Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer's disease

Alzheimer's disease is associated with progressively dysfunctional gene expression in the limbic system of the brain. The thalamus and primary visual cortex are thought to be initially spared of Alzheimer-type changes that ravage the association neocortex. In this study, using DNA arrays and Western immunoassay, gene expression patterns were examined in the thalamus and primary visual cortex of moderate-stage and late-stage Alzheimer's disease and age-matched controls using a set of proinflammatory genes known to be upregulated in the temporal lobe neocortex and hippocampus of moderate-stage Alzheimer's disease. The data indicate that, in late-stage Alzheimer's disease, proinflammatory and proapoptotic gene expression spreads into the primary visual sensory cortex. This upregulation of pathological gene expression could be, in part, responsible for the visual disturbances associated with end-stages of the Alzheimer process.     

Substance P-like immunoreactivity is reduced in Alzheimer's disease cerebral cortex

Substance P is an undecapeptide which has been found in human cortical neurons. We measured concentrations of this peptide in Alzheimer's disease (AD) and control postmortem tissue by radioimmunoassay. Using high-performance liquid chromatography, most of the immunoreactivity from AD or control temporal cortex comigrated with synthetic standards. Significant reductions of 20 to 40% in substance P-like immunoreactivity were found in AD cerebral cortex and hippocampus, most severe in the inferior temporal gyrus. Substance P neurons or their terminals are vulnerable to the pathophysiologic process in AD.     

Reduction of choline acetyltransferase activity in primary visual cortex in mild to moderate Alzheimer's disease

BACKGROUND: Cholinergic deficits in the primary visual cortex (PVC) may underlie some of the abnormalities in visual processing and global cognitive performance in Alzheimer's disease (AD). OBJECTIVE: To correlate measures of general cognition (Mini-Mental State Examination and Global Cognitive Score) and visuospatial function with choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activities, and nerve growth factor protein levels in the PVC. DESIGN: The ChAT and AChE enzyme assays and a nerve growth factor protein enzyme-linked immunoabsorbent assay were performed on PVC tissue samples from subjects clinically diagnosed as having mild cognitive impairment (MCI), AD, or no cognitive impairment (NCI). SETTING AND PATIENTS: Nuns, priests and brothers enrolled in the Religious Order Study, with annual premortem records of neuropsychological testing. RESULTS: Significant differences in ChAT activity, but not in AChE activity or nerve growth factor protein levels, were found among diagnostic groups (P = .049). The ChAT activity was lower in AD than in MCI or NCI (P<.01); MCI was not different from NCI. The PVC ChAT activity correlated with measures of overall cognitive function (Mini-Mental State Examination and Global Cognitive Score), but less so with a composite measure of visuospatial function. CONCLUSIONS: The reduction in ChAT activity in the PVC of mild to moderate AD, but not in MCI, might serve to distinguish between clinical and preclinical forms of the disease. It appears that this change relates to generalized cognitive abnormalities but not specifically to visuospatial function.     

Neuropeptide Y immunoreactivity is reduced in cerebral cortex in Alzheimer's disease

Neuropeptide Y is a 36-amino acid peptide that is found in high concentrations in cerebral cortex and is contained in cortical neurons. We measured concentrations of this peptide in postmortem tissue from patients with Alzheimer's disease and controls using a sensitive and specific radioimmunoassay. High-performance liquid chromatography showed that more than 95% of immunoreactivity co-migrated with synthetic standards in both Alzheimer's disease and control frontal cortex. Significant reductions in neuropeptide Y-like immunoreactivity were found in eleven cortical regions, the hippocampus, and the locus ceruleus. The regions particularly affected included the temporal lobe, frontal lobe, and occipital cortex. As neuropeptide Y is co-localized with somatostatin in a considerable proportion of cortical neurons, the loss of immunoreactivity may in part reflect degeneration of these neurons. Further study of the selective vulnerability of these neurons in Alzheimer's disease cortex may provide clues to the nature of the underlying disease process.     

Widespread reduction of somatostatin-like immunoreactivity in the cerebral cortex in Alzheimer's disease

Although several studies have documented reduced concentrations of somatostatin-like immunoreactivity (SLI) in the cerebral cortex in Alzheimer's disease, there is controversy concerning the extent and importance of these changes. We measured SLI in brains obtained post mortem from 12 patients with pathologically confirmed Alzheimer's disease and from 13 neurologically normal controls. All major cortical and subcortical regions were examined. Widespread reductions of SLI in Alzheimer's disease cerebral cortex were found, with the most profound changes seen in temporal lobe; but there also were major reductions in both the frontal and occipital cortex. There were no significant reductions in subcortical regions. Characterization of SLI by high-pressure liquid chromatography showed no significant difference in profiles between Alzheimer's disease and control frontal cortex. These results suggest that the reduction in somatostatin immunoreactivity in Alzheimer's disease may be caused by degeneration of intrinsic somatostatin cortical neurons.     

Decreased somatostatin-like immunoreactivity in cerebral cortex and cerebrospinal fluid in Alzheimer's disease

To investigate changes in the somatostatinergic neurons of patients with Alzheimer's disease (AD), we determined the somatostatin-like immunoreactivity (SLI) in post-mortem brain tissue of histopathologically confirmed AD patients and in CSF of probable AD patients (according to DSM III). The CSF values were then correlated with psychological test scores. In 6 AD patients the SLI values were decreased 42% (P less than 0.005) in the frontal cortex, 28% (P less than 0.05) in the temporal cortex and 42% (P less than 0.01) in the parietal cortex but not in the thalamus and putamen compared to 11 control patients. In some brain areas there were statistical correlations between SLI values and cholinergic markers, choline acetyltransferase and acetylcholine esterase activities, suggesting a relationship between these two neurotransmitter systems. In the CSF among 75 AD patients SLI was 35% lower (P less than 0.001) than in controls. Severely demented power (P less than 0.001) than in controls. Severely demented patients showed lower SLI values than moderately demented individuals, but this difference was not significant. There was a weak but statistically significant correlation between SLI values in CSF and neuropsychological test scores. This study further confirms the involvement of somatostatinergic neurons in AD and suggests that this involvement may be related to the progression of dementia symptoms.     

beta-Endorphin-like immunoreactivity in cerebrospinal fluid of patients with Alzheimer's disease and Parkinson's disease

beta-Endorphin-like immunoreactivity (beta-EP-LI) in cerebrospinal fluid (CSF) was measured in 42 patients with Alzheimer's disease (AD), 36 patients with Parkinson's disease (PD), and 35 controls. Values for patients with Alzheimer's disease (10.9 +/- 2.8 pmol/l) seemed to be lower than those for controls (12.9 +/- 2.5 pmol/l) (P less than 0.05). In addition, the severely demented patients had lower values than the moderately demented (P less than 0.01). In patients with Parkinson's disease no significant difference in beta-EP-LI values was observed compared to the controls. The data suggest, that processing of pro-opiomelanocortin, precursor of beta-endorphin, and the mechanism of cognitive impairment may differ in Alzheimer's disease and Parkinson's disease.     

A quantitative study of frontal cortex dendritic microtubules in patients with Alzheimer's disease

The dendritic microtubules (MT) of the frontal cortex layers II and III were studied in 9 patients with Alzheimer's disease (AD) and the results compared with 9 case controls. Dendrites with abnormally oriented MTs and others depleted of these structures were seen. A significant reduction in the number of MTs per unit area was found in AD. It is suggested that microtubular changes in AD can interfere with neuroplasmic transport and thus, be implicated with the dendritic degeneration present in this disease.     

Propionibacterium acnes in the cortex of patients with Alzheimer's disease

Propionibacterium acnes was found in the cortex of three patients with Alzheimer's disease and in one frontal cortex of an elderly patient with cardiovascular risk factors and hypoxia due to a large glioblastoma of the right frontal lobe with severely increased intracranial pressure.Propionibacterium acnes is an atypical anaerobic bacterium which is sensitive to cephalosporins, but insensitive to metronidazole. It is concluded that a capillary microangiopathy (in consequence of old age and cardiovascular risk factors such as high blood pressure) leads to cortical hypoxia and reduced resistance of the cortical immune system. Prevention by dietary regimes counteracting microangiopathy and treatment with cephalosporins are recommended.     

TrkB-like immunoreactivity is present on geniculocortical afferents in layer IV of kitten primary visual cortex.

Exogenous administration of the neurotrophins brain-derived neurotrophic factor (BDNF) or neurotrophin-4/5 (NT-4/5), or blockade of their endogenous actions, have been reported to affect the anatomic organization and physiological responses of neurons in developing mammalian primary visual cortex. Experimental alteration of levels of these neurotrophic factors can also influence the morphology of the geniculocortical afferents that project from the lateral geniculate nucleus (LGN) to primary visual cortex. BDNF and NT-4/5 are ligands of the TrkB tyrosine kinase receptor. Although multiple populations of cortical neurons express TrkB, it is not known whether geniculocortical afferents express this receptor on their axon branches in visual cortex. We have anatomically labeled geniculocortical afferents of postnatal day 40 kittens with the anterograde neuronal tracer Phaseolus vulgaris leucoagglutinin (PHA-L) and performed double-label immunofluorescence with a panel of anti-TrkB antibodies. Confocal microscopy and object-based colocalization analysis were used to measure levels of TrkB-like immunoreactivity (IR) on geniculocortical afferents in layer IV of primary visual cortex. By using a conservative analysis involving a comparison of measured colocalization with the amount of colocalization expected based on random overlap of TrkB puncta and PHA-L--labeled afferents, 3 of 5 anti-TrkB antibodies tested showed significant colocalization with the geniculocortical axons. Results for the other two antibodies were indeterminate. The indices obtained for colocalization of TrkB and geniculocortical afferents were also compared with the equivalent index obtained for GAD65, a protein that has a similar overall expression pattern to that of TrkB but is not expressed on geniculocortical axons. This analysis indicated that TrkB was present on geniculocortical axons for all five TrkB antibodies tested. TrkB-like IR was also observed on neuronal somata in the LGN. These results indicate that TrkB receptors on geniculocortical afferents are potential mediators of the actions of BDNF and NT-4/5 in developing visual cortex.     

Alternative splicing of the beta A4 amyloid gene of Alzheimer's disease in cortex of control and Alzheimer's disease patients.

An S1 nuclease protection assay was designed to study the splicing pattern of the alternatively spliced beta A4 amyloid gene (APP gene) of Alzheimer's disease (AD). We determined the splicing pattern of the APP gene in fetal, adult, aged adult and AD human cortex. The results suggest that alternative splicing of the APP gene in AD is not significantly different from age-matched controls, but distinct from the developing fetal brain.     

Contrast sensitivity and visual acuity in patients with Alzheimer's disease

Alzheimer's disease is a disorder which is typified by a deterioration in cognition and a range of behavioural problems which result in a loss of functional ability and often necessitate transfer to residential care. This article looks at a growing body of research which is revealing the presence of changes in vision, particularly contrast sensitivity and acuity. We discuss the possible pathological basis for such deficits, and examine the possibility that such changes in vision may impact on the behavioural and functional outcomes of the demented individual.     

Enhancement of immunoreactivity for NF-κB in the hippocampal formation and cerebral cortex of Alzheimer's disease

The distribution of nuclear factor-kappa B (NF-κB) was investigated immunohistochemically in the hippocampal formation, entorhinal cortex, middle temporal gyrus and visual cortex of Alzheimer's disease (AD) and control postmortem cases using a polyclonal antibody against the (NF-κB) p65 subunit. In AD cases, prominent staining for (NF-κB) was seen in neurons and their processes, neurofibrillary tangles and dystrophic neurites. In control cases, only weak staining of some neurons was obtained. The neuronal staining observed in AD was strongest in the hippocampal formation and entorhinal cortex, less in the middle temporal gyrus and least in the visual cortex. There was no difference between AD and control cases in the staining of glial cells and vascular walls. These results suggest that enhanced expression of neuronal (NF-κB) occurs in areas affected by AD pathology.     

Reductions in corticotropin releasing factor-like immunoreactivity in cerebral cortex in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy

Dementias occurring in Alzheimer's disease, Parkinson's disease, and progressive supranuclear palsy are associated with dysfunction and death of neurons in a variety of cell populations, including cholinergic, monoaminergic, and peptidergic systems. In the present investigation of these three disorders, we demonstrated decreased levels of corticotropin releasing factor (CRF)-like immunoreactivity in the frontal, temporal, and occipital poles of the neocortex. Moreover, reductions in peptidergic immunoreactivity correlated with reductions in the activity of choline acetyltransferase, the enzyme that catalyzes the formation of acetylcholine. The reduction in cortical CRF levels may be due to abnormalities of intrinsic cortical neurons or to dysfunction in neurons that contain CRF and innervate cortex.     

Three-dimensional visual feature representation in the primary visual cortex

In the cat primary visual cortex, it is accepted that neurons optimally responding to similar stimulus orientations are clustered in a column extending from the superficial to deep layers. The cerebral cortex is, however, folded inside a skull, which makes gyri and fundi. The primary visual area of cats, area 17, is located on the fold of the cortex called the lateral gyrus. These facts raise the question of how to reconcile the tangential arrangement of the orientation columns with the curvature of the gyrus.In the present study, we show a possible configuration of feature representation in the visual cortex using a three-dimensional (3D) self-organization model. We took into account preferred orientation, preferred direction, ocular dominance and retinotopy, assuming isotropic interaction. We performed computer simulation only in the middle layer at the beginning and expanded the range of simulation gradually to other layers, which was found to be a unique method in the present model for obtaining orientation columns spanning all the layers in the flat cortex. Vertical columns of preferred orientations were found in the flat parts of the model cortex. On the other hand, in the curved parts, preferred orientations were represented in wedge-like columns rather than straight columns, and preferred directions were frequently reversed in the deeper layers. Singularities associated with orientation representation appeared as warped lines in the 3D model cortex. Direction reversal appeared on the sheets that were delimited by orientation-singularity lines. These structures emerged from the balance between periodic arrangements of preferred orientations and vertical alignment of the same orientations. Our theoretical predictions about orientation representation were confirmed by multi-slice, high-resolution functional MRI in the cat visual cortex. We obtained a close agreement between theoretical predictions and experimental observations. The present study throws a doubt about the conventional columnar view of orientation representation, although more experimental data are needed.     

Entorhinal cortex dysfunction in Alzheimer's disease

The entorhinal cortex (EC) is the brain region that often exhibits the earliest histological alterations in Alzheimer's disease (AD), including the formation of neurofibrillary tangles and cell death. Recently, brain imaging studies from preclinical AD patients and electrophysiological recordings from AD animal models have shown that impaired neuronal activity in the EC precedes neurodegeneration. This implies that memory impairments and spatial navigation deficits at the initial stage of AD are likely caused by activity dysfunction rather than by cell death. This review focuses on recent findings on EC dysfunction in AD, and discusses the potential pathways for mitigating AD progression by protecting the EC.     

Bleomycin hydrolase immunoreactivity in senile plaque in the brains of patients with Alzheimer's disease

Bleomycin hydrolase (BH), a cysteine protease belonging to the papain superfamily, is one of the candidate beta secretases. We performed immunohistochemical studies of Alzheimer's disease (AD) brains using an antibody to BH. Polyclonal antibody to BH immunostained neocortical neurons. The immunoreactivity was also found in senile plaques in AD. These results may suggest a role of BH in amyloid formation.     

Hemispatial visual defect in Alzheimer's disease

We describe a 56-year-old woman with Alzheimer's disease with left hemispatial neglect and left homonymous hemianopsia with macular sparing considered a manifestation of Alzheimer's disease resulting from severe degenerative change in the right primary visual cortex. Hemispatial neglect normally results from brain damage to the right cerebral hemisphere. Homonymous hemianopsia is commonly the result of localized brain disease, especially cerebral infarction or hemorrhage. To our knowledge, a patient with Alzheimer's disease showing hemispatial neglect and homonymous hemianopsia with macular sparing has not previously been reported.