Ernst N.H. Jansen Steur

Staging of brain pathology related to sporadic Parkinson's disease.

Sporadic Parkinsons disease involves multiple neuronal systems and results from changes developing in a few susceptible types of nerve cells. Essential for neuropathological diagnosis are alpha-synuclein-immunopositive Lewy neurites and Lewy bodies. The pathological process targets specific induction sites: lesions initially occur in the dorsal motor nucleus of the glossopharyngeal and vagal nerves and anterior olfactory nucleus. Thereafter, less vulnerable nuclear grays and cortical areas gradually become affected. The disease process in the brain stem pursues an ascending course with little interindividual variation. The pathology in the anterior olfactory nucleus makes fewer incursions into related areas than that developing in the brain stem. Cortical involvement ensues, beginning with the anteromedial temporal mesocortex. From there, the neocortex succumbs, commencing with high order sensory association and prefrontal areas. First order sensory association/premotor areas and primary sensory/motor fields then follow suit. This study traces the course of the pathology in incidental and symptomatic Parkinson cases proposing a staging procedure based upon the readily recognizable topographical extent of the lesions.

Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients

Cholinergic transmission has for long been known to be one of the most severely affected systems in Alzheimers disease (AD), resulting clinically in massive cognitive deficits. The molecular basis of this dysfunction--on both the pre- and the postsynaptic sites--is still a matter of ongoing investigations. Here, we report on the quantitative assessment of nicotinic acetylcholine receptor isoform expression in AD vs. control cortices. For both subunit proteins assessed, the alpha4 and the alpha7 isoform, highly significant decreases in diseased vs. normal cortices were observed. Both alpha4 and alpha7 subunits are known to be important constituents in hetero- (alpha4beta2) and homooligomeric (alpha7) receptor subtypes. Their decreased expression may contribute to the decreased nicotinic binding known to be accompanied by AD and severe cognitive deficits. The quantitative assessment of nicotinic acetylcholine receptor expression will help to determine those subunits suited as targets for pharmacological stimulation.

Disease-specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain

Molecular misreading of the ubiquitin‐B (UBB) gene results in a dinucleotide deletion in UBB mRNA. The resulting mutant protein, UBB+1, accumulates in the neuropathological hallmarks of Alzheimer disease. In vitro, UBB+1 inhibits proteasomal proteolysis, although it is also an ubiquitin fusion degradation substrate for the proteasome. Using the ligase chain reaction to detect dinucleotide deletions, we report here that UBB+1 transcripts are present in each neurodegenerative disease studied (tauo‐ and synucleinopathies) and even in control brain samples. In contrast to UBB+1 transcripts, UBB+1 protein accumulation in the ubiquitin‐containing neuropathological hallmarks is restricted to the tauopathies such as Pick disease, frontotemporal dementia, progressive supranuclear palsy, and argyrophilic grain disease. Remarkably, UBB+1 protein is not detected in the major forms of synucleinopathies (Lewy body disease and multiple system atrophy). The neurologically intact brain can cope with UBB+1 as lentivirally delivered UBB+1 protein is rapidly degraded in rat hippocampus, whereas the K29,48R mutant of UBB+1, which is not ubiquitinated, is abundantly expressed. The finding that UBB+1 protein only accumulates in tauopathies thus implies that the ubiquitin‐proteasome system is impaired specifically in this group of neurodegenerative diseases and not in synucleinopathies and that the presence of UBB+1 protein reports proteasomal dysfunction in the brain.—Fischer, D. F., de Vos, R. A. I., van Dijk, R., de Vrij, F. M. S., Proper, E. A., Sonnemans, M. A. F., Verhage, M. C., Sluijs, J. A., Hobo, B., Zouambia, M., Jansen Steur, E. N. H., Kamphorst, W., Hol, E. M., van Leeuwen, F. W. Disease‐specific accumulation of mutant ubiquitin as a marker for proteasomal dysfunction in the brain. FASEB J. 17, 2014–2024 (2003)

Pathological features of cerebral cortical capillaries are doubled in Alzheimer's disease and Parkinson's disease

Abstract Cerebral capillaries represent a major interface between the general circulation and the central nervous system and are responsible for sufficient and selective nutrient transport to the brain. Structural damage or dysfunctioning carrier systems of such an active barrier leads to compromised nutrient trafficking. Subsequently, a decreased nutrient availability in the neural tissue may contribute to hampered neuronal metabolism, hence to behavioral and cognitive functional deficiencies. Here we focus on the ultrastrucutral abnormalities of cerebral microvessels in Alzheimer’s disease (AD; n = 5) and Parkinson’s diseasse (PD; n = 10). The capillary microanatomy in samples from the cingulate cortex was investigated by electron microscopy and severe damage to the vessel walls was observed. Characteristic pathological changes including capillary basement membrane thickening and collagen accumulation in the basement membrane were enhanced in both AD and PD. The incidence of capillaries with basement membrane deposits was two times higher in AD and PD than in age-matched controls. Degenerative pericytes in all groups appeared at a similar frequency. The data indicate that basement membrane deposists, as opposed to pericytic degeneration, represent an important pathological feature of AD and PD and suggest that capillary dysfunction may play a causal role in the development of these two major neurodegenerative diseases.

α-Synuclein immunopositive Parkinson's disease-related inclusion bodies in lower brain stem nuclei

Abstract. Advanced silver stains and immunohistochemical reactions against α-synuclein were used to detect Parkinsons disease-related cytoskeletal abnormalities in select lower brain stem nuclei. Various types of inclusion bodies including inconspicuous and heretofore unnoted granular particles and thread-like Lewy neurites were visualized. Of the nuclei investigated (gigantocellular reticular nucleus, bulbar raphe nuclei, coeruleus-subcoeruleus area), only lipofuscin- or neuromelanin-laden neuronal types showed a propensity to develop the pathological changes. Neuronal types devoid of pigment deposits remained free of the cytoskeletal abnormalities. Fine, dust-like particles and small globular Lewy bodies were encountered solely within the limits of intraneuronal lipofuscin or neuromelanin deposits.

Parkinsonism, pyramidal signs, polyneuropathy, and cognitive decline after long-term occupational solvent exposure.

Abstract It is well known that exposure to manganese, solvents, or carbon monoxide in an occupational setting may lead to central nervous system damage and parkinsonism. The most important solvents in this respect are methanol, toluene, carbon disulfide, and n-hexane. We describe three patients who had been exposed to various solvents for more than 20 years (25, 34, and 46 years). They presented with parkinsonism, pyramidal signs, mild cognitive decline, and unresponsiveness to levodopa. Two patients had a predominantly axonal and sensory polyneuropathy of the lower legs with fasciculations in one of them. Parkinsonian features were progressive, even after the patients had stopped work. We present clinical data, neuropsychological findings, and results of brain computed tomography or magnetic resonance imaging, electroneuromyography, evoked potentials, single photon emission computed tomography, and positron-emission tomography. There is growing evidence that various organic solvents give rise to a parkinsonism syndrome with pyramidal features in susceptible individuals.

Expression of nicotinic acetylcholine receptors in Alzheimer’s disease: postmortem investigations and experimental approaches

Nicotinic ligand binding studies have shown rather early that the cholinoceptive system is affected in Alzheimers disease (AD). Today, molecular histochemistry enables one to study the nicotinic acetylcholine receptor (nAChR) subunit expression on the cellular level in human autopsy brains, in animal models and in in vitro approaches, thus deciphering the distribution of nAChRs and their role as potential therapeutic targets. The studies on the nAChR expression in the frontal and temporal cortex of AD patients and age-matched controls could demonstrate that both, the numbers of alpha4- and alpha7-immunoreactive neurons and the quantitative amount, in particular of the alpha4 protein, were markedly decreased in AD. Because the number of the corresponding mRNA expressing neurons was unchanged these findings point to a translational/posttranslational rather than a transcriptional event as an underlying cause. This assumption is supported by direct mutation screening of the CHRNA4 gene which showed no functionally important mutations. To get more insight into the underlying mechanisms, two model systems organotypic culture and primary hippocampal culture - have been established, both allowing to mimic nAChR expression in vitro. In ongoing studies the possible impact of beta-amyloid (Abeta) on nAChR expression is tested. Preliminary results obtained from primary cultures point to an impaired nAChR expression following Abeta exposure.

Similar ultrastructural breakdown of cerebrocortical capillaries in Alzheimer's disease, Parkinson's disease, and experimental hypertension - What is the functional link?

Abstract: The brain, as an intensely active organ, is highly dependent on a sufficient nutrient and oxygen availability in order to reach its optimal working capacity. It is well known that the vital supply of energy substrates is provided by the circulatory system, which splits up into a fine, terminal capillary network in target tissues. These capillaries are considered as important sites, since the actual nutrient trafficking takes place through their walls. That is why an intact, preserved structure of the microvessels is crucial to fulfill their function. Since the brain is known to be particularly vulnerable to suboptimal oxygen and glucose delivery, the intact morphology of capillaries is of paramount importance.

Are Alzheimer's disease, hypertension, and cerebrocapillary damage related?.

Alzheimers disease (AD) patients are often subject to vascular dysfunction besides their specific CNS pathology, which warrants further examination of the interaction between vascular factors and the development of dementia. The association of decreased cerebral blood flow (CBF) or hypertension with AD has been a target of growing interest. Parallel with physiological changes, the cerebral capillaries in AD are also prone to degenerative processes. The microvascular abnormalities that are the result of such degeneration may be the morphological correlates of the vascular pathophysiology pointing to a compromised nutrient transport through the capillaries. Animal models have been developed to study the consequences of hypertension and reduced CBF. Spontaneously hypertensive rats are widely used in hypertension research whereas ligation of the carotid arteries has become a method to produce cerebral hypoperfusion. Based on these models, we propose a relationship between hypertension, cerebral hypoperfusion, cerebral capillary malformation and cognitive decline as it occurs in AD. We suggest that the above conditions are functionally related and can contribute to the progression of AD.

Moclobemide and selegeline in the treatment of depression in Parkinson’s disease

Monoamine oxidase (MAO) is the predominant enzyme implied in the catabolism of the monoamines dopamine, noradrenaline, and serotonin.1 Dopamine is a substrate for both isoforms of MAO: the extraneuronal MAO-B; and MAO-A which is found both extraneuronally and intraneuronally.2 Intraneuronal MAO-A is active for dopamine, noradrenaline, and serotonin, which have a paramount influence in the pathogenesis of depression. The combination of MAO-A and MAO-B inhibition results in a strong increase of both dopamine, noradrenaline, and serotonin. Depression is the most frequent psychopathological finding in Parkinson’s disease. In this study we compared moclobemide monotherapy with combined therapy with moclobemide and selegeline, under tyramine restriction. Ten patients with idiopathic Parkinson’s disease of two to 15 years in duration contributed to the study. The actions of moclobemide and selegeline were described in the informed consent. Inclusion criteria were Parkinson’s disease disability Hoehn and Yahr stages II-IV, major depression using DSM III.R criteria, mini mental state examination (MMSE) score of 21 or above, and self recorded “on-off” patient …