Meeting Report

Special Expert Conference Dementia with Lewy Bodies Was Focus of Budapest Meeting in November

John O'Brien

IPA special expert conferences are becoming a model of efficiency and productivity, with previous highly successful examples in the fields of Behavioural and Psychological Symptoms of Dementia (BPSD), the diagnosis of Alzheimer’s disease and Vascular Cognitive Impairment. The basis of these meetings is to convene an internationally representative group of experts in the field in order to appraise each other of state of the art science in their respective areas of expertise and to allow discussion and, hopefully, consensus around key areas. The aims are to define current knowledge in the field, attempt to resolve areas of conflict and uncertainty where this is possible and map out a future research agenda. To facilitate discussion, meetings are closed and strictly limit presenters to 10 minutes each, whilst allowing a lengthy period of discussion at the end of each topic during which all attendees are invited to participate. 

Dementia with Lewy Bodies and Dementia in Parkinson’s Disease

The Special Experts Conference in Budapest this past November was convened by Ian McKeith and Jacobo Mintzer to discuss the topic of Dementia with Lewy Bodies (DLB) and Dementia in Parkinson’s Disease (PD). As with other meetings, approximately 50 experts from 16 different countries were present. Attendees included psychiatrists, geriatricians, neurologists and others with a wealth of experience both in the fields of dementia and movement disorder.

The meeting was held at the Hilton in Budapest, a perfect venue with tasteful architecture that blends in with the old city that surrounds it, while affording dramatic views over the River Danube and the rest of the city during the brief breaks in the academic programme.

Scientific Content

The scientific content was expected to be extremely high and did not disappoint:

Ian McKeith introduced the meeting and highlighted the development of the current clinical consensus criteria for DLB, which have become the gold standard for clinical diagnosis.

Murat Emre explained the limitations of clinical criteria for PD Dementia (PDD), with the lack of operationalized criteria within DSM-IV, even though the category is mentioned (though notably DLB itself is not contained within ICD10 or DSM-IV).

Dennis Dixon pointed out that neuropathologically it is impossible to discriminate between DLB and PDD, as both are associated with cortical and subcortical Lewy bodies and similar other pathological changes.

Carol Brayne highlighted the paucity of epidemiological studies of DLB and PDD, though pointing out a recent study from London had showed a prevalence rate of 11 percent of all dementia—a figure not out of keeping with the frequency of DLB in many pathological studies.

Dag Aarsland described his series of studies from Norway comparing PDD and DLB from clinical and neuropsychological perspectives, showing that these disorders actually appeared to be very closely related.

Clinical phenomenology was outlined by Florence Pasquier, Serge Gathier, DavidBurn, Bradley Boeve, Rose Anne Kenny (via an impressive slide show, since she unfortunately had to cancel at the last moment) and Zuzana Walker. Cognitive changes include predominant attentional and visuospatial problems with preserved memory. Motor features of Parkinsonism in DLB may be as severe as in Parkinson’s disease, contrary to previous thoughts. The issue of sleep disorder is emerging as a very interesting concept. Many patients with REM sleep behavior disorder go on to develop Parkinson’s disease whilst DLB may be uniquely associated with REM sleep behavior disorder—at least as assessed electrophysiologically in sleep labs. Earlier reports of a more rapid progression in DLB have not been substantiated by more recent reports which generally show a very variable progression, with similar mean cognitive decline to that seen in AD. Earlier samples may have been biased towards shorter duration because of exposure to neuroleptics.

The diagnosis of DLB was discussed by David Salmon, Jim Leverenz, Oscar Lopez, Yolande Pijnenburg and John O’Brien. The high specificity of the consensus criteria is universally acknowledged though sensitivity can be low, only 20 percent to 30 percent in some studies. Ways to improve this need to be found. Neuroimaging may prove helpful as DLB is associated with relative preservation of the medial temporal lobes and hippocampus on MRI and occipital hypoperfusion and loss of the dopamine transporter on SPECT and PET imaging. Dopaminergic loss in the striatum may prove particularly helpful in diagnosis.

In an interesting neuropathological session, Glenda Halliday of Sydney outlined her autopsy findings that Lewy Bodies appear to contribute both to the cognitive decline (when present in the hippocampus) and hallucinations (when in the amygdala and temporal lobe areas) that occur in DLB. In general, dementia was found to correlate with both Lewy Body and plaque density in DLB.

Robert Perry outlined the superiority of alpha-synuclein as a means for identifying Lewy Bodies as opposed to ubiquitin. This has led to a change in classification of many cases since those previously identified as “limbic” often become “neocortical,” while those identified as “neocortical” can become “diffuse.”

Carol Lippa highlighted the co-occurrence of Lewy Bodies in the amygdala in many cases of AD, and also showed that AD pathology can modify the clinical features of DLB, in that the classic triad of Parkinsonism, hallucinations and fluctuation became less prominent as tangle pathology increased in DLB cases.

Rejko Krueger gave an overview of animal models (in mice and fruit fly) of alphasynuclein accumulation, which lead to selective degeneration of the dopaminergic system, a progressive age-related neurological deficit and Lewy Body-like inter-neuronal inclusions. The over expression of alphasynuclein or the factors which increase its aggregation may therefore directly be involved in the neuronal loss which occurs in PD and DLB. Genetic factors have been shown to operate in both PD and DLB, though mutations in the alpha-synuclein and parkin genes, which have been described in some familial PD cases do not appear to occur in DLB. ApoE4 is a risk factor for DLB, as it is for AD, and may influence the degree of pathological change which occurs.

Dementia developing during the course of established Parkinson’s disease was contrasted with DLB in a session with Bruno Dubois, Juha Rinne, Tony Broe, Hulya Apaydin, Werne Poewe and Wayne Reid. In a comparison between DLB and PD dementia (PDD), cognitive profile was very similar but more frontal impairment was noted in DLB and greater learning deficits (implying more involvement of the hippocampus) in DLB than PDD. Rinne pointed out that 90 percent of patients with Parkinson’s disease have demonstrable cognitive impairment while long-term follow-up studies have shown incredibly higher rates of dementia, developing in around 80 percent of older PD patients followed for eight years. Broe described risk factors such as advancing age, increased severity of motor features, the degree of cognitive impairment at baseline and the presence of ApoE4, depression and hallucinations. In the Sydney Older People’s Study, a relationship between dementia and akinetic rigid syndrome has been noted which may relate to frontal pathology. Pathological correlates of dementia in Parkinson’s disease include a tenfold increase in Lewy Bodies in neocortex, limbic areas (amygdala) and cell loss in the nucleus basalis of Meynert and the substantia nigra. Poewe outlined the risk factors for psychosis in PD which include age, duration of disease, the presence of cognitive impairment, depression and sleep disorder as well as dopaminergic agents and anti-cholinergic medication. However, psychosis occurs in 17 percent of untreated patients. Reid described neuropsychological findings from a longitudinal study of idiopathic Parkinson’s disease, demonstrating associations between the presence of bradykinesia and bilateral disease with cognitive impairment. The presence of dyskinesias was associated with preserved cognitive functioning while late onset (after 70) of PD was associated with symmetrical disease, more cognitive impairment and a poorer response to treatment. The subsequent development of dementia was associated with bradykinesia, late age of onset and impairments on verbal learning at baseline.

Potential treatments were discussed by Elaine Perry, Urs Mosimann, Jacobo Mintzer, Gregor Wenning, John Duda and Jiska Cohen-Mansfield. The well recognized cholinergic loss with preserved muscarinic receptors in the cortex may be associated with the particularly beneficial response to cholinergic therapy in DLB. Studies have demonstrated usefulness of clozapine in the psychosis in PD and olanzepine in AD patients with “Lewy Body type” symptoms, though efficacy in probable DLB is unclear. Several delegates urged caution in the use of any antipsychotics in DLB until more is known. There is a dearth of studies of nonpharmacological management specifically undertaken in DLB, though initial management along these lines appears clinically prudent. There was real promise of neuroprotective therapies emerging and some provisional evidence for dopamine agonists which slow in progression according to PET scanning data is now emerging in PD.

Technology Helps Connect Discussants for Drug Regulation Session

Perhaps the highlight of the meeting was the discussion of the likely views various drug regulators might take—not only because of the interesting perspectives provided, but because of the superb technology that linked those of us in Budapest with discussants in the United States by Web camera, and to discussants in Canada by telephone. This allowed a real time discussion in which everyone could participate.

It was felt that the FDA view was that for an entity to be recognized it should be broadly accepted by experts in the field and needed to be operationalized by valid and reliable criteria. The question was whether DLB met these criteria at the current time. The consensus of the meeting was that it clearly did and the real issue is whether or not it covered all of cognitive change which occurred in PD. Somewhat ironically, dementia in Parkinson’s disease might be better accepted by regulatory authorities than DLB simply because it is described (though not operationalised) in DSM-IV, even though there is less broad agreement regarding its nature than for DLB. It was felt that the FDA view may vary depending on whether DLB could be clearly clinically and pathologically distinguished from AD. If it was believed to be distinct, then approval for pharmacotherapy would be likely to depend on results from two randomised placebo-controlled trials. If, however, it was felt to be a variant of AD then one study might be adequate. It was recognised that primary outcomes in DLB might need to be quite different from AD. It was felt that the view from CPMP was likely to be broadly similar, though one robust trial (rather than two) may be adequate. It was thought unlikely that any regulatory body would accept a broad indication for a therapy such as “dementia.”

An extremely positive outcome from the meeting was that all involved in the discussion expressed an interest in entering further dialogue between regulators, experts and the pharmaceutical industry regarding the nosological status of DLB with a view to clarifying these issues and so opening the way for further properly conducted randomised studies.

Differences around the world in acceptance and knowledge about DLB was outlined by Joao Machada, Helen Chiu, Keith Edwards and Tony Broe. Clearly a large amount remains to be done in terms of spreading the message about DLB as an important subtype of dementia, and the resources to do this may be substantial.

Undoubtedly the highlight of the meeting was a talk by Peter Ashley, a patient with DLB who bravely explained to an absolutely silent audience his personal experience of being diagnosed with DLB, the shock trauma and grief which ensued as well as the realization that any years of life left were certainly “worth fighting for.” He gave an excellent description of how he has mastered technology, including microphone, digital camera and computer that has become his “memory,” as well as describing the great benefit he personally obtained from cholinesterase therapy. His poignant final remark “I am living with dementia not dying with dementia” made a great impression with all attendees.

The final session was on trial design, and conducted by Jacobo Mintzer, Jeremy Playfer, Howard Feldman, Keith Wesnes, Clive Ballard, Brian Lawlor and Teodoro del Ser. The importance of using appropriate outcome measures was addressed, particularly for dealing with fluctuation, and modifications to the global outcome measures such as the CGI to include physical and Parkinsonian features were suggested. There was considerable debate but no resolution as to the appropriate target group for trials, whether these should be DLB, PDD or both; and whether there should be a distinction made between cognitive impairment in the presence of Parkinsonism (irrespective of the duration currently set at one year) and without.

Conclusions and Congratulations

The meeting was a tremendous success and should result in a state-of-the-art publication. Ian McKeith and Jacobo Mintzer skillfully assembled a balanced and representative group of experts and they ably and smoothly chaired proceedings at all times. The meeting was superbly organized by IPA’s Fern Finkel, Diane Nickolson and Kerri Leo. Kerri Leo, in particular, should be congratulated for the technological breakthrough in the regulatory session.

Overall there was a conversion—if not a meeting of minds—from those in the psychiatry and movement disorder camps with recognition that DLB is an important part of dementia in Parkinson’s disease, but that it is too early to conclude that these are the same disorder. While only further research can address this question, the progress with regard to regulatory issues was helpful and should enable clinical trials to proceed, to the benefit of all patients.

John T. O’Brien is Professor of Old Age Psychiatry at the Institute for Aging and Health Wolfram Research Center, Newcastle General Hospital, and a Research Editor of the IPA Bulletin. Contact him at J.T.O’Brien@ncl.ac.uk.

Reprinted from IPA Bulletin, Volume 20, Number 1