Biomedical subjects

P R Hof

Publications and source records attributed to P R Hof.

At least 19 recordsLinked to original sources

PubMed2000

Restoration of cognitive and motor functions by ciliary neurotrophic factor in a primate model of Huntington's disease.

Huntington's disease (HD) is an inherited disorder characterized by cognitive impairments, motor deficits, and progressive dementia. These symptoms result from progressive neurodegenerative changes mainly affecting the neostriatum. This pathology is fatal in 10 to 20 years and there is currently no treatment for HD. Early in the course of the disease, initial clinical manifestations are due to striatal neuronal dysfunction, which is later followed by massive neuronal death. A major therapeutic objective is therefore to reverse striatal dysfunction prior to cell death. Using a primate model reproducing the clinical features and the progressive neuronal degeneration typical of HD, we tested the therapeutic effects of direct intrastriatal infusion of ciliary neurotrophic factor (CNTF). To achieve a continuous delivery of CNTF over the full period of evaluation, we took advantage of the macroencapsulation technique. Baby hamster kidney (BHK) cells previously engineered to produce human CNTF were encapsulated into semipermeable membranes and implanted bilaterally into striata. We show here that intracerebral delivery of low doses of CNTF at the onset of symptoms not only protects neurons from degeneration but also restores neostriatal functions. CNTF-treated primates recovered, in particular, cognitive and motor functions dependent on the anatomofunctional integrity of frontostriatal pathways that were distinctively altered in this HD model. These results support the hypothesis that CNTF infusion into the striatum of HD patients not only could block the degeneration of neurons but also alleviated motor and cognitive symptoms associated with persistent neuronal dysfunction.

Animals↗

PubMed2000

Numbers of meynert and layer IVB cells in area V1: a stereologic analysis in young and aged macaque monkeys.

Visual impairments that are not related to optical changes are not uncommon during aging, and a number of psychophysical investigations have documented deficits in motion detection as well as in spatiotemporal contrast sensitivity in elderly people. However, little is known about the extent and nature of age-related changes in neural structure and how they may affect visual function in aging. To address this question, the authors analyzed the effect of aging on two well-characterized neuronal populations in the primary visual cortex (area V1) of macaque monkeys. Four young adult (ages, 7-11 years) and four aged (ages, 26-32 years) rhesus monkeys were analyzed. The animals were perfused, and their brains were prepared for immunohistochemistry with an antibody to neurofilament protein. Unbiased stereologic estimates of the total numbers of neurofilament protein-containing layer IVB cells and Meynert cells were obtained by using the optical fractionator method for the calcarine cortex and the opercular cortex separately. Stereologic estimates of the volume of these parts of area V1 also were calculated by using the Cavalieri principle. A considerable degree of interindividual variability in neuron numbers and cortical volume was observed among animals of both groups. However, there were no differences in either Meynert cell numbers or layer IVB cell numbers between the aged group and the young group. It is noteworthy that the oldest animal in the sample had the lowest numbers of Meynert cells, indicating that, despite the small size of the available sample, it is possible that some animals have a certain degree of neuronal loss in area V1 during aging. No change in the volume of area V1 was observed as a function of aging. These data suggest that the deficits that occur during aging in the visual system are not due to the loss of highly specific neocortical neuronal populations, such as those analyzed in this study. Rather, it is possible that more subtle alterations in the neurochemical characteristics or synaptic organization of the functional pathways subserving the different visual modalities are responsible for these deficits.

Age Factors↗

PubMed2000

Visual cortical projections and chemoarchitecture of macaque monkey pulvinar.

We investigated the patterns of projections from the pulvinar to visual areas V1, V2, V4, and MT, and their relationships to pulvinar subdivisions based on patterns of calbindin (CB) immunostaining and estimates of visual field maps (P(1), P(2) and P(3)). Multiple retrograde tracers were placed into V1, V2, V4, and/or MT in 11 adult macaque monkeys. The inferior pulvinar (PI) was subdivided into medial (PI(M)), posterior (PI(P)), central medial (PI(CM)), and central lateral (PI(CL)) regions, confirming earlier CB studies. The P(1) map includes PI(CL) and the ventromedial portion of the lateral pulvinar (PL), P(2) is found in ventrolateral PL, and P(3) includes PI(P), PI(M), and PI(CM). Projections to areas V1 and V2 were found to be overlapping in P(1) and P(2), but those from P(2) to V2 were denser than those to V1. V2 also received light projections from PI(CM) and, less reliably, from PI(M). Neurons projecting to V4 and MT were more abundant than those projecting to V1 and V2. Those projecting to V4 were observed in P(1), densely in P(2), and also in PI(CM) and PI(P) of P(3). Those projecting to MT were found in P(1)- P(3), with the heaviest projection from P(3). Projections from P(3) to MT and V4 were mainly interdigitated, with the densest to MT arising from PI(M) and the densest to V4 arising from PI(P) and PI(CM). Because the calbindin-rich and -poor regions of P(3) corresponded to differential patterns of cortical connectivity, the results suggest that CB may further delineate functional subdivisions in the pulvinar.

Animals↗

PubMed2000

Differential vulnerability of oculomotor, facial, and hypoglossal nuclei in G86R superoxide dismutase transgenic mice.

In recent years, several mouse models of amyotrophic lateral sclerosis (ALS) have been developed. One, caused by a G86R mutation in the superoxide dismutase-1 (SOD-1) gene associated with familial ALS, has been subjected to extensive quantitative analyses in the spinal cord. However, the human form of ALS includes pathology elsewhere in the nervous system. In the present study, analyses were extended to three motor nuclei in the brainstem. Mutant mice and control littermates were evaluated daily, and mutants, along with their littermate controls, were killed when they were severely affected. Brains were removed after perfusion and processed for Nissl staining, the samples were randomized, and the investigators were blinded to their genetic status. Stereologic methods were used to estimate the number of neurons, mean neuronal volumes, and nuclear volume in three brainstem motor nuclei known to be differentially involved in the human form of the disease, the oculomotor, facial, and hypoglossal nuclei. In the facial nucleus, neuron number consistently declined (48%), an effect that was correlated with disease severity. The nuclear volume of the facial nucleus was smaller in the SOD-1 mutant mice (45.7% difference from control mice) and correlated significantly with neuron number. The oculomotor and hypoglossal nuclei showed less extreme involvement (<10% neuronal loss overall), with a trend toward fewer neurons in the hypoglossal nucleus of animals with severe facial nucleus involvement. In the oculomotor nucleus, neuronal loss was seen only once in five mice, associated with very severe disease. There was no significant change in the volume of individual neurons in any of these three nuclei in any transgenic mouse. These results suggest that different brainstem motor nuclei are differentially affected in this SOD-1 mutant model of ALS. The relatively moderate and late involvement of the hypoglossal nucleus indicates that, although the general patterns of neuronal pathology match closely those seen in ALS patients, some differences exist in this transgenic model compared with the progression of the disease in humans. However, these patterns of cellular vulnerability may provide clues for understanding the differential susceptibility of neural structures in ALS and other neurodegenerative diseases.

Amino Acid Substitution↗

PubMed2000

Neuronal subclass-selective loss of pyruvate dehydrogenase immunoreactivity following canine cardiac arrest and resuscitation.

Chronic impairment of aerobic energy metabolism accompanies global cerebral ischemia and reperfusion and likely contributes to delayed neuronal cell death. Reperfusion-dependent inhibition of pyruvate dehydrogenase complex (PDHC) enzyme activity has been described and proposed to be at least partially responsible for this metabolic abnormality. This study tested the hypothesis that global cerebral ischemia and reperfusion results in the loss of pyruvate dehydrogenase immunoreactivity and that such loss is associated with selective neuronal vulnerability to transient ischemia. Following 10 min canine cardiac arrest, resuscitation, and 2 or 24 h of restoration of spontaneous circulation, brains were either perfusion fixed for immunohistochemical analyses or biopsy samples were removed for Western immunoblot analyses of PDHC immunoreactivity. A significant decrease in immunoreactivity was observed in frontal cortex homogenates from both 2 and 24 h reperfused animals compared to samples from nonischemic control animals. These results were supported by confocal microscopic immunohistochemical determinations of pyruvate dehydrogenase immunoreactivity in the neuronal cell bodies located within different layers of the frontal cortex. Loss of immunoreactivity was greatest for pyramidal neurons located in layer V compared to neurons in layers IIIc/IV, which correlates with a greater vulnerability of layer V neurons to delayed death caused by transient global cerebral ischemia.

Animals↗

PubMed2000

Clinical validity of Braak neuropathological staging in the oldest-old.

Several studies have demonstrated a good correlation between clinical severity and Braak's neuropathological staging in Alzheimer's disease (AD). However, nonagenarians and centenarians display a different pattern of cortical vulnerability to the neurodegenerative process compared to younger elderly, and it is not known whether correlations between clinical severity and neuropathological stages remain valid in this age group. To address this issue we compared Clinical Dementia Rating scale (CDR) scores and Braak stages in 116 patients over 90 years of age with either no cognitive impairment or very mild to severe AD. There is a strong positive correlation between CDR scores and Braak staging (Spearman coefficient = 0.66; P < 0.01). However, neuropathological staging does not distinguish cases with normal cognition (CDR 0) from those with mild cognitive changes (CDR 0.5). Unlike younger cohorts, Braak stages I and II are frequently associated with questionable dementia in this age group. Braak stage III overlaps with all CDR levels and correlates poorly with cognitive function. Braak stages IV or greater are consistently associated with at least mild dementia. Consistent with our previous neuropathological analyses of nonagenarians and centenarians, the present data suggest that the substantial involvement of the hippocampus which characterizes Braak stage IV is a key step in the development of overt clinical signs of dementia in the oldest-old. Moreover, they indicate that Braak staging represents a broad concept of the evolution of neurofibrillary tangles rather than a precise hierarchical model associated with a stepwise deterioration of cognitive abilities near the upper limit of life.

Aged↗

PubMed2000

Targeted disruption of the dopamine D(2) and D(3) receptor genes leads to different alterations in the expression of striatal calbindin-D(28k).

The present study used mice deficient for dopamine D(2) and D(3) receptors to test whether the expression of these two members of the D(2) class of receptors is essential for the normal expression of three markers that characterize the neurochemical differentiation of the striatum: the calcium-binding protein calbindin, tyrosine hydroxylase and acetylcholinesterase. Results from these experiments revealed that the expression of striatal tyrosine hydroxylase (the rate-limiting enzyme of dopamine synthesis) and acetylcholinesterase is unaffected even by the combined knockout of D(2) and D(3) receptors. However, D(2) and D(3) receptor knockouts differently affect the striatal expression of calbindin-D(28k) immunoreactivity. Prominent changes in the cellular distribution of calbindin are detected in striatal neurons of D(2) mutant mice. Whereas calbindin immunolabeling of wild-type neurons is prominent in the nuclei and the cytoplasm of medium spiny neurons, in D(2) mutant mice, calbindin immunoreactivity is concentrated exclusively in the cytoplasmic rim of these neurons. Such changes in the cellular distribution of calbindin expression are not detected in mice lacking D(3) receptors. In these mutants, however, a lesser density of calbindin-immunoreactive neuropil is detected in the ventral portions of the striatum, i.e. in regions in which D(3) receptors are thought to be expressed at highest levels. Mice lacking both D(2) and D(3) receptors show both phenotypes. The altered cellular distribution of calbindin in D(2) mutants is likely to have functional consequences for some of the Ca(2+)-mediated cellular functions. The topography of the decreased density of striatal calbindin immunorectivity in D(3) mutants suggests a role for D(3) receptors in supporting the expression of striatal calbindin. The observation that mice lacking both D(2) and D(3) receptors show a combination of the D(2) and D(3) mutant phenotypes indicates that each of the different phenotypes detected in the single mutants is indeed related to the lack of the two different D(2)-like receptor subtypes.

Acetylcholinesterase↗

PubMed1999

Neurodegenerative diseases of Guam: analysis of TAU.

Mutations in the tau gene have been described in families affected by frontotemporal dementia with parkinsonism linked to chromosome 17. The authors performed a genetic and biochemical analysis of this gene and its product in the parkinsonism dementia complex of Guam, a disorder characterized by the extensive formation of neurofibrillary tangles. The tau gene is not a primary cause of the parkinsonism dementia complex of Guam.

Aged↗

PubMed1999

A neuronal morphologic type unique to humans and great apes.

We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal possible adaptive changes and functional modifications over the last 15-20 million years in the anterior cingulate cortex, a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes. That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer's disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related dementing illnesses may have appeared only recently during primate evolution.

Alzheimer Disease↗

PubMed1999

Neuroanatomic correlates of visual agnosia in Alzheimer's disease: a clinicopathologic study.

OBJECTIVE: To examine the neuroanatomic correlates of visual agnosia in AD. METHODS: The authors performed an anterograde clinicopathologic study of 23 patients with clinically and neuropathologically confirmed AD in a 305-bed acute care geriatric hospital and a 165-bed acute care psychiatric hospital. The presence of apperceptive visual agnosia was assessed using the Ghent's overlapping figure test and the Gottschaldt's hidden figure test. Associative visual agnosia was examined using the conceptual items of the Columbia Mental Maturity Test. Correlations between neurofibrillary tangle (NFT) and senile plaque (SP) densities and visual agnosia were studied using forward stepwise logistic regression. RESULTS: A statistically significant relation was found between NFT densities in Brodmann's areas 18, 19, and 37, and associative visual agnosia, whereas NFT densities in the areas studied did not correlate with the presence of apperceptive visual agnosia. Senile plaque counts did not correlate with any of the neuropsychological parameters. CONCLUSIONS: These results support the existence of a dichotomy between associative and apperceptive agnosia, and show that only the former is related to the damage of secondary and high-order visual association areas in AD. In addition, the results suggest that SP densities do not represent a valuable pathologic correlate of visual agnosia in this disorder.

Aged↗

PubMed1999

Preservation of prefrontal cortical volume in behaviorally characterized aged macaque monkeys.

Normal aging is frequently accompanied by a decline in cognitive capacities supported by the prefrontal cortex. The principal aim of the present study was to determine whether these impairments are coupled to morphometric alterations affecting the volume of the prefrontal cortex in an established nonhuman primate model. A large sample of 19 young (4-11 years old) and 40 aged (20-32 years old) rhesus monkeys was tested using a delayed response procedure known to require the functional integrity of area 46 of the prefrontal cortex. Aged monkeys displayed robust delayed response deficits that were specifically related to the demands of testing on memory. Modern stereological methods were then used to estimate the total volume of area 46 and the volume of layer I in brains from 21 young and aged monkeys. Prefrontal cortex volume was entirely preserved in the aged monkeys as a group and among the subset of aged subjects that displayed the most severe behavioral impairment. These findings indicate that gross morphometric alterations affecting cortical volume are unlikely to account for age-related decline in the information processing capacities of area 46 in primates. Taken together, current evidence instead suggests that changes in the functional connectivity of critical cortical circuits may contribute to normal cognitive aging.

Aging↗

PubMed1999

Phosphorylated serine422 on tau proteins is a pathological epitope found in several diseases with neurofibrillary degeneration.

Neuronal inclusions with bundles of abnormal filaments made of tau polymers are found in numerous diseases with neurofibrillary degeneration. Tau proteins are the basic components of paired helical filaments (PHF) in Alzheimer's disease (AD), and are abnormally phosphorylated. A disease-specific phosphorylation site at serine422 was demonstrated on PHF, but not on tau proteins from biopsy-derived brain samples. In the present study, we report the characterization of a polyclonal antibody (988) against the serine422 phosphorylation site. By using biochemical and immunohistochemical methods, we confirmed that it is not found on tau proteins from biopsy- or autopsy-derived control samples, and we investigated the presence of this epitope on tau proteins in several neurodegenerative disorders, including AD, Down syndrome (DS), Guamanian amyotrophic lateral sclerosis/Parkinsonism-dementia complex (ALS/PDC), corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), postencephalitic parkinsonism (PEP) and Pick's disease (PiD). By Western blotting, antibody 988 labeled the characteristic tau triplet (tau 55, 64, 69) in AD, DS, Guamanian ALS/PDC and PEP. PSP and CBD exhibited their typical tau doublet (tau 64, 69), whereas the doublet tau 55 and 64 was detected in PiD. In all of these neurodegenerative disorders, antibody 988 clearly labeled NFT and dystrophic neurites, as well as Pick bodies in PiD cases, whereas no staining was observed in control cases. These data indicate that phosphorylation of serine422 on tau proteins is a common feature among neurodegenerative disorders and is therefore not specific of AD. Moreover, phosphorylation of this epitope permits the distinction between normal tau proteins and pathological tau proteins.

Adult↗

PubMed1999

Differential distribution of presenilin-1, Bax, and Bcl-X(L) in Alzheimer's disease and frontotemporal dementia.

We have previously reported that presenilin-1 (PS-1)-immunoreactive neurons survive in late-onset sporadic Alzheimer's disease (AD). To examine if this is also the case in other dementing conditions, and if it is associated with changes in the expression of the main apoptosis-related proteins, a quantitative immunocytochemical study of presenilin-1, Bax, and Bcl-X(L) in the cerebral cortex of non-demented and AD patients, and patients with frontotemporal dementia (FTD) was performed. In non-demented cases, the frequency of neurons showing PS-1 immunoreactivity was 25-60%, Bax immunoreactivity 36-54%, and Bcl-X(L) immunoreactivity 26-63% depending on the cortical area. The frequency of NFT-free neurons which contained PS-1 or Bax was consistently increased in all of the areas in AD. In FTD cases, the percentage of PS-I-, but not Bax-immunoreactive neurons was increased only in areas displaying a substantial neuronal loss. Conversely, there was no difference in the densities of Bcl-X(L)-containing neurons among the three diagnosis groups. These data suggest that surviving neurons in affected cortical areas in AD show a high expression of PS-1 and Bax, indicating that these proteins play a key role in the mechanisms of cell death in this disorder. In FTD, neurons containing PS-1 are preserved, further supporting a neuroprotective role for this protein in other neurodegenerative disorders.

Aged↗

PubMed1999

Presenilin-1 expression in Pick's disease.

Recent studies have reported that neuronal populations expressing low levels of presenilin-1 (PS-1) display increased vulnerability in late-onset sporadic Alzheimer's disease (AD). To examine whether this phenomenon also occurs in other neurodegenerative diseases, we performed a quantitative immunocytochemical study of PS-1 distribution in the cerebral cortex of Pick's disease (PiD) cases and non-demented individuals. In PiD cases, the percentage of PS-1-containing, Pick body (PB)-free neurons was significantly elevated only in cortical areas showing neuronal loss. In these areas, PS-1 levels, measured by immunoblotting, were often higher in PiD compared to non-demented cases. Moreover, PS-1 immunoreactivity was significantly reduced in PB-containing neurons. These data suggest that as previously shown in AD, low cellular expression of PS-1 may be associated with increased neuronal loss and cellular degeneration.

Aged↗

PubMed1999

Cellular distribution of the calcium-binding proteins parvalbumin, calbindin, and calretinin in the neocortex of mammals: phylogenetic and developmental patterns.

The three calcium-binding proteins parvalbumin, calbindin, and calretinin are found in morphologically distinct classes of inhibitory interneurons as well as in some pyramidal neurons in the mammalian neocortex. Although there is a wide variability in the qualitative and quantitative characteristics of the neocortical subpopulations of calcium-binding protein-immunoreactive neurons in mammals, most of the available data show that there is a fundamental similarity among the mammalian species investigated so far, in terms of the distribution of parvalbumin, calbindin, and calretinin across the depth of the neocortex. Thus, calbindin- and calretinin-immunoreactive neurons are predominant in layers II and III, but are present across all cortical layers, whereas parvalbumin-immunoreactive neurons are more prevalent in the middle and lower cortical layers. These different neuronal populations have well defined regional and laminar distribution, neurochemical characteristics and synaptic connections, and each of these cell types displays a particular developmental sequence. Most of the available data on the development, distribution and morphological characteristics of these calcium-binding proteins are from studies in common laboratory animals such as the rat, mouse, cat, macaque monkey, as well as from postmortem analyses in humans, but there are virtually no data on other species aside of a few incidental reports. In the context of the evolution of mammalian neocortex, the distribution and morphological characteristics of calcium-binding protein-immunoreactive neurons may help defining taxon-specific patterns that may be used as reliable phylogenetic traits. It would be interesting to extend such neurochemical analyses of neuronal subpopulations to other species to assess the degree to which neurochemical specialization of particular neuronal subtypes, as well as their regional and laminar distribution in the cerebral cortex, may represent sets of derived features in any given mammalian order. This could be particularly interesting in view of the consistent differences in neurochemical typology observed in considerably divergent orders such as cetaceans and certain families of insectivores and metatherians, as well as in monotremes. The present article provides an overview of calcium-binding protein distribution across a large number of representative mammalian species and a review of their developmental patterns in the species where data are available. This analysis demonstrates that while it is likely that the developmental patterns are quite consistent across species, at least based on the limited number of species for which ontogenetic data exist, the distribution and morphology of calcium-binding protein-containingneurons varies substantially among mammalian orders and that certain species show highly divergent patterns compared to closely related taxa. Interestingly, primates, carnivores, rodents and tree shrews appear closely related on the basis of the observed patterns, marsupials show some affinities with that group, whereas prototherians have unique patterns. Our findings also support the relationships of cetaceans and ungulates, and demonstrates possible affinities between carnivores and ungulates, as well as the existence of common, probably primitive, traits in cetaceans and insectivores.

Animals↗

PubMed1998

Selective vulnerability of neocortical association areas in Alzheimer's disease.

This article reviews the possible relationships between the localization of cellular pathologic changes in Alzheimer's disease (AD), and the distribution of neuronal components of the neocortical circuitry that are affected by these alterations. In particular, evidence from the study of large autopsy series supporting the role of the inferior temporal cortex as a key area in the progression of the dementing process is presented. The notion of selective vulnerability in AD at the level of affected neocortical association areas, layers, and specific cell populations is discussed to provide insight into the molecular background of the development of neurofibrillary tangles within the cerebral cortex. Moreover, recent data on pathological correlates of apraxia in AD are examined in the light of the hypothesis of global corticocortical disconnection in this disorder.

Age Factors↗

PubMed1998

Pathologic correlates of apraxia in Alzheimer disease.

OBJECTIVE: To examine the neuroanatomical correlates of apraxia in Alzheimer disease. PATIENTS: Twenty-three patients with clinically overt Alzheimer disease. DESIGN: Anterograde study and neuropathologic case series. Clinical severity was assessed using the Global Deterioration Scale. Ideomotor praxis was examined on transitive and intransitive movements and meaningless gestures, and dressing ability was evaluated clinically. Constructive praxis was tested using a 3-dimensional figure copying task. Correlations between neurofibrillary tangle and senile plaque densities and praxis test performance were studied using stepwise logistic regression models. SETTING: Studies were conducted at the Psychiatric and Geriatric Hospitals of the University of Geneva School of Medicine, Geneva, Switzerland. MAIN OUTCOME MEASURES: Odds ratios to estimate the associations between neurofibrillary tangle and senile plaque densities in each neocortical area and the presence of ideomotor, dressing, and constructional apraxia. RESULTS: Statistically significant relationships were found between neurofibrillary tangle densities in the anterior cingulate cortex and ideomotor and dressing apraxia and between neurofibrillary tangle densities in the superior parietal, posterior cingulate, and occipital cortex and constructional apraxia. Senile plaque counts did not correlate with praxic performance. CONCLUSIONS: These results suggest that ideomotor and dressing apraxia are associated with mild damage of the anterior cingulate cortex, whereas constructional apraxia is related to the disruption of cortical pathways mediating visuospatial cognition in Alzheimer disease. Senile plaque densities do not represent a valuable pathologic correlate of apraxia in this disorder.

Aged↗

PubMed1998

Determinants of neuronal vulnerability in neurodegenerative diseases.

Selective neuronal vulnerability can be defined anatomically by the differential vulnerability of circuits and neurochemically by the vulnerability of neurons that differentially express particular proteins. The anatomic perspective is exemplified by the vulnerability of the nigrostriatal projection in Parkinson's disease (PD), the degeneration of upper and lower motor neurons in amyotrophic lateral sclerosis (ALS), and the preferential loss of long corticocortical projections in Alzheimer's disease (AD). The neurochemical perspective is reflected in the heightened vulnerability of neurons that normally express high somatodendritic levels of neurofilament (eg, entorhinal and association cortices in AD, the spinal cord in a mouse model of ALS, and the retina in a primate model of glaucoma), as well as the reduced vulnerability of neurons that express calcium-binding proteins (eg, neocortex of AD patients, the spinal cord and brainstem of ALS patients, and the spinal cord of a mouse model of ALS). By combining neurochemical and anatomic correlates of vulnerability, an integrated view of vulnerable neurons is emerging in which characteristics of vulnerable neurons appear to transcend both brain region and disease state, suggesting that neurodegenerative disorders share common mechanisms of degeneration.

Alzheimer Disease↗