A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders - PDF

A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders Kurt A. Jellinger To cite this version: Kurt A. Jellinger. A critical evaluation of current staging of α-synuclein

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A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders Kurt A. Jellinger To cite this version: Kurt A. Jellinger. A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders. BBA - Molecular Basis of Disease, Elsevier, 2009, 1792 (7), pp.730. /j.bbadis . hal HAL Id: hal https://hal.archives-ouvertes.fr/hal Submitted on 15 Jun 2010 HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. Accepted Manuscript A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders Kurt A. Jellinger PII: S (08) DOI: doi: /j.bbadis Reference: BBADIS To appear in: BBA - Molecular Basis of Disease Received date: 1 May 2008 Accepted date: 23 July 2008 Please cite this article as: Kurt A. Jellinger, A critical evaluation of current staging of α-synuclein pathology in Lewy body disorders, BBA - Molecular Basis of Disease (2008), doi: /j.bbadis This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 Biochim Biophys Acta A critical evaluation of current staging of a-synuclein pathology in Lewy body disorders Kurt A. Jellinger Institute of Clinical Neurobiology, A-1070 Vienna, Austria Kurt A. Jellinger, MD Institute of Clinical Neurobiology Kenyongasse 18, A-1070 Vienna, Austria Phone and Fax: Keywords: a-synucleinopathies; dementia with Lewy bodies; Parkinson disease; disease staging; Braak Lewy body stages; DLB consensus pathologic guidelines Summary 2 The two most frequent synucleinopathies, Parkinson disease (PD) or brainstem predominant type of Lewy body disease, and dementia with Lewy bodies (DLB), are neurodegenerative multisystem disorders with widespread occurrence of a-synuclein containing deposits in the central and peripheral autonomic systems. For both Lewy bodyrelated disorders staging/classification systems based on semiquantitative assessment of the distribution and progression pattern of a-synuclein pathology are used that are considered to be linked to clinical dysfunctions. In PD a six-stage system is suggested to indicate a predictable sequence of lesions with ascending progression from medullary and olfactory nuclei to the cortex, the first two presymptomatic stages related to incidental Lewy body disease, stages 3 and 4 presenting with motor symptoms and the last two (cortical) stages frequently associated with cognitive impairment. DLB, according to consensus pathologic guidelines, by semiquantitative scoring of a-synuclein pathology (Lewy body density and distribution) in specific brain regions, is distinguished into three phenotypes (brainstem, transitory/limbic and diffuse cortical), also considering concomitant Alzheimer-related pathology. Recent retrospective clinico-pathologic studies, although largely confirming the staging system, particularly for younger onset PD with long duration, have shown that between 6.3 and 43% of cases did not follow the proposed caudo-rostral progression pattern of a-synuclein pathology. In 7 to 8.3% of clinically manifested PD cases with synuclein inclusions in midbrain and cortex corresponding to LB stages 4-5 the medullary nuclei were spared, whereas mild parkinsonian symptoms were already observed in stages 2 and 3. There is considerable clinical and pathologic overlap between PD (with or without dementia) and DLB, corresponding to Braak LB stages 5 and 6, both frequently associated with variable Alzheimer-type pathology. Dementia often does not correlate with progressed stages of Lewy body pathology, but often is related to concomitant Alzheimer lesions or mixed pathologies. The relation between cortical Lewy body lesions and cognitive impairment is under discussion. On the other hand, in large unselected autopsy series 30 to 55% of elderly subjects with widespread a-synuclein pathology (Braak stages 5-6) revealed no definite neuropsychiatric symptoms or were not classifiable, indicating compensatory mechanisms of the brain. The causes and molecular basis of rather frequent deviations from the proposed caudo-rostral progression of a-synuclein pathology in PD, its relation to the onset of classical parkinsonian symptoms, the causes for the lack of definite clinical symptoms despite widespread a-synuclein pathology in the nervous system, their relations to Alzheimer-type lesions, and the pathophysiologic impact of both pathologies remain to be further elucidated. Introduction 3 Among proteinopathies, a heterogenous group of neurodegenerative disorders, characterized by intra- and extracellular accumulation of abnormal filament proteins, Lewy body (LB)-associated disorders, such as Parkinson disease (PD) and dementia with Lewy bodies (DLB) show protein inclusions in neurons and neurites (LBs and Lewy neurites/lns), glia, and presynaptic terminals [1], with a-synuclein (asyn) as their major component [for rev see 2]). Given the fundamental nature of the asyn containing lesions, these and other disorders, such as autonomic failure, LB dysphagia, and multiple system atrophy (MSA) have been summarized as a-synucleinopathies [3,4]. PD or brainstem type of LB disease [5,6] is the most common neurodegenerative movement disorder in the elderly, with progressive degeneration of the dopaminergic nigrostriatal system and other neuronal networks caused by loss of pigmented neurons in the substantia nigra compacta (SNc) and many other subcortical nuclei associated with widespread occurrence of LBs and LNs in the brain and specific nuclei of the spinal cord. PD-related lesions are not confined to the central nervous system, but also involve autonomic nuclei, sympathetic ganglia, cardiac and pelvic plexuses, and nerves as well as adrenal medulla, salvary gland and skin [7-23], clearly indicating that PD is a multisystem disorder [for rev. see 2,8]. DLB, the second most frequent cause of dementia in the elderly after Alzheimer disease (AD), with the core neuropsychiatric features of fluctuating consciousness, visual hallucinations and parkinsonism, is morphologically featured by a variable burden of a synucleinopathy with (often widespread) cortical LBs and various degrees of AD-related pathology [5,6]. The distribution pattern of asyn pathology within selectively vulnerable neuronal populations is considered to be intimately linked to the clinical dysfunctions seen in both disorders, asyn lesions in the brainstem been mainly claimed to be responsibe for extrapyramidal motor symptoms, whereas cognitive impairment has been attributed to the limbic and neocortical spread of LB lesions [24-28]. Thus, PD and DLB are believed to represent phenotypes in a continuum within the spectrum of LB disorders, wherein the clinical manifestations predominantly depend on the anatomical distribution and load of asyn pathology [6,13,29-31]. Despite clinical, biochemical and morphological similarities and dissimilarities, the relations between the two disorders have been discussed controversially [2,32-37]. Two morphological staging/classification systems are currently used for the assessment of the progressive regional distribution of asyn pathology in PD and DLB [5,6,29,38], the applicability and clinical relevance of which has been critically discussed recently [39]. Both staging systems, the Braak hypothesis of LB staging in PD [29] and the 4 DLB consensus guidelines [5,6] were developed in non-population-based cohorts. The essentials and validity of these two systems will be critically evaluated based on recent literature and personal studies. Staging of asyn inclusion body pathology in sporadic PD Based on semiquantitative assessment of asyn-positive inclusions in 413 postmortem cases including 41 PD cases, 69 with asyn inclusions and and 58 aged-matched controls, a hypothetic staging system of brain pathology indicating a predictable sequence with increasing severity throughout the brain and ascending progression has been proposed [9,29,40-42]. asyn pathology was divided into six successive stages: The earliest lesions were seen in the lower medulla oblongata with a few LNs in the dorsal motor nucleus of the vagus nerve (DMV), in anterior olfactory structures, chiefly affecting the anterior olfactory nucleus embedded in the olfactory tract, and some asyn-positive aggregates in preganglionic vagal axons [10], with the nucleus basalis of Meynert (NBM) and midbrain regions being preserved (Stage 1). More severe lesions in the DMV with extension to the caudal raphe nuclei and gigantocellular portions of the adjoining reticular formation, and some LNs in the noradrenergic locus ceruleus (LC) are seen in stage 2. These initial stages (observed in 7% of the cohort) were considered a(pre)symptomatic and may explain early non-motor (autonomic and olfactory) symptoms that preceed the somato-motor dysfunctions [43-46]. In stage 3, the LC, the central nucleus of the amygdala, the tegmental pedunculopontine nucleus and cholinergic nuclei of the basal forebrain including the NMB are the focus of cytoskeletal changes and neuronal depletions, the posterolateral and posteromedial parts of SNc showing pale bodies (precursors of LBs) [47] and LBs without neuronal loss, while the allocortex and neocortex are preserved. In stage 4, the anteromedial temporal limbic (transentorhinal) and mesocortex and amygdala are additionally affected. Stages 3 and 4 have been correlated with clinical motor symptoms (11% of their cohort). In stage 5, the lesions in the temporal mesocortex are more striking and from there progress to adjoining association fields of the temporal and prefrontal neocortex, while in stage 6, the lesions involve the neocortex, first affecting the high-order sensory association cortex and prefrontal areas, later progressing to the primary sensory and motor areas or involving the whole neocortex (Fig. 1). The cases with severe pathology (stage 5-6) accounting for 6% of their cohort, frequently show cognitive decline that relates to the severity of the neuropathologic stage [10,38]. In another retrospective study of 25 individuals (17 with PD, 8 with incidental asyn inclusions) LB pathology and glial cytoplasmic inclusions in striatum were seen for the first time in stage 3 in the medium-sized GABA-ergic spiny projection neurons that reach both the pallidum and SN reticulata (SNr), and at stages 5-6 in the large cholinergic interneurons [48]. 5 Consensus pathologic guidelines for the diagnosis of DLB According to the initial consensus pathologic guidelines, LBs are scored semiquantiatively according to the severity and anatomical distribution, separating brainstem predominant (PD), limbic/transitional and diffuse neocortical types, depending on the anatomical distribution of the asyn-positive structures [5]. The revised consensus guidelines [6] proposed semiquantitative assessment of LB density, based on asyn immunohistochemistry, in five cortical regions (Table 1a). However, the stage of AD pathology is usually not associated with the particular pattern of asyn lesions [49]. A third pattern concentrated on asyn pathology in cortical areas [50]. Considering the significance and clinical impact of concomitant ADrelated pathology frequently seen in aged subjects with and without dementia, the revised consensus criteria for DLB have recommended to take it into account seriously [6] (Table 1b). This protocol was simplified by excluding the frontal region because of the common occurrence of occasional LBs in this regions in PD in the absence of dementia [51]. These guidelines did not provide definitie diagnostic criteria as it is sometimes mistakenly assumed, and were not included in the CERAD protocol, which is used for the semiquantitative evaluation of neuritic plaques and neurofibrillary tangles [52]. Studies to evaluate the reliability of asyn-related stagings The proposed staging procedure for asyn pathology in PD rested, in part, on the assumption that incidental LB pathology is the first step along a disease continuum [42], but that sporadic PD, like most neurodegenerative disorders, is not a static but a dynamic biologic process and that so-called incidental lesions (LBs/LNs seen in subjects without PD related signs and symptoms) represent presymptomatic (subclinical) correlates of a pathologic condition ultimately leading to a manifest clinical disease [10,53-55]. Incidental LB disease (ilbd) is the term when LBs are found in the nervous system in subjects without clinically documented parkinsonism or cognitive impairment [54,56]. Epidemiological studies indicated that autonomic symptoms, REM sleep behavioral disorder and olfactory dysfunction may precede overt extrapyramidal motor symptoms by years [57-59], resulting from LBs and LNs in the enteric plexus [10,60], affection of lower brainstem nuclei [61,62] and the sympathetic cardiac nervous system [63]. Recent studies of ilbd cases have shown a distribution of LBs similar to that in PD, involving one or multiple brain areas, some also with sparse LBs in limbic or temporal cortex (average Braak stage 2.7 ± 0.3) in comparison to definite PD cases with more numerous LBs in all regions and significantly higher Braak PD stage (average 4.4 ± 0.3). When both groups were taken together, a significant inverse correlation existed between neuronal densities in the three anatomical regions studied and the Braak PD stage [64]. Furthermore, there was decreased TH immunoreactivity in both the striatum and sympathetic epicardial nerve fibers in cases with incidental LB pathology compared to normal controls but not in the same extent as in PD [64,65]. On the other hand, incidental asyn pathology may affect solely the LC and SN without affection of the medullary nuclei [66-69]. Incidental LBs are not considered as a normal aging phenomenon, whereas neurofibrillary tangles increase with age in the SN [70], and are associated with increasing neuritic AD stages [71]. These findings suggest that ilbd is likely a precursor to or preclinical form of PD, and the lack of symptoms is due to subthreshold asyn pathology. Some recent studies have largely confirmed this staging of LB-related pathology in sporadic PD, showing that all brains of subjects with clinical PD revealed asyn-positive inclusions and neuronal losses in medullary and pontine nuclei and SN, and additional lesions in NBM (90-98 %), limbic cortex (50-60%), cingulate area (32-46%), frontal cortex (29-31%), and amygdala (25%), corresponding to LB stages 4 to 6 [3,66]. In a previous study, LBs in SN were found in 99.2% of clinico-pathologically confirmed PD cases [72]. LB pathology first appears in the ventrolateral part of SNc, spreads to the paranigral nucleus and then to the medial part, and finally to the dorsal part of SNc [73]. There is severe depletion of melanized neurons (45-66%) and of dopaminergic neurons immunoreactive for tyrosine hydroxylase (TH) (60-85%) in the A-9 group of SNc, particularly in the ventrolateral tier (91%) projecting to striosomal compartments of the striatum [74], followed by the ventromedial (71%) and dorsal parts (56%) [75]. The calbindin (CAB)-rich compartments show greater cell loss in the caudal and mediolateral region (98%) than the adjacent matrix. From there, it spreads to other nigrosomes and finally to the matrix along a caudorostral, lateromedial and ventrodorsal progression [76]. These changes differ from age-related lesions in the dorsal tier of SNc that is involved only in late stages of PD [75,77]. The A-10 group of dopaminergic neurons - ventral tegmental area, nucleus parabrachialis, and parabrachialis pigmentosus - projecting to the striatal matrix, thalamus [78], cortical and limbic areas (mesocortico-limbic system) [79] in PD show less severe involvement (40-50% cell loss), the retrorubral A-8 region containing only few dopaminergic but CAB-rich neurons, and the 6 central periventricular gray suffer little or no degeneration [80]. Others reported greater cell loss in LC (area A-6) than in SN in both PD and AD [81]. Morphometric studies showed a 35-41% reduction of pigmented SN cells, with severe loss of dopamine transporter (DAT)- immunoreactive neurons in older persons [82] and increase in the volume of these cells [83]. Some studies have estimated the neuronal loss as 4.3% per decade [83], while others have reported almost 10% [84]. Recent morphometric stereologic studies of the human SN revealed a significant loss of pigmented (-28.3%) and TH-positive (-36.2%) neurons in older controls compared to younger subjects, with hypertrophy of cells in older controls, interpreted as a compensatory mechanism to allow normal motor function despite cell loss. PD showed a massive loss of SN neurons with significant atrophy of remaining cells (20% of controls), but most of the examined cases were in the end stage of the disease [85]. A prerequisite of the proposed staging system of asyn inclusion pathology is that the extent and severity of lesions increase as the disease progresses [41]. A study of 21 PD brains by six observers from five different institutions examining 11 different brain areas revealed highly significant inter- and intra-rater reliability and supported the suitability of the staging procedure of asyn pathology for application in routie neuropathology and brain banking [86]. However, the reliability of this staging system has recently been challenged [3,49,66-68,87,88]. In Braak s cohort of 301 cases (including 176 clinical PD and 106 with incidental LB pathology), only 6.3% of PD brains diverged from the hypothetical staging scheme of asyn pathology, with predominant involvement of olfactory structures and amygdala, and advanced concomitant AD-related neuritic pathology [10,41]. However, among 71 cases of PD from the London brain tissue bank only 53% showed a distribution pattern of asyn compatible with the caudo-rostral spreading suggested by Braak et al [29] and 43% did not fit the predicted spread of asyn inclusion pathology. The most frequently affected regions were SN and NBM (100 and 98.5%, respectively), followed by LC and DMV (97 and 92.9%, respectively). In 7% the DMV was not affected, although asyn inclusions were found in SN and/or cortical regions [87]. On the other hand, in a 68-year-old woman with late-onset, doparesponsive parkinsonism of almost 13 years duration, autopsy revealed severe neuronal loss with many LBs in DMV but only moderate neuron depletion (60%) in SNc without any LBs and moderate cell loss with diffuse asyn cytoplasmic staining in LC, suggesting unusual manifestation of LB disease in clinically definite PD [60]. In an autopsy series of 260 elderly subjects including 71 cases of autopsy proven PD, 38 of DLB, 116 AD and 26 age-matched controls (with positive asyn pathology in 51% of AD and 31% of controls), 30% of AD cases with multifocal asyn pathology but without clinical EPS showed no involvement of the 7 medullary nuclei [66]. In another autopsy series of 60 autopsy-confirmed cases of PD (29 PD with dementia /PDD/ and 31 without dementia, mean age at death 82.5 years), some early PD symptoms were shown to occur already in rare cases with LB st
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