AD-type Pathology Research Articles

Cell cycle markers in the hippocampus in Alzheimer's disease.

Using immunohistochemistry we have analysed the nuclear expression of cyclins A, B, D, and E in neurones in the hippocampi of control subjects and patients suffering from various neurodegenerative disorders including. Alzheimer's disease (AD). Cyclins A and D could not be detected but varying degrees of cyclin E expression were found in all patient groups including control subjects. Cyclin B expression was not detected in control subjects but it was expressed in the subiculum, dentate gyrus and CA1 region in patients with AD-type pathology and in the CA2 region and the dentate gyrus of cases of Pick's disease. These results suggest that some neurones may have re-entered the cell cycle. The expression of cyclin E without cyclin A expression may indicate an arrest in G1 with the possibility of re-differentiation and exit from G1 to G0. The expression pattern of cyclin E indicates that re-entry into the cell cycle is possible even in control patients, but it is accentuated in patients with AD-related pathology. However, cyclin B was only expressed in AD patients and occurred in areas that were severely affected by pathology. Neurones with cyclin B-reactive nuclei in AD were AT8 positive but did not contain fully developed tangles. In neurones, where cyclin B is expressed, it would appear that the G1/S checkpoint has been bypassed and that the cell cycle is arrested in G2. It is proposed that these neurones do not have the opportunity for subsequent re-differentiation. Since factors known to be present in G2 seem to be responsible for microtubule destabilisation and hyperphosphorylation of tau we hypothesise that cell cycle disturbances may be important in the pathogenesis of AD.

Criteria for Alzheimer's disease and the nosology of dementia with Lewy bodies.

Dementia with brainstem and neocortical Lewy bodies (LB) is a source of ongoing nosologic controversy and confusion. Differing opinions about concomitant Alzheimer's disease (AD) have produced competing nomenclatures. We applied neocortical plaque-based criteria for the diagnosis of AD from the National Institute on Aging and from the Consortium to Establish a Registry for AD for definite, probable, and possible AD to 58 dementia brains with LB, 10 elderly nondemented controls, and 58 brains with neuropathologically pure AD. We also employed diagnostic criteria requiring both neocortical plaques and tangles, and assessed the extent of neurofibrillary pathology in all 126 specimens using a modified version of the Braak and Braak staging protocol for changes related to AD. The percentages of mixed LB disease and AD versus pure LB disease varied from 91% mixed and 9% pure to 34% mixed and 66% pure, depending upon which diagnostic criteria for AD were employed. Most dementia brains with LB occupied higher modified Braak stages than controls, but lower ones than pure AD specimens. A minority of the dementia brains with LB had no more AD-type pathology than controls.

Comparative Investigation of Neurofibrillary Damage in the Temporal Lobe in Alzheimer's Disease, Down's Syndrome and Dementia Pugilistica

Neurofibrillary lesions such as neurofibrillary tangles, neurites and neuropil threads are used as neuropathological markers of Alzheimer's disease (AD). However these lesions are also seen in non-demented elderly cases as well as in several other disorders such as Down's syndrome (DS), dementia pugilistica (DP) and Parkinson's disease. Quantitative studies may therefore help in understanding the pathophysiological role of these lesions. Using a novel image analysis technique we have quantified the extent of neurofibrillary damage in AD, DS and DP. We have found that the extent of neurofibrillary change did not significantly differ beween AD and DS, though there were also strong parallels between AD and DP. We conclude that both genetic (as in DS) and environmental (as in DP) risk factors for AD-type pathology provide a similar pattern of neurofibrillary degeneration to that in AD itself suggesting that similar degenerative mechanisms might be triggered in all three conditions.

Artifactual strain-specific signs of incipient brain amyloidosis in APP transgenic mice

In an attempt to generate transgenic mice modeling Alzheimer-type amyloidogenesis, the COON-terminal 103 residue human APP segment was expressed in brain regions known to be vulnerable in AD. Transfected cells overexpressing this transgene were previously shown to develop intracytoplasmic inclusions that were immunoreactive with antibodies to the APP COOH-terminus. Transgenic C57B6/SJL mice produced transgene-coded mRNA in their brains at levels up to sixfold above endogenous APP, most abundantly within cortical and hippocampal pyramidal neurons. Immunocytochemistry with anti-Aβ antibodies revealed occasional structures that resembled diffuse amyloid, but which could not be detected on serial sections. Immunolabeling with antibodies to APP regions NH 2-terminal to the transgene-coded domain revealed elevated immunoreactivity within perikarya and neurites in regions expressing the highest transgene and endogenous APP mRNA levels, similar to observations previously reported within vulnerable neurons in AD brain. However, subsequent breeding revealed that this phenotype segregated with the B6/SJL background rather than the transgene, thus emphasizing the importance of genetic background to observations of putative AD-type pathology in transgenic animals.

209 Unawareness of memory impairment in dementia of Alzheimer type and cerebrovascular disease

Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared with Alzheimer's disease dementia (AD) on magnetic resonance imaging. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from 2 serial MRIs in autopsy-confirmed DLB patients (n = 20) and mixed DLB/AD patients (n = 22), compared with AD (n = 30) and elderly nondemented control subjects (n = 15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to control subjects. The mixed DLB/AD patients displayed greater atrophy rates in the whole brain, temporoparietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline, and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and these rates can be used as biomarkers of AD progression in patients with LB pathology.

Lewy Body Diseases with Dementia - Pathophysiology and Treatment

There are four major Lewy body disorders with dementia: Parkinsons disease (PD), PD with Alzheimers disease (AD), cortical Lewy bodies and neuritic plaques, and cortical Lewy bodies and no concomitant AD-type pathology. A variety of pathogenetic processes may underly this panoply of diseases including oxidative stress, excitatory amino acid toxicity, amyloidogenesis, neurofibrillary tangle formation, inflammation, apoptotic cell death, and neurotransmitter deficiency. Treatment strategies include transmitter replacement, neuroprotection, agents to limit AD-type pathology, iron chelation, and anti-inflammatory drugs. Patients with Lewy body disorders exhibit cognitive decline resulting from a variety of disease processes and treatment must address the disease-specific pathogenesis.

Nerve growth factor receptor immunoreactivity within the nucleus basalis (Ch4) in Parkinson's disease: reduced cell numbers and co-localization with cholinergic neurons

In a effort to better define the role cholinergic basal forebrain neurons play in human cognitive processes, a quantitative assessment of cholinergic nucleus basalis (Ch4) neurons was carried out in 5 patients with Parkinson's disease (PD; 4 non-demented and 1 demented) and 4 age-matched controls using nerve growth factor (NGF) receptor immunohistochemistry as a direct marker for cholinergic basal forebrain neurons. Virtually all (>90%) NGF receptor-containing neurons co-localize with the specific cholinergic marker choline acetyltransferase (ChAT) within the nucleus basalis in PD. NGF receptor-containing neurons were reduced on average by 68% (range 38.6–87.4%) in the non-demented PD cases and by 88.6% in the demented PD patient. Loss of these neurons was heterogeneous across the nucleus basalis subfields with only the anterolateral and posterior Ch4 subregions demonstrating significant reductions of NGF receptor-containing neurons. The reduction in NGF receptor-containing neurons was accompanied by a decrease of acetylcholinesterase (AChE) containing fibers within temporal cortex and in some cases ChAT immunoreactivity in the basolateral amygdaloid nucleus. The numerous non-cholinergic AChE-rich pyramidal cells which were observed throughout the cortex of aged controls were also virtually absent in PD. Although PD patients exhibited severe reductions in Ch4 neurons, few neuritic plaques or neurofibrillary tangles were observed within the PD cortex or Ch4 and similar numbers of these AD-type pathologies were seen within age-matched controls. This suggests that Ch4 degeneration alone is not sufficient to induce such cytoskeletal abnormalities and that the neuron loss seen within Ch4 in AD and PD may be mediated through different processes. These results, coupled with the extensive basic and clinical literature linking acetylcholine and memory function, further indicate that Ch4 degeneration without additional cortical and/or subcortical pathology is not sufficient to impair cognition in PD. Perhaps additional pathology must be superimposed upon nucleus basalis degeneration to induce dementia in humans.

Gangliosides in the brain in adult Down’s syndrome and Alzheimer’s disease

Quantitative analysis of total gangliosides and of ganglioside composition by HPTLC has been carried out on the gray matter of frontal cerebral cortex of six brains from Down's syndrome (DS) adults, six age-matched controls, six Alzheimer's disease (AD) adults, and six controls matched for age with the AD brains, as well as on three DS and six control cerebellum specimens. In addition, the analyses were carried out on specimens of corpus callosum of five adult DS and five control brains. No abnormalities were found in the gangliosides of DS corpus callosum. In DS frontal cortex, the concentration of total gangliosides was reduced, and there was a decrease in the fraction of GT1b and GD1b, and an increase in those of GT1a, GD3, GM1 and GM2; the ratio of total b-series to a-series gangliosides was decreased. Very similar abnormalities were found in the gangliosides of DS cerebellum. In AD frontal cortex, by contrast, the total gangliosides and their composition were normal by comparison with age-matched controls, with the minor exception of reductions in the fractions of GQ1b and GT1L. It is concluded that abnormalities in gangliosides exist in the brain in DS that are unrelated to AD-type pathology and may reflect developmental disturbances.

Lipid abnormalities in the brain in adult Down’s syndrome and Alzheimer’s disease

Quantitative analysis by HPTLC of the major lipid classes and dolichol, and of fatty acyl groups of separated phosphoglycerides by capillary GLC, has been carried out on the gray matter of frontal cerebral cortex of brains from six Down's syndrome (DS) and six Alzheimer's disease (AD) adults, and six each of two corresponding sets of age-matched controls; specimens of DS and control cerebellum and corpus callosum were also analyzed. In DS frontal cortex, but not in AD frontal cortex, compared to their respective controls there was a decrease in the fraction of phosphatidylethanolamine (PE) and an increase in the fractions of sphingomyelin (SPM) and phosphatidylserine (PS). Abnormalities were not found in the proportions of major lipid classes in DS cerebellum or corpus callosum. The concentration of dolichol was elevated for age in the frontal cortex of DS and of AD. In the phosphoglycerides of DS frontal cortex, the fatty acyl composition showed small, but statistically significant, differences from those of age-matched controls, and some slight abnormalities were also detected in DS corpus callosum. The alterations in DS frontal cortex included decreases in (n-6) and increases in (n-3) groups in choline and ethanolamine phosphoglycerides (CPG and EPG), as had previously been found in EPG and serine phosphoglyceride (SPG) of the DS fetal brain. In DS frontal cortex, the proportion of 22:4(n-6) groups was decreased in SPG, and in inositol phosphoglyceride (IPG) 18:1(n-9) was increased. There were also small but significant alterations in DS frontal cortex in the fractions of shorter chain groups in CPG. In marked contrast, most of the fatty acyl abnormalities seen in DS were absent in the AD frontal cortex. It is therefore suggested that some abnormalities in the composition of cerebral membranes present prenatally in DS may persist into adulthood, and are not directly related to AD-type pathology.