PubMed Health⌕ Search

Biomedical subjects

Kurt A Jellinger

Publications and source records attributed to Kurt A Jellinger.

At least 37 records · Page 2Linked to original sources
PubMed2004

Prevalence and pathogenic role of cerebrovascular lesions in Alzheimer disease.

Cerebrovascular lesions in Alzheimer disease (AD) being significantly more frequent than in nondemented elderly subjects suggest overlaps and synergistic effects between both pathologies. Examination of a consecutive series of autopsy-proven AD cases and age-matched controls revealed a higher frequency of vascular lesions and of cerebral amyloid angiopathy (CAA) in AD (57.34% vs. 33.2% and 94.1% vs. 33.3%, respectively). These and previous data on vascular pathology in Parkinson disease emphasize its importance in these disorders. A study comparing the frequency and extent of general CAA and capillary CAA (CapCAA) in the postmortem frontal cortex of cases with high and low Braak stages showed no correlation between general CAA and dementia, only a low one with other vascular lesions except for cerebral hemorrhages. However, it was higher in AD than in controls with vascular pathology. The severity of CapCAA not correlating with general CAA showed high correlation with AD pathology, suggesting different pathogenesis of both types of CAA. Its elucidation may have implications for new therapeutic strategies. Considering the variability of vascular pathology in both AD and aged brains, the mechanisms behind their interactions are largely unknown, and further studies are needed to clarify their impact on cognitive impairment.

Aged↗
PubMed2004

Understanding the pathology of vascular cognitive impairment.

The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive impairment (VCI), and of mixed dementia (Alzheimer disease+vascular encephalopathy) are a matter of discussion and no validated neuropathologic criteria for these disorders are currently available. In Western memory clinic-based series, VaD/CVI is suggested in 8-10% of cognitively impaired elderly; its prevalence in autopsy series ranges from 0.03% to 58% (mean 5-15%). Fairly unusual as an isolated nosological entity, CVI appears to correlate with focal, multifocal or diffuse cortical and/or subcortical microinfarcts and lacunes often affecting strategically important brain areas (thalamus, frontobasal, limbic system), hemispheric white matter and, less often, large brain areas. They result from systemic, cardiac or local large or small vessel disease. The lesion pattern in "pure" VCI with predominant multiple small (subcortical) lesions related to microangiopathies differs from that in "mixed dementia" (AD+VaD), more often associated with large infarcts, suggesting different pathogenesis. In very old subjects, selective hippocampal sclerosis may be accompanied by multiple other vascular pathologies. Minor cerebrovascular lesions (CVL), except for severe amyloid angiopathy, appear not essential for cognitive decline in full-blown AD, while both mild AD-type pathology and small vessel disease may interact synergistically in "unmasking" or promoting dementia. AD pathology is significantly less severe in the presence of cerebrovascular lesions. Further studies are needed to validate diagnostic criteria for VCI and to clarify the impact of vascular lesions on cognitive impairment.

Aged↗
PubMed2004

Failure of caspase inhibition in the double-lesion rat model of striatonigral degeneration (multiple system atrophy).

In the present study we assessed the neuroprotective effects of the pan-caspase inhibitor z-VAD.fmk [N-benzyloxycarbony-valine-alanine-aspartate-(OMe)-fluoromethylketone], and the caspase-3 inhibitor Ac-DEVD.CHO (acetyl-aspartate-chloromethylketone) in the double-lesion rat model of striatonigral degeneration (SND), the core pathology underlying levodopa-unresponsive parkinsonism associated with multiple system atrophy (MSA). Male Wistar rats were divided into three groups, receiving either Ac-DEVD.CHO, z-VAD.fmk or normal saline before lesion surgery, comprising a sequential unilateral quinolinic acid (QA) lesion of the striatum followed by a 6-hydroxydopamine (6-OHDA) lesion of the ipsilateral medial forebrain bundle. At 2 weeks post lesion, all rats underwent testing of spontaneous nocturnal locomotor behavior in an automated Photobeam Activity System (FlexField). Immunohistochemistry was performed with tyrosine hydroxylase, dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein and glial fibrillary acidic protein antibodies. Morphometry was performed using computerized image analysis. Behavioral and morphological analysis failed to show striatal or nigral protection in caspase inhibitor-treated animals. Our findings suggest that anti-apoptotic strategies are unrewarding in the SND rat model and, therefore, alternative neuroprotective interventions such as anti-glutamatergic agents or inhibitors of microglial activation should be explored instead.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Amyloid beta peptide 1-42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology.

Recent studies reported both positive [Thal et al. (2003) J Neuropathol Exp Neurol 62:1287-1301] and negative [Tian et al. (2003) Neurosci Lett 352:137-140] correlations between cerebral amyloid angiopathy (CAA) and Alzheimer's disease (AD) pathology. We have recently shown high correlations between neuritic AD pathology and amyloid beta peptide (Abeta) deposits in the capillary/pericapillary compartment (CapCAA) with only low correlations to general CAA (non-capillary). We have now studied the relationship between CapCAA and AD pathology with respect to the distribution of Abeta40 and 42 in the frontal cortex of 100 human postmortem brains from both male and female, demented and non-demented patients (mean age +/- SD 84.3 +/- 9.3 years). Using polyclonal antibodies to Abeta40 and 42, capillary and plaques positivity were assessed semiquantiatively on a four-point scale. Abeta42 deposits in capillaries correlated highly with both Abeta42 deposits in plaques and morphological AD criteria (CERAD, Braak stages, and NIA-Reagan-Institute criteria), while only a low correlation with CAA was observed. Abeta40 deposits in capillaries differed morphologically from Abeta42 ones: they were limited to capillary walls, were significantly less frequent in both capillaries and plaques compared to Abeta42 ( P < 0.01), and showed a low correlation with morphological AD criteria ( P < 0.05) and general CAA ( P < 0.01). By contrast, Abeta42 deposits were seen in the glia limitans rather than in capillary walls themselves, and showed high correlation with morphological AD criteria ( P < 0.01). These data indicate that CapCAA is characterized by Abeta42 deposits in pericapillary spaces or in the glia limitans. A low correlation between CAA and CapCAA, but high correlations between morphological AD criteria and CapCAA suggest different pathomechanisms for both types of CAA, and a close relation between CapCAA and AD pathology (both neuritic and plaque type). These data support the concept of a neuronal origin of Abeta via drainage from interstitial fluid from the central nervous system along basement membranes to capillaries.

Aged↗
PubMed2004

Chromogranin peptides in Alzheimer's disease.

Synaptic disturbances may play a key role in the pathophysiology of Alzheimer's disease. To characterize differential synaptic alterations in the brains of Alzheimer patients, chromogranin A, chromogranin B and secretoneurin were applied as soluble constituents for large dense core vesicles, synaptophysin as a vesicle membrane marker and calbindin as a cytosolic protein. In controls, chromogranin B and secretogranin are largely co-contained in interneurons, whereas chromogranin A is mostly found in pyramidal neurons. In Alzheimer's disease, about 30% of beta-amyloid plaques co-labelled with chromogranin A, 20% with secretoneurin and 15% with chromogranin B. Less than 5% of beta-amyloid plaques contained synaptophysin or calbindin, respectively. Semiquantitative immunohistochemistry revealed a significant loss for chromogranin B- and secretoneurin-like immunoreactivity in the dorsolateral, the entorhinal, and orbitofrontal cortex. Chromogranin A displayed more complex changes. It was the only chromogranin peptide to be expressed in glial fibrillary acidic protein containing cells. About 40% of chromogranin A immunopositive plaques and extracellular deposits were surrounded and pervaded by activated microglia. The present study demonstrates a loss of presynaptic proteins involved in distinct steps of exocytosis. An imbalanced availability of chromogranins may be responsible for impaired neurotransmission and a reduced functioning of dense core vesicles. Chromogranin A is likely to be a mediator between neuronal, glial and inflammatory mechanisms found in Alzheimer disease.

Aged↗
PubMed2004

Head injury and dementia.

PURPOSE OF REVIEW: The link between head injury and dementia/Alzheimer's disease is controversial. This review discusses some recent epidemiological, human autopsy and experimental studies on the relationship between traumatic head injury and dementia. RECENT FINDINGS: Recent epidemiological studies have shown that head injury is a risk factor for the development of dementia/Alzheimer's disease, whereas others have not. After experimental brain trauma the long-term accumulation of amyloid beta peptide suggests that neurodegeneration is influenced by apolipoprotein E epsilon 4, and after human brain injury both amyloid beta peptide deposition and tau pathology are seen, even in younger patients. Amyloid beta peptide levels in the cerebrospinal fluid and the overproduction of beta amyloid precursor protein in humans and animals after traumatic brain injury are increased. Repeated mild head trauma in both animals and humans accelerates amyloid beta peptide accumulation and cognitive impairment. Retrospective autopsy data support clinical studies suggesting that severe traumatic brain injury with long-lasting morphological residuals are a risk factor for the development of dementia/Alzheimer's disease. The influence of the apolipoprotein E genotype on the prognosis of traumatic brain injury is under discussion. SUMMARY: Although epidemiological studies and retrospective autopsy data provide evidence that a later cognitive decline may occur after severe traumatic brain injury, the relationship between dementia after head/brain trauma and apolipoprotein E status is still ambiguous. Both human postmortem and experimental studies showing apolipoprotein beta deposition and tau pathology after head injury support the link between traumatic brain injury and dementia, and further studies are warranted to clarify this relationship.

Alzheimer Disease↗
PubMed2003

Only cerebral capillary amyloid angiopathy correlates with Alzheimer pathology--a pilot study.

Data on the relationship between cerebral amyloid angiopathy (CAA) ("congophilic angiopathy") and Alzheimer's disease (AD) pathology are conflicting. In the present study, CAA and capillary CAA (CapCAA) ("dyshoric angiopathy") were examined in the frontal cortex of 100 human brains obtained at autopsy from both male and female, demented and non-demented patients (mean age +/- SD 84.3+/-9.3 years); 50 brains with high (mean 5.0) and 50 with low (mean 2.4) Braak stages. CAA was assessed according to the method of Olichney et al. [25]; CapCAA was grouped into four grades by counting the affected capillaries in 10 high power fields. General CAA was present in 61% (87.5% demented, 55.6% non-demented; 70% with high and 52% low Braak stages). CAA did not correlate with either clinical diagnosis of dementia or high-grade AD pathology; CapCAA showed a low correlation with dementia and a medium positive correlation with high Braak stages. The severity of both lesions did not correlate with clinical dementia; whereas that of CAA showed low correlation with CERAD, Braak, and NIA-Reagan-Institute criteria, the severity of CapCAA correlated significantly with all three AD criteria. The presence and severity of CAA and CapCAA showed only low correlation, suggesting a different pathogenesis of these types of lesion. Since CapCAA represents insoluble amyloid peptide (Abeta) deposits in and around capillaries, its correlation with neuritic AD pathology supports the concept of neuronal origin of Abeta via drainage from interstitial fluid from the central nervous system to capillary walls. Studies to answer the question whether CapCAA represents an epiphenomenon or an indicator of a pathogenic association between tau cytopathology and Abeta deposition in capillaries are in progress.

Aged↗
PubMed2003

Alpha-synuclein pathology in Parkinson's and Alzheimer's disease brain: incidence and topographic distribution--a pilot study.

To study the incidence and topographic distribution of alpha-synuclein-positive inclusions in Parkinson's disease (PD), dementia with LB (DLB), and Alzheimer's disease (AD), 206 brains of elderly patients, including 53 patients with clinical PD, 110 autopsy-proven AD cases, 22 with dementia with LB (DLB), 1 case with essential tremor, and 20 age-matched controls were investigated using alpha-synuclein immunohistochemistry. For technical reasons, the olfactory system was not studied. In all PD brains, alpha-synuclein-positive inclusions and neuronal losses were present in medullary and pontine nuclei, locus coeruleus, and substantia nigra, with additional lesions in amygdala (24%), allocortex (58%), cingulate area (34%), and isocortex (26.5%). All PD cases corresponded to pathology stage 4-6 suggested by Braak et al. (2003, Neurobiol Aging 24:197). In most cases of DLB, the distribution of alpha-synuclein pathology and neurodegeneration corresponded to stages 5 and 6 of PD pathology. The case with essential tremor and 48.2% of the AD cases showed no LB pathology; in the other AD brains alpha-synuclein-positive inclusions were seen in various brain areas. None of the controls showed LB pathology. Among 12 cases of incidental Lewy body disease (without clinical parkinsonian signs), 7 corresponded morphologically to PD stage 3 or 4. In further 6 AD cases, 2 with parkinsonian symptoms, considerable damage to locus coeruleus, substantia nigra, nucleus basalis and allocortex with preservation of the medullary nuclei was seen. The preliminary data largely confirm the Braak staging of brain pathology, although some of the clinical PD cases corresponded to stage 3 often considered as "preclinical". In addition, some cases without demonstrable involvement of medullary nuclei showed extensive PD-like pathology in other brain areas, suggesting deviation from the proposed stereotypic expansion pattern and that incidental LB pathology may affect solely the locus coeruleus and substantia nigra. Striking similarity of LB pathology between DLB and PD suggests close morphological relationship between both disorders. Widespread LB lesions occurred in many sporadic AD cases without parkinsonian symptoms, the pathogenesis and clinical impact of which are unclear. The relationship between AD and PD with particular reference to alpha-synuclein-positive lesions needs further elucidation [corrected].

Aged↗
PubMed2003

Neuropathological and behavioral changes induced by various treatment paradigms with MPTP and 3-nitropropionic acid in mice: towards a model of striatonigral degeneration (multiple system atrophy).

We characterized two models of dual nigral and striatal lesions replicating the lesion pattern of striatonigral degeneration, the neuropathological hallmark of parkinsonism associated with multiple system atrophy (SND/MSA-P). For this purpose, we used systemic administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP) in C57BL mice. One group of animals was first injected with MPTP followed by 3NP (MPTP+3-NP model). In the second group 3-NP was injected first, followed by MPTP (3-NP+MPTP model). The behavioral and neuropathological characteristics of these two models were compared to those observed after single 3-NP or MPTP intoxication. Results showed that, compared to control mice, spontaneous nocturnal locomotor activity was preserved in the MPTP+3-NP model, whereas it was reduced by 27% ( P<0.05) in the 3-NP+MPTP model and in animals treated with either 3-NP (27%, P<0.05) or MPTP (23%, P<0.05) alone. Quantitative histological evaluation based on Nissl staining and DARPP-32 immunohistochemistry revealed that 3-NP alone and 3-NP+MPTP treatment produced a marked (greater than 50%) loss of striatal neurons, whereas MPTP+3-NP treatment attenuated loss of striatal neurons by 43%. Further, loss of tyrosine hydroxylase-positive neurons in substantia nigra pars compacta (SNc) was attenuated after 3-NP+MPTP treatment compared to that observed after MPTP (40% vs 74%, P<0.001) and MPTP+3NP treatment (55% vs 74%, P<0.01). Our results show that MPTP-induced nigral lesions attenuate 3-NP toxicity and, reciprocally, that 3-NP-induced striatal lesions reduce MPTP toxicity. This suggests that complex integrative mechanisms are likely to regulate the vulnerability of the striatum and SNc to cell death in SND/MSA-P.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Prevalence of cerebrovascular lesions in Parkinson's disease. A postmortem study.

Data on the relationship between Parkinson's disease (PD) and stroke have been conflicting, some studies showing a reduced risk of stroke during life, and others indicating an increased risk of stroke-related death. Consecutive cases (n=617) of autopsy-proven idiopathic PD (Lewy body disease of the brain stem type) and age-matched controls (n=535) were compared using current routine and immunohistochemical methods. The total frequency of cerebrovascular lesions (lacunes, amyloid angiopathy, white matter lesions, old and recent ischemic infarcts and hemorrhages) in PD (44.0%) was higher than in controls (32.8%), while acute, often fatal ischemic or hemorrhagic strokes were less frequent in parkinsonian patients (1.8% vs 2.6%). Like previous postmortem findings in a smaller cohort, these findings neither indicate a protective effect against stroke nor a greater susceptibility to death from stroke in the populations studied. Cognitive impairment in PD appears to be largely independent from coexistent vascular pathology except in cases with severe cerebrovascular lesions.

Aged↗
PubMed2003

Neuropathological spectrum of synucleinopathies.

Synucleinopathies comprise a diverse group of neurodegenerative proteinopathies that share common pathological lesions composed of aggregates of conformational and posttranslational modifications of alpha-synuclein in selected populations of neurons and glia. Abnormal filamentous aggregates of misfolded alpha-synuclein protein are the major components of Lewy bodies, dystrophic (Lewy) neurites, and the Papp-Lantos filaments in oligodendroglia and neurons in multiple system atrophy linked to degeneration of affected brain regions. The synucleinopathies include (1) Lewy body disorders and dementia with Lewy bodies, (2) multiple system atrophy (MSA), and (3) Hallervorden-Spatz disease. (1) The pathological diagnosis of Lewy body disorders and dementia with Lewy bodies is established by validated consensus criteria based on semiquantitative assessment of subcortical and cortical Lewy bodies as their common hallmarks. They are accompanied by subcortical multisystem degeneration with neuronal loss and gliosis with or without Alzheimer pathologic state. Lewy bodies also occur in numerous other disorders, including pure autonomic failure, neuroaxonal dystrophies, and various amyloidoses and tauopathies. (2) Multiple system atrophy, a sporadic, adult-onset degenerative movement disorder of unknown cause, is characterized by alpha-synuclein-positive glial cytoplasmic and rare neuronal inclusions throughout the central nervous system associated with striatonigral degeneration, olivopontocerebellar atrophy, and involvement of medullar and spinal autonomic nuclei. (3) In neurodegeneration with brain iron accumulation type I, or Hallervorden-Spatz disease, alpha-synuclein is present in axonal spheroids and glial and neuronal inclusions. While the identity of the major components of Lewy bodies suggests that a pathway leading from normal soluble to abnormal misfolded filamentous proteins is central for their pathogenesis, regardless of the primary disorder, there are conformational differences in alpha-synuclein between neuronal and glial aggregates, showing nonuniform mapping for its epitopes. Despite several cellular and transgenic models, it is not clear whether inclusion body formation is an adaptive/neuroprotective or a pathogenic reaction/process generated in response to different, mostly undetermined, functional triggers linked to neurodegeneration.

Brain↗