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1.
Sequestration of iron by Lewy bodies in Parkinson’s disease 总被引:4,自引:0,他引:4
Central to the oxidative stress hypothesis of Parkinson’s disease (PD) pathogenesis is the ability of iron to generate hydroxyl
radicals via the Fenton reaction, and the consistent demonstration of iron elevation in the pars compacta region of the substantia
nigra. However, uncertainty exists as to whether the excess iron exists in a state suitable for redox chemistry. Here, using
a method we developed that detects redox-active iron in situ, we were able to demonstrate strong labeling of Lewy bodies in
substantia nigra pars compacta neurons in PD. In contrast, cortical Lewy bodies in cases of Lewy body variant of Alzheimer’s
disease were unstained. While the presence of elevated iron in PD substantiates the oxidative stress hypothesis, one must
remember that these are viable neurons, indicating that Lewy bodies may act to sequester iron in PD brains in a protective,
rather than degenerative, mechanism. The absence of redox-active iron in neocortical Lewy bodies highlights a fundamental
difference between cortical and brain stem Lewy bodies.
Received: 9 February 2000 / Revised: 31 March 2000 / Accepted: 2 April 2000 相似文献
2.
Onofrj M Monaco D Bonanni L Onofrj V Bifolchetti S Manzoli L Thomas A 《Journal of neurology》2011,258(8):1542-1544
Journal of Neurology - 相似文献
3.
Walter J. Schulz-Schaeffer 《Acta neuropathologica》2010,120(2):131-143
Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are usually associated with loss of dopaminergic neurons. Loss
of substantia nigra neurons and presence of Lewy body inclusions in some of the remaining neurons are the hallmark pathology
seen in the final stages of the disease. Attempts to correlate Lewy body pathology to either cell death or severity of clinical
symptoms, however, have not been successful. While the pathophysiology of the neurodegenerative process can hardly be explained
by Lewy bodies, the clinical symptoms do indicate a degenerative process located at the presynapse resulting in a neurotransmitter
deficiency. Recently it was shown that 90% or even more of α-synuclein aggregates in DLB cases were located at the presynapses
in the form of very small deposits. In parallel, dendritic spines are retracted, whereas the presynapses are relatively preserved,
suggesting a neurotransmitter deprivation. The same α-synuclein pathology can be demonstrated for PD. These findings give
rise to the notion that not cell death but rather α-synuclein aggregate-related synaptic dysfunction causes the neurodegeneration.
This opens new perspectives for understanding PD and DLB. If presynaptic α-synuclein aggregation, not neuronal loss, is the
key issue of the neurodegenerative process, then PD and DLB may eventually be treatable in the future. The disease may progress
via trans-synaptical spread, suggesting that stem cell transplants are of limited use. Future therapies may focus on the regeneration
of synapses. 相似文献
4.
Hofer A Berg D Asmus F Niwar M Ransmayr G Riemenschneider M Bonelli SB Steffelbauer M Ceballos-Baumann A Haussermann P Behnke S Krüger R Prestel J Sharma M Zimprich A Riess O Gasser T 《Journal of neural transmission (Vienna, Austria : 1996)》2005,112(9):1249-1254
Summary. Background: A triplication of the α-synuclein gene was found to cause autosomal dominant Lewy body disease in two distinct families. Method: We searched for alterations of α-synuclein gene dosage and analysed the entire coding region for point mutations in 54 dementia with Lewy body disease (DLB) and in 103 young onset Parkinson’s disease (PD) patients from Central Europe. Results: We could not detect any quantitative alterations in the gene dosage of α-synuclein. Mutational screening of the entire coding region of α-synuclein revealed only one silent mutation V3V (adenine9guanine) in one case. Conclusions: Thus, this phenomenon appears not to be a major cause in the pathogenesis of sporadic DLB and young onset PD in this European population. 相似文献
5.
Alpha-synuclein immunoreactive Lewy bodies and Lewy neurites in Parkinson’s disease are detectable by an advanced silver-staining technique 总被引:1,自引:1,他引:0
Daniele Sandmann-Keil H. Braak Masayasu Okochi Christian Haass Eva Braak 《Acta neuropathologica》1999,98(5):461-464
Immunostaining with anti-α-synuclein is used to detect Lewy bodies and Lewy neurites in cases of Parkinson’s disease and related disorders. To prove that the result of a modern silver method is equivalent to that achieved with immunoreactions for α-synuclein, individual sections were successively processed using both methods. The silver-stained sections showed all of the immunoreactive Lewy bodies, and thin Lewy neurites were detected equally well by both techniques. The present study, therefore, points to the capabilities of a modern silver-staining method which is less time consuming and less expensive than immunocytochemical techniques. Received: 2 December 1998 / Revised, accepted: 25 March 1999 相似文献
6.
7.
Halliday GM Song YJ Harding AJ 《Journal of neural transmission (Vienna, Austria : 1996)》2011,118(5):713-719
Professor Jellinger first identified that striatal Aβ deposition at postmortem seemed to differentiate cases of dementia with
Lewy bodies (DLB) from those with Parkinson’s disease dementia (PDD), a finding subsequently questioned. Our replication study
in 34 prospectively studied cases assessed the ability of striatal Aβ deposition to differentiate DLB from PDD, and also assessed
the relationship between striatal and cortical Aβ deposition and α-synuclein-immunoreactive pathologies, using previously
published protocols. Cases with DLB had significantly shorter durations and greater dementia severities compared with cases
with PDD. Striatal Aβ-immunoreactive plaques were only consistently found in cases with DLB and correlated with both the severity
(positive correlation) and duration (negative correlation) of dementia. Striatal Aβ-immunoreactive plaques also positively
correlated with the severity of α-synuclein-immunoreactive pathologies as well as cortical Aβ-positive plaques. Striatal Aβ
deposition positively predicted dementia in Lewy body cases with high specificity and had the greatest sensitivity to differentiate
DLB from PDD with 100% negative predictive value. These data suggest that striatal Aβ deposition in Lewy body diseases contributes
to early dementia and in these cases may impact on the efficacy of treatments targeting the striatum. 相似文献
8.
Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive impairment in Parkinson’s disease 总被引:11,自引:3,他引:8
Amygdala, hippocampus and six cortical gyri were examined for the Lewy body (LB) degeneration and Alzheimer’s disease (AD)
type changes in 45 patients with Parkinson’s disease (PD). For detection of LBs, the brain areas were stained with an antibody
against alpha-synuclein. The extent of neuropathological lesions was investigated in relation to cognitive dysfunction and
apolipoprotein E (apoE) ɛ4 allele dosage. At least one cortical LB was found in 95% of cases (43/45). Furthermore, 40% of
cases (18/45) had histological findings of definite AD (CERAD class C). Those PD cases with the apoE ɛ4 allele had a significantly
greater number of cortical LBs than those without the apoE ɛ4 allele, but this was statistically significant only in precentral,
angular and temporal gyri. The LB density correlated better with the number of plaques than with the density of tangles. The
number of LBs in several cortical areas correlated significantly with the cognitive impairment. In stepwise linear regression
analysis, the number of LBs in the cingulate gyrus and the amount of tangles in the temporal cortex remained statistically
significant. When the CERAD class C was excluded, the correlation between cognitive decline and the number of LBs in cortical
areas became even more pronounced. A stepwise linear regression analysis in these cases found the number of LBs in the frontal
gyrus to be the statistically most significant predictor of cognitive impairment. This study shows, for the first time, that
in PD, alpha-synuclein-positive cortical LBs are associated with cognitive impairment independent of AD-type pathology.
Received: 20 August 1999 / Revised, accepted: 4 November 1999 相似文献
9.
Bibl M Mollenhauer B Esselmann H Lewczuk P Trenkwalder C Brechlin P Rüther E Kornhuber J Otto M Wiltfang J 《Journal of neural transmission (Vienna, Austria : 1996)》2006,113(11):1771-1778
Summary. Differential diagnosis of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often crucial. CSF Tau protein and
Amyloid-beta (Aβ) peptides have shown diagnostic value for the diagnosis of AD, but discrimination from DLB was poor.
Herein, we investigate CSF of 18 patients with probable AD, 25 with probable DLB and 14 non-demented disease controls (NDC)
by Aβ-SDS-PAGE/immunoblot and commercially available ELISAs for Aβ1-42 and tau. CSF Aβ peptide patterns and tau exhibited
disease specific alterations among AD and DLB. The ratio of Aβ1-42 to Aβ1-38 and Aβ1-42 to Aβ1-37, respectively, in combination
with absolute tau, yielded a sensitivity and specificity of 100 and 92%, respectively. We conclude that CSF Aβ peptide patterns
and tau levels reflect disease-specific pathophysiological pathways of these dementias as distinct neurochemical phenotypes.
Combined evaluation of these biomarkers provides a reasonable accuracy for differential diagnosis of AD and DLB. 相似文献
10.
Gmitterová Karin Gawinecka Joanna Llorens Franc Varges Daniela Valkovič Peter Zerr Inga 《European archives of psychiatry and clinical neuroscience》2020,270(4):461-470
European Archives of Psychiatry and Clinical Neuroscience - Dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) share a couple of clinical similarities that is often a... 相似文献
11.
Sara Varanese Bernardo Perfetti Daniela Monaco Astrid Thomas Laura Bonanni Pietro Tiraboschi Marco Onofrj 《Journal of neurology》2010,257(6):1004-1011
To examine the occurrence of fluctuating cognition (FC) in a group of patients with Parkinson’s disease with dementia (PDD),
and to determine whether the presence of FC in PDD is associated with a pattern of cognitive and behavioural disturbances
similar to the one shown by patients affected by dementia with Lewy bodies (DLB), a cluster analysis was carried out on the
scores obtained by 27 PDD patients on the Clinician Assessment of Fluctuation Scale (CAF). The analysis separated the PDD
patients into two subgroups, called PDD non-fluctuators (PDDNF; CAF ≤ 2) and PDD fluctuators (PDDF; CAF > 2). The two groups
underwent a cognitive and behavioural evaluation. Their scores were compared with those obtained by DLB and Alzheimer’s disease
(AD) patients. When exploring the cognitive performance of the patients with the Dementia Rating Scale-2 (DRS-2), PDDF had
a similar pattern of impairments compared to DLB, which involved prevalently the attention and initiation/perseveration domains,
and which was significantly more pronounced compared to that shown by PDDNF. The main behavioural finding of the study was
the similar incidence of visual hallucinations in the PDDF and DLB groups, which was significantly higher compared to PDDNF
and AD. Our results confirmed the hypothesis that subgroups with different cognitive profiles exist within PDD and that the
occurrence of FC is the clinical variable associated with a DLB pattern of impairment in PDD. In conclusion, our study suggests
that when FC occurs in PDD this syndrome becomes clinically undistinguishable from DLB. 相似文献
12.
Glutathione peroxidase (GPx-1) is regarded as one of the mammalian cell’s main antioxidant enzymes inactivating hydrogen peroxide
and protecting against oxidative stress. Using control, Parkinson’s disease (PD), and dementia with Lewy bodies tissue (DLB)
we have shown that GPx-1 is a 21-kD protein under reducing conditions in all tissues examined but is not in high abundance
in human brain. Using immunohistochemistry we have mapped the cellular distribution of GPx-1 and have shown it to be in highest
levels in microglia and with lower levels in neurons. Only a trace amount was detectable in astrocytes using immunofluorescence
and GPx-1 was not detectable in oligodendrocytes. GPx-1 positive microglia were hypertrophied and more abundant in PD and
DLB tissues and were seen to be making multiple contacts with neurons. In some cases neurons containing Lewy bodies were surrounded
by microglia. Unstructured Lewy bodies were enveloped with a layer of GPx-1 that was partially colocalized with α-synuclein
whereas concentric Lewy bodies had discrete deposits of GPx-1 around the periphery which appeared to be involved in the degradation
of the Lewy bodies. These results suggest that abnormal α-synuclein as found in Lewy bodies produce hydrogen peroxide and
these neurons are capable of directing antioxidant enzymes to regions of oxidative stress. These results also suggest that
GPx-1 positive microglia are involved in neuroprotection in PD and DLB and that GPx-1 is an important antioxidant enzyme in
neuronal defences. 相似文献
13.
Kelly Del Tredici Christopher H. Hawkes Estifanos Ghebremedhin Heiko Braak 《Acta neuropathologica》2010,119(6):703-713
A retrospective autopsy-based study of the human submandibular gland, one of the three major salivary glands, together with
anatomically related peripheral structures (cervical superior ganglion, cervical sympathetic trunk, vagal nerve at the level
of the carotid bifurcation), was conducted on a cohort consisting of 33 individuals, including 9 patients with neuropathologically
confirmed Parkinson’s disease (PD), three individuals with incidental Lewy body disease (iLBD), 2 individuals with neuropathologically
confirmed multiple system atrophy (MSA), and 19 controls, using α-synuclein immunohistochemistry in 100 μm polyethylene glycol-embedded
tissue sections. Lewy pathology (LP) was present in the submandibular glands and cervical superior ganglia in PD (9/9 cases)
and iLBD (2/3 cases) but not in MSA or controls. The cervical sympathetic trunk (7/9 PD cases, 2/3 iLBD cases) and peripheral
vagal nerves (9/9 PD cases, 2/3 iLBD cases) also displayed LP. The results are discussed within the context of hyposmia as
well as autonomic dysfunction in PD (sialorrhea, sialopenia, dysphagia). Potential disease-related changes in salivary volume,
contents, and viscosity might make it possible, in combination with other tests, to employ human saliva as a biomarker. 相似文献
14.
Dickson DW Fujishiro H DelleDonne A Menke J Ahmed Z Klos KJ Josephs KA Frigerio R Burnett M Parisi JE Ahlskog JE 《Acta neuropathologica》2008,115(4):437-444
Lewy bodies, the histologic hallmark of Parkinson’s disease (PD), are detected in the brains of about 10% of clinically normal
people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as
incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal
populations vulnerable to Lewy bodies do not show significant neuronal loss in iLBD. It remains unknown if Lewy bodies in
this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identified
cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there
were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve fibers was decreased
in iLBD compared to normal controls, but not to the same extent as in PD. The findings suggest that iLBD is preclinical PD
and that the lack of symptoms is due to subthreshold pathology. 相似文献
15.
Tetsuaki Arai Ian R. A. Mackenzie Masato Hasegawa Takashi Nonoka Kazhuhiro Niizato Kuniaki Tsuchiya Shuji Iritani Mitsumoto Onaya Haruhiko Akiyama 《Acta neuropathologica》2009,117(2):125-136
Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common
pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a
subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies
(DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features
of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still
unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent
anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously
reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated
with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense
staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern
of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated
with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD
or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein. 相似文献
16.
Nardone R Bratti A Tezzon F 《Journal of neural transmission (Vienna, Austria : 1996)》2006,113(11):1679-1684
Summary. To determine whether a peculiar neurophysiological profile may contribute to characterize dementia with Lewy bodies (DLB)
vs. Alzheimer disease (AD), we used transcranial magnetic stimulation to examine the excitability of two different inhibitory
systems of the motor cortex, short latency intracortical inhibition (SICI) and short latency afferent inhibition (SAI) in
10 patients with DLB, in 13 patients with AD and in 15 healthy subjects. SICI and SAI were significantly reduced in AD patients,
while both were not significantly different from the controls in DLB patients. The differential pattern of SICI and SAI exhibited
by AD vs. DLB may have diagnostic significance in discriminating DLB from AD. Furthermore, this technique may help to clarify
the pathophysiological entity of DLB; since SAI is a cortical phenomenon that depends on central cholinergic activity, our
findings suggest that the mechanisms of cholinergic depletion in DLB may be different from that in AD, while normal SICI may
reflect a less pronounced dysregulation of the intracortical GABAergic inhibitory circuitries in DLB. 相似文献
17.
Michel J. Grothe Christina Schuster Florian Bauer Helmut Heinsen Johannes Prudlo Stefan J. Teipel 《Journal of neurology》2014,261(10):1939-1948
Similar to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer’s disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20–25 %, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions. 相似文献
18.
Mollenhauer B Bibl M Trenkwalder C Stiens G Cepek L Steinacker P Ciesielczyk B Neubert K Wiltfang J Kretzschmar HA Poser S Otto M 《Journal of neural transmission (Vienna, Austria : 1996)》2005,112(7):933-948
Summary. Measuring proteins in cerebrospinal fluid (CSF) has gained wide acceptance for the differential diagnosis of dementia. Some groups have already extended these investigations in Alzheimers disease (AD) by asking how stable these markers are in follow-up analysis, if they depend on the stage of disease and whether they can be used to monitor the progression and biological effects of treatment. We evaluated 21 patients with dementia with Lewy bodies (DLB) and 19 patients with AD, on two occasions, with regard to levels of tau protein, tau protein phosphorylated at threonine 181 (p-tau), A42, A40 and S-100B protein, using a set of commercially available assays.Tau protein levels were lower in DLB in first and second LP compared to AD and decreased during course of both groups. P-tau levels were increased in AD and DLB and decreased during follow-up. A42 and A40 remained relatively stable during follow-up but we found a slight increase of the median A42 level in DLB, whereas in AD, A42 tends to decrease during follow-up. S-100B protein increased during follow-up in both diseases.The protein dynamics in DLB and AD are relatively similar. S-100B protein may be a useful marker for follow-up in neurodegenerative diseases but has to be analysed in longer follow-up periods. Tau protein may be used to differentiate between DLB and AD.Follow-up CSF analyses are of limited value for the differentiation of AD and DLB. We conclude that more specific markers have to be established for the differentiation and follow-up of these diseases. 相似文献
19.
Pezzoli Gianni Cereda Emanuele Amami Paolo Colosimo Santo Barichella Michela Sacilotto Giorgio Zecchinelli Anna Zini Michela Ferri Valentina Bolliri Carlotta Calandrella Daniela Bonelli Maria Grazia Cereda Viviana Reali Elisa Caronni Serena Cassani Erica Canesi Margherita del Sorbo Francesca Soliveri Paola Zecca Luigi Klersy Catherine Cilia Roberto Isaias Ioannis U. 《Journal of neurology》2023,270(3):1564-1572
Journal of Neurology - There is growing evidence that Parkinson’s disease and diabetes are partially related diseases; however, the association between the two, and the impact of specific... 相似文献
20.
Li Qian Patrick M. Flood Jau-Shyong Hong 《Journal of neural transmission (Vienna, Austria : 1996)》2010,117(8):971-979
Parkinson’s disease (PD) is a neurodegenerative movement disorder characterized by the progressive loss of dopaminergic neurons
in the substantia nigra and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities.
Increasing evidence has demonstrated that inflammation is the fundamental process contributing to neuron death in PD. Neuroinflammation,
which is characterized by activated microglia and infiltrating T cells at sites of neuronal injury, is a prominent contributor
to the pathogenesis of progressive PD. Microglia play a critical role in forming a self-propelling cycle leading to sustained
chronic neuroinflammation and driving the progressive neurodegeneration in PD. This activation depends heavily on the respiratory
burst within the microglia, which in turn regulates a number of downstream pro-inflammatory activities. On the other hand,
the adaptive immune responses, most notably T cells, are now emerging as important components of the inflammatory response
that contribute to the pathogenesis of PD. This review paper focus on the understanding of the inflammatory etiology of PD,
as well as the molecular signaling involved in this inflammatory response, with the aim to provide more effective treatments
to slow down or halt the progression of chronic inflammation-induced CNS disorders, such as PD. 相似文献