Showing papers by "Patrick R. Hof published in 1996"

Specific pathological Tau protein variants characterize Pick's disease.

Abstract: Pick's disease (PiD) is characterized by a pan-laminar frontotemporal cortical atrophy, widespread degeneration of the white matter, chromatolytic neurons, and Pick bodies (PB). Microtubule-associated Tau proteins are the main cytoskeletal components modified during these neurodegenerative changes. In the present study, pathological alterations of Tau proteins were investigated in the brains of five PiD cases at both neuropathological and biochemical levels, using the monoclonal antibody AD2 which recognizes a phosphorylation-dependent Tau epitope and strongly labeled PB. A large number of cortical and subcortical regions were studied on frozen materials. Tau proteins were analyzed on mono- and two-dimensional gel electrophoreses using a quantitative western blot approach. In all specimens, a 55 and 64 kDa Tau doublet was observed in limbic, frontal, and temporal cortices as well as in striatum and substantia nigra. In contrast, Alzheimer's disease (AD) brains are characterized by the presence of the 55, 64, and 69 kDa Tau triplet whereas the 64 and 69 kDa doublet is more typical of progressive supranuclear palsy and corticobasal degeneration. Thus, the 55 and 64 kDa doublet appears to be specific to PiD, less acidic than AD Tau proteins, and well correlated with the presence of PB.

The 2.8 A crystal structure of Gla-domainless activated protein C.

Abstract: The structure of the Gla-domainless form of the human anticoagulant enzyme activated protein C has been solved at 2.8 A resolution. The light chain is composed of two domains: an epidermal growth factor (EGF)-like domain modified by a large insert containing an additional disulfide, followed by a typical EGF-like domain. The arrangement of the long axis of these domains describes an angle of approximately 80 degrees. Disulfide linked to the light chain is the catalytic domain, which is generally trypsin-like but contains a large insertion loop at the edge of the active site, a third helical segment, a prominent cationic patch analogous to the anion binding exosite I of thrombin and a trypsin-like Ca[II] binding site. The arrangement of loops around the active site partially restricts access to the cleft. The S2 and S4 subsites are much more polar than in factor Xa and thrombin, and the S2 site is unrestricted. While quite open and exposed, the active site contains a prominent groove, the surface of which is very polar with evidence for binding sites on the primed side, in addition to those typical of the trypsin class found on the non-primed side.

The 1.8 A crystal structure of human cathepsin G in complex with Suc-Val-Pro-PheP-(OPh)2: a Janus-faced proteinase with two opposite specificities.

Abstract: The crystal structure of human neutrophil cathepsin G, complexed with the peptidyl phosphonate inhibitor Suc-Val-Pro-PheP-(OPh)2, has been determined to a resolution of 1.8 A using Patterson search techniques. The cathepsin G structure shows the polypeptide fold characteristic of trypsin-like serine proteinases and is especially similar to rat mast cell proteinase II. Unique to cathepsin G, however, is the presence of Glu226 (chymotrypsinogen numbering), which is situated at the bottom of the S1 specificity pocket, dividing it into two compartments. For this reason, the benzyl side chain of the inhibitor PheP residue does not fully occupy the pocket but is, instead, located at its entrance. Its positively charged equatorial edge is involved in a favourable electrostatic interaction with the negatively charged carboxylate group of Glu226. Arrangement of this Glu226 carboxylate would also allow accommodation of a Lys side chain in this S1 pocket, in agreement with the recently observed cathepsin G preference for Lys and Phe at P1. The cathepsin G complex with the covalently bound phosphonate inhibitor mimics a tetrahedral substrate intermediate. A comparison of the Arg surface distributions of cathepsin G, leukocyte elastase and rat mast cell protease II shows no simple common recognition pattern for a mannose-6-phosphate receptor-independent targeting mechanism for sorting of these granular proteinases.

Hyperphosphorylated tau proteins differentiate corticobasal degeneration and Pick’s disease

Abstract: In neurodegenerative disorders, hyperphosphorylated tau proteins aggregate into abnormal filaments. In the present study, tau protein alterations were studied in one corticobasal degeneration and seven Pick's disease cases using specific immunological probes. The typical lesions of corticobasal degeneration and Pick's disease were revealed by immunohistochemistry, including the presence of Pick bodies and achromatic swollen neurons, neuritic alterations, and neurofibrillary tangles. Tau-immunoreactive glial tangles were also observed. By immunoblotting, the case of corticobasal degeneration was characterized by the tau profile previously reported to occur in progressive supranuclear palsy with an intense labeling of the two tau 64 and 69 bands, while tau 55 was not visualized. In Pick's disease cases with Pick bodies and neurofibrillary tangles, a tau triplet similar to that encountered in Alzheimer's disease (tau 55, 64 and 69) was detected. Furthermore, a particular tau profile was found in four Pick's disease cases showing only Pick bodies and no neurofibrillary tangles. In these cases, tau 55 and 64 were strongly immunoreactive, whereas tau 69 was almost unlabeled. These differences are likely to be related to particular pools of tau isoforms present within the degenerating neurons. Since there is a great diversity of neurodegenerative disorders with substantial clinical and neuropathological overlap, the electrophoretic profile of tau proteins could represent a useful marker for the type of neurodegeneration.

Neurochemical, morphologic, and laminar characterization of cortical projection neurons in the cingulate motor areas of the macaque monkey

Abstract: The primate cingulate gyrus contains multiple cortical areas that can be distinguished by several neurochemical features, including the distribution of neurofilament protein-enriched pyramidal neurons. In addition, connectivity and functional properties indicate that there are multiple motor areas in the cortex lining the cingulate sulcus. These motor areas were targeted for analysis of potential interactions among regional specialization, connectivity, and cellular characteristics such as neurochemical profile and morphology. Specifically, intracortical injections of retrogradely transported dyes and intracellular injection were combined with immunocytochemistry to investigate neurons projecting from the cingulate motor areas to the putative forelimb region of the primary motor cortex, area M1. Two separate groups of neurons projecting to area M1 emanated from the cingulate sulcus, one anterior and one posterior, both of which furnished commissural and ipsilateral connections with area M1. The primary difference between the two populations was laminar origin, with the anterior projection originating largely in deep layers, and the posterior projection taking origin equally in superficial and deep layers. With regard to cellular morphology, the anterior projection exhibited more morphologic diversity than the posterior projection. Commissural projections from both anterior and posterior fields originated largely in layer VI. Neurofilament protein distribution was a reliable tool for localizing the two projections and for discriminating between them. Comparable proportions of the two sets of projection neurons contained neurofilament protein, although the density and distribution of the total population of neurofilament protein-enriched neurons was very different in the two subareas of origin. Within a projection, the participating neurons exhibited a high degree of morphologic heterogeneity, and no correlation was observed between somatodendritic morphology and neurofilament protein content. Thus, although the neurons that provide the anterior and posterior cingulate motor projections to area M1 differ morphologically and in laminar origin, their neurochemical profiles are similar with respect to neurofilament protein. This suggests that neurochemical phenotype may be a more important unifying feature for corticocortical projections than morphology.

Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson's disease cases.

Abstract: Changes in the distribution of the iron-binding protein lactotransferrin have recently been described in the central nervous system during a variety of neurodegenerative disorders. To investigate whether lactotransferrin is associated with the neuropathological changes that characterize Parkinson’s disease, we analyzed the distribution of this protein in the mesencephalon of neurologically normal individuals and patients affected with Parkinson’s disease using quantitative immunohistochemical methods. High levels of lactotransferrin were observed in a large population of neurons in the substantia nigra of control cases. Lactotransferrin-positive neurons were severely affected by the neurodegenerative process that occurs in Parkinson’s disease as indicated by a severe decrease in the number of immunolabeled neurons in all of these cases. Quantitative analysis also demonstrated higher immunolabeling levels of lactotransferrin in the surviving neurons in the substantia nigra and ventral tegmental area of Parkinson’s disease cases compared to control cases. These results suggest that lactotransferrin may participate actively in the mechanism of neuronal degeneration in Parkinson’s disease.

Neurofilament protein is differentially distributed in subpopulations of corticocortical projection neurons in the macaque monkey visual pathways

Abstract: Previous studies of the primate cerebral cortex have shown that neurofilament protein is present in pyramidal neuron subpopulations displaying specific regional and laminar distribution patterns. In order to characterize further the neurochemical phenotype of the neurons furnishing feedforward and feedback pathways in the visual cortex of the macaque monkey, we performed an analysis of the distribution of neurofilament protein in corticocortical projection neurons in areas V1, V2, V3, V3A, V4, and MT. Injections of the retrogradely transported dyes Fast Blue and Diamidino Yellow were placed within areas V4 and MT, or in areas V1 and V2, in 14 adult rhesus monkeys, and the brains of these animals were processed for immunohistochemistry with an antibody to nonphosphorylated epitopes of the medium and heavy molecular weight subunits of the neurofilament protein. Overall, there was a higher proportion of neurons projecting from areas V1, V2, V3, and V3A to area MT that were neurofilament protein-immunoreactive (57-100%), than to area V4 (25-36%). In contrast, feedback projections from areas MT, V4, and V3 exhibited a more consistent proportion of neurofilament protein-containing neurons (70-80%), regardless of their target areas (V1 or V2). In addition, the vast majority of feedback neurons projecting to areas V1 and V2 were located in layers V and VI in areas V4 and MT, while they were observed in both supragranular and infragranular layers in area V3. The laminar distribution of feedforward projecting neurons was heterogeneous. In area V1, Meynert and layer IVB cells were found to project to area MT, while neurons projecting to area V4 were particularly dense in layer III within the foveal representation. In area V2, almost all neurons projecting to areas MT or V4 were located in layer III, whereas they were found in both layers II-III and V-VI in areas V3 and V3A. These results suggest that neurofilament protein identifies particular subpopulations of corticocortically projecting neurons with distinct regional and laminar distribution in the monkey visual system. It is possible that the preferential distribution of neurofilament protein within feedforward connections to area MT and all feedback projections is related to other distinctive properties of these corticocortical projection neurons.

The neuropathological changes associated with normal brain aging.

Abstract: Neurofibrillary tangles and senile plaques are common neuropathological features in both normal brain aging and Alzheimer's disease In order to examine the patterns of lesion distribution in cerebral aging, we review the clinicopathological analysis of 1144 nondemented cases comparing their neuropathologic features to that reported in cases with mild cognitive impairment and cases with Alzheimer's disease Regardless of cognitive status, layer II of the entorhinal cortex is involved with neurofibrillary tangle formation in all of the cases, while the CA1 field of the hippocampus and the subiculum are less consistently affected Neocortical area 20 is particularly prone to develop neurofibrillary tangles in intellectually preserved elders, whereas other neocortical areas are relatively spared Substantial senile plaque formation is seen in the neocortex of non-demented cases Quantitatively, mild cognitive impairment is correlated with neurofibrillary tangle densities in layer II of the entorhinal cortex, and clinically overt Alzheimer's disease with neurofibrillary tangle densities in area 20 In non-demented centenarians, there is an early development of neurofibrillary tangles in areas usually spared in the course of the degenerative process in younger individuals These observations demonstrate that mesial and inferior temporal lobe structures are affected more frequently than originally thought in normal brain aging In this respect, neurofibrillary tangle formation in area 20 may represent a crucial step of the degenerative process, because it may precede the emergence of the neuropsychological deficits characteristic of Alzheimer's disease In addition, this study reveals age-related heterogeneity in the regional vulnerability of the cerebral cortex during normal brain aging

Distinct Patterns of Neuronal Loss and Alzheimer's Disease Lesion Distribution in Elderly Individuals Older than 90 Years

Abstract: To explore the characteristics of brain aging in very old individuals, we performed a quantitative analysis of neurofibrillary tangle (NFT) and senile plaque (SP) distribution and neuron densities in 13 nondemented patients, 15 patients with very mild cognitive impairment, and 22 patients with Alzheimer's disease (AD), all older than 96 years of age. Non-demented cases displayed substantial NFT formation in the CAI field and entorhinal cortex only. Very mild cognitive impairment cases were characterized by the presence of high NFT densities in layers V and VI of area 20, and AD cases had very high NFT densities in the CAI field compared to nondemented cases. Moreover, high SP densities were found in areas 9 and 20 in AD, but not in cases with very mild cognitive impairment and nondemented cases. In contrast to previous reports concerning younger demented patients, neuron densities were preserved in the CAI field, dentate hilus, and subiculum in centenarians with AD. In these cases, there was a marked neuronal loss in layers II and V of the entorhinal cortex, and in areas 9 and 20. In the present series, no correlation was found between neurofibrillary tangle and neuron densities in the areas studied, whereas there was a negative correlation between senile plaque and neuron densities in area 20. The comparison between the present data and those reported previously concerning younger cohorts suggests that there is a differential cortical vulnerability to the degenerative process near the upper age-limit of life.

Altered distribution of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit GluR2(4) and the N-methyl-d-aspartate receptor subunit NMDAR1 in the hippocampus of patients with temporal lobe epilepsy

Abstract: In patients with therapy-refractory temporal lobe epilepsy (TLE), alterations of glutamate receptors have been proposed as a mechanism for enhanced excitability. Using commercially available monoclonal antibodies specific for the N-methyl-d-aspartate (NMDA) receptor subunit NMDAR1 and for the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit GluR2(4), we have examined the distribution of these polypeptides in human hippocampal tissue that was surgically removed from patients with intractable TLE. Surgical specimens were classified according to the presence of Ammon’s horn sclerosis (AHS) or a focal lesion in the temporal lobe. Cell counts and a densitometric analysis of the immunoreactivity patterns were carried out for all hippocampal subfields. NMDAR1 and GluR2(4) levels were markedly reduced in patients with AHS, primarily in those subfields with substantial neuronal cell loss (in particular CA1, CA4 and CA3), compared to those seen in patients with focal lesions and in control specimens obtained at autopsy. In contrast, the molecular layer of the dentate gyrus (DG-ML) showed significantly higher levels of GluR2(4) immunoreactivity in AHS compared to control tissue, while NMDAR1 showed no significant up-regulation in this sublayer. When the receptor staining intensity was normalized for alterations in neuronal density, no significant alterations could be detected except for an increase in GluR2(4) in the DG-ML of patients with AHS. These changes may reflect synaptic reorganization observed in the DG-ML of specimens from patients with chronic intractable TLE.

A laser microprobe mass analysis of trace elements in brain mineralizations and capillaries in Fahr's disease.

Abstract: We report a detailed analysis of the content of aluminum, iron, zinc, copper, calcium, and magnesium in the non-vascular and pericapillary mineralizations and the normal capillaries of the globus pallidus and dentate nucleus of the cerebellum in two patients with clinically and neuropathologically confirmed Fahr's disease. The study employed laser microprobe mass analysis, a technique that enables highly sensitive detection of the levels of trace elements. In the globus pallidus, there was a significant increase in aluminum-, iron-, zinc-, and calcium-related peak intensity in the pericapillary and non-vascular mineralizations compared to the normal capillaries. The pericapillary and non-vascular mineralizations had comparable concentrations of these elements. No difference was found in copper levels between the different probe sites. Magnesium was almost absent in pericapillary mineralizations and normal capillaries, while it accumulated within non-vascular mineralizations. In the cerebellar dentate nucleus, non-vascular mineralizations displayed higher concentrations of all of these elements than normal capillaries, while pericapillary mineralizations had a higher aluminum and lower iron, copper, and calcium content than did non-vascular mineralizations. Zinc and magnesium were selectively deposited within the non-vascular mineralizations in this nucleus. Furthermore, the element composition of non-vascular mineralizations differed between the globus pallidus and dentate nucleus. These findings indicate that the formation of pericapillary and non-vascular mineralizations may be two independent phenomena which coexist in the course of Fahr's disease. The marked qualitative and quantitative differences in trace element content in non-vascular mineralizations between the globus pallidus and cerebellar dentate nucleus suggest that the involvement of trace elements in the pathogenesis of Fahr's disease is probably indirect.

Early-onset dementias: clinical, neuropathological and genetic characteristics

Abstract: The term “early-onset dementias” defines all dementing conditions with onset below 65 years of age [61]. Neurodegenerative disorders, cerebrovascular diseases, encephalitis, tumors, and cerebral traumas are the major clinical entities associated with massive cognitive decline in young and middle-aged individuals. Among them, neurodegenerative disorders represent the most frequent cause of early-onset dementia [54], and include early-onset Alzheimer’s disease (EOAD), Pick’s disease (PD), and dementia lacking distinctive histopathology (DLDH). The clinical distinction of these disorders is problematic. In spite of the introduction of formal clinical criteria for EOAD, the level of accuracy of this diagnosis remains low, particularly in young patients [111, 113]. Furthermore, PD and DLDH are indistinguishable clinically [22]. Neuropathological analysis is thus necessary to confirm the clinical diagnosis of early-onset dementia and elucidate the underlying pathogenetic processes [81]. The present review summarizes the main epidemiological, clinical, neuropathological, and genetic features of EOAD, PD, and DLDH with particular reference to clinicopathological correlations in familial and sporadic cases.

Apolipoprotein E in Guamanian amyotrophic lateral sclerosis/ parkinsonism-dementia complex: genotype analysis and relationships to neuropathological changes

Abstract: Apolipoprotein E (Apo E) has been recently identified within amyloid deposits and neurofibrillary tangles in the brains of Alzheimer's disease (AD) patients. A strong association of the Apo E e4 allele with higher risk of developing AD has also been reported. In the present study, the distribution of Apo E and the possible relationship between Apo E alleles and neuropathological alterations were analyzed in a series of Guamanian amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) cases, a neurodegenerative condition characterized neuropathologically by widespread, severe neurofibrillary tangle formation but rare amyloid deposits. ApoE immunoreactivity was consistently observed in both type of lesions in these cases. Compared to tau protein immunoreactivity, there were generally fewer Apo E-immunoreactive neurofibrillary tangles, particularly in the deep layers of the neocortex and in the hippocampus. Genotype analysis revealed that the e4 allele frequency was 5.9%, the e3 allele frequency 88.2%, and the e2 allele frequency 5.9% in this series. Recent data suggest that the Apo E4 variant may induce amyloidogenesis, while E2 could have a neuroprotective role. However, the rare Guamanian patients with amyloid deposits in cortical areas were not related to the e4 allele, since all cases with senile plaques were e3/e3. In addition, compared to unaffected Guamanian cases and other Asian-Pacific populations previously reported, the observed low frequency of the e2 allele in the present cases, which may be consistent with the notion that this allele, may represent a neuroprotective factor in several neurodegenerative disorders. The present data indicate that there is a strong interaction between Apo E deposition and neurofibrillary changes in Guamanian ALS-PDC.

GERIATRIC BIOSCIENCE: Hippocampal and Neocortical Involvement in Normal Brain Aging and Dementia: Morphological and Neurochemical Profile of the Vulnerable Circuits

Abstract: Alzheimer's disease (AD) is the most common form of dementia in older individuals. Approximately 11% of the population older than 65 and up to 50% of individuals older than 85 qualify as having \"probable AD\" on the basis of clinical evaluation. 1 Since the early description of the clinical symptoms and neuropathological features of AD, there has been an extraordinary growth in the knowledge of the morphological and molecular characteristics of AD. Although the pathogenetic events that lead to dementia are not yet fully understood, several hypotheses regarding the formation of the typical lesions of AD have been proposed. In this context, the use of specific histochemical techniques in the primate brain has greatly expanded our understanding of neuron typology, connectivity, and circuit distribution in relation to neurochemical identity. In particular, certain neuronal types within the cerebral cortex and some of the major cortical afferent systems have now been characterized as to the presence of key structural proteins and neurotransmitters. 5 In this article, we discuss the possible relationships between the distribution of pathological changes in AD and related dementing conditions and the localization of specific elements of the hippocampal and neocortical circuitry that are affected by these alterations. Also, evidence for links between the neurochemical phenotype of a given neuron and its relative vulnerability or resistance to the degenerative process are presented in order to correlate the distribution of cellular pathological changes, neurochemical characteristics related to vulnerability, and affected hippocampal and neocortical circuits. It should be kept in mind that several subcortical systems, in particular the monoaminergic and cholinergic systems in the brainstem that project to the cerebral cortex, are consistently affected in AD. Although the pro-