Carol F. Lippa

Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: Evidence for early up-regulation of the endosomal-lysosomal system

In Alzheimers disease brains, more than 90% of pyramidal neurons in lamina V and 70% in lamina III displayed 2- to 5-fold elevated levels of cathepsin D (Cat D) mRNA by in situ hybridization compared with neurologically normal controls. Most of these cells appeared histologically normal. The less vulnerable nonpyramidal neuron population in lamina IV had relatively normal message levels. Neuronal populations expressing more Cat D mRNA also displayed quantitatively increased Cat D immunoreactive protein. Cat D mRNA expression was only moderately increased in astrocytes. Degenerating neurons exhibited intense immunoreactivity but lowered Cat D mRNA levels. The upregulation of Cat D synthesis and accumulation of hydrolase-laden lysosomes indicate an early activation of the endosomal-lysosomal system in vulnerable neuronal populations, possibly reflecting early regenerative or repair processes. These abnormalities also represent a basis for altered regulation of amyloid precursor protein processing.

Altered expression of transforming growth factor-beta in Alzheimer's disease

We compared immunohistochemical expression of the transforming growth factor-beta s (TGF-beta 1, TGF-beta 2, and TGF-beta 3) using brain tissue from patients with nondominantly inherited Alzheimers disease (NDAD) (n equals 9), autosomal dominantly inherited Alzheimers disease with linkage to 14q24.3 (FAD-14) (n equals 4), and cognitively normal controls (n equals 10) to determine whether their pathologic changes are associated with an altered distribution of the TGF-beta s. We found increased expression of TGF-beta 2 in large, tangle-bearing neurons with widespread staining of glia in NDAD and FAD-14 patients compared with control cases. This result was confirmed with sandwich ELISA assays of brain tissue, which showed TGF-beta 2 levels in AD and NDAD to average 3.2 times the average level of control cases. Despite proximity of TGF-beta 1 and TGF-beta 3 to the sites of susceptibility loci on chromosomes 19 and 14, we did not find that TGF-beta 1 and TGF-beta 3 were selectively altered in any AD subtypes. However, selective induction of TGF-beta 2 may occur in NDAD and FAD-14.

Alzheimer's disease and aging: effects on perforant pathway perikarya and synapses.

The hippocampal perforant pathway originates in the entorhinal cortex (ERC) and terminates in the outer molecular layer of the dentate gyrus (DG). To compare the effects of normal aging and Alzheimers disease (AD) on the elements of the perforant pathway, we compared relative perikaryal numbers (determined by counting cell bodies and estimating volumes) in layer II of the ERC with synaptic quantities (estimated from immunoreactivity for the synaptic terminal protein synapsin I and DG volume) in the molecular layer of the DG. The brains of 5 young and 9 elderly cognitively normal individuals, and of 9 AD patients were studied. In normal aging we found a significant age-related decline in perikaryal numbers in the ERC without demonstrable synaptic loss in the DG. In AD there was marked and equivalent, (or proportional) reduction in both ERC perikaryal numbers and DG synapses. These data suggest that in normal aging remaining neurons may continue to support a full array of synapses, perhaps due to mechanisms such as axonal sprouting, synaptic enlargement, or synaptic ingrowth. In AD, however, the accelerated neuronal loss may overwhelm such compensatory mechanisms or alternatively, independent synaptic and perikaryal losses may occur.

Ki-67 Immunoreactivity in Alzheimer's Disease and Other Neurodegenerative Disorders

Cell cycle-associated nuclear proteins may have more specialized functions in the adult nervous system in addition to those directly associated with cell proliferation, as suggested by a recent study showing that neurofibrillary tangles (NFT) and dystrophic neurites in Alzheimers disease (AD) are immunoreactive for the proliferation-associated antigen p105. To further investigate this hypothesis, we studied the expression of another proliferation-associated antigen, Ki-67, in the brains of patients with AD and other neurodegenerative disorders. Formalin-fixed, paraffin-embedded sections from autopsy cases of AD, Downs syndrome with dementia and AD pathology (DS/AD), Picks disease (PiD), progressive supranuclear palsy (PSP), Lewy body disease (LBD), Parkinsons disease (PD), corticobasal degeneration (CBD), and young and aged normal brains, and from two surgically resected gangliogliomas were immunostained using antibodies to Ki-67 (MIB-1 clone equivalent) and tau (τ). Ki-67 staining was performed following antigen retrieval by microwave heating. Ki-67 labeled NFT that were observed in the AD, DS/AD, PiD, PSP, LBD, and PD cases, one aged normal brain, and one ganglioglioma. Ki-67 generally labeled fewer NFT compared to τ. Pick bodies, ballooned neurons (Pick cells) in CBD and PiD, and nigral corticobasal inclusions in CBD were immunoreactive for τ but not Ki-67. Neither antibody labeled cortical or subcortical Lewy bodies. Our findings suggest that Ki-67 may be involved in the pathogenesis of neurofibrillary degeneration in AD, other neurodegenerative disorders, normal aging, and neoplasms such as ganglioglioma. We postulate a possible role for Ki-67 in the production of the abnormally phosphorylated τ protein that leads to the formation of paired helical filaments within susceptible neurons.

Dementia with Lewy bodies: choline acetyltransferase parallels nucleus basalis pathology

Summary. The biological substrate underlying the reduced cortical choline acetyltransferase (ChAT) in dementia with Lewy bodies (DLB) is incompletely understood. We compared cortical ChAT levels with Lewy body densities and neuronal loss in the nucleus basalis of Meynert (nbM) and cerebral cortex in six DLB, seven Alzheimers disease (AD), and six control cases. We found greater neuronal loss in the nbM in DLB compared to AD (U = 9.500, p = 0.049). Mean ChAT levels in the cortex were lower in dementia patients than controls (t = 17.500, p = 0.001), and DLB cases had slightly lower ChAT levels than AD cases, but this difference was not significant (t = −0.332, p = 0.746). Overall, cortical ChAT levels correlated inversely with neuronal loss in the nbM (Spearman rank correlation coefficient = −0.53). The correlation between ChAT level and the combined factor of nbM LBs and neuronal loss was −0.59. A similar correlation between ChAT level and the combined factor of nbM neurofibrillary tangles and neuronal loss was −0.72. The correlation between ChAT and the combined factor of nbM LBs and neuronal loss was −0.81 when AD cases were excluded from the analysis. Local cortical pathology was not related to ChAT level. We conclude that neuronal loss and Lewy body formation in the nbM may contribute to the reduction in cortical ChAT in DLB.

Apolipoprotein E genotype and Lewy body disease

Article abstract-To determine whether apolipoprotein E (APOE) genotype affects neuropathology in Lewy body disease (LBD), we examined 18 cases of LBD that did not have concurrent Alzheimers disease by the CERAD criteria. We obtained APOE genotypes, determined diffuse beta-amyloid plaque (AbetaP) and Lewy body densities in multiple brain regions, and graded the intensity of CA2-3 ubiquitin-positive neurites, vacuolar change, nigral pathology, amyloid angiopathy, and subpial amyloid deposition. The APOE allele frequencies were as follows: epsilon2, 0.14 +- 0.07; epsilon3, 0.64 +- 0.08; and epsilon4, 0.22 +- 0.03. The mean AbetaP density was lower in APOE epsilon3/3 cases (14.5 AbetaPs per mm2) than in the groups with the APOE epsilon2 (67.0) or APOE epsilon4 (46.6) alleles. This difference was due largely to the difference between AbetaP density in the APOE epsilon2 group and the APOE epsilon3/3 group (F = 5.525, p < 0.02). CA2-3 neuritic degeneration was greater in those with the APOE epsilon4 allele than in those with the APOE epsilon3/3 genotype (grade = 1.9 +- 1.3 versus 0.938 +- 0.9; Kruskal-Wallis test statistic = 6.962, p < 0.05). These data are consistent with the hypothesis that APOE genotype may affect neuropathology in LBD. NEUROLOGY 1995;45: 97-103

Corticonigral degeneration with neuronal achromasia: A clinicopathologic study of two cases

We describe the clinical and neuropathological features of two patients having corticonigral degeneration with neuronal achromasia (CND). Both patients had cognitive decline and movement disorders. Magnetic resonance (MR) scans showed cortical atrophy, which in one case was most prominent in the parasylvian region, and ventricular enlargement in both cases. Neuropathological examination revealed swollen achromasic neurons within the cerebral cortex and marked neuronal loss in the substantia nigra. No Pick bodies, Lewy bodies, histologic changes of Alzheimers disease, or spongiform change were present in either case. The diagnosis of CND should be considered in patients with complex movement disorders, with or without abnormalities in cognitive function.

Apolipoprotein E-epsilon 2 and Alzheimer's disease: Genotype influences pathologic phenotype

Article abstract-To determine whether apolipoprotein E epsilon 2 (APOE-epsilon 2) affects neuropathology in aging and Alzheimers disease (AD), we compared beta-amyloid plaque (A beta P) and neurofibrillary tangle densities, neuropil thread formation, and amyloid angiopathy in five APOE-epsilon 2/3 AD patients, five APOE-epsilon 3/3 AD patients, five APOE-epsilon 2/3 control patients, and five APOE-epsilon 3/3 control patients. We examined the (frontal and parietal) neocortex, hippocampus, entorhinal cortex, and cerebellum and found A beta P densities to be lower (t = 3.121, p = 0.011) in the cortex of APOE-epsilon 2/3 AD patients than in APOE-epsilon 3/3 AD patients. Amyloid angiopathy was also less in APOE-epsilon 2/3 patients than in APOE-3/3 patients (U = 4.500, p = 0.027). Control APOE-epsilon 2/3 brains had little AD-related pathology; even our 102-year-old control case showed few A beta Ps compared with the elderly APOE-epsilon 3/3 cases. The APOE-epsilon 2/3 genotype may influence pathologic phenotype in some aged normal and AD populations. NEUROLOGY 1997;48: 515-519

Electrical source analysis of auditory ERPs in medial temporal lobe amnestic syndrome

Auditory event-related potential (ERP) components have been anatomically linked to temporal lobe structures and functionally related to attentional and memory processes. We recorded auditory ERPs using an oddball paradigm from two patients with amnestic syndromes secondary to medial temporal lobe encephalitic infections. The oddball paradigm elicits the exogenous N1 and P2 components, and the endogenous N2 and P3 components. Electrical source analysis was used to test for alterations in source strength and orientation in these patients compared to control subjects. Symmetric dipoles placed in the temporal lobe region were used to measure ERP component activity. In the patient with a lesion confined to the left, medial temporal lobe, including the posterior hippocampus, dipole orientation was displaced anteriorally. In the patient with lesions to the anterior medial temporal lobe, temporal poles, and orbital frontal cortex, the negative components of the ERP (N1 and N2) were reduced in the right hemisphere, accompanied by disturbed orientation. These findings are consistent with other evidence that the different components of the auditory ERP can be dissociated on the basis of lesion effects, and that the antero-posterior extent of encephalitic lesions may play an important role in modulating ERP abnormalities.

Chromatolytic neurons in Werdnig-Hoffmann disease contain phosphorylated neurofilaments

SummaryTwo cases of Werdnig-Hoffman disease are described. Chromatolytic neurons were found within the ventral horns of the spinal cord as well as in dorsal root ganglia, Clarkes column, cranial nerve nuclei and thalamus. Immunohistochemical staining demonstrated ohosphorylated neurofilament antigen within the cytoplasm of the chromatolytic neurons. This finding suggests that a defect in slow axonal transport or in the regulation of neurofilament phosphorylation may play a role in the pathogenesis of this disorder.