Sci. Aging Knowl. Environ., 22 October 2003
Vol. 2003, Issue 42, p. pe29
[DOI: 10.1126/sageke.2003.42.pe29]


Research on the Brain

Virginia M.-Y. Lee, and John Q. Trojanowski

The authors are in the Center for Neurodegenerative Disease Research, Institute on Aging, and Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. E-mail: vmylee{at} (V.M.-Y.L.).;2003/42/pe29

Key Words: Lewy bodies • dementia • Parkinson's disease • meeting • symposium • movement disorders


The 3rd International Workshop on Dementia with Lewy Bodies (DLB) and Parkinson's Disease Dementia (PDD) was held from 17 to 20 September 2003 at the Newcastle Civic Centre in Newcastle upon Tyne, United Kingdom (for more details on the meeting, see its agenda). Like each of the previous workshops, this one was organized by Ian McKeith and his Newcastle colleagues, one of the leading groups in this field. There were several hundred participants at the workshop, who attended 3 days of platform presentations by more than 50 international experts on DLB and PDD. In addition, numerous posters displayed data from a wide range of clinical and basic fields of research related to DLB and PDD.

The formal presentations were followed on the last day of the meeting by parallel sessions on the clinical features and neuropathologies of DLB and PDD. The objectives of these sessions were (i) to reexamine current criteria for the antemortem and postmortem diagnosis of DLB and PDD and (ii) to forge much-needed revised and updated versions of these criteria that incorporate the relevant advances in the DLB and PDD fields that have emerged since the second international DLB workshop in 1998. These deliberations on how to improve the diagnostic criteria for DLB and PDD are still in progress, and a consensus report on this aspect of the workshop will appear at some time in the future. Therefore, this meeting report summarizes highlights of the scientific presentations at this international workshop, which was the third in a series of similar workshops that have been held on DLB since 1995.

Background on DLB and PDD

PD is a common age-related neurodegenerative disease characterized by a decreased ability to initiate voluntary motor movement. This symptom results from the loss of neurons that contain the neurotransmitter dopamine from a region of the brain called the substantia nigra (SN) (see Andersen Review). The cause of dopaminergic cell loss in PD remains unclear. It is now clearly recognized that PD also is associated with neurodegenerative pathologies that are widely distributed throughout the brain and that these abberations likely account for other behavioral impairments (for example, dementia) observed in PD patients. The current therapy for PD is the oral administration of the dopamine precursor L-3,4-dihydroxyphenylalanine (L-DOPA), which up-regulates the production of dopamine in the remaining cells of the SN. This treatment suppresses symptoms but does not prevent disease progression or the accompanying dementia.

Lewy bodies (LBs) are filamentous cytoplasmic inclusions that were originally identified in certain neurons of patients with PD, but were later found to occur in a fairly large number of patients with age-related dementia, a disorder that is now referred to as DLB (Fig. 1). LBs contain many proteins, including alpha-synuclein, a protein involved in neuronal plasticity that, when mutated, aggregates and fails to be degraded; ubiquitin, a protein involved in the degradation of polypeptides; and neurofilament, the major cytoskeletal protein complex in nerve axons and dendrites, and other neuronal proteins. Inclusions containing ubiquitinated proteins occur in many neurodegenerative diseases (see Gray Review).

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Fig. 1. Alpha-synuclein pathological inclusions.

Scope and Significance of the Workshop

Because of the increasing number of individuals over 60 years of age throughout the world, DLB and PDD have grown in clinical importance. Thus, the recent workshop in Newcastle was extremely relevant to clinical and basic researchers worldwide who study aging-related neurodegenerative dementias. The significance of improved diagnostic criteria for distinguishing DLB from other middle- to late-life neurodegenerative diseases stems from the increasing recognition that DLB may account for up to 20% of all patients who present with cognitive decline after age 60. This dementia may be a consequence of PD in the majority of affected individuals, especially if the cognitive performance of PD patients is monitored into the later stages of the disease course [see (1) for a recent review of the conceptual underpinnings of DLB and PDD, as well as of the historical evolution of these concepts]. Although credit for the early descriptions of what is now known as DLB and PDD dates back to studies reported by Okasaki et al. in 1961 and later by Kosaka et al. in 1976 [see (1) for these and other citations regarding earlier descriptions of DLB and PDD], this and the previous two international workshops on DLB and PDD have contributed significantly to an increase in awareness of the burden that these diseases place on society as it continues to age. Moreover, these meetings have raised awareness of emerging insights into mechanisms that underlie dementia linked to LBs that occur throughout the central nervous system (CNS).

Clinical Features of DLB and PDD

Many of the sessions on the first day of scientific presentations at the workshop focused on the clinical features of DLB/PDD; neuroimaging, diagnosis, and management of these diseases; and newly emerging as well as currently used symptomatic treatments. Further, on the morning of the second day of the workshop, there were two forums on clinicopathological correlations in patients with DLB/PDD. These sessions once again made clear the need for revisions in the current diagnostic criteria for DLB/PDD. Although many of the speakers in the sessions on the first 2 days of the workshop pointed out the importance of distinguishing between DLB and PDD, there also was agreement that this is a daunting task. For example, David Burn noted that this distinction, when based on differences in the temporal evolution of extrapyramidal signs (EPSs) (tremors, rigidity, and slowness of movement), is arbitrary, because it seems doubtful to him that a 12-month difference in the onset of EPSs should mark a fundamental difference in the parkinsonism (that is, rigidity, loss of balance, tremors, or bent posture) associated with DLB as compared with PDD. Indeed, Burn noted that EPSs occur frequently in DLB, both at diagnosis and, in >60% of cases, later during disease progression. Moreover, he emphasized that the pattern of this parkinsonian phenotype in DLB, which has been postulated to reflect greater nondopaminergic involvement, is similar to that seen in PDD, although the EPSs of DLB are generally less responsive to levodopa than are those of PDD. Burn concluded that, based on available evidence, the clinical profile of EPSs in DLB and PDD suggests that these disorders are part of a spectrum of diseases that have a similar underlying biological origin that gives rise to the parkinsonism. Nonetheless, Hiroyuki Arai and Matsahito Yamado presented data suggesting that DLB might be distinguished by at least some diagnostic assays, such as CNS neuroimaging (for example, positron emission tomography) and myocardial scintigraphy, a method that allows the quantification of cardiac innervation by postganglionic sympathetic neurons. These imaging modalities appear to distinguish DLB from other conditions on the basis of metabolic alterations in the brain and heart. These metabolic changes may be due to LB pathologies, although the precise causes of these changes are not known at this time. Serge Gauthier and other speakers in the session on treatment strategies noted that efforts to distinguish DLB from PDD and other dementias such as Alzheimer's disease (AD) are of more than academic importance, because of the reported sensitivity reactions of DLB patients to neuroleptic drugs given to PDD patients. Neuroleptic drugs include several different classes of therepeutic agents that modify behavior.

These controversies notwithstanding, three major conclusions emerged from these sessions on clinical research into DLB and PDD: (i) To be informative, the current criteria for the antemortem and postmortem diagnoses of DLB and PDD are in need of further emendations and refinements in order to increase their sensitivity and specificity. (ii) Current therapies for DLB/PDD are largely symptomatic and have only modest efficacy in ameliorating symptoms. Therapies that target the underlying mechanisms of DLB/PDD and arrest disease onset or progression currently are not available. (iii) The discovery of mutations in the alpha-synuclein gene that cause familial PD has dramatically and irrevocably revolutionized our understanding of PD, DLB/PDD, and related disorders now known collectively as synucleinopathies or alpha-synucleinopathies (Fig. 2) [for recent reviews, see (1-8)]. This revolution is reflected in the large number of dramatic new insights into these diseases, which are enumerated in the next section. The same can be said for mutations in other genes that cause PDD-like phenotypes, such as the tau and DJ-1 genes. The tau protein stabilizes microtubules in the cell and is present in a polymerized filamentous form in the neurofibrillary tangles associated with AD (see "Detangling Alzheimer's Disease"). It has been postulated that the DJ-1 protein is involved in the stress response and regulation of transcription.

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Fig. 2. Sporadic and hereditary neurodegenerative diseases characterized by filamentous alpha-synuclein brain lesions.

Integration of Previous Findings with Workshop Highlights

The genetics and molecular pathology of DLB/PDD were the major themes of the scientific presentations on the afternoon of the second day of the workshop. These sessions highlighted the fact that a paradigm shift has occurred in our understanding of disease mechanisms that cause PD, DLB/PDD, and other synucleinopathies (Fig. 2), as well as sporadic and familial AD, wherein alpha-synuclein-laden LBs also occur. Researchers now recognize that a connection exists between neurodegeneration and alpha-synuclein aggregation, although the detailed progression from alpha-synuclein mismetabolism and aggregation to the dysfunction and death of brain cells is still unclear and is being investigated.

The presenters attempted to synthesize their new results with an assortment of findings from studies reported over the past 5 years that have brought about this paradigm shift. For example, it was shown that mutations in the alpha-synuclein gene cause familial PD, and antibodies to alpha-synuclein can detect LBs and Lewy neurites (LNs) (Fig. 1) in PD, DLB, the LB variant of AD (LBVAD), most familial AD, and elderly Down's syndrome (DS) brains. In addition, LNs, which are aggregates of alpha-synuclein in the processes of nerve cells (rather than in the nerve cell bodies, where LBs form), appear to harbor the largest burden of filamentous deposits of alpha-synuclein in neurons. Researchers also recovered alpha-synuclein filaments from purified LBs and showed that residues 71 to 82 in alpha-synuclein are essential for the fibrilization of recombinant mutant and wild-type alpha-synuclein in vitro.

Another crucial set of previous findings was that transgenic (TG) animals that overexpress normal or express mutated human alpha-synuclein (for example, flies, worms, and mice) develop neurodegeneration with alpha-synuclein inclusions in neurons and/or glial cells, whereas double-TG mice that overexpress mutated human amyloid-beta precursor proteins (APP) and normal human alpha-synuclein show an augmentation of alpha-synuclein inclusions. In most people with alpha-synucleinopathies, wild-type alpha-synuclein aggregates to form inclusions. Only very rarely does disease result from aggregation of the mutant protein, although disease onset is earlier in mutation-bearing people, and the disease is usually more aggressive. There are no examples reported of spontaneous alpha-synuclein aggregates or lesions in mice, and neither flies nor worms express proteins similar to human alpha-synuclein. Thus, these animals have never been reported to develop anything similar to LNs or LBs. In another neurodegenerative disease, multiple system atrophy (MSA), alpha-synuclein forms filamentous glial cytoplasmic inclusions (GCIs) (Fig. 1); MSA is unique among synucleinopathies, because it appears to be driven by alpha-synuclein pathologies that accumulate predominantly in glial cells.

Still another collection of previous findings revealed a possible connection between neurodegeneration and alpha-synuclein aggregation that might result from posttranslational modification of this protein. For example, filamentous alpha-synuclein in LBs, GCIs, and related lesions were shown to be abnormally nitrated, phosphorylated, and ubiquitinated in patients and in some mouse models, which indicates that these inclusions contain forms of alpha-synuclein that have been pathologically modified in ways that distinguish the disease variant from normal alpha-synuclein. Also, when cells transfected with a gene that encodes alpha-synuclein are treated with nitric oxide generators, they develop LB-like alpha-synuclein-positive inclusions. This finding implies that alpha-synuclein may be pathologically nitrated in the disease state by oxidative/nitrative mechanisms and implicates these posttranslational reactions in the formation of LBs, GCIs, and LNs. It has also been shown that the coexpression of heat shock proteins (HSPs) with alpha-synuclein in flies and with beta-synuclein and alpha-synuclein in mice leads to an amelioration of the disease phenotype, whereas treatment of alpha-synuclein TG flies with the drug geldanamycin induces HSPs and prevents the degeneration of LB-containing neurons. HSPs respond to a variety of cellular stresses and function as molecular chaperones: agents that stabilize proteins during folding, assembly, degradation, and movement within the cell.

Taken together, these previous findings illustrate that mechanisms that underlie neurodegeneration in alpha-synuclein-based brain amyloidoses such as DLB/PDD are linked to the toxic accumulation of fibrillar alpha-synuclein protein aggregates.

Fueled by this plethora of previous findings, extensive debates ensued at the workshop about exactly how LBs and LNs might cause dementia in DLB/PDD, especially because cortical neuron loss is not prominent in these diseases. Although a definitive answer to this important question is not yet available, John Duda reported on the previously unrecognized abundance of LNs in PD, DLB, PDD, and other synucleinopathies and speculated that, in the absence of neuron loss, LNs could result in damage to the processes of neurons or to the synapses between affected axons and dendrites. This disconnection then would lead to the dysfunction of affected neurons in the absence of overt neuron loss. Therefore, if LNs do indeed play a substantial role in cognitive and other behavioral impairments in patients with DLB/PDD, researchers and clinicians will need to begin to consider these structures when formulating new diagnostic criteria.

These interpretations of the spectacular advances in DLB/PDD research over the past 5 years were reinforced by the startling and provocative revelations presented by John Hardy. He and his colleagues have recently completed studies led by Andrew Singleton and Matthew Farrer, showing that familial DLB is caused by pathogenic duplications of the alpha-synuclein gene (as well as regions flanking this gene on chromosome 4). Recall that DS is caused by a trisomy of chromosome 21, which includes the APP gene and leads to the early emergence of AD pathology in all DS individuals by age 40. Thus, by analogy with DS, excess copies of the region of chromosome 4 that contains the wild-type alpha-synuclein gene also can lead to neurodegeneration. This is the first instance of familial PD or DLB caused by duplication of the wild-type protein rather than a mutation leading to the generation of a mutant protein. Presumably, in both situations it is the overproduction of the wild-type protein throughout the life span, rather than production of a mutant form of the protein, that results in the onset of disease, although the exact mechanisms by which disease onset occurs in DS and familial DLB remain to be elucidated. However, we do know that in familial DLB and in related diseases caused by mutations in the alpha-synuclein gene (such as PD), the underlying neuropathology is an abundance of cortical LBs and LNs formed by filamentous aggregates of alpha-synuclein.

Moreover, in several studies, tissue from individuals with familial PD caused by the pathogenic A53T alpha-synuclein gene mutation (some of whom also were known to have cognitive impairments) were examined by histochemical and immunohistochemical methods. These studies showed that tau lesions similar to those seen in AD and other tauopathies are present in many affected brain regions in close juxtaposition to the massive burden of alpha-synuclein-positive LBs and LNs. Indeed, this co-occurrence of alpha-synuclein and tau neuropathology suggests that the A53T mutation might induce the pathological accumulation of tau. Similar speculations have been prompted by reports of the extensive co-occurrence of LBs and LNs in familial AD patients with mutations in the APP, presenilin 1, and presenilin 2 genes. It is not yet known whether this observation implies that pathological interactions among multiple amyloidogenic proteins lead to neurodegeneration caused by double and triple brain amyloidoses or whether other disease mechanisms play a role (9, 10). A single amyloidosis is exemplfied by Pick's disease, in which there is only one form of amyloid deposit, the Pick body, which is formed by filamentous tau. In contrast, AD is a double brain amyloidosis, because there are {beta}-amyloid deposits in senile plaques and tangles formed by {beta}-amyloid and filamentous tau deposits. The LB variant of AD, or LBVAD, has LBs, plaques, and tangles and thus is considered to be a triple brain amyloidosis (9, 10).

Despite these and other controversies, as well as the compelling need for more sensitive and specific diagnostic criteria for DLB/PDD, the 3rd International Workshop on DLB/PDD concluded with an optimistic tenor. Indeed, it was appreciated by many participants that enormous progress had been made toward elucidating LB diseases since the second workshop, including the development of many diverse animal models (fly, worm, and mouse) of alpha-synuclein pathologies. The development of animal models that recapitulate many of the phenotypic features of synucleinopathies represents a significant achievement. These animal models enable experimental studies of the biological changes and pathological pathways that underlie this class of neurodegenerative disorders. We expect that further studies of the existing as well as more refined animal models of synucleinopathies, together with novel insights into DLB/PDD gleaned from patient-oriented research, will accelerate progress toward the development of a better understanding of the pathobiology of these diseases, as well as the discovery of novel therapies.

October 22, 2003
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Citation: V. M.-Y. Lee, J. Q. Trojanowski, Research on the Brain. Sci. SAGE KE 2003 (42), pe29 (2003).

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