The Etiopathogenesis of Parkinson Disease and Suggestions for Future Research. Part I

We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors and, although there is extensive new information on the etiology and pathogenesis of PD that may advance its treatment, new syntheses of this information are needed. The first part of this two-part, state-of-the-art review by leaders in Parkinson research critically examines the field to identify where new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part I include the definition of the disease, neuropathologic contributions, and epidemiologic, environmental, and demographic issues. The definition of idiopathic Parkinson disease (PD) remains controversial. Classically, it includes a characteristic motor phenotype (1) and a distinctive neuropathology and substantial loss of dopaminergic neurons from the substantia nigra associated with the presence of α-synuclein-positive inclusions in the cell body (Lewy bodies) and processes (Lewy neurites) of specific neurons of the brainstem. Some genetically determined Parkinson syndromes resemble, sometimes closely, idiopathic PD, but differ from it neuropathologically, sometimes substantially. In particular, a number of juvenile-onset autosomal recessive cases of familial Parkinson syndrome do not have α-synuclein lesions (2), contrasting with the autosomal dominant forms of the disease which often have unusual types of lesions (3-5). The recently identified leucine-rich repeat kinase 2 (LRRK2, Park-8) mutations produce variable pathologic phenotypes. Although the most common is Lewy body disease, nigral degeneration with ubiquitin inclusions or, in a few cases, even pathologic changes more typical of frontotemporal lobar degeneration or progressive supranuclear palsy have been described in patients with LRRK2 mutations (6). Two recent reports insist on the high prevalence of Lewy bodies in the LRRK2 mutations (7) but also describe a family with tau pathology (8). Neuropathology has revealed the considerable frequency with which idiopathic PD is associated with other degenerative conditions, notably Alzheimer disease, particularly in advanced age, even though the clinical consequences of multiple pathologies remain poorly defined. Moreover, an association with genetic variants that increase tau transcription occurs in all forms of Lewy body diseases (sporadic and familial), providing additional support for the involvement of tau in the pathogenic process (9, 10). Unfortunately, the cellular mechanisms by which this or other potential detrimental processes interact to produce the features of any form of PD remain purely speculative. Other synucleinopathies (disorders with α-synuclein aggregates) include dementia with Lewy bodies (DLB), multiple system atrophy in which α-synuclein constitutes characteristic inclusions, predominantly in oligodendrocyte cell bodies (11), and neurodegeneration with brain iron accumulation in which α-synuclein accumulates in axonal spheroids (12). The recognition of such varied disorders associated with abnormal α-synuclein aggregation in multiple cell types and cell compartments has broad implications for the etiopathogenesis of this group of disorders, suggesting that the selective disruption of diverse intracellular events utilizing α-synuclein leads to distinctive anatomical and cellular patterns of pathology. In particular, some patients with DLB have patterns of α-synuclein deposition identical to those seen in idiopathic PD but have no parkinsonism (13, 14). Moreover, as olfactory dysfunction, constipation, rapid eye movement sleep behavior disorder, and depression may precede or present commonly in early PD, they are proposed to be prodromic signs of PD (15). These symptoms correlate well with the deposition of α-synuclein in Braak stages 1 (olfactory bulb and peripheral and central medullary autonomic neurons) and 2 (locus ceruleus and pontine tegmentum), which are proposed to precede the clinical symptoms of PD (stage 3 with α-synuclein deposition in the substantia nigra) (16). Should the definition of PD rely on clinical (the extrapyramidal syndrome), pathologic (the α-synuclein deposition), or genetic data? When the full spectrum of clinical PD is present, there is a high probability of finding a devastating loss of dopamine neurons (17) with α-synuclein accumulation. Moreover, the loss of nigral neurons is correlated with the severity of akinesia and rigidity (18). However, the accumulation of α-synuclein may be absent in patients with genetically determined clinical PD. Mild parkinsonian symptoms in the elderly may also relate to the loss of dopamine neurons in the absence of α-synuclein deposition (19). In most if not all of these α-synuclein-negative cases, clinical PD is determined by lesions of the nigrostriatal pathway. Should we then use the term "PD" for any type of pathology as soon as it induces an alteration of the nigrostriatal pathway sufficient to cause the PD clinical phenotype? Should we reserve it for cases in which clinical PD and nigrostriatal degeneration are associated with an alteration of α-synuclein metabolism responsible for Lewy bodies and Lewy neurites formation? Or, should we reserve it for the widespread disorder that in addition to the nigrostriatal system affects serotoninergic, noradrenergic, and cholinergic brainstem nuclei and the olfactory, peripheral sympathetic, and myenteric nervous system? (16). The latter will include now better-recognized nonmotor PD symptoms (i.e. anosmia, constipation, rapid eye movement sleep disorder, and depression). Large autopsy series of community samples show that the majority of people harbor multiple cellular neuropathologies as they age (20-22). This finding suggests that clinical parkinsonism in the elderly could arise from differing pathologies within the dopamine pathways. Alzheimer disease can be responsible for such alterations that induce an extrapyramidal syndrome (23, 24), which is important to remember when epidemiologic data of age-related prevalence are being discussed, as there is a much greater likelihood of nonsynuclein-related pathologies contributing to clinical features with advancing age. The impact of overlapping pathologies in PD is poorly understood, although the identification of cases with high burdens of α-synuclein accumulation but without clinical deficits (25) suggests that the etiopathogenesis may be related to additional, more toxic pathologies that are worthy of investigation. Whereas several clinicopathologic studies support the concept that increasing cortical Lewy body burden contributes to clinical dementia in PD, additional pathologies and/or cell loss may also underlie substantive clinical deficits (14) and warrant further investigation. Is there any clue that could assist in recognizing the α-synuclein phenotype? In other words, do all of the synucleinopathies (i.e. Lewy body diseases, multiple system atrophy, or neurodegeneration with brain iron accumulation) have something in common? α-Synuclein aggregations concentrate in different cell types in various patterns in different diseases with diverse pathogenesis. What clinical features, if any, do these disorders have in common? Without a biologic marker, how good are we at identifying this broader group of patients in a clinical setting? There is an urgent need for clarification of the nomenclature. Inasmuch as the aim of the nosologic classification is to orient research and suggest therapy, it appears that similarity in the topography of the lesions does not imply similarity in the full spectrum of disease pathogenesis. We think it advisable to carefully distinguish the various Parkinsonian syndromes by their pathologic and genetic characteristics, including those syndromes with and without Lewy bodies. On the other hand, lesions of the nigrostriatal pathway, responsible for clinical parkinsonism, do not necessarily imply α-synuclein dysfunction and could be related to alterations in other intracellular pathways that also justify research. For these reasons, we would favor the "splitter" approach that combines clinical and pathologic phenotypes with the study of genotype, rather than lumping all cases under the common name of idiopathic PD. We would restrict the term "idiopathic PD" to cases with clinical parkinsonism associated with Lewy body pathology for which we are not sure of the genetic etiology (i.e. no known or suspected genetic abnormality). This would require that the "idiopathic" form of the disease be pathologically confirmed with genetic screening to ensure similar cellular etiology. We therefore propose that the clinical use of the terms possible and probable clinical PD be more routinely adopted and genetic testing be performed when possible and warranted. Neuropathologic studies have been essential in defining and characterizing the Lewy body inclusions of idiopathic PD. More than 30 proteins have been identified within these inclusions (26) with the core filament composed of α-synuclein (27). These studies provide crucial information for the laboratory modeling of PD. Lewy bodies and Lewy neurites are either asymptomatic or found in pathologic conditions, grouped under the heading "Lewy body disease" that include idiopathic PD, PD with dementia, and DLB (28). From a neuropathologic point of view, the distribution of Lewy pathology follows three schematic profiles: brainstem, transitional (equal to limbic Lewy body disease), and diffuse (equal to neocortical Lewy body disease) (29), with additional widespread occurrence in olfactory and central and peripheral autonomic neurons in most cases (16, 30). In Alzheimer disease, Lewy body pathology can be limited to the amygdala, which does not fit into any of these categories. The brainstem type is generally associated with clinical PD, whereas the transitional and diffuse types are generally linked to dementia, either PD with dementia (a long history of PD followed by dementia) or DLB (dementia early in the course), usually associated with varying degrees of concurrent Alzheimer-type pathology (14). In prospectively studied patients with PD with dementia in particular, cortical Lewy bodies appear to be the main substrate driving the progression of cognitive impairment (31). However, as discussed above, in synucleinopathies without PD, the diffuse type of Lewy body disease can occur without significant evidence of parkinsonism or dementia (25) and other pathologies associated with dementia in PD (14). The effects of widespread Lewy body pathology in central and peripheral autonomic regions require further clarification (32, 33). Analysis of the cellular events occurring in PD can only be done at cross-section with comparison between cases at different disease stages identifying any cellular dynamics, assuming the disease tempo and processes are relatively homogeneous. There is a substantial body of evidence showing that, in most autopsy cases with clinical PD, pathology is not restricted to the substantia nigra but reaches widespread areas within the brain, spinal cord, and peripheral nervous system. On the other hand, recent studies confirm that a proportion of the elderly population have α-synuclein aggregates without substantive clinical symptoms (25, 32, 33). These patients may, however, have relevant nonmotor symptoms such as rapid eye movement sleep behavior disorder, constipation, or other subtle features that may be reflective of this pathology (34). There may nevertheless be a significant preclinical period in which a threshold of pathology needs to be reached (both cell loss and α-synuclein accumulation) before onset of any symptoms (16). Analysis of the similarities and differences between cases with Lewy body pathology has led to the proposal of progressive disease stages in which the intracellular deposition of α-synuclein affects medullary sites before more rostral brain regions, with the last stages associated with involvement of cortical association neurons (16). This scheme of progression raises difficulties: the proposal suggests that autonomic centers in the medulla are initially affected, yet marked autonomic symptoms are not an early prominent disease feature in idiopathic PD or associated with the degree of cell loss (35), and predominant autonomic symptoms and cell loss in relevant medullary sites rather suggest a diagnosis of multiple system atrophy (36). Thus, it is possible that the pathologic deposition of α-synuclein does not produce profound cellular deficits, except in association with additional pathologies and/or cell loss, a finding consistent with recent clinicopathologic studies of these medullary regions (36). In the late stages, cortical deposition of α-synuclein correlates with progressive cognitive decline (31, 37), although in DLB the dementia is an early not a late dominating clinical feature. Because of the considerable dopamine cell loss observed in PD, it has always been assumed that Lewy bodies cause cell loss. However, to determine whether Lewy body cell loss is a consistent feature in all brain regions would require the analysis of longitudinally followed patients who do not exhibit the common overlapping pathologies of the aged. There has also been considerable debate over the role of α-synuclein aggregation in contributing to cortical dementia, but the bulk of studies support a strong association between the presence of this cellular pathology and clinical dementia. The initial controversy was largely due to overlapping pathologies in the majority of cases analyzed and the difficulty in attributing clinical deficits to any single pathology. The current debate is whether α-synuclein deposition in Lewy bodies is detrimental or protective (38), a concept also difficult to determine in cases with limited clinical history and multiple pathologies. The few studies of prospectively collected, autopsy-confirmed pure DLB with neocortical Lewy bodies have shown limited gross tissue atrophy (39) and restricted cell loss (40). α-Synuclein aggregates do not accumulate extracellularly and disappear when the neuron dies, in contrast to what occurs in Alzheimer disease in which the accumulation of tau protein remains visible in the extracellular space (ghost tangles). The presence of numerous α-synuclein depositions in cases with long disease durations (e.g. PD with dementia) suggests that the neurons harboring these inclusions may remain viable within the tissue for a long time, particularly if Lewy bodies are thought to start accumulating intracellularly before onset of symptoms. Autopsy studies are necessary to determine whether there are indeed predictable stages in the progression of Lewy pathology, and because these studies require a large number of patients, collaboration of multiple centers would be beneficial. In the Braak scheme, Lewy pathology is four times more frequently in motorically asymptomatic (stages 1-3) than associated with clinical motor syndromes (stages 4-6); therefore, such studies have to be planned in the general population without the bias of selecting cases. The duration of the stages may be extrapolated from their prevalence. With respect to clinical motor PD, substantial dopamine cell loss only occurs at stage 4 and greater, with severe dementia associated with stage 6. Cases without clinical PD but with dominant dementia also need to be analyzed to determine the likelihood of a "top down" versus a "bottom up" disease process. Large autopsy series are also necessary to elucidate clinicopathologic correlations in prospectively studied cohorts to identify symptoms linked with specific brain regions (dorsal nucleus of the vagus nerve, ceruleus-subceruleus complex, amygdala, and the CA2-3 sectors, to name a few). Clear assessment of clinical stages that would fit with such increasing burdens of pathology should be determined, in addition to the current emphasis on searching for any earlier clinical phenomena. The second purpose of a large study is to determine whether the presence of α-synuclein pathology alone causes symptoms with or without cell loss. Control subjects, without symptoms, should also be studied to determine the frequency of the lesions in the general population-a precaution that has rarely been taken in the past. Better knowledge of the association between Alzheimer-type, Lewy-type, and vascular lesions needs to be acquired. The frequency with which Alzheimer-type pathology causes or contributes to the cognitive deficit or to the extrapyramidal syndrome has to be determined. In summary, α-synuclein pathology must be better studied in human material in parallel with the experimental models to determine the normal expression of the molecule in glia and neurons, the parts of the molecule involved in different types of inclusions, its relationship with ubiquitin and the proteasome, and the reasons for the sensitivity of dopamine (and other) neurons in this pathology. Many of the answers to the questions that have been raised here depend on series of autopsy cases involving not only patients but also control subjects. The project of increasing the number of systematic autopsies needs to be planned in general hospitals and in conjunction with movement disorder clinics. Such an action implies better awareness of the role of neuropathology in the medical community, the public, patient associations, and in the administrative staff of the hospitals. Although single gene defects (e.g. in the Parkin gene), single environmental toxins (e.g. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), or single infectious agents (e.g. encephalitis lethargica) have been associated with rare forms of relatively pure parkinsonism, current pathogenic theories concerning idiopathic PD focus on a combination of genetic susceptibility and environmental risk factors (41, 42). Putative environmental and demographic factors that may predispose individuals to idiopathic PD include age, sex, estrogen status, race or to not not and not In and whether genetically or determined, may a all age is the most linked to the of PD with age in and The late by of a in PD has been confirmed studies this to (e.g. estrogen (e.g. different in and or genetic factors (e.g. on remains of estrogen in show that with PD are more likely to have and without or and more early than control subjects. 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