Trojanowski , Z . K . Wszolek and for the DLB / PDD Working Group

For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse “Lewy body disorders” as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of -synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal -synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of -synuclein should be a major focus of efforts to develop new diseasemodifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for -synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases. NEUROLOGY 2007;68:812–819 The diagnostic designation of dementia with Lewy bodies (DLB) was formalized in 1996 to bring attention to a group of patients with symptoms that differ from those of Alzheimer disease (AD) and vascular dementia.1 Since then, and with increased recognition by clinical researchers, DLB is now considered to be the second most common subgroup of dementia,1 with widespread Lewy bodies occurring in more than 20%2,3 and focal Lewy body formation in nearly 50% of dementia patients.4 In parallel, cognitive impairment in idiopathic or Lewy body PD occurs early and becomes an important nonmotor feature of the disease in its later stages. The term Parkinson disease dementia (PDD) has been applied to this frequent complication of the typical motor disorder.5 The discovery of -synuclein as a component of PD pathogenesis in 19976 gave PDD and DLB a common biologic theme, spurring interest in the relationship between these disorders. The third report of the DLB Consortium7 made a brief statement about the PDD/ DLB interface to 1) highlight the overall clinical and pathologic similarities between the two syndromes; 2) reinforce the need to make a clinical distinction between DLB and PDD, using the timing of the onset of cognitive symptoms in relation to motor symptoms (1 year or less DLB; more than 1 year PDD) as the basis; and 3) recognize the need to address boundary issues in more detail. This ongoing debate prompted the formation of the current DLB/PDD Working Group. Here, we address boundary issues *Author affiliations are listed in the appendix. Supported by Forest Laboratories, Inc.; Lehigh Valley PD Support Group; The Movement Disorder Society; National Parkinson Foundation, Inc.; Novartis Pharmaceuticals Corporations; PD Foundation, Inc.; Schwarz Pharma, Inc.; NINDS/NIH (conference grant NS054546-01 and grants AG09215 and AG10124); the intramural program of the National Institute on Aging, NIH, DHHS. Disclosure: Research support/grants more than $10,000/year: Duda, National Parkinson’s Foundation; Emre, Novartis; Fahn, NINDS, Parkinson’s Disease Foundation; Lippa, NINDS; Tanner, NINDS and National Parkinson’s Foundation; Wszolek, NINDS. Honoraria less than $10,000/year: Galvin, Forest; Leverenz, Forest; Lippa, Novartis and Pfizer. Honoraria more than $10,000/year: Leverenz, Novartis; Olanow, Novartis. Given expert testimony related to the subject of this study, less than $10,000: Hurtig. Received June 23, 2006. Accepted in final form November 7, 2006. Address correspondence and reprint requests to Dr. Carol F. Lippa, Department of Neurology, Drexel University College of Medicine, Mail Stop 423, 245 N. 15th Street, Philadelphia, PA 19102; e-mail: [email protected] 812 Copyright © 2007 by AAN Enterprises, Inc. by Renzo Rozzini on June 26, 2007 www.neurology.org Downloaded from as an extension of a global concerted effort to fully understand the Lewy body diseases (LBDs). Clinical. When the hallmark clinical features of the Lewy body disorders are present, our diagnostic specificity is high. Specialists in movement disorders regularly follow patients with PD for years before cognitive dysfunction becomes noteworthy enough to suggest the onset of dementia. However, the definition of when cognitive decline in PD is sufficient to constitute dementia needs to be clarified. Specialists in cognitive disorders evaluate dementia patients with the classic symptoms of DLB, which allow clinicians to distinguish the Lewy body disorders from other dementia subtypes. Difficulty with diagnosis arises when patients fall in between the two classic profiles of DLB and PDD. Distinguishing the Lewy body disorders from non-Lewy body dementias remains difficult when atypical presentations occur.8-10 Non-Lewy pathology, particularly the neurofibrillary degeneration of AD, may obscure the clinical features of the Lewy body disorders when the two pathologies occur together (e.g., LBVAD) and dominate the clinical picture with features of AD instead of DLB.11 Vascular pathology is also frequent in DLB10 and can also potentially modify symptoms and signs. In addition, differences between all dementia subtypes are stage dependent with greater overlap in clinical features between all dementia groups in advanced disease. Although diagnostic criteria have not yet been defined for PDD, similar issues blur the boundaries that “separate” these disorders. Many patients fall into an overlapping “gray zone” because DLB patients may present with parkinsonism around the same time as the cognitive symptoms, and early cognitive change is recognized in PD. In addition, there is no clinical symptom that absolutely distinguishes DLB and PDD as both may have psychiatric symptomatology, autonomic symptoms, REM-sleep behavior disorder,12 cognitive fluctuations, and neuroleptic sensitivity reactions.13 The neuropsychological profiles in PDD and DLB share basic similarities including prominent abnormalities in attention, executive function, visuospatial function, language function, memory retrieval, and behavior.14-19 However, differences in clinical features have been described in studies of DLB and PDD patients characterized by consensus criteria. Subtle cognitive differences have been found between PDD and DLB, with DLB subjects making more conceptual and attentional errors than PDD subjects, even after controlling for dementia severity.14,20 Psychiatric symptoms that differ quantitatively more than qualitatively occur in DLB and PDD, with DLB patients having more hallucinations and psychoses than those with PDD.17,21 Adverse reactions to antipsychotic agents may also be more frequent in DLB, whereas patients with PDD are more likely to be taking a wider variety of potentially psychotogenic doses of antiparkinson drugs.13 Saccadic eye movements are similar in DLB and PDD.22 PDD subjects have more asymmetry in motor features, at least initially, and DLB subjects tend to have fewer signs of parkinsonism, although the majority of DLB patients eventually develop parkinsonism characterized by generalized slowing and postural and gait disturbances, without prominent tremor.23 The clinical diagnostic criteria set forth in the third DLB consensus conference7 can be applied to PDD, although there are no published validation studies. The need exists for 1) a clear definition statement on the diagnosis of PDD to enable research progress and large-scale studies and 2) improved methods for defining and distinguishing the relative functional contributions of cognitive and motor impairment to overall disability. A Movement Disorder Society Task Force is currently developing diagnostic criteria for PDD. Once these criteria are established, additional prospective studies involving both PDD and DLB subjects are needed to clarify the similarities and differences in clinical features in these disorders. Cellular and molecular pathology. The presence of widespread Lewy bodies differentiates the Lewy body disorders from other dementia subtypes. Cortical Lewy bodies and Lewy neurites are often widespread in PDD and DLB and correlate with the severity of the dementia.24,25 and DLB cases almost always have limbic Lewy bodies; however, spread of Lewy bodies to neocortical areas in high quantities is uncommon in PD subjects in the absence of cognitive impairment. There are no hallmark neuropathologic features that distinguish PDD from DLB, in part because most patients die with end-stage disease at which point the brain is diffusely involved and clinical phenotypes of the two disorders are indistinguishable. The brain regions where pathologic differences occur include the substantia nigra (where neuronal loss is greater in PDD than DLB) and possibly the striatum (where -synuclein pathology may be greater in DLB than PDD).26 Pathologic substrates of PDD and DLB are heterogeneous and include neuronal loss, basal forebrain (cholinergic) degeneration, AD, and vascular pathology in addition to Lewy body pathology. -Amyloid pathology is a more consistent feature of DLB, and a recent study demonstrated that diffuse plaques, resembling those that typify DLB, are associated with subtle impairments in cognition in AD.27 The influence of -amyloid pathology, if any, on the clinical phenotype in the Lewy body disorders is unknown. However, neuritic AD pathology strongly affects clinical phenotype in DLB.11,28 -Synuclein aggregates into fibrils in Lewy bodies and Lewy neurites in PDD, DLB, and PD.29 The structure of the Lewy body is indistinguishable in all three conditions, with -synuclein as its principal pathologic protein. Solubility and epitope studies show similar features in -synuclein between diseases.29 Although the brainstem and olfactory system are the March 13, 2007 NEUROLOGY 68 813 by Renzo Rozzini on June 26, 2007 www.neurology.org Downloaded from first and most common regions to undergo neurodegeneration in PD, the disorder is often clinically unapparent at that stage and only becomes clearly symptomatic when the substantia nigra and other midbrain nuclei are affected. Later, multiple additional brain regions are affected as these disorders progress so that their clinical manifestations commonly extend beyond those attributable to the nigrostriatal system alone.30,31 As such, PD, DLB, and PDD may be different points on a continuum with motor and nonmotor features reflecting the regional burden and distribution of pathology. Factors that determine the regional distribution of pathology in relation to the symptoms of DLB, PDD, and PD are incompletely understood. Age may play a role in regional susceptibility because younger individuals are more likely to present without cognitive impairment (pure PD), whereas meaningful cognitive change (either PDD or DLB) occurs in the older adult. Hallucinations in DLB are associated with Lewy body counts in posterior temporal regions.32 The greater executive dysfunction in DLB has been associated with disruption of medial temporal lobe projections to frontal regions. Differential striatal pathology may account for some of the differences in motor features and motor responses to medications with differences in the burden of Lewy pathology,26 the regional distribution and severity of dopaminergic losses, and the level of dopaminergic upregulation. Preliminary results from a recent autopsy study of patients with PDD show that brain pathology is similar to that of DLB (with Lewy pathology and AD changes) if dementia began within 10 years of PD onset, whereas in PD patients with onset of dementia more than 10 years after PD onset, morphologic changes were less pronounced and the more prominent finding was a marked cholinergic deficit.33 These results, if substantiated, call into question the 1-year rule that currently distinguishes DLB from PDD. Overall, there are multiple reasons to implicate Lewy bodies and pathologic species of -synuclein in PD, PDD, and DLB: 1. Mutations/multiplications in the -synuclein gene cause familial PD/PDD/DLB. 2. Lewy bodies and Lewy neurites are hallmark PD/ PDD/DLB amyloids detected by -synuclein–specific antibodies. 3. Epitope mapping demonstrates that regions spanning -synuclein are present in Lewy bodies. 4. Filamentous -synuclein aggregates in Lewy bodies and Lewy neurites contain abnormally nitrated, phosphorylated, and ubiquitinated residues. 5. -Synuclein filaments are recovered from PD/ PDD/DLB brains as well as from Lewy bodies purified from these brains. 6. Recombinant -synuclein forms Lewy body–like amyloid fibrils and amino acids 71 to 82 in -synuclein are essential for filament assembly. 7. -Synuclein single transgenic mice/worms/flies develop a neurodegenerative disease with filamentous -synuclein amyloid deposits. 8. Cortical Lewy bodies detected with antibodies to -synuclein correlate with dementia in