjects. Structures modeled included: cortical surfaces, all major superficial and deep cortical sulci, callosal and hippocampal surfaces, 14 ventricular regions and 36 gyral boundaries. An elastic warping approach, driven by anatomical features, was then used to measure gyral pattern variations. Measures of gray matter distribution were made in corresponding regions of cortex across all 46 subjects. Statistical variations in cortical patterning, asymmetry, gray matter distribution and average gray matter loss were then encoded locally across the cortex. Maps of group differences were generated. Average maps revealed complex profiles of gray matter loss in disease. Greatest deficits (20-30% loss, P<0.001-0.0001) were mapped in the temporo-parietal cortices. The sensorimotor and occipital cortices were comparatively spared (0-5% loss, P>0.05). Gray matter loss was greater in the left hemisphere, with different patterns in the heteromodal and idiotypic cortex. Gyral pattern variability also differed in cortical regions appearing at different embryonic phases. 3D mapping revealed profiles of structural deficits consistent with the cognitive, metabolic and histological changes in early AD. These deficits can therefore be (i) charted in a living population and (ii) compared across individuals and groups, facilitating longitudinal, genetic and interventional studies of dementia.     

Cortical bone remodeling in normal rat

Summary Cortical bone remodeling along the femur diaphysis was determined in normal female rats (Sprague-Dawley) with the tetracycline technique.Three segments on the cortical bone circumference (the anterolateral, the medial, and the posterior) were found to be most suitable for the study of the remodeling process. Oxytetracycline was administered at age 60 and 75 days, and groups of animals were killed at age 75, 85, 95, and 105 days.The accumulated endosteal growth during age 60 to 75 days in the anterolateral segment was found to increase uniformly in the distal direction along the femur diaphysis. A method is described where this accumulated endosteal growth is used. This method eliminates the use of calipers to determine the section level and makes it possible to study comparable sections even after varying periods of time.The proximal part of the diaphysis showed periosteal apposition in all three segments. The periosteal apposition turned into resorption in the distal part of the diaphysis in the anterolateral and medial segments, whereas the periosteal appsition increased in the posterior segment.The endosteal growth increased in the distal direction in the anterolateral and medial segments. Irregular OTC bands made measurements of endosteal remodeling in the posterior segment impossible.The cortical width decreased in the distal direction along the femoral shaft. Comparison between the different age groups is described and also the relation between the accumulated endosteal growth and the diameter of the medullary cavity.     

Alzheimer's disease

The changes which Alzheimer associated with this disease are still a major focus of interest in pathological studies, but their relative importance and association to symptoms is still not clear. The diagnosis of early Alzheimer's disease (AD) is a very difficult clinical problem since there is no pathognomic test. It can be particularly difficult to differentiate the condition from depressive illness. Despite doubts about the significance and specificity of the cholinergic deficit in AD, attempts at therapy with cholinergic drugs have been made. Physostigmine has produced some small improvements, but it is not yet known whether the drug is clinically useful or not. Its utility may be limited by its short half-life. Other approaches to management of AD should not be neglected. Increased publicity concerning AD is a potential source of stress to the elderly generally, but increased awareness of this disease both by the general public and health professionals has probably helped support and management of AD.     

Hypertension and Alzheimer's disease

Case-control transversal studies have suggested the existence of an association between low blood pressure and Alzheimer's disease, although there is some doubt on the cause to effect relationship. A drop in blood pressure preceding the onset of dementia has been evoked but never confirmed. Longitudinal studies, with long term follow-up on the existence of hypertension during middle-age, have demonstrated a significant increase in the risk of developing Alzheimer's disease in cohorts of hypertensive patients compared to normotensive subjects. The potential benefit of preventive treatment with antihypertensive drugs in decreasing the risk of Alzheimer's disease has not been confirmed in clinical trials. The hypothesis of the formation of a cerebrovascular disease that would combine with the neuropathological lesions has been evoked, raising doubts on the diagnostic criteria used to define Alzheimer's disease. The novel concept that vascular risk factors could directly induce the formation of neuropathological lesions is interesting but warrants confirmation.     

Alzheimer's disease and anaesthesia

Editor—It was with particular interest that we read thereview article by Fodale and colleagues¹ on Alzheimer's disease(AD) and anaesthesia. In the same month, our department receiveda letter from the family of an 80-yr-old lady diagnosed 4 yrpreviously with AD. She had undergone an elective hip replacementin 1998. The patient received a general anaesthetic using isofluraneand the operation, lasting 2 h, was unremarkable. At aroundthis time, the family report that the patient started experiencingincreasing problems with her memory. Having read a recent article²in the New Scientist titled ‘Alzheimer's alert over anaesthetics’,in which Mandal is quoted as saying ‘It's a seriouslydeadly     

Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains

In this immunohistochemical study, the age- and stage-dependent accumulation of advanced glycation end-products (AGEs) in Alzheimer's disease (AD) and their relation to the formation of neurofibrillary tangles and neuronal cell death was investigated. For this purpose, the distribution of AGEs in neurons and glia was analyzed in the auditory association area of superior temporal gyrus (Brodmann area 22) of young and old non-demented controls and compared with early- and late-stage AD. A possible co-localization of AGEs with typical hallmarks of AD, such as hyperphosphorylated tau (as a marker for disturbed kinase/phosphatase activity), nNOS (as a marker for nitroxidative stress) and caspase-3 (as a marker of apoptotic cell death), was also investigated. Our results show that the percentage of AGE-positive neurons (and astroglia) increase both with age and, in AD patients, with the progression of the disease (Braak stages). Interestingly, nearly all if those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphoryated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles. Many, but not all, neurons show a co-localization of AGEs with other markers of neurodegeneration, such as nNOS and caspase-3.     

Scoliosis and growth. Patterns of asymmetry in normal vertebral growth

This study reviews published observations of asymmetrical appearance of primary ossification centres in human fetal vertebral arches. It reports studies of vertebral asymmetry in 39 vertebral columns of infants and children including asymmetry in pedicle length and vertebral arch height, asymmetry in neurocentral fusion, and vertebral body flattening on its left anterior aspect. It relates these patterns of asymmetry to the commonly observed left thoracic scoliosis of infancy and right thoracic scoliosis of adolescents and adults. It discusses the implications of these observed asymmetries of normal vertebral growth in the aetiology of scoliosis, and the possible influences of handedness and aortic pressure in the production of these vertebral asymmetries in adolescence.     

Vertebral rotation and pedicle length asymmetry in the normal adult spine

Summary Rotation in the horizontal plane of vertebra T8, T9 or T10 was determined on CT scans of 25 male and 25 female patients with normal spines. The pedicle length was measured using a new method, and the right/left pedicle length index was calculated. In 38 (76%) of the patients there was vertebral rotation to the right with a mean Cobb angle of 3.0°, and in 4 (8%) rotation to the left, mean Cobb angle 2.2° (P0.01). In 8(16%) there was no measurable rotation. The pedicle length index was greater than 1.05 in 9 subjects, between 0.95 and 1.05 in 16 and less than 0.95 in 25, indicating a predominance of longer pedicles on the left side. In 21 out of the 38 patients with vertebral rotation to the right, the left pedicle was longer than the right one (P0.01). The results indicate that the normal spine is afflicted with a vertebral rotation to the right in association with a longer pedicle on the left. The significance of these observations for the pathogenesis of idiopathic scoliosis remain uncertain.     

Microanatomical correlates of cognitive ability and decline: normal ageing, MCI, and Alzheimer's disease

Few microanatomical measures have been reliably correlated with cognitive measures in aging and Alzheimer's disease (AD), particularly in the early stages of degeneration, such as mild cognitive impairment (MCI). However, cortical minicolumn organization has been shown to correlate with cognitive ability in aging monkeys, and the present study extends this finding to humans. We have previously reported that minicolumn spacing of cells in human association cortex is selectively reduced in normal aging (minicolumn thinning). The present study found that such measures detected early disease changes in MCI as well as further minicolumn thinning and disruption in AD. Plaques, tangles, and minicolumns were quantified, postmortem, for 20 controls, 10 MCI, and 20 AD subjects. Minicolumn changes were correlated with premortem cognitive scores (mini-mental state examination and verbal fluency). Two regions were studied from each brain: association cortex in the planum temporale (BA22) and primary auditory cortex (BA41). The relationship between minicolumns and cognitive function was strongest in association cortex, whereas in primary auditory cortex, it appeared to be an epiphenomenon of overall brain atrophy. Microanatomical changes reflecting selective regional vulnerability to AD pathology and differential involvement in the cognitive deficit of AD are therefore detectable in the early stage of MCI.     

Multiconceptual therapy in Alzheimer's disease

SOCIAL AND ECONOMICAL IMPACT: Alzheimer's disease is a neurodegenerative dementia raising major public health concern in industrialized countries. The consequences are not only medical but also social and economical. PERSPECTIVES: It is thus important to establish diagnostic principles, therapeutic goals, and global strategies guiding the behavior of physicians, family and patients faced with this dreaded disease. Currently, only a few rare symptomatic treatments are available, but research in this field points to potentially effective preventive and etiopathogentic therapeutic protocols associating drugs, social support, and psychotherapy.     

Systematic Regional Variations in the Loss of Cortical Cholinergic Fibers in Alzheimer's Disease

The loss of cortical cholinergic fibers in Alzheimer's diseasewas investigated using choline acetyltransferase immunohistochemistryand acetylcholinesterase histochemistry. Within both the normaland Alzheimer's cerebral cortex, the two methods revealed anidentical pattern of fiber staining. In the normal brain, cholinergicfiber density was highest in limbic and paralimbic corticalzones, intermediate in most sensory-motor and association zones,and lowest within the primary visual and visual associationareas of the occipital lobe. In general, supragranular corticallayers contained a higher density of cholinergic fibers, andmost of these were oriented vertically. In Alzheimer's disease,an overall 55% loss of cortical cholinergic fibers was detected.There was, however, marked regional variations in the extentof this loss in different cortical areas. Cortical areas withinthe temporal lobe, particularly the temporal association areas,displayed a dramatic loss of cholinergic fibers. By contrast,the anterior cingulate cortex, primary visual, primary somatosensory,and primary motor cortex displayed a relative preservation ofcholinergic fibers. As a whole, greater loss of cholinergicfibers was detected in supragranular layers and in fibers orientedvertical to the cortical surface. These results indicate thatcholinomimetic therapies are likely to have different effectson cholinergic transmission in various cortical areas. The precisemechanisms that lead to the regional variations in corticalcholinergic denervation in Alzheimer's disease remain to beelucidated.     

Successful aging and disease prevention

Substantial increases in the relative and absolute number of older persons in our society pose a challenge for biology, social and behavioral science, and medicine. Successful aging is multidimensional, encompassing the avoidance of disease and disability, the maintenance of high physical and cognitive function, and sustained engagement in social and productive activities. Research has identified factors predictive of success in these critical domains. Two additional research domains, resilience and wisdom, are suggested, and a national initiative in health promotion and disease prevention is proposed.     

Ethical issues in aging and renal disease

The incidence of elderly patients reaching end-stage renal disease (ESRD) and requiring renal replacement is increasing. Better medical care is helping patients live longer but, at the same time, is raising ethical questions. Treatment decisions for ESRD patients present a forum for the consideration of ethical questions surrounding the issues of scarce health care resource allocation and the withholding or withdrawal of life-sustaining treatment. As background for the consideration of ethical issues in ESRD patients, the quality of life they experience and what they may expect as death approaches also are discussed.     

Orbitofrontal cortex pathology in Alzheimer's disease

The orbitofrontal cortex has been examined in Alzheimer's disease (AD) from the viewpoint of neurofibrillary tangle (NFT) pathology, its laminar distribution and topography. NFT pathology in the orbitofrontal cortex is extensive in AD. In cases with extensive cortical pathology, NFTs extend from the pole of the frontal lobe to the orbitoinsular junction. In lesser affected cases, the anterior granular part of the orbital cortex is less invested by NFTs. Layers III and V contain the greatest density of NFTs and these are most dense in the dysgranular areas, posterior to the transverse orbital sulcus. Posterior and medial orbitofrontal areas, forming area 13 and the posterior tip of the paraolfactory gyrus, are the most severely damaged, as are the smaller agranular fields that surround the olfactory tract and cortex. The widespread orbitofrontal damage in AD affecting projection neurons suggests that this pathology may contribute heavily to the many non-memory-related behavior changes observed in this disorder.     

Alzheimer's disease with refluxes

This is a report concerning a unique combination of Alzheimer's disease with the following refluxes: buccosalivary, gastroesophageal, vesicoureteral, urethroprostatic and urethrovesicular, along with neurogenic bowel and neuropathic bladder. A second patient with Alzheimer's disease and vesicoureteral reflux is reported. The possible etiopathology of these unusual refluxes and their relation to Alzheimer's disease are discussed.     

Small-world networks and functional connectivity in Alzheimer's disease

We investigated whether functional brain networks are abnormally organized in Alzheimer's disease (AD). To this end, graph theoretical analysis was applied to matrices of functional connectivity of beta band-filtered electroencephalography (EEG) channels, in 15 Alzheimer patients and 13 control subjects. Correlations between all pairwise combinations of EEG channels were determined with the synchronization likelihood. The resulting synchronization matrices were converted to graphs by applying a threshold, and cluster coefficients and path lengths were computed as a function of threshold or as a function of degree K. For a wide range of thresholds, the characteristic path length L was significantly longer in the Alzheimer patients, whereas the cluster coefficient C showed no significant changes. This pattern was still present when L and C were computed as a function of K. A longer path length with a relatively preserved cluster coefficient suggests a loss of complexity and a less optimal organization. The present study provides further support for the presence of "small-world" features in functional brain networks and demonstrates that AD is characterized by a loss of small-world network characteristics. Graph theoretical analysis may be a useful approach to study the complexity of patterns of interrelations between EEG channels.