Highlights of the 7th International Conference AD/PD 2005
The International AD/PD Conferences are held biannually, bringing together scientists from around the world who are not only interested in Alzheimer's disease (AD) and Parkinson's disease (PD), but also the spectrum of neurodegenerative diseases that represent the continuum of diseases affecting amyloid deposition, tauopathies, and synucleopathies. There is increasing interest in defining neurodegenerative diseases by etiology, when possible rather than clinical or pathologic criteria. For example, although Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) have different features upon initial expression and are distinct clinical entities, neuropathologic examination and neurochemical evaluation reveal that there is no distinction between these 2 diseases at the time of autopsy. Much of the research presented at this 7th AD/PD Conference supported these ideas.

Several oral and poster presentations discussed the growing understanding and accumulating evidence for the continuum of the dementias, especially as the clinical progression increases in severity. D. Calne, of the Pacific Parkinson's Research Centre, Vancouver, Canada, presented a discussion entitled "Neurodegenerative Overlap." In this discussion, Dr. Calne presented the recent discovery of the pleomorphic findings in the PARK8 parkinsonism. New conceptual questions have been generated because the pathologic "hallmarks" are mixed in the same brain, ie, 1 etiology can be seen to produce the pathologic elements of 3 major degenerative disorders (PD, AD, and amyotrophic lateral sclerosis).

Rather than considering that aspects of several diseases exist in the same brain, Dr. Calne presented the following 5 conclusions: (1) Neurodegenerative disorders should be defined by etiology rather than pathologic or clinical features; (2) the clinical expression of a neurodegenerative disorder derives exclusively from the anatomic regions of the brain that lose neurons; (3) morphologic markers, such as Lewy bodies and neurofibrillary tangles, are not specific to any particular etiology; (4) the accumulation of deleterious proteins, some of which have not yet been identified, are central to the mechanism of neuronal decay; and (5) if patients live long enough, there is a tendency for the various forms of neurodegeneration to converge. The relevance of these conclusions was reflected in several presentations.

A. Hake, from the Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, presented a case of a 67-year-old woman who presented with treatment-resistant PD symptoms. During a 5-year period, the patient developed worsening rigidity, orthostatic hypotension, syncope, and visual hallucinations. Diffuse Lewy body disease was considered as a diagnosis, but because of the prominence of the autonomic findings, doctors diagnosed multisystem atrophy. Seven years after the original diagnosis, the patient died, and neuropathologic examination showed alpha-synuclein immunopositive Lewy bodies in the neocortex, nucleus basalis, amygdala, substantia nigra, oculomotor nuclei, locus coeruleus, and the nucleus of the intermediolateral column of the spinal cord. Striatal degeneration was not seen. This case also illustrates the importance of a careful examination of the spinal cord in cases of PD with autonomic dysfunction.

Professor I. S. Preobrazhenskaya, of the Department of Neurology at the Moscow Medical Academy, Moscow, Russia, presented a series of 50 patients with probable DLB and 100 patients with PD and autonomic disturbances. The study employed an autonomous rating-scale questionnaire and evoked cutaneous sympathetic potentials and orthostatic testing, which suggested that autonomic dysfunction is common throughout the spectrum of diffuse Lewy body diseases.

Professor K. Kosaka, a pioneer in the delineation and classification of DLB, from Fukushimura Hospital, Toyohaski, Japan, discussed DLB as part of the spectrum of Lewy body disease. He proposed 2 forms of diffuse Lewy body disease: a common form, which includes a degree of AD pathology, and a "pure form," or DLB, which has little or no concomitant AD pathology.

Two papers highlighted the difficulty in distinguishing PDD and DLB, presenting patients with 3 years of PD symptoms before demonstrating obvious dementia and visual hallucinations. Professor C. Guarda, from the Neurology Department, Hospital Farcia De Orat, Almada, Portugal, described a patient who experienced 3 years of PD symptoms before fluctuating cognition, confusion, and visual hallucinations began. She became resistant to levodopa therapy. A 123I-Ioflupane brain scintigraphy (DaTScan) and a positron emission tomographic (PET) scan were both consistent with DLB, and a brain biopsy was confirmatory.

Professor M. P. Perriol, from the Memory Clinic at Lille University Hospital, Lille, France, described a study of 19 DLB patients and 20 PDD patients who were evaluated by behavior, social, and pharmacologic management, and caregiver burden. The results showed that shorter durations of PD before dementia are associated with more severe behavioral disorders and are closer to the diagnostic criteria of DLB. These data support the concept of a continuum between DLB and PDD as part of the synucleopathy spectrum.

Neuropathologic data from the University of Newcastle upon Tyne, Newcastle upon Tyne, United Kingdom, found that all patients with PDD actually have DLB upon autopsy evaluation. Professor M. Piggott also performed prospective neurochemical analyses on patients who were clinically diagnosed as having DLB or PDD. Investigators correlated cognitive impairment with reductions in cortical choline acetyltransferase (ChAT) and elevations in butyrylcholinesterase (BuChE) as well as reduced dopamine transporters in the nucleus accumbens and D2 receptors in the temporal cortex. In this study, visual hallucinations were associated with reductions in cortical ChAT and the nicotinic alpha7 receptor subtype as well as increases in muscarinic M4 receptors. Auditory hallucinations were associated with reduced dopamine transporters in the putamen and nucleus accumbens. Fluctuating cognition and disturbances of consciousness were associated with higher numbers of cortical and thalamic nicotinic alpha4-beta2 receptors, cingulated cortex M4 muscarinic receptors, and thalamic D2 receptors. Delusions were associated with higher cortical M1 and M2 muscarinic receptors and higher thalamic centromedian ChAT.

Professor Piggott discussed therapeutic strategies in light of this neurochemical analysis of DLB/PPD. She mentioned evidence that cholinesterase inhibitors have been shown to be neuroprotective, particularly at the alpha7 and alpha4 nicotinic receptors. Conversely, other data have shown that some neuroleptics, and especially anticholinergic drugs, have neurotoxic effects on nicotinic receptors.

The use of cholinesterase inhibitors is supported by the final results of a multicenter study of galantamine for the treatment of DLB. In this study, 50 patients with DLB were treated with galantamine for a period of 6 months. The results showed statistically significant improvements in behavior on the Neuropsychiatric Inventory (NPI), in global assessment on the Alzheimer's Disease Assessment Scale-Clinical Global Impression of Change (ADAS-CGIC), cognition on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog), and in clinical fluctuations and sleep disturbances.

K. M. Ko, from The Hong Kong University of Science and Technology, Hong Kong, China, presented results of a study of a "Yang-invigorating" Chinese herbal suppository preparation for symptoms of PD. The suppository is a combination of 20% Radix Ginseng , 20% Cornu Cervi , 10% Cordyceps , 12% Radix Salviae , 12% Semen Allii , 8% Fructus Cnidii , 8% Fructus Evodiae , and 10% Kaempferiae . The participants included refractory PD patients who were also taking levodopa, bromocriptine, and/or selegilene. All 9 patients tested during 6-month, open-label observation improved 67% to 86%, especially in the amount of rigidity. The "Yang"-promoting effect was thought to enhance red cell antioxidant status and combat free-radical-mediated pathogenesis of PD.

In a summary of work from several centers, S. Petanceska, from the Center for Dementia Research at the Nathan Kline Institute/New York University in Orangeburg, New York, presented data supporting several mechanisms of action of how treatment with statins can be of benefit in AD. Data from mouse models of Alzheimer's amyloidosis have shown one such mechanism to be reduction of beta-amyloid deposition. Statins have also been shown to reverse abnormal nonamyloidogenic processing of amyloid precursor protein (APP) involving altered subcellular distribution of endosomol markers, rab5 and rab7. This action appears to be independent of the cholesterol-lowering activity of statins. Other effects of statins that may reduce AD risks include vasoprotective, anti-inflammatory, and antioxidant effects.

In a parallel paper, work by Gandy and associates, from the Farber Institute for the Neurosciences at Thomas Jefferson University in Philadelphia, Pennsylvania, showed that Rho-kinase (ROCK) quadruples sAPPalpha secretion, but this activity is blocked by cotreatment with statins. The data suggested that the Rho-ROCK pathway may play a pivotal role in APP metabolism, and that treatment with statins may provide therapeutic opportunities to alter APP formation.

The next International AD/PD Conference, entitled Alzheimer's and Parkinson's Diseases: Progress and New Perspectives, will be held in March 2007, in Salzburg, Austria. All those interested in AD, PD, DLB, and Mozart should attend.