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B Pakkenberg

Publications and source records attributed to B Pakkenberg.

At least 19 recordsLinked to original sources
PubMed2007

A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25-35.

By means of i.c.v. administration of preaggregated oligomeric beta-amyloid (Abeta)25-35 peptide it was possible in rats to generate neuropathological signs related to those of early stages of Alzheimer's disease (AD). Abeta25-35-administration induced the deposition of endogenously produced amyloid protein. Furthermore, quantitative immunohistochemistry demonstrated time-related statistically significant increases in amyloid immunoreactivity, tau phosphorylation, microglial activation, and astrocytosis, and stereological investigations demonstrated statistically significant increased neuronal cell death and brain atrophy in response to Abeta25-35. Finally, the Abeta25-35-administration led to a reduced short-term memory as determined by the social recognition test. A synthetic peptide termed FGL derived from the neural cell adhesion molecule (NCAM) was able to prevent or, if already manifest, strongly reduce all investigated signs of Abeta25-35-induced neuropathology and cognitive impairment. The FGL peptide was recently demonstrated to be able to cross the blood-brain-barrier. Accordingly, we found that the beneficial effects of FGL were achieved not only by intracisternal, but also by intranasal and s.c. administration of the peptide. Furthermore, FGL-treatment was shown to inhibit the activity of GSK3beta, a kinase implicated in signaling regulating cell survival, tau phosphorylation and the processing of the amyloid precursor protein (APP). Thus, the peptide induced a statistically significant increase in the fraction of GSK3beta phosphorylated on the Ser9-position, a posttranslational modification known to inhibit the activity of the kinase. Hence, the mode of action of FGL with respect to the preventive and curative effects on Abeta25-35-induced neuropathological manifestations and cognitive impairment involves the modulation of intracellular signal-transduction mediated through GSK3beta.

Amyloid beta-Peptides↗
PubMed2006

Total number of cells in the human newborn telencephalic wall.

The total cell numbers were estimated in the neocortical part of the human telencephalon in 10 normal brains of newborn babies within four major developmental zones: the cortical plate/marginal zone, the subplate, the intermediate zone and the ventricular/subventricular zone. Furthermore, the total number of neuron and glial cells was estimated in the cortical plate. The gestational ages ranged from 38 + 0-42 + 5 weeks + days of gestation. The mean total cell number was 32.6 x 10(9) (coefficient of error = 0.04) and the total number of neurons in the cortical plate 19.8 x 10(9) (coefficient of error = 0.06). This indicates that the total number of neocortical neurons equals the total number in the adults, which, however, is not the case for the glial cells.

Cell Count↗
PubMed2006

Hippocampal neuron and glial cell numbers in Parkinson's disease--a stereological study.

Hippocampal atrophy and neuron loss are early and reproducible findings in Alzheimer's disease, and recent magnetic resonance imaging studies indicate that hippocampal atrophy may also be present in Parkinson's disease (PD). To determine whether or not cell loss occurs in PD, we estimated the total neuron and glial cell numbers as well as the total volume unilaterally in the hippocampi of eight demented PD patients and eight control subjects. Cell numbers were estimated in the neuron-containing layers of CA1, CA2-(3), CA4, the dentate gyrus, and subiculum using the optical-fractionator technique. The Cavalieri method was used to estimate the volume of the total hippocampus and its subregions. We did not find significant differences in cell numbers or volumes in PD brains when compared with control subjects. Our results thus indicate that hippocampal atrophy and cell loss are not necessarily involved in the memory impairment and dementia observed in PD.

Age Factors↗
PubMed2005

A volumetric screening procedure for the Göttingen minipig brain.

A screening procedure was developed to provide quantitative estimates of structural parameters, regional volumes and neuron number, in a neurotoxicologic study of the Göttingen minipig brain. The study material consisted of normal controls and brains collected from young minipigs which had been exposed in utero to the mitotic inhibitor methylazoxymethanol acetate (MAM). Based on stereological principles and systematic sampling techniques, volumetric data from pre-selected regions of the pig brain was obtained using Cavalieri's principles and point-counting. Secondarily, estimates of total hemispheric neocortical cell numbers were obtained from pre-selected groups to test the potential effect of MAM on neuron number. No significant differences were observed in volume of the pre-selected regions of MAM intoxicated pigs nor in estimates of total neocortical neuron number.

Algorithms↗
PubMed2004

Histological changes of the dopaminergic nigrostriatal system in aging.

Although the maximum human lifespan has not increased in recent history, average life expectancy has risen dramatically since the beginning of the last century. Lengthening of lifespan has little merit if the quality of life is not preserved. In the elderly, the decline in memory and cognitive abilities is of great concern, as is motor weakening, which increases with age. The dopaminergic system mediates some aspects of manual dexterity, in addition to cognition and emotion, and may be especially vulnerable to aging. Therefore, the aging of this system has both clinical and vocational aspects. This review includes studies quantitating age-related changes of the nigrostriatal system, with emphasis on the use of stereological methods, and provides tables of stereological studies performed in the nigrostriatal system.

Aging↗
PubMed2004

No evidence for loss of hippocampal neurons in non-Alzheimer dementia patients.

OBJECTIVE: To use stereological methods for estimating the total number of neurons in hippocampi of non-Alzheimer demented patients. MATERIAL AND METHODS: Hippocampi from six women with severely impaired memory but without Alzheimer pathology were compared with six mentally intact age-matched female controls. The total number of neurons was estimated in the granule cell layer of the dentate gyrus, the hilus of the dentate gyrus, the pyramidal cell layer of CA3 and CA2, the pyramidal cell layer of CA1 and the cellular layer of subiculum using the optical fractionator. RESULTS: The total neuron number was the same in the dementia cases, 22.4 x 106, compared with 22.7 x 106 in the controls (P = 0.85). No region-specific group differences or side difference were found. Two cases without clinical signs of dementia but with abundant plaques and tangles in hippocampus and neocortex had total neuron numbers within normal limits. CONCLUSION: Our results indicate that severely impaired memory can occur in the presence of intact numbers of hippocampal neurons in non-Alzheimer dementia and that nerve cell loss in the hippocampus might be characteristic for Alzheimer's disease, and perhaps other forms of primary cortical dementia.

Aged↗
PubMed2004

Nitric oxide synthase expression and enzymatic activity in multiple sclerosis.

We used post-mortem magnetic resonance imaging (MRI) guidance to obtain paired biopsies from the brains of four patients with clinical definite multiple sclerosis (MS). Samples were analyzed for the immunoreactivity (IR) of the three nitric oxide (NO) synthase isoforms [inducible, neuronal and endothelial nitric oxide synthase (NOS)], and enzymatic NO synthase activity. MRI guided biopsies documented more active plaques than macroscopic examination, and histological examination revealed further lesions. Inducible NOS (iNOS) was the dominant IR isoform, while reactive astrocytes were the dominant iNOS expressing cells in active lesions. NOS IR expressing cells were widely distributed in plaques, in white and gray matter that appeared normal macroscopically, and on MR. Endothelial NOS (eNOS) was highly expressed in intraparenchymal vascular endothelial cells of MS patients. A control group matched for age and sex showed no such changes. Our data support the hypothesis that NO is a pathogenic factor in MS, and that NOS IR is strongly expressed in brain regions appearing normal by MRI.

Adult↗
PubMed2003

The postnatal growth of the beta-cell mass in pigs.

Studies of the postnatal growth of the beta-cell mass in rats have revealed some unexpected and apparently paradoxical results, the most prominent being a beta-cell mass plateau in the early phase of life. We have studied the postnatal growth of the beta-cell mass in the domestic pig to investigate its development in a larger mammal. The pancreases from a total of 86 male pigs from 5 to 100 days of age were studied. The beta-cell mass increased linearly from day 5 to day 40, reached a plateau from day 40 to day 60, and then increased further into adulthood. The relative beta-cell mass (beta-cell mass per body mass) was increased in the early postnatal period but reached a constant level from day 60, after which there was a linear relationship between the beta-cell mass and the body mass. There were high rates of both beta-cell apoptosis and mitosis at 50 and 60 days of age, while the Volume-weighted mean islet Volume increased from birth and reached a plateau at approximately 60 days of age. A beta-cell mass plateau early in life accompanied by a wave of beta-cell apoptosis coinciding with the relative beta-cell mass decreasing to reach a constant level, and a linear relationship between the beta-cell mass and the body mass in later life is exactly what has previously been reported in rats. The coincidence of these events in both rats and pigs, although occurring at different ages in the two species, suggests a causal relationship as previously suggested in a proposed explanatory model for postnatal beta-cell growth.

Animals↗
PubMed2002

Ageing of substantia nigra in humans: cell loss may be compensated by hypertrophy.

In a stereological study of the human substantia nigra (SN), the total number of melanin-positive and melanin-negative neurones from 28 male subjects aged 19-92 years was estimated using a uniform sampling design and optical disectors. There was a significant decrease in the total number of melanin-positive neurones as a function of age (r(2)=0.18, residual-CV=0.35, 2P=0.032). Using the rotator method, the size distribution of the melanin-positive neurones was estimated and showed a significant difference in mean cell volume of melanin-positive neurones between the seven youngest (21,077 microm(3)) and the seven oldest individuals (32,011 microm(3)), 2P=0.022. Using a combination of the total number of melanin-positive neurones and their size distribution, the total perikaryon volume of melanin-positive neurones could be estimated and showed no decrease with increasing age (r(2)=0.01, residual-CV=0.41, 2P=0.62). Age-related decline in dopamine-transporter neurones within the SN might explain the occurrence of extrapyramidal symptoms in many elderly individuals. Although age-related cell hypertrophy is usually considered to be an indication of cell degeneration or necrosis, this might not always be the case. The fact that motor symptoms, although present in many of the elderly, are of a limited nature despite the high percentage of lost neurones could be due to a compensatory increase in the cell body of dopamine-producing SN neurones. Thus, the total amount of cell substance capable of producing the essential transmitters might not be reduced to a critically low level as a result of ageing.

Adaptation, Physiological↗
PubMed2001

High levels of CD8-positive lymphocytes expressing CD45R0, granzyme B, and Ki-67 in lymph nodes of HIV-infected individuals are not associated with increased mortality.

Lymph nodes constitute the major site of HIV replication and of immunological response to HIV. To study the role of cytotoxic and mitotic active CD8(+) lymphocytes in lymph nodes during HIV infection we examined 28 formalin-fixed, paraffin-embedded lymph nodes sampled from 1984 to 1986 from 21 HIV-seropositive patients and seven HIV-negative patients. Eleven of the HIV-positive patients died within 78 months of biopsy time and 10 patients were alive on July 1, 1998. Double immunohistochemical staining procedures were developed to identify CD8(+) cells expressing CD45R0, granzyme B, and Ki-67. A stereological method was used to count the different cell types in the lymph nodes. There were no significant differences in the total cell (nucleated) and CD3(+) cell concentrations between the three groups. However, there were significantly higher concentrations of CD3(+)CD8(+), CD8(+)CD45R0(+), and CD8(+)Ki-67(+) lymphocytes in the HIV patients compared with the control group. Furthermore, there was a tendency for the HIV-deceased group to have lower levels of CD8(+)granzyme B(+) and CD8(+)Ki-67(+) lymphocyte concentrations compared with the HIV-alive group. Three HIV patients, who progressed to death within 49 months of biopsy time, were among the patients with the lowest concentrations of CD8(+)granzyme B(+) and CD8(+)Ki-67(+) lymphocytes. This finding allowed us to conclude that CD8(+) lymphocytes expressing high levels of CD45R0, granzyme B, and Ki-67 in lymph nodes of HIV patients are not related to increased mortality, whereas low concentrations of CD8(+) granzyme B(+) and CD8(+)Ki-67(+) lymphocytes may be associated with poor prognosis.

Adult↗
PubMed2001

Size of neocortical neurons in control subjects and in Alzheimer's disease.

The aim of the present study was to estimate mean neuronal volume and absolute size distributions of the neocortical neurons in brains from controls and AD patients using stereological methods based on unbiased principles to determine whether changes in absolute cell size are part of the neuropathological pattern of Alzheimer's disease. The neocortex of 8 patients with Alzheimer's disease (AD), mean age 81.1 (68-94) y was compared with 9 nondemented controls, mean age 80.9 (65-101) y. The brains came from Johns Hopkins University Hospital (JHUH) in Baltimore, USA, the Netherlands Brain Bank (NBB), and from a large brain repository in Denmark. The rotator method was used to obtain an estimate of cell volumes providing absolute size distributions of the volume of both cell perikaryon and cell nuclei. The geometric mean volume of cell nuclei in neocortical neurons was 328 microm3 (interindividual CV = 0.15) in the Alzheimer group compared with 277 microm3 (interindividual CV = 0.17) in controls which was a statistically significant increase (P = 0.049). The perikaryal volume was 1117 microm3 in the Alzheimer group compared with 999 microm3 in controls which was a nonsignificant difference (P = 0.20). There was a highly significant correlation between the nuclear and perikaryal volumes in all individuals. The average slope of the regression lines was significantly higher in the Alzheimer patients than in the controls, illustrating that nuclear hypertrophy was more pronounced in the largest neurons.

Aged↗
PubMed2001

Linear correlation between the total islet mass and the volume-weighted mean islet volume.

To understand the dynamics of islet population, especially during conditions with growth of the total islet mass, it is important to have reliable estimators of parameters describing the quantitative appearance of the islet population. We describe a stereological estimator of the volume-weighted mean islet volume based on unbiased assumption-free stereological principles. The volume-weighted mean islet volume is the mean islet volume if the islets are weighted (sampled) proportional to their volume. This method allows simultaneously unbiased estimation of the total islet mass. With use of this method, 22 male Sprague-Dawley rats within the age span of 34-102 days old were investigated. We found a linear correlation (P < 0.001) between total islet mass and the volume-weighted mean islet volume. The results support models demonstrating that the physiological growth of the total islet mass in the period studied is totally or mainly caused by proportional growth of existing islets. The functional meaning of the volume-weighted mean islet volume is discussed, and previous methods to study the mean islet volume and islet number are critically evaluated. We propose the volume-weighted mean islet volume to be a biologically useful parameter when describing the mean volume of the pancreatic islets and investigating the differences between experimental groups.

Aging↗
PubMed2000

Unchanged total number of neurons in motor cortex and neocortex in amyotrophic lateral sclerosis: a stereological study.

Modern stereological methods provide precise and reliable estimates of the number of neurons in specific regions of the brain. The total number of neurons in the neocortex and motor cortex from eight patients suffering from amyotrophic lateral sclerosis (ALS) and nine controls was estimated. No attempt was made to estimate subpopulations of neurons such as the number of giant pyramidal cells of Betz. No difference was found in the average number of neurons in neocortex in ALS and controls, 21.7 and 22.3 x 10(9), respectively, and 1.33 and 1.29 x 10(9) in motor cortex, respectively. In the light of our stereological measurements, results obtained from in-vivo proton magnetic resonance spectroscopy (1H-MRS), suggesting neuronal loss in ALS, may instead be due to neuronal metabolic dysfunction and/or alteration in the size or the volume fraction of the neurons.

Aged↗
PubMed2000

Stereological studies of the schizophrenic brain.

Stereological studies have contributed with important results to the understanding of brain abnormalities in schizophrenia. The data obtained from stereological studies of brains from schizophrenic patients, including studies of the thalamus, hippocampus, and cortex, are discussed and suggest a central role of the thalamic nuclei in the etiology of the disease. The basic stereological tools are presented and possible biases in quantification studies are discussed.

Brain↗
PubMed2000

Quantitation of regional cerebral blood flow corrected for partial volume effect using O-15 water and PET: I. Theory, error analysis, and stereologic comparison.

Limited spatial resolution of positron emission tomography (PET) can cause significant underestimation in the observed regional radioactivity concentration (so-called partial volume effect or PVE) resulting in systematic errors in estimating quantitative physiologic parameters. The authors have formulated four mathematical models that describe the dynamic behavior of a freely diffusible tracer (H215O) in a region of interest (ROI) incorporating estimates of regional tissue flow that are independent of PVE. The current study was intended to evaluate the feasibility of these models and to establish a methodology to accurately quantify regional cerebral blood flow (CBF) corrected for PVE in cortical gray matter regions. Five monkeys were studied with PET after IV H2(15)O two times (n = 3) or three times (n = 2) in a row. Two ROIs were drawn on structural magnetic resonance imaging (MRI) scans and projected onto the PET images in which regional CBF values and the water perfusable tissue fraction for the cortical gray matter tissue (hence the volume of gray matter) were estimated. After the PET study, the animals were killed and stereologic analysis was performed to assess the gray matter mass in the corresponding ROIs. Reproducibility of the estimated parameters and sensitivity to various error sources were also evaluated. All models tested in the current study yielded PVE-corrected regional CBF values (approximately 0.8 mL x min(-1) x g(-1) for models with a term for gray matter tissue and 0.5 mL x min(-1) x g(-1) for models with a term for a mixture of gray matter and white matter tissues). These values were greater than those obtained from ROIs tracing the gray matter cortex using conventional H2(15)O autoradiography (approximately 0.40 mL x min(-1) x g(-1)). Among the four models, configurations that included two parallel tissue compartments demonstrated better results with regards to the agreement of tissue time-activity curve and the Akaike's Information Criteria. Error sensitivity analysis suggested the model that fits three parameters of the gray matter CBF, the gray matter fraction, and the white matter fraction with fixed white matter CBF as the most reliable and suitable for estimating the gray matter CBF. Reproducibility with this model was 11% for estimating the gray matter CBF. The volume of gray matter tissue can also be estimated using this model and was significantly correlated with the results from the stereologic analysis. However, values were significantly smaller compared with those measured by stereologic analysis by 40%, which can not be explained by the methodologic errors. In conclusion, the partial volume correction was essential in quantitation of regional CBF. The method presented in this article provided the PVE-corrected regional CBF in the cortical gray matter tissue. This study also suggests that further studies are required before using MRI derived anatomic information for PVE correction in PET.

Animals↗
PubMed1999

Preferential loss of large neocortical neurons during HIV infection: a study of the size distribution of neocortical neurons in the human brain.

The infection with human immunodeficiency virus (HIV) is associated with a global and severe loss of neocortical neurons. However, there is limited knowledge concerning whether all neurons are equally susceptible to damage during HIV infection. Other studies have reported low vulnerability of small interneurons and high vulnerability of large motor neurons. Thus, it is natural to suggest that HIV infection, which causes damage to neurons in several ways, may predominantly affect large neurons in the neocortex. In this study we have used three unbiased stereological probes: Cavalieri's principle, the optical dissector and the rotator method, to obtain both total neocortical neuron number and their size distribution in formalin-fixed brains from six male acquired immunodeficiency syndrome (AIDS) patients and six male controls. The material is a selection of a large material choosing the youngest. The number of neurons in neocortex was reduced by 25% from 24.4 x 10(9) in controls to 18.3 x 10(9) in the AIDS patients; the reduction is similar to that of 27% found in the large material. In the normal size distribution of the neocortical neurons most neurons were smaller than 5000 micron3 and no sampled neurons were larger than 28,000 micron3. In addition, the absolute size distribution of neocortical neurons showed a significant decrease of the largest group of neurons by 50% (2p = 0.01) in the AIDS group, while there was no significant difference between controls and AIDS patients in the number of small neurons. The pattern of reduction in the number of large neocortical neurons was found in frontal, temporal, parietal as well as in occipital regions. This suggests that large neurons are more sensitive than small neurons to the destruction caused by the HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Unbiased estimation of total beta-cell number and mean beta-cell volume in rodent pancreas.

We describe a method for unbiased assumption-free estimation of the total number of beta-cells and the mean beta-cell volume in mouse and rat pancreas based on light microscopy. Such a method, which takes advantage of one of the most recent developments in stereology, the fractionator, has not previously been described. It relies on repeated fractionation of the tissue using systematic uniform random sampling combined with an unbiased counting principle. The method was applied to eight BALB/cBom male mice (56 days) and six Lewis/MOL male rats (47 days). In mice, the total number of beta-cells was 1.06 +/- 0.07 x 10(6) (mean +/- SEM) per pancreas with a mean beta-cell volume of 1280 +/- 17 microm3, while in rats the total beta-cell number was 2.76 +/- 0.42 x 10(6) per pancreas with a mean beta-cell volume of 1170 +/- 65 microm3. Furthermore, the results showed that in both species the biological variability in the total beta-cell volume is due to differences in the number of beta-cells rather than variability of the mean beta-cell volume. The method can be used to give a precise description of number and volume of beta-cells at different ages, and will make it possible to estimate the contributions of hyper/hypotrophia and hyper/hypoplasia to a given induced or spontaneous change in the total beta-cell mass.

Animals↗