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Biomedical subjects

Patrick R Hof

Publications and source records attributed to Patrick R Hof.

At least 55 records · Page 3Linked to original sources

Environmental reduplicative paramnesia in a case of atypical Alzheimer's disease.

A 79-year-old patient with neuropathologically confirmed Alzheimer's disease (AD) presented with a selective environmental reduplicative paramnesia (RP), the belief that one or more environments exist simultaneously in two or more physical locations. Clinical presentation and neuropathological examination revealed an atypical form of AD. High neurofibrillary tangle densities were observed in the frontal and temporal association cortex, whereas the parietal and entorhinal cortex, as well as the hippocampus, were nearly spared. These findings are compared to those reported in frontal and frontotemporal variants of AD and discussed in the light of current anatomoclinical models for environmental RP.

Activities of Daily Living↗

Evolution of the brainstem orofacial motor system in primates: a comparative study of trigeminal, facial, and hypoglossal nuclei.

The trigeminal motor (Vmo), facial (VII), and hypoglossal (XII) nuclei of the brainstem comprise the final common output for neural control of most orofacial muscles. Hence, these cranial motor nuclei are involved in the production of adaptive behaviors such as feeding, facial expression, and vocalization. We measured the volume and Grey Level Index (GLI) of Vmo, VII, and XII in 47 species of primates and examined these nuclei for scaling patterns and phylogenetic specializations. Allometric regression, using medulla volume as an independent variable, did not reveal a significant difference between strepsirrhines and haplorhines in the scaling of Vmo volume. In addition, correlation analysis using independent contrasts did not find a relationship between Vmo size or GLI and the percent of leaves in the diet. The scaling trajectory of VII volume, in contrast, differed significantly between suborders. Great ape and human VII volumes, furthermore, were significantly larger than predicted by the haplorhine regression. Enlargement of VII in these taxa may reflect increased differentiation of the facial muscles of expression and greater utilization of the visual channel in social communication. The independent contrasts of VII volume and GLI, however, were not correlated with social group size. To examine whether the human hypoglossal motor system is specialized to control the tongue for speech, we tested human XII volume and GLI for departures from nonhuman haplorhine prediction lines. Although human XII volumes were observed above the regression line, they did not exceed prediction intervals. Of note, orang-utan XII volumes had greater residuals than humans. Human XII GLI values also did not differ from allometric prediction. In sum, these findings indicate that the cranial orofacial motor nuclei evince a mosaic of phylogenetic specializations for innervation of the facial muscles of expression in the context of a generally conservative scaling relationship with respect to medulla size.

Animals↗

Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention.

Mice lacking dopamine D2 and D3 receptors and wildtype littermates were tested in a two-choice perceptual discrimination test that is dependent upon optimal functioning of the prefrontal cortex. Both mutants showed no deficits in attending to the perceptual stimuli or in shifting attention between stimulus dimensions. However, the performance of both mutants differed from the wildtype in different test phases. D2 mutants exhibited significant impairment in the first compound discrimination, indicating deficits in the initial acquisition of the task-governing rules. In contrast, D3 mutants performed significantly better in a set-shifting phase that required reversal learning. The higher response accuracy of D3 mutants was also accompanied by significantly increased response latency. A stereological assessment of test-induced expression of the c-fos gene in neurons of the anterior cingulate and prelimbic/infralimbic cortices revealed highest activation in D3 mutants, intermediate activation in wildtype and lowest activation in D2 mutants, indicating that response accuracy in the cognitive test correlates with the magnitude of prefrontal cortical activation regardless of which test phases revealed different performances. The study illustrates that dopamine differentially modulates prefrontal cortical activity during tasks requiring attention depending upon the type of D2-like receptor that is activated.

Animals↗

Humoral immunity in brain aging and Alzheimer's disease.

Although the contribution of inflammatory processes in the etiology of late-onset Alzheimer's disease (AD) has been suspected for years, most studies were confined to the analysis of cell-mediated immunological reactions thought to represent an epiphenomenon of AD lesion development. Based on the traditional view of the "immunological privilege" of the brain, which excludes a direct access of human immunoglobulins (Ig) to the central nervous system under normal conditions, little attention has been paid to a possible role of humoral immunity in AD pathogenesis. In the first part of this review, we summarize evidences for a blood-brain barrier (BBB) dysfunction in this disorder and critically comment on earlier observations supporting the presence of anti-brain autoantibodies and immunoglobulins (Ig) in AD brains. Current concepts regarding the Ig turnover in the central nervous system and the mechanisms of glial and neuronal Fc receptors activation are also discussed. In the second part, we present new ex vivo and in vitro data suggesting that human immunoglobulins can interact with tau protein and alter both the dynamics and structural organization of microtubules. Subsequent experiments needed to test this new working hypothesis are addressed at the end of the review.

Aging↗

Neuropathological findings in autism.

Autism is currently viewed as a largely genetically determined neurodevelopmental disorder, although its underlying biological causes remain to be established. In this review, we examine the available neuropathological literature on autism and discuss the findings that have emerged. Classic neuropathological observations are rather consistent with respect to the limbic system (nine of 14 studied cases showed increased cell packing density and smaller neuronal size), the cerebellum (21 of 29 studied cases showed a decreased number of Purkinje cells, and in all of five cases that were examined for age-related morphological alterations, these changes were found in cerebellar nuclei and inferior olive) and the cerebral cortex (>50% of the studied cases showed features of cortical dysgenesis). However, all reported studies had to contend with the problem of small sample sizes, the use of quantification techniques not free of bias and assumptions, and high percentages of autistic subjects with comorbid mental retardation (at least 70%) or epilepsy (at least 40%). Furthermore, data from the limbic system and on age-related changes lack replication by independent groups. It is anticipated that future neuropathological studies hold great promise, especially as new techniques such as design-based stereology and gene expression are increasingly implemented and combined, larger samples are analysed, and younger subjects free of comorbidities are investigated.

Adolescent↗

Interlaminar astroglial processes in the cerebral cortex of great apes.

The present study was designed to document the architecture of neocortical astroglia in great apes, following glial fibrillary acidic protein immunohistochemistry. These anthropoid species were missing from previous phylogenetic descriptions of astroglia with interlaminar processes, a characteristic event of the cerebral cortex within the Primate Order. Pongo pygmaeus (orangutan), Gorilla gorilla (gorilla) and Pan troglodytes (chimpanzee) brain samples showed the typical "palisade" of interlaminar processes. Yet, those from Pan troglodytes were less uniform, showing extended cortical segments with astrocytic ("syncytial-type") appearance, intermingled with segments expressing the interlaminar "palisade". Present observations contribute to fill in missing data on the phylogenetic emergence of the cerebral cortex astroglial interlaminar processes. Considering the extreme consistency of the expression of astroglial interlaminar "palisades" among anthropoid species, this apparent variability among Pan individuals could be due to various possibilities, which are considered in this report.

Animals↗

Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease.

Recent epidemiological evidence indicates that insulin resistance, a proximal cause of Type II diabetes [a non-insulin dependent form of diabetes mellitus (NIDDM)], is associated with an increased relative risk for Alzheimer's disease (AD). In this study we examined the role of dietary conditions leading to NIDDM-like insulin resistance on amyloidosis in Tg2576 mice, which model AD-like neuropathology. We found that diet-induced insulin resistance promoted amyloidogenic beta-amyloid (Abeta) Abeta1-40 and Abeta1-42 peptide generation in the brain that corresponded with increased gamma-secretase activities and decreased insulin degrading enzyme (IDE) activities. Moreover, increased Abeta production also coincided with increased AD-type amyloid plaque burden in the brain and impaired performance in a spatial water maze task. Further exploration of the apparent interrelationship of insulin resistance to brain amyloidosis revealed a functional decrease in insulin receptor (IR)-mediated signal transduction in the brain, as suggested by decreased IR beta-subunit (IRbeta) Y1162/1163 autophosphorylation and reduced phosphatidylinositol 3 (PI3)-kinase/pS473-AKT/Protein kinase (PK)-B in these same brain regions. This latter finding is of particular interest given the known inhibitory role of AKT/PKB on glycogen synthase kinase (GSK)-3alpha activity, which has previously been shown to promote Abeta peptide generation. Most interestingly, we found that decreased pS21-GSK-3alpha and pS9-GSK-3beta phosphorylation, which is an index of GSK activation, positively correlated with the generation of brain C-terminal fragment (CTF)-gamma cleavage product of amyloid precursor protein, an index of gamma-secretase activity, in the brain of insulin-resistant relative to normoglycemic Tg2576 mice. Our study is consistent with the hypothesis that insulin resistance may be an underlying mechanism responsible for the observed increased relative risk for AD neuropathology, and presents the first evidence to suggest that IR signaling can influence Abeta production in the brain.

Alzheimer Disease↗

Occurrence of alpha-synuclein pathology in the cerebellum of Guamanian patients with parkinsonism-dementia complex.

Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a progressive neurodegenerative disease affecting the indigenous Chamorro population of Guam. Neuropathologically, PDC is characterized by neuronal loss in the substantia nigra pars compacta with severe widespread neurofibrillary tangles (NFTs) similar to those observed in Alzheimer's disease (AD), and is thus considered a tauopathy. Following reports of alpha-synuclein pathology in PDC patients of Guam, PDC has also been neuropathologically classified as a synucleinopathy. Recently, the presence of alpha-synuclein-positive bodies has been reported in the cerebellum of some patients with Parkinson's disease (PD), diffuse Lewy body disease (DLBD), or multiple system atrophy (MSA). Using immunohistochemical techniques, we investigated the deposition of alpha-synuclein in the cerebellum of Guamanian PDC patients. Numerous alpha-synuclein-immunoreactive spherical structures were found in the molecular layer of the cerebellum of 63.6% of PDC patients. These structures were only seen in patients showing alpha-synuclein pathology in the amygdala. The average density of alpha-synuclein-immunoreactive structures in the cerebellum of Guamanian PDC patients was almost an order of magnitude higher than in non-Guamanian PD patients, and this alpha-synuclein pathology was much more pronounced in the hemisphere than in the vermis. In addition, double immunohistochemistry revealed that cerebellar alpha-synuclein is co-localized with the neuronal marker calbindin and with glial-fibrillary acidic protein, suggesting the involvement of Purkinje cells and Bergmann glia. These findings demonstrate that the alpha-synuclein pathology in PDC of Guam affects not only the amygdala, but also the cerebellum, where it appears to involve both Purkinje cells and specialized astrocytes.

Aged↗

Sister grouping of chimpanzees and humans as revealed by genome-wide phylogenetic analysis of brain gene expression profiles.

Gene expression profiles from the anterior cingulate cortex (ACC) of human, chimpanzee, gorilla, and macaque samples provide clues about genetic regulatory changes in human and other catarrhine primate brains. The ACC, a cerebral neocortical region, has human-specific histological features. Physiologically, an individual's ACC displays increased activity during that individual's performance of cognitive tasks. Of approximately 45,000 probe sets on microarray chips representing transcripts of all or most human genes, approximately 16,000 were commonly detected in human ACC samples and comparable numbers, 14,000-15,000, in gorilla and chimpanzee ACC samples. Phylogenetic results obtained from gene expression profiles contradict the traditional expectation that the non-human African apes (i.e., chimpanzee and gorilla) should be more like each other than either should be like humans. Instead, the chimpanzee ACC profiles are more like the human than like the gorilla; these profiles demonstrate that chimpanzees are the sister group of humans. Moreover, for those unambiguous expression changes mapping to important biological processes and molecular functions that statistically are significantly represented in the data, the chimpanzee clade shows at least as much apparent regulatory evolution as does the human clade. Among important changes in the ancestry of both humans and chimpanzees, but to a greater extent in humans, are the up-regulated expression profiles of aerobic energy metabolism genes and neuronal function-related genes, suggesting that increased neuronal activity required increased supplies of energy.

Animals↗

Cortical microinfarcts and demyelination significantly affect cognition in brain aging.

BACKGROUND AND PURPOSE: Microvascular lesions are common in brain aging, but their clinical impact is debated. Methodological problems such as the masking effect of concomitant pathologies may explain discrepancies among previous studies. To evaluate the cognitive consequences of such lesions, we prospectively investigated elderly individuals with various degrees of cognitive impairment but without significant neurofibrillary tangle pathology or macrovascular lesions. METHODS: This was a clinicopathological study of 45 elderly individuals. Cognitive status was assessed prospectively with the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included Abeta-protein deposition staging and bilateral semiquantitative assessment of cortical microinfarcts, focal cortical and white matter glioses, and diffuse white matter and periventricular demyelination. RESULTS: In a univariate logistic regression model, cortical microinfarcts explained 36.1% of the variability in CDR; periventricular demyelination, 10.6%; and diffuse white matter demyelination, 4.6%. After controlling for age and Abeta-protein deposition, cortical microinfarcts were the best predictor of cognitive status (19.9% of CDR variability), whereas periventricular and diffuse white matter demyelination accounted for 9.7% and 5.4% of CDR variability, respectively. Altogether, these 3 types of microvascular lesions explained 27.9% of the clinical variability. Focal cortical and white matter glioses were not related to clinical outcome. CONCLUSIONS: Our data imply that cortical microinfarcts and both periventricular and deep white matter demyelination contribute significantly to the progression of cognitive deficits in brain aging. In contrast, the neuropathological evaluation of focal cortical and white matter gliosis has no clinical validity.

Aged↗

Brain structure variation in great apes, with attention to the mountain gorilla (Gorilla beringei beringei).

This report presents data regarding the brain structure of mountain gorillas (Gorilla beringei beringei) in comparison with other great apes. Magnetic resonance (MR) images of three mountain gorilla brains were obtained with a 3T scanner, and the volume of major neuroanatomical structures (neocortical gray matter, hippocampus, thalamus, striatum, and cerebellum) was measured. These data were included with our existing database that includes 23 chimpanzees, three western lowland gorillas, and six orangutans. We defined a multidimensional space by calculating the principal components (PCs) from the correlation matrix of brain structure fractions in the well-represented sample of chimpanzees. We then plotted data from all of the taxa in this space to examine phyletic variation in neural organization. Most of the variance in mountain gorillas, as well as other great apes, was contained within the chimpanzee range along the first two PCs, which accounted for 61.73% of the total variance. Thus, the majority of interspecific variation in brain structure observed among these ape taxa was no greater than the within-species variation seen in chimpanzees. The loadings on PCs indicated that the brain structure of great apes differs among taxa mostly in the relative sizes of the striatum, cerebellum, and hippocampus. These findings suggest possible functional differences among taxa in terms of neural adaptations for ecological and locomotor capacities. Importantly, these results fill a critical gap in current knowledge regarding great ape neuroanatomical diversity.

Animals↗

Neuroanatomy of the killer whale (Orcinus orca) from magnetic resonance images.

This article presents the first series of MRI-based anatomically labeled sectioned images of the brain of the killer whale (Orcinus orca). Magnetic resonance images of the brain of an adult killer whale were acquired in the coronal and axial planes. The gross morphology of the killer whale brain is comparable in some respects to that of other odontocete brains, including the unusual spatial arrangement of midbrain structures. There are also intriguing differences. Cerebral hemispheres appear extremely convoluted and, in contrast to smaller cetacean species, the killer whale brain possesses an exceptional degree of cortical elaboration in the insular cortex, temporal operculum, and the cortical limbic lobe. The functional and evolutionary implications of these features are discussed.

Animals↗

The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice.

The functions of presenilin 1 (PS1) and how PS1 mutations cause familial Alzheimer's disease (FAD) are incompletely understood. PS1 expression is essential for neurogenesis during embryonic development and may also influence neurogenesis in adult brain. We examined how increasing PS1 expression or expressing an FAD mutant would affect neurogenesis in the adult hippocampus. A neuron-specific enolase (NSE) promoter was used to drive neuronal overexpression of either wild-type human PS1 or the FAD mutant P117L in transgenic mice, and the animals were studied under standard-housing conditions or after environmental enrichment. As judged by bromodeoxyuridine (BrdU) labeling, neural progenitor proliferation rate was mostly unaffected by increasing expression of either wild-type or FAD mutant PS1. However, in both housing conditions, the FAD mutant impaired the survival of BrdU-labeled neural progenitor cells leading to fewer new beta-III-tubulin-immunoreactive neurons being generated in FAD mutant animals during the 4-week postlabeling period. The effect was FAD mutant specific in that neural progenitor survival and differentiation in mice overexpressing wild-type human PS1 were similar to nontransgenic controls. Two additional lines of PS1 wild-type and FAD mutant transgenic mice showed similar changes indicating that the effects were not integration site-dependent. These studies demonstrate that a PS1 FAD mutant impairs new neuron production in adult hippocampus by decreasing neural progenitor survival. They also identify a new mechanism whereby PS1 FAD mutants may impair normal neuronal function and may have implications for the physiological functioning of the hippocampus in FAD.

Alzheimer Disease↗

The aging brain: morphomolecular senescence of cortical circuits.

The human brain is uniquely powerful with respect to cognitive abilities, yet the hippocampal and neocortical circuits that mediate such complex functions are highly vulnerable to aging. Their selective vulnerability is profoundly manifested in Alzheimer's disease (AD), where degeneration of select neurons leads to a near complete loss of cognitive abilities. Most of us will avoid AD as we age. However, many will experience age-associated cognitive impairment - a decline in cognitive status presenting as deficits in memory and key capacities for strategic use of acquired information. Animal studies suggest that both AD and age-associated cognitive impairment reflect vulnerability of the same circuits. However, neuron death predominates in the former, whereas the latter is probably mediated by synaptic alterations in otherwise intact circuits. Fortunately, such age-related synaptic alterations could be reversible, as suggested by recent studies of hormone replacement.

Aging↗

Changes in the expression of the NR2B subunit during aging in macaque monkeys.

Humans, non-human primates and rodents show declines in spatial memory abilities with increased age. Some of these declines in mice are related to changes in the expression of the epsilon2 (epsilon2) (NR2B) subunit of the N-methyl-D-aspartate receptor. The purpose of this study was to determine whether primates show changes during aging in the mRNA expression of the NR2B subunit. In situ hybridization was performed on tissue sections from three different ages of Rhesus monkeys (Macaca mulatta; 6-8, 10-12, and 24-26 years). There was a significant decrease in the mRNA expression of the NR2B subunit overall in the prefrontal cortex and in the caudate nucleus between young and old monkeys. There were no significant changes in NR2B mRNA expression in the hippocampus or the parahippocampal gyrus. The results in the prefrontal cortex, caudate and hippocampus were similar to those seen previously in C57BL/6 mice during aging, which suggests that mice may be useful as a model for primates to further examine the age-related changes in the expression of the NR2B subunit of the NMDA receptor in several important regions of the brain.

Aging↗

Estrogen replacement increases spinophilin-immunoreactive spine number in the prefrontal cortex of female rhesus monkeys.

While studies have shown that estrogen affects hippocampal spine density and function, behavioral studies in humans and nonhuman primates have also implicated the prefrontal cortex in the effects of estrogen on cognition. However, the potential for similar estrogen-induced increases in spines and synapses in the prefrontal cortex has not been investigated in primates. Moreover, it is not known if such an estrogen effect would be manifested throughout the neocortex or primarily in the regions involved in cognition. Therefore, we investigated the effects of estrogen on dendritic spines in the prefrontal and primary visual cortices of young rhesus monkeys. Young female monkeys were ovariectomized and administered either estradiol cypionate or vehicle by intramuscular injection. Using an antibody against the spine-associated protein, spinophilin, spine numbers were estimated in layer I of area 46 and in layer I of the opercular portion of area V1 (V1o). Spine numbers in layer I of area 46 were significantly increased (55%) in the ovariectomy + estrogen group compared to the ovariectomy + vehicle group, yet spine numbers in layer I of area V1o were equivalent across the two groups. The present results suggest that estrogen's effects on synaptic organization influence select neocortical layers and regions in a primate model, and provide a morphological basis for enhanced prefrontal cortical functions following estrogen replacement.

Animals↗

Automated algorithms for multiscale morphometry of neuronal dendrites.

We describe the synthesis of automated neuron branching morphology and spine detection algorithms to provide multiscale three-dimensional morphological analysis of neurons. The resulting software is applied to the analysis of a high-resolution (0.098 microm x 0.098 microm x 0.081 microm) image of an entire pyramidal neuron from layer III of the superior temporal cortex in rhesus macaque monkey. The approach provides a highly automated, complete morphological analysis of the entire neuron; each dendritic branch segment is characterized by several parameters, including branch order, length, and radius as a function of distance along the branch, as well as by the locations, lengths, shape classification (e.g., mushroom, stubby, thin), and density distribution of spines on the branch. Results for this automated analysis are compared to published results obtained by other computer-assisted manual means.

Algorithms↗