Course Description
Parkinson's Disease (PD) affects both men and women in almost equal numbers. It shows no social, ethnic, economic or geographic boundaries. In the United States, it is estimated that 60,000 new cases are diagnosed each year, joining the 1.5 million Americans who currently have PD. While the condition usually develops after the age of 65, 15% of those diagnosed are under 50.

The process of diagnosing PD can be difficult.There are no biological markers for its diagnosis. Recent advances in the fields of pathology, genetics, clinical and neuroimaging question current definitions of the disease.

This meeting goal is to redefine the diagnostic criteria for Parkinson's disease in view of recent advances. The interaction between world-known basic scientists and clinicians in the proposed setting will facilitate reviewing current knowledge, developing a broader understanding of PD, from the bench to the bedside, refining diagnostic criteria for PD to move the field forward. It will also help develop fruitful collaborations.

The purpose of this Second International Brainstorming Conference is therefore to contribute to improve the nosology of PD. This will be done through critical review of current knowledge, discussion, dissemination and collaboration between participants.


Target Audience
This course is designed for researchers and physicians serving in the Parkinson's Disease area.


Agenda
Friday, May 16, 2008
Location: Jewish Hospital Rudd Heart & Lung Conference Center

8:00 AM
Registration & Continental Breakfast

PD Nosology I
Chair: Eldad Melamed, MD

8:30 AM
Welcoming Remarks
Irene Litvan, MD

8:35 AM
Neuropathology: Staging
Heiko Braak, MD

8:45 AM
Pitfalls in Current Studies
Charles Duyckaerts, MD

8:55 AM
Olfaction Testing and PD Staging
John Duda, MD

9:05 AM
Caveats in the Interpretation of Olfaction Study Data
Anthony E. Lang

9:15 AM
Neuroimaging and PD Staging
David Brooks, MD

9:25 AM
Caveats in the Interpretation of Neuroimaging Data
David Eidelberg, MD

9:35 AM
Question and Answers
Chaired by Glenda Halliday, PhD

10:35 AM
Break

10:50 AM
Lessons from Familial PD Mutations
Zbigniew Wszolek, MD

11:00 AM
Caveats in the Interpretation of Genetic Data
John Hardy, PhD

11:10 AM
Lessons from the Difference in Pathology in Genetic Studies
Dennis W. Dickson, MD

11:20 AM
Caveats in the Interpretation of Available Genetic Pathologic Data
James B. Leverenz, MD

11:30 AM
Question and Answers
Panel & Participants; Chaired by Thomas Gasser, MD

12:30 PM
Summary Remarks
Eldad Melamed, MD

12:40 PM
Poster Session, Light Lunch

PD Nosology II
Chair: Yves Agid, MD, PhD

1:40 PM
Contributions from Neuropsychological and Neuropsychiatric Studies in PD
Staging
Alexander I. Tröster, PhD

1:50 PM
Caveats in the Interpretation of Neuropsychological and Neuropsychiatric Studies
Bruno Dubois, MD

2:00 PM
Contributions from Longitudinal Studies in PD Staging
David Burn, MD

2:10 PM
Caveats in the Interpretation of Longitudinal Studies
G. Webster Ross, MD

2:20 PM
Question and Answers
Chaired by Mark Hallett, MD

3:20 PM
Break

3:45 PM
Where To Go From Here
Panel & Participants; Chaired by Bill Langston, MD

5:00 PM
Evaluation and Adjournment

7:00 PM
The Marquess of Queensberry Gala ... A Black Tie Affair to Champion Parkinson's
Muhammad Ali Center

Saturday, May 17, 2008
Location: Jewish Hospital Rudd Heart & Lung Conference Center
8:00 AM
Continental Breakfast

PD Nosology III

8:30 AM
Subgroup Discussions:

Neuropathologic Diagnostic Criteria
Location: Great Hall I
Chaired by Dennis Dickson, MD

Clinical Diagnostic Criteria
Location: Great Hall II
Chaired by Irene Litvan, MD

10:30 AM
Break

10:45 AM
Diagnostic Criteria
Subgroup representatives and all participants;
Chaired by Yves Agid, MD, PhD

11:45 AM
Concluding Remarks
Yves Agid, MD, PhD

12:00 PM
Evaluation and Adjournment

1:00 PM - 6:00 PM
Lunch, Afternoon at Churchill Down (Preakness Day)


Poster/Abstract Submission
Registration for this meeting will be limited and will give priority to investigators submitting abstracts for the meeting. The deadline for poster submission is April 16, 2008.

Abstracts will be accepted in electronic format only. To submit your abstract, please e-mail it to chse@louisville.edu

Abstract Guidelines
All abstracts MUST be organized under the following headings:

• Background
• Objective
• Methods
• Conclusions

Abstracts must include the following:

• Title
• Learning objectives and key words
• Presentation preference
• Topic area
• Author contact information
• Abstract body (350 word limit)
• Complete presenter biography

Presentation Format
Poster: This session will be held from 10:30 AM to 12:30 PM Friday, May 16, 2008. Presenters are required to be present for presentation. Presenters must set up their poster before 10:30 AM. Posters should measure 56 inches wide x 36 inches tall.

Criteria For Acceptance
The Scientific Program Committee will consider the following criteria in their review of submitted abstracts:

• Quality of scientific research
• Relevance to the topic
• Newness of information
• Potential impact on Parkinson's disease research
• Review & Notification Procedures

All abstract submitters will receive confirmation of receipt of completed submissions by email.

Submissions will be reviewed by the scientific program committee and scored according to the above-mentioned criteria.

Submitters will be notified of their acceptance status no later than April 30, 2008.

General Guidelines:
All presenters are required to register for the conference and pay the full registration fee.

Presenters are responsible for their own expenses including registration, travel, hotel and any other costs incurred by their conference participation.

Presentations may not promote an organization or product for purchase.

The committee will review only complete submissions.

Abstracts Submitted To Date:

Using siRNA Screening Technology to Identify Mediators of Neuronal Toxicity
Brendan Looyenga*, Jeffery MacKeigan & James Resau
Van Andel Research Institute, Grand Rapids, Michigan

*Corresponding author

Email: brendan.looyenga@vai.org
Address: 333 Bostwick Ave NE, Grand Rapids, MI 49503
Phone: 616-234-5503

Preferred Format: Poster
Topic area: Neuroprotection
Key Words: oxidative stress, 6-OHDA, RNA-interference, high-throughput screening

Background: Numerous studies have shown that oxidative stress is a central contributor to dopaminergic neuronal toxicity associated with Parkinson's Disease. While both exogenous and endogenous sources of oxidative stress can lead to dopaminergic cell death, the precise reason why these neurons are so sensitive to these insults in unclear. Identification of molecules that mediate dopaminergic neuronal toxicity will provide insights into why dopamergic neurons are exquisitely sensitive to oxidative stress, and may also provide important targets for pharmacologic neuroprotection.

Neuroblastoma cell lines such as SH-SY5Y and SK-N-SH present viable models of dopaminergic neuron behavior that-unlike primary neurons-are amenable to transfection and in vitro expansion. Differentiation of these cells causes cell cycle exit, outgrowth of neurites and an increase in the expression of key markers of dopaminergic neurons. These cells also demonstrate a distinct dose-response to oxidative compounds such as 6-hydroxydomamine (6-OHDA), making them a useful model of oxidative stress-induced cell death.

Objective: Using SH-SY5Y and SK-N-SH cells as a cellular model, we are seeking to identify genes that mediate sensitivity to oxidative stress by high-throughput RNA-interference (RNAi) technology.

Methods: By evaluating several different cationic lipids as delivery vehicles, we have identified methods by which to efficiently and reproducibly transfect SH-SY5Y and SK-N-SH cells with small interfering RNAs (siRNA). In combination with large libraries of siRNAs, we are able to use these transfection methods to specifically knock down expression of all the individual members of specific gene families in a 96-well format. This approach allows us to rapidly screen for genes that mediate sensitivity to 6-OHDA, which is measured as the ratio of surviving cells in treated versus untreated cells after 24 hours of treatment.
Conclusions: To date we have screened all phosphatases in the human genome for their effect on 6-OHDA sensitivity. We have shown that three members of this gene family-PP2CB, CDC25A and PTPN14-show a statistically significant decrease in sensitivity to 6-OHDA when knocked down by RNAi. We are currently validating the protective effect of downregulating these molecules, and have also begun screening other pharmacologically tractable gene families including kinases and G-protein coupled receptors.


Alpha-synuclein positive astrocytes in Lewy body dementia
Y. Huang, G. Halliday
Prince of Wales Medical Research Institute and University of New South Wales, Sydney, 2031, Australia

Key words: Lewy body dementia, Parkinson's disease with dementia, -synuclein

Presentation preference: Poster presentation

Topic area: Neuropathology

Author contact information:
Dr. Yue Huang,
NHMRC Senior Research Officer
Prince of Wales Medical Research Institute
Villa 1, Barker Street, Randwick
Sydney, NSW, 2031, Australia
Phone: 61 2 9399 1041
Fax: 61 2 9399 1005
Email: yue.huang@unsw.edu.au

Complete presenter biography:
MBBS, MD, and clinical practice: Dr Huang obtained her MBBS degree in 1991 and MD degree in 1999. After graduating from Harbin Medical University, China, she practiced medicine at the Harbin First Public Hospital of China for nine years until 2000. After a further five years of clinical training, Dr Huang became a Geriatrician, specialising in Neurology in 1996. Her MD thesis is on cerebral infarction.
PhD and Post-Doc: During her PhD studies (2000-2003), Dr Huang learned molecular biology and cell biology from Prof. Piu Chan at the Beijing Geriatrics Institution, China, and proteomic techniques from Dr. Weiping Gai at Flinders University of South Australia. Her PhD thesis is composed of two parts: the application of pharmacogenomics to epilepsy therapy and proteomic analysis of a-synucleinopathies. Since 2003, Dr Huang has worked with Prof. Glenda Halliday as an NHMRC research officer, participating in research on the genetics of Parkinson's disease and brain bank management. In 2007, Dr. Huang was promoted as Senior Research Officer.

Abstract body
Alpha-synuclein positive astrocytes in Lewy body dementia

Y. Huang, G. Halliday
Prince of Wales Medical Research Institute and University of New South Wales, Sydney, 2031, Australia

Background:
Three dementia types are related to Lewy body pathology (Weisman, 2007): Type 1 is Parkinson's disease with dementia and is equivalent to Braak stages 5 and 6 of Parkinson's disease (PD) (Braak, 2003); Type 2 is diffuse Lewy body disease in cases with dementia and no other significant neuropathologies; Type 3 is Lewy body variant of Alzheimer's disease, and is the most common type (Weisman, 2007). Cases with the advanced stages of PD (Type 1 pathology) have alpha-synuclein-immunoreactive astrocytes which are thought to have metabolised synaptic alpha-synuclein (Braak, 2007).

Objective:
The objective of this study is to determine whether similar astrocytic uptake of alpha-synuclein occurs in cases with type 2 and type 3 pathology.

Methods: Alpha-synuclein and beta-amyloid immunostaining were performed in the entorhinal and hippocampal cortices at the level of the lateral geniculate body from 11 Lewy body dementia cases (3 type 1, 1 type 2 and 7 type 3). Lewy body counts were performed and graded at 200x field, mild=maximal 1-2 cortical Lewy bodies, moderate=maximal 3-6 cortical Lewy bodies, and severe=over 6 cortical Lewy bodies. Plaque load was estimated using Braak plaque phases (Thal, 2006) and Braak stage was used to evaluate the pathological severity of PD (Braak, 2003).

Results: Alpha-synuclein positive astrocytes were found in all types of Lewy body dementia and were evenly distributed throughout the entorhinal grey matter. There were no differences between Lewy body types in the amount of cortical Lewy bodies (mild to severe). Increased numbers of cortical alpha-synuclein positive astrocytes associated with increased Lewy body burden, but not senile plaque load (between I-V depending on case type).

Conclusion: Similar to Lewy bodies, alpha-synuclein positive astrocytes are a common pathological feature in all cases of Lewy body dementia.


Assessment of PD, its progression, and treatment effects with imaging
David J Brooks MD DSc FRCP
(Imperial College London, UK)

Imaging is now in a position to examine both the structural and functional changes associated with Parkinson's disease (PD) and how these progress over time. Magnetic resonance imaging can sensitively detect volumetric changes and has shown that brain atrophy in non-demented PD progresses at a similar rate to that of healthy controls while demented PD patients show 5 fold faster brain shrinkage. Transcranial sonography can detect hyperechogenicity in PD midbrain though this appears to remain static despite clinical progression of disease. Function of striatal dopamine terminals has been examined with dopamine transporter and vesicular momoamine transporter radioligands and 18F-dopa PET. The microglial reaction to Lewy body pathology can be imaged with 11C-PK11195 PET.
In this talk the value of structural and functional imaging in aiding the diagnosis and management of Parkinson's disease will be reviewed. The underlying pathological mechanisms leading to tremor, coexistent dementia and depression in PD are considered and the role of imaging as a biomarker for testing neuroprotective agents debated.
L-dopa treated patients show comparable rates of loss of striatal dopaminergic function with these modalities ranging from 6-12% per annum. One third slower rates of loss of striatal dopaminergic function have been reported in patients receiving agonist therapies. Intraputaminal infusions of the nerve growth factor GDNF and implantation of fetal midbrain tissue both act to increase putamen dopamine storage capacity but clinical response to these approaches has been variable.
In summary, while imaging provides a potential biomarker for demonstrating treatment effects on the dopaminergic system and brain volume in PD and can help establish drug mechanisms of action it cannot yet be used as a surrogate marker of outcome in therapeutic trials.


New genes for Parkinsonisms: do they point to a pathway?
John Hardy, j.hardy@ion.ucl.ac.uk. Institute of Neurology, University
College, London

The establiished genes for Lewy body parkinsonisms are alpha-synuclein
and lrrk2. However, recently glucosecerebrosidase (GBA) has been
conclusively shown to be a risk locus by many groups and I wll argue
that PANK2 and the recently identified PLA2G6 also deserve inclusion
among the list of relevant genes, as possibly does ATP13A2. I will
discuss these findings in the context of finding a final common pathway
to Lewy body disease.


Caveats of the Neuropathology of Familial PD and DLB.
James B. Leverenz

The study of the neuropathology of familial forms of PD, and related disorders, can play an important role in expanding our understanding of PD. For example, it allows the observation of pathologic change within a sample of cases with a clear single etiology (i.e. specific mutation), something not possible with sporadic disease. However, certain caveats should be taken into consideration when interpreting results from these studies.

First, and perhaps most obvious, does the mutation-associated disease truly represent of sporadic disease? Recent evidence of neuropathological differences between sporadic ALS and SOD mutation-associated familial ALS suggest caution in over interpretation of apparent familial forms of a disease. The pathological data available for LRRK2 and parkin mutation-associated disease also suggest there may be some fundamental differences between these familial diseases and sporadic PD.

Second, the presence, or absence, of Lewy related pathology (LRP) does not necessarily imply PD. The frequent, and almost universal, presence of LRP in PS1 mutation-associated familial AD does not suggest that these patients have PD. In addition, LRP in AD does not appear to follow similar anatomic progression, as observed in sporadic PD. The atypical distribution and presence of other pathologic changes in LRRK2 mutations also raises doubt about its suitability as a "model" for sporadic PD. Finally, in parkin-associated PD LRP is relatively uncommon. It is not yet apparent if this means that parkin mutation-associated PD is not pathophysiologically linked to sporadic disease.

Thus, caution is advised when interpreting neuropathological data from familial PD, particularly as it relates to PD nosology and diagnosis. However, despite these caveats, it is still critical to search for common and divergent neuropathologic change in familial and sporadic PD and in other related neurodegenerative diseases.


The Association of Preclinical Indicators of Parkinson's Disease
With Early Stages of Synuclein Deposition

Helen Petrovitch MD, Robert D. Abbott PhD, John E. Duda MD, Joseph V. Noorigian MPH, Lon R. White MD MPH, G. Webster Ross MD,

BACKGROUND: Constipation, excessive daytime sleepiness and impairment in olfactory function may occur years before the classic motor features of Parkinson's disease (PD). Pathological observations indicate that the earliest sites of alpha-synuclein deposition are the dorsal motor nucleus of the vagus nerve and the olfactory bulb, followed by several other brainstem areas including the locus ceruleus (LC), the raphe nuclei and the magnocellular portions of the reticular formation, all of which would be expected to produce symptoms prior to the onset of the cardinal motor signs of PD that appear when Lewy pathology has reached the SN.

OBJECTIVE: To determine the association of preclinical indicators of PD with early stages of synuclein deposition in the brain

METHODS: During repeat Honolulu-Asia Aging Study examinations, elderly Japanese-American men were asked about constipation and sleep problems and grip strength and olfactory ability were measured. Among those who later had post mortem exams, alpha-synuclein immunostaining was used to identify Lewy pathology in the olfactory bulb. H&E staining was used to identify Lewy bodies in the LC and SN. Individuals who died within 5 years of their last evaluation for the preclinical indicators were included in this analysis.

RESULTS: There were 60 decedents who had no synuclein pathology (stage 0), 10 with synuclein pathology restricted to the olfactory bulb (early stage), 26 with involvement of the LC or SN but without clinical PD during life (mid-stage), and 30 with clinical PD during life (late stage). Those in early stage had significantly fewer bowel movements per day (1.6) than those in stage 0 (2.3) (p<0.05). Excessive daytime sleepiness and poor olfaction were more common in mid-stage then in earlier stages. Olfaction and grip strength decreased significantly across the stages from 0 to late stage (p<0.04).

CONCLUSIONS: Bowel movement frequency, grip strength, olfaction, and likelihood of excessive daytime sleepiness appear to be affected early in the course of synuclein deposition prior to the classical motor features of PD.


Lessons from Pathologic Heterogeneity in Genetically-Determined Parkinson's Disease
Dennis W. Dickson, M.D., Mayo Clinic, Jacksonville, FL 32224

The most common postmortem finding in Parkinson's disease (PD) is neuronal loss in the substantia nigra and Lewy bodies (LBs) in residual neurons. LBs are granulofilamentous intraneuronal inclusions composed of ?-synuclein. Neurons that are most vulnerable to LBs include monoaminergic neurons of the substantia nigra, locus ceruleus and raphe nuclei, as well as cholinergic neurons of the basal forebrain. Neurons in the dorsal motor nucleus of the vagus and the medullary and pontine reticular formation are also vulnerable. Neuronal loss in the substantia nigra correlates with dopaminergic deficiencies in the striatum and with extrapyramidal motor signs and symptoms in PD. While LBs are a sine qua non of widely used pathologic criteria for PD, LBs are also found in a wide range of non-Parkinsonian disorders and in 10% of the clinically normal elderly (so-called "incidental" LBs), presumably representing mixed or preclinical pathology, respectively. LBs are the most common pathologic substrate of genetically determined PD. Autosomal dominant PD caused by mutations in ?-synuclein (SNCA) and leucine rich repeat kinase-2 (LRRK2) are associated with LBs. In a very small subset of LRRK2 mutation carriers, non-LB pathology has been described, including nonspecific nigral neuronal loss or tau pathology. In contrast, autosomal recessive PD, particularly due to mutations in the gene for Parkin (PRKN), is most often associated with nonspecific nigral neuronal loss without LBs; but there are exceptions with LBs. For other genetically determined PD (e.g., mutations in DJ-1 and PINK1) pathology is not available. Mutations in glucocerebrosidase (GBA), which causes autosomal recessive Gaucher's disease, may cause PD with LBs. Rare families with mutations in autosomal dominant genes that cause spinocerebellar ataxias (SCA2 and SCA3), disorders not associated with LBs, have a parkinsonian phenotype. In summary, the extrapyramidal motor syndrome of parkinsonian disorders reflects pathology in the nigrostriatal dopaminergic system that can have multiple pathologic substrates. In the overwhelming majority of sporadic PD and most genetically-determined PD, neuronal loss is associated with LBs, but there are exceptions that challenge narrow clinical or pathologic criteria for PD.


Title: Caveats in the Interpretation of Longitudinal Studies
Presenter: Webster Ross, MD

Longitudinal studies of community populations, as well as panels of Parkinson's disease (PD) cases can be employed for studying natural history of disease including the progression of motor signs, response to therapy, and development of non-motor symptoms such as cognitive impairment and dementia. Knowledge of risk factors associated with progression can lead to improved understanding of disease mechanisms and to therapies aimed at slowing disease progression and preventing complications. Certain caveats must be kept in mind when interpreting these studies. First, in longitudinal studies, PD is not diagnosed until the middle stages of disease when the motor syndrome is apparent. Methods to identify persons with PD in the earliest stages are needed. Screening for symptoms linked to the early stages is possible; however, low specificity currently limits usefulness. For example, data from the community based Honolulu Asia Aging Study suggest that screening for olfactory impairment, excessive daytime sleepiness, and slow reaction time identifies a group with 10 times higher incidence of PD than others. Even so, the probability that persons who screen positive actually have early stage PD remains low.

Another caveat is the important contribution of co-morbid brain lesions to declining neurologic functioning with advancing age. It is estimated that dementia eventually occurs in 40% of PD patients, however, this approaches the prevalence of dementia in an aged population. In a recent report from the Rush Memory and Aging Project, over half of older persons with dementia whose brains were examined had multiple diagnoses (Alzheimer's disease, PD / Lewy body disease, and infarcts). Development of dementia may not be specific for progression to higher stages of PD.

Finally, there are issues related to staging in a disease associated with progression that is non-linear, highly variable between individuals, and masked by medications. Better tools must be developed to measure progression exemplified by motor impairment, cognitive decline, and disability that are devoid of floor and ceiling effects, and allow accurate comparison of patients in different stages of disease.


Caveats in the interpretation of olfaction studies
Anthony E. Lang, MD, FRCPC

Loss of olfactory function is widely acknowledged as an early feature of Parkinson's disease (PD). Indeed, it is probably as common as resting tremor, although clearly less specific. Some have suggested that the diagnosis should be questioned in patients with normal smell identification. Clinical evaluation ranges from simple screening of odor identification to a combination of olfactory detection, identification and discrimination tasks. Olfactory event-related potentials are prolonged in patients with PD. One study has demonstrated diffusion-weighted magnetic resonance imaging evidence of disruption of the olfactory tract, however, MRI evaluation of olfactory bulb volume has failed to show a difference between Parkinson's disease and controls. Patients with established Parkinson's disease may misidentify specific odors more often than others and odor discrimination is variably affected and has been correlated with the severity of the disease in some studies. The pathological basis of olfactory dysfunction probably relates to a combination of disturbances of the olfactory bulb, anterior olfactory nucleus, and cortical nucleus of the amygdala. Olfactory dysfunction is variably present in monogenetic forms of Parkinson's disease; for example, it may be normal in Parkin-related PD and abnormal in patients with LRRK2 mutations. Given the very early presence of olfactory dysfunction in PD, typically predating the motor manifestations, it has been suggested that this may be a useful biomarker for the subsequent development of the disease. Indeed, "idiopathic Lewy body disease" is found at autopsy more often in individuals in the lowest tertile (17.4%) compared to the highest tertile (1.8%) of odor identification. The presence of olfactory dysfunction as evaluated by a combination of tests of olfactory detection, identification and discrimination, combined with functional imaging of the nigrostriatal dopamine system may predict the subsequent development of parkinsonism in first-degree relatives of patients with PD. On the other hand, more routine olfactory screening of smell identification (the UPSIT) has not been found to be a sensitive indicator of subsequent Parkinson's disease in originally unaffected twins of patients with Parkinson's disease seven or more years before the development of motor signs. Furthermore, olfactory dysfunction may be present in other parkinsonian disorders, particularly multiple system atrophy where neuronal loss and glial cytoplasmic inclusions have been described in the anterior olfactory nucleus. Finally, abnormal performance on olfactory function testing may also be explained by impaired sniffing as well as disturbances in cognitive processing, for example executive dysfunction. In summary, tests for olfactory dysfunction have high sensitivity but low specificity for established Parkinson's disease. Screening for olfactory dysfunction may define populations at risk for the subsequent development of Parkinson's disease, however, these will almost certainly need to be supplemented by additional biomarkers and it is not clear that simple screening of odor identification, particularly many years in advance of the development of motor features, will be sensitive enough to be a practical value.


Alexander I. Tröster, PhD

Parkinson's disease (PD), Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are -synucleinopathies. Temporal differences in the emergence of symptoms and clinical features warrant the continued clinical distinction between PD, DLB and PDD. While DLB and PDD groups' neuropsychological profiles often differ from those in Alzheimer's disease (AD), PDD and DLB neuropsychological profiles share sufficient similarity to resist accurate and reliable differentiation. A prominent role of neuropsychology is anticipated in the characterization and detection of the very earliest cognitive changes in PD. Neuropsychology has been critical in recently revealing that cognitive changes (predominantly in memory and executive function) may manifest earlier and more frequently than previously appreciated in PD, and executive deficits may be early harbingers of dementia. Subtypes of cognitive impairment, perhaps by virtue of definition, parallel those seen in Mild Cognitive Impairment (MCI), but recent enthusiasm to extend the concept of MCI to PD is confronted by several hurdles. Future research might strive to identify the precise neuropsychological characteristics of the prodromal stages of PD, PDD, and DLB which, in conjunction with other potential biomarkers, facilitate early and accurate diagnosis and the definition of neuroprotective, neurorestorative, and symptomatic treatment endpoints.


Neuropathology: Early Stages
Heiko Braak, MD
Professor, Sencenberg Anatomical Institute
Frankfurt, Germany

The synucleinopathy idiopathic Parkinson's disease is a multisystem disorder that involves only a few predisposed nerve cell types in specific regions of the human nervous system irrespective of transmitter type. The intracerebral formation of abnormal proteinaceous Lewy bodies and Lewy neurites begins in defined induction sites and advances in a topographically predictable sequence. During the presymptomatic stages 1-2, the inclusion body pathology is confined to the medulla oblongata/pontine tegmentum and olfactory bulb/anterior olfactory nucleus. In stages 3-4, the substantia nigra and other nuclear grays of the mid- and forebrain become the focus of initially slight and, then, severe pathological changes. At this point, most individuals probably cross the threshold to the symptomatic phase of the illness.

Neuropsychological Approach of Parkinson's Disease Dementia
Bruno Dubois for the MDS Task Force of Parkinson's Disease Dementia
Hôpital de la Salpêtrière - Centre des Maladies Cognitives et Comportementales et INSERM U610

As potential therapeutic approaches for Parkinson's disease dementia (PD-D) become available, there is a need to establish diagnostic procedures PD-D that can be used internationally. To address this challenge, the Movement Disorder Society Task Force on Dementia in Parkinson's Disease developed recommendation for two levels of assessment. There is first a practical set (Level I) that can be used by any clinicians and requiring no particular expertise in neuropsychological methods. The tests within the battery proposed are well known and can be rapidly completed. In many cases, this battery, coupled with a careful accompanying account from the caregiver, will be adequate to confirm the diagnosis of PD-D, according to the criteria proposed. The tests will also highlight domains of particular concern to the patient and their family and may be useful in prioritizing treatment decisions. Level II testing is more detailed and requires greater expertise in neuropsychological methods, and the availability of the relevant instruments. Level II testing may be suitable for research studies or pharmaceutical trials where there is a need to document the efficacy of drugs under investigation. It may also be required when diagnostic doubt exists, and the Level I assessment produces equivocal results. In this case, when the practitioner is unable to arrive at the diagnosis of PD-D because of these concerns, a referral for neuropsychological evaluation will be needed and the consultation can specifically include a request to follow the Level II battery. Given the number of neuropsychological tests currently available we hope the carefully selected range given here will facilitate more direct comparison between different studies in future. The dementia syndrome associated with PD is not simply a disorder of cognition. Fundamental to the diagnosis of PD-D is the fact that there is an impact upon daily living resulting from cognitive deficits, over and above those imposed by motor and autonomic problems. In addition, neuropsychiatric disturbances may be prominent and a source of major distress to the patient and their family. The operationalization of these behavioral and neuropsychiatric features is not straightforward, given their diversity and the current lack of validated tools in several key areas (for example visual hallucinations). We have suggested widely used instruments to detect these features, which have also been employed in several studies of PD-D, but acknowledge that this is no substitute for further work in this area to develop disease-specific instruments that are sensitive to change. A validation of all these tests and instruments for PD-D is recommended by the Task Force.


Longitudinal Studies in PD: Predictors of Cognitive Decline
David J. Burn, Newcastle University, UK

Increasing age is the most important risk factor currently identified for PDD. Increasing motor disability is also predictive of dementia and is synergistic with current age. A non-tremor dominant motor phenotype is over-represented in PDD and associated with a four-fold increased risk of dementia. Longer disease duration and male gender have also been associated with increased risk of PDD. Less well-established risk factors include low educational attainment, current smoking habit (contrasting with the well established inverse association of smoking and PD), depression, excessive daytime somnolence, REM sleep behaviour disorder and orthostatic hypotension (OH). Regarding OH, differences in sustained attention have been shown to be highly significant between PD subjects with and without OH, a difference that remained robust on re-assessment 12 months later. Dementia may be associated with weight loss in PD, together with worsening of parkinsonism, age at diagnosis and emergence of visual hallucinations, but the predictive value of antecedent weight loss is not known. Several of these features could relate to increasing cholinergic neuronal dysfunction, particularly within the pedunculopontine nucleus, "modulating" the clinical phenotype and simultaneously producing a range of non-motor problems, including cognitive impairment.
Regarding drug effects, anticholinergics may be a risk factor for PDD, and prolonged use of these agents has been associated with an increased frequency of cortical plaques and tangles in non-demented PD patients. Poor response to L-dopa and hallucinations on dopaminergic treatment may also predict dementia. L-dopa-induced elevation in plasma homocysteine levels could contribute towards cognitive failure while amantadine may delay and attenuate dementia. Visual hallucinations in PD predict more rapid cognitive deterioration.
Psychosis requiring antipsychotic therapy has been associated with development and progression of dementia, while the use of atypical antipsychotics may have adverse disease modifying effects. Deficits in auditory verbal learning and nonverbal reasoning, picture completion, Stroop interference and verbal fluency have all been independently associated with an increased risk of cognitive failure in PD. Two simple bedside tests, pentagon copying and semantic fluency, may also be predictive of cognitive decline and dementia. There is an association between apathy and cognitive dysfunction, particularly executive impairment, but it is unknown whether apathy is independently predictive of dementia.


Parkinson Disease: Pitfalls In Current Studies
Charles Duyckaerts. Laboratoire de Neuropathologie Escourolle. Hôpital de La Salpêtrière. Paris. France.

The presence of Lewy bodies is presently considered as the hallmark of Parkinson disease (PD). However, studies associating Lewy bodies and PD have not taken into account two major factors that could modify our point of view : 1) Lewy bodies are present in abundance in the aging control population and it is presently impossible to determine if they would have inexorably be associated with PD if the patient had lived longer 2) Lewy bodies do not accumulate (as neurofibrillary tangles do) but disappear with the neurons they kill. The quantity of Lewy alterations (Lewy bodies and neurites) may therefore be uncorrelated with the severity of the pathology. Neuronal loss in the substantia nigra appears as the key lesion directly correlated with the extrapyramidal syndrome but the loss of neurons is much more difficult to evaluate in the cortical pathology associated with Lewy bodies.


"Caveats In The Interpretation Of Neuroimaging Data"
David Eidelberg, MD
Professor & Director, Susan and Leonard Feinstein Center for Neurosciences, North Shore-LIJ Research Institute
Manhasset, New York

Controversy exists regarding the selection of optimal imaging markers for the early diagnosis and detection of parkinsonian disorders, as well as for using the measures to quantify rates of disease progression in these conditions. A particular challenge lies in the capacity of imaging targets to be regulated by the disease process, by its treatment, or both. Paradoxically though, these changes can have a positive effect on the measurement of the ensuing rate of change of the process in question. For example, up-regulation of striatal dopa decarboxylase (DDC) activity in early Parkinson's disease (PD) broadens the dynamic range of the measured decline in 18F-fluorodopa (FDOPA) uptake that is typically measured in longitudinal imaging studies. Likewise, concurrent dopaminergic therapy may alter the expression of the dopamine transporter (DAT) in a way that can influence the interpretation of longitudinal assessments based on selective binding ligands for this molecule. Such assessments can also be biased by potential non-linearities in the disease process itself.

Other caveats involve the potential lack of specificity of these methods in discriminating typical from atypical parkinsonian syndromes. A number of recent techniques have evolved to identify descriptors that are more disease-specific. While it appears that several of these MRI or PET-based approaches have added sensitivity/specificity for differential diagnosis, very few have been validated by blinded assessments in large prospective patient populations. Indeed, very little is known about the within-subject variability of these potential biomarkers of disease progression. The ultimate use of neuroimaging biomarkers in the diagnosis and staging of PD and related disorders will be determined by their validation in test-retest reproducibility studies. Rigorously conducted washout studies will also be needed to assess the influence of potential therapeutic agents on the biomarker in question.


Olfactory Testing and PD Staging
John Duda, MD
Co-Director
Parkinson's Disease Research, Education and Clinical Center
Philadelphia VAMC
Philadelphia, Pennsylvania

Loss of Olfactory function is an early symptom of Parkinson's disease (PD) and predates the onset of the cardinal motor manifestations of the disease. Both neuropathological and clinical stiudies of at-risk populations suggest that the olfactory bulb may be an early target of pathology in PD and that smell loss may occur years before a clinical diagnosis of PD can be made. Preliminary studies suggest that olfactory dysfunction may also be useful as a biomarker of disease progression in early PD. Examination of a large community-based cohort of non-diseased elderly suggests that Lewy pathology of the olfactory bulb may contribute to olfactory impairment in as many as one-third of elderly individuals. Further investigation of olfactory impairment in at-risk individuals will help to determine the relationship between incidental Lewy body pathology and the Lewy body disorders.


Lessons From Familial PD Mutations
Zbigniew K. Wszolek, MD
Mayo Clinic, Jacksonville, Florida

OBJECTIVE: To describe the current status of our knowledge of the genetics of parkinsonism. BACKGROUND/DESIGN: To date, 13 PARK loci, 6 causative genes (SNCA, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2), and 2 provisional genes (UCHL1, Omi/HtrA2) have been discovered. The PRKN gene is the most common autosomal recessive gene implicated in patients with early-onset parkinsonism. Mutations in the recently identified LRRK2 gene represent the most common cause of late-onset autosomal dominant Parkinson disease. The LRRK2 G2019S mutation has been found throughout the world, but it is most prevalent in North African Arabs and Ashkenazi Jews. Recently assembled large series of patients homozygous for the G2019S mutation found no observable differences between the homozygote and heterozygote phenotypes. The second most common LRRK2 gene mutation is R1441C. The pathologic studies performed on LRRK2 gene carriers demonstrate variable pathologies: pure nigral degeneration, tau depositions, or the presence of brainstem or cortical Lewy bodies. The LRRK2 G2385R variant is a particular risk factor among Chinese people, and represents the strongest genetic risk factor for PD so far. In patients with atypical autosomal dominant parkinsonism associated with frontotemporal dementia, the MAPT and PGRN genes, both located on chromosome 17, should be considered. Parkinsonism with accompanying ataxia is seen in patients with mutations in the gene for spinocerebellar ataxia, particularly SCA2 and SCA3. Both Chinese and white families with affected members having parkinsonism alone due to the SCA2 gene have been identified. RESULTS/RELEVANCE: It is hoped that genetic discoveries will eventually translate into clinical practice, revolutionizing the treatment and management of parkinsonian disorders.
Supported by: NIH/NINDS, M. K. Udall Parkinson's Disease Center of Excellence grant awarded to the Mayo Clinic Jacksonville (P50NS40256) and NIH/NIA P01AG017216 grant.

Poster Abstracts:

NEW SCREENING GROUPS IN PD-DIAGNOSIS ACCORDING TO COST/EFFICIENCY THRESHOLDS IN NEW NEUROLOGICAL DEPARTMENTS

Dr S G Echebarria MD
Neurologist
Neurology Service A-B
Spain
e-mail: arpon9@yahoo.com

INTRODUCTION : Typical-traditional and recent classifications and typologies adscribed to PD samples ( diagnostic criteria ) and evolutive forms may be supervened in recent years by novel descriptive approaches , regarding precission of diagnostics , variability in office-based work-up and movement criteria application on new diagnostic subsizing.

METHODS : Application of logit model : year/cost and Ordinary least square ( OLS ) regression to log-transformed and CPI- adjusted year health care costs.

RESULTS / CONCLUSIONS : Temptative classification may be obtained according to correlation UPDRS unities increase / decrease:

-Years with dyskinesias - PD Screening A
-Adverse effects PD - Screening A
-Health District Neurological Service : PPV , sensibility , specificity in PD diagnostics.

-Trembling predominant forms with cost / efficiency grade I
-Trembling predominant forms with cost / efficiency grade II


¹H-MRS experiences after bilateral DBS of the STN in Parkinson's disease

Llumiguano C, Kosztolanyi P, Kovacs N, Schwarcz A, Doczi T, Balas I.
Department of Neurosurgery¹, Department of Neurology² University of Pecs, Diagnostic Center of Pecs³, Hungary

Correspondence: carlos.llumiguano@aok.pte.hu
Name: Llumiguano Carlos M.D.
Department of Neurosurgery, University of Pecs, Hungary
Address: H-7623, Pecs, Ret utca 2 sz.
Telephone: +3672 535 900
Fax:+3672 535 931

Key words: DBS, MR Spectroscopy, Parkinson's disease, STN
Presentation preference: Poster
Topic area: Diagnostic - Imaging

Background: Proton magnetic resonance spectroscopy (¹H -MRS) is a useful noninvasive method used to study central nervous system pathologies, and allows in vivo investigation of a number of cerebral metabolites such as N- acetylaspartate (NAA), choline (Cho), creatine (Cr), myoinositol (My), phosphocreatine (PCr) and lactate. The objective of this study was to evaluate the changes of the brain metabolites concentrations (NAA - N acethyl aspartate, Cho - choline, Crea - creatinine) in patients with Parkinson disease (PD) before and after bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN).

Material and methods: 13 patients were evaluated at baseline and repeatedly 3 months after surgery. The NAA/Chol, NAA/Crea, Chol/Crea ratios were determined by single voxel ¹H-MRS studies on 1.0 T unit using stimulated echo acquisition mode (STEAM) sequence (TR/TM/TE:2000/10/30 ms). Spectra were obtained from right and left globus pallidus (Gp), and fronto-basal cortex (FBC).

The patients were also assessed according to the Unified Parkinson's Disease Rating Scale (UPDRS) part III, in the "medication-on" and "medication-off' conditions. Results: in all patients motor scores (UPDRS III) improved significantly (Student's T test: p< 0.01). In all patients, decreased NAA/Cho ratios were observed from the selected voxels in left and right Gp, however significant increase of NAA/Cho, NAA/Crea, and decrease of Chol/crea ratio was observed in FBC after surgery in patients with clinical improvement.

Complications: in one case transient and in other case permanent complication developed following STN DBS implantations. Conclusions: significant improvements were observed in the motor scores (UPDRS III) and in cortex NAA/Cho, NAA/Crea ratio increased significantly following bilateral DBS of the STN. These improvements were strongly correlated with improvements in motor function, primarily with regard to bradykinesia.

Our results suggest that NAA/Cho and NAA/Crea ratio may be a valuable criterion for evaluation of Parkinson's disease patients with the clinical improvement following DBS of the STN. ¹H-MRS may be a useful utility for the aid in better understanding the pathophysiologic process in Parkinson's disease patients on the basis of the variation of NAA/Cho, NAA/Crea ratio.

Llumiguano Carlos, Dep. of Neurosurgery University of Pecs - Hungary
Kosztolanyi P, Dep. of Neurosurgery University of Pecs - Hungary
Kovacs N, Dep. of Neurology University of Pecs - Hungary
Schwarcz A, Dep. of Neurosurgery University of Pecs - Hungary
Doczi T, Dep. of Neurosurgery University of Pecs - Hungary
Balas I, Dep. of Neurosurgery University of Pecs - Hungary


Faculty
Irene Litvan, MD
Raymond Lee Lebby Professor of Parkinson’s Disease Research
Chief, Division of Movement Disorders
Univ. of Louisville Neurology Dept.
Louisville, Kentucky
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Yves Agid, MD, PhD
Professor & Director Neurosciences
Hospital de la Salpêtrière
Paris, France
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Heiko Braak, MD
Professor, Sencenberg Anatomical Institute
Frankfurt, Germany
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David Brooks, MD
Professor, Imperial College, Hammersmith Hospital
Middlesex, England
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Alexander I. Tröster, PhD
Associate Professor
Department of Neurology
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

David Burn, MD
Professor, Regional Neuroscience Center
Newcastle General Hospital
Newcastle Upon Tyne, England
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Dennis W. Dickson, MD
Professor, Mayo Clinic
Jacksonville, Florida
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Bruno Dubois, MD, PhD
Professor, Hospital de la Salpêtrière
Paris, France
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John Duda, MD
Co-Director
Parkinson's Disease Research, Education and Clinical Center
Philadelphia VAMC
Philadelphia, Pennsylvania

Charles Duyckaerts, MD
Professor, Hospital de la Salpêtrière
Neuropathology Laboratory
Paris, France
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David Eidelberg, MD
Professor & Director, Susan and Leonard Feinstein Center for Neurosciences, North Shore-LIJ Research Institute
Manhasset, New York
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Thomas Gasser, MD
Director of the Hertie Institute for Clinical Brain Research University of Tubingen
Tubingen, Germany
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Mark Hallett, MD
Chief, Human Motor Control Section
NINDS, National Institutes of Health
Bethesda, Maryland
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Glenda Halliday, PhD
Professor, Prince of Wales Medical Research Institute Randwick, Australia
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John Hardy, PhD
Chief of the Laboratory of Neurogenetics
Laboratory of Neurogenetics NIA/ NIH
Bethesda, Maryland
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Anthony E. Lang
Professor & Director, Morton and Gloria Shulman
Movement Disorders Centre, Toronto Western Hospital Division of Neurology
Toronto, Canada
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Bill Langston, MD
Scientific Director of the Parkinson's Institute
Sunnyvale, California
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James B. Leverenz, MD
Associate Professor, Neurology and Psychiatry and
Behavioral Sciences
University of Washington
Seattle, Washington
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Eldad Melamed, MD
Professor and Chairman, Department of Neurology
Rabin Medical Center-Beilinson Campus
Sackler School of Medicine
Tel Aviv, Israel
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G. Webster Ross, MD
Honolulu-Asia Aging Study,
Kuakini Medical Center,
Honolulu, Hawaii
Departments of Geriatric Medicine and Internal Medicine,
John A. Burns School of Medicine,
University of Hawaii, Honolulu, Hawaii
Honolulu Department of Veterans Affairs, Honolulu, HI

Zbigniew Wszolek, MD
Professor of Neurology
Mayo Clinic Jacksonville
Jacksonville, Florida
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Continuing Education Credit
Physician - Physician - The University of Louisville Continuing Health Sciences Education office designates this educational activity for a maximum of 7.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.


Registration
Registration for this meeting will be limited and will give priority to investigators submitting abstracts for the meeting. For more information regarding abstract submission, click here.

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Meeting Participants:
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UofL Full-Time Students & Residents/Fellows CHURCHILL DOWNS ONLY: $65


Cancellation Policy
Requests for cancellation must be e-mailed to chse@louisville.edu by May 2, 2008. Requests received by May 2 will receive a full refund less a $50 processing fee. There will be no refunds for cancellations after May 2, 2008.


Hotel Information
A block of rooms has been reserved at the conference rate of $135.00 plus tax per night (single or double occupancy) at The Galt House East Hotel, 140 N. Fourth Street, Louisville, Kentucky, 40202. All rooms are located in the Rivue Tower (west tower - rooms have all been remodeled).

You must reserve your room(s) by Tuesday, April 15, 2008 to qualify for this special rate. Hotel reservations are to be made directly with the hotel by calling 1-800-843-4258. Be sure to mention the "International Brainstorming Meeting for Parkinson's" when making your reservation in order to receive the conference rate.


Brochure
Click here for a copy of the course brochure, which contains information regarding speakers, topics, etc. To download the file, right click on the link and select save as.

You must have Adobe Acrobat Reader to view the course brochure file. If you don't have it, it is a free program that can be easily installed by clicking here. If you have installed Acrobat Reader and the file still doesn't open, try right clicking on the brochure link and selecting "save target as" to download the file to your computer.


Learning Objectives & Outcomes
OBJECTIVE: Describe the neuropathologic stages in Parkinson's disease and caveats of current neuropathologic staging studies.
OUTCOME: So that these aspects can be incorporated in redefining PD for patients and physicians.

OBJECTIVE: Learn the impact of PD genetic mutations in the nosology of PD, in specific how the difference in pathology may affect our nosologic definition.
OUTCOME: So that a better understanding of genetics and difference in pathology is understood to help redefine this disorder.

OBJECTIVE: Understand the role of olfaction testing in PD staging and the caveats in interpreting the data.
OUTCOME: So that these aspects can be incorporated in redefining PD for patients and physicians.

OBJECTIVE: Understand the role of neuroimaging in the diagnosis of PD and the caveats in interpreting the data.
OUTCOME: So that these aspects can be incorporated in redefining PD for patients and physicians.

OBJECTIVE: Understand the role of neuropsychological testing in the diagnosis and staging of PD and the caveats in interpreting the data.
OUTCOME: So that these aspects can be incorporated in redefining PD for patients and physicians.

OBJECTIVE: Recognize how longitudinal studies impact on the staging of PD and the caveats in the interpretation.
OUTCOME: So that a better understanding of staging in PD can be incorporated in defining this disorder for patients and physicians.


Acknowledgement
Supported by The Movement Disorder Society (MDS) and the National Institutes of Health, 1R13NS062643-01.


Louisville Tourist Attractions
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Special Services
If you need special accommodations due to a disability, or for an alternative form of the materials, please contact Continuing Health Sciences Education at chse@louisville.edu or (502) 852-5329 at least 14 days prior to the program. University of Louisville Continuing Health Sciences Education fully complies with the legal requirements of the ADA and the rules and regulations thereof.


Accreditation
The University of Louisville School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.