The Parkinson's Disease Foundation broadcast their annual two-day educational symposium on the web today and yesterday. You can find the agenda online at: http://event.netbriefings.com/event/pdf/Live/50th/
I listened to some of the presentations yesterday -- many of the "Clinical and Quality of Life" sessions and three of the "Basic Science" sessions (because I wanted to hear Dr. Caroline Tanner from The Parkinson's Institute and I wanted to know about the role of inflammation in PD).
There were two presentations that I found very interesting and will definitely go back online at some later point to view those presentations again and take better notes. The two best were: Dr. Ron Pfeiffer, a neurologist from the Univ of TN, whom I've heard speak before on the same topic of nonmotor symptoms of PD; and Dr. Carli Tanner from The Parkinson's Institute, who gave an epidemiology update on PD. Time was short and they both flew through their slides.
Second place would go to Dr. Blair Ford who spoke about pain in PD, and a nurse Julie Carter who spoke about depression.
One item was new for me: The lower the level of uric acid the greater the risk of getting PD. Perhaps one day this could be a diagnostic test for PD and perhaps lead to treatment to slow the progression of PD.
At some point, hopefully soon, the webcasts (with audio, video, and presentation slides) will be available on the Parkinson's Disease Foundation website (pdf.org). The archives will be available online for up to a year.
These notes are in chronological order. My guess is that most of you are interested in the notes on the presentations by Dr. Ron Pfeiffer and Dr. Blair Ford.
Preclinical Diagnosis of PD- Matthew Stern, M.D.
Univ of Penn School of Medicine
Seems to indicate that there is a marker of PD that doesn't change with time
Is this marker there before PD symptoms appear?
This sonogram could be done in a clinic
Univ of PA Smell Identification Test (UPSIT)
Significant loss of smell not associated with severity or duration of PD
Olfactory bulb may be early pathological target of PD
Honolulu Heart Program (and Study)
Objective: identify early indicators of PD
Looked at: smell loss, constipation, reaction time, daytime sleepiness, QT interval (from electrocardiogram)
Neurology '06, Postuma article
RBD is an early indicator of PD
Those with RBD (without a clinical diagnosis of PD) were shown to have risk factors of PD
Risk factors of PD: olfactory dysfunction, color discrimination, subtle motor impairment
Pilot data from UPenn study of first degree relatives of those with PD
Caffeine intake lower in PD patients than normal controls
If you have olfactory dysfunction, the less likely you are to drink caffeine
If you smoke, you are more likely to have good smell function
If you don't smoke and have olfactory dysfunction, the more likely you are to have PD
The UPenn study may find people also at risk for AD.
We can't determine how to prevent the development of neurodegenerative diseases until we know more about what happens in the preclinical stages of these diseases.
Question: is olfactory dysfunction caused by inflammation or breathing in toxins?
Answer: no, this is part of the pathological process.
Question: is there higher risk of PD with Agent Orange exposure?
Answer: no evidence of this.
Question: does smell improve?
Answer: no, it gets worse.
Question: AD also has smell loss. What's the relationship between PD and AD?
Answer: pathological processes may be similar (in terms of proteins misfolding) but these are different diseases.
Question: if you can find someone at risk for PD, what treatment can be given?
Answer: we think there are drugs available now that can slow the onset of PD. There will certainly be drugs available later that can do this.
Question: what's the relationship between PD onset and pesticide exposure?
Answer: PD has been linked to earlier exposures to pesticides and herbicides. To date, no single toxin has been identified as causing PD.
Genetic Testing Issues- Tatiana Foroud, Ph.D.
Indiana Univ School of Medicine
She's involved in identifying/studying genes involved in late-onset disorders such as PD and AD.
Each cell has 23 pairs of chromosomes. In each pair, one came from father and one from mother.
Both genes and environmental factors are both important in the development of PD. We don't know the proportion of these. For some families, genes determines the risk of PD. She studies these families.
There are eight genetic variations identified for the PARK gene that cause PD.
There can be variations in age of onset within a family. Early-onset could have one cause and late-onset another cause.
If you think your family has some unusual things going on, contact her or another genetics researcher! She wants to study you!
New Therapeutic Directions- Ira Shoulson, M.D.
Univ of Rochester (Experimental Therapeutics)
(I missed the first half of the presentation.....sounds like it would be interesting.)
The lower the level of uric acid the greater the risk of getting PD.
(See Am J Epidemiology '07 article)
The lower the uric acid the faster the progression of PD (based on imaging markers).
DATATOP study participants provided blood, CSF, and urine.
Concentration of uric acid in inverse fashion predicted how quickly people progressed in their PD.
Uric acid is a powerful antioxidant.
Too high uric acid is not good either.
Can we use uric acid to treat or prevent PD?
PostCEPT study is a follow up to PRECEPT study.
Neuroprotection = disease modification
He believes "neuroprotection" as a term has limited meaning in clinical trials. It's an important term for basic science.
Need large-scale, multi-site, multi-year studies of "pre-manifest PD" and manifest PD.
Question: can we give someone a uric acid test to diagnose PD or predictive of course of PD?
Answer: no, this is still in the research stages.
Biology and Pathology of LRRK2- William Dauer, M.D.
LRRK2 (pronounced lurk-2*) has additional associations with FTD, PPA, CBD, amylotrophy.
Is there a common pathway to some neurodegenerative diseases?
LRRK2 has recently been identified.
(*pronounced lark-2 by another presenter)
Genetic and Other Approaches to Early Diagnosis and Treatment: Questions, Answers and Controversies- Susan Bressman, M.D.
Very little is known about genetic counseling in the clinical setting.
What do MDs know about genetic counseling? What are their opinions? What do the patients feel?
Many clinicians don't talk to patients at length about the role of genetics in PD or offer genetics testing.
Why? Lack of specific treatment based on gene status. Counseling is time consuming. Testing is expensive.
Adult vs. childhood onset: parents may want to know about their child's disease vs. affected parents want to know the risks of passing disease on to parents.
In all studies, should we be collecting samples (DNA, serum, skin bx, etc)?
In studies, should we be collecting additional info (sleep, vision, autonomic, imaging, lifestyles, exercise, exposure)?
Have we adequately investigated longterm effects of medication?
Have we considered the effects of other (non-PD) meds and other illnesses? (NSAIDs, calcium channel blockers, statins, cancer, hypertension) Different effects on different populations (eg, sex) and disabling symptoms (eg, cognition, freezing).
Respiratory, Gastrointestinal, Urological and Sexual Issues- Ron Pfeiffer, M.D.
Univ of TN
Four cardinal features of PD - tremor, rigidity, bradykinesia, postural instability
His speech focuses on non-motor dysfunction, and, in particular, autonomic dysfunction.
Within autonomic dsyfunction, there are many topics including cardiac, GI,
GI dysfunction includes bowel dysfunction, excess saliva (including drooling), dysphagia, progressive weight loss, nausea (gastroparesis),
Weight loss occurs in 52% of PD patients.
Reason for weight loss is unclear. Less intake? No. Reduced expenditure? No.
Salivary excess occurs in 70-80% of PD patients.
Too much saliva produced? No, PD patients make less saliva than normal and they swallow it less efficiently.
Also, mouth is often open and posture is stopped so drool comes from the saliva.
Anticholinergic drugs (Artane, Coginex, eg) have bad effects
Robinul doesn't get to brain but you can still have other bad effects.
Atropine eye drops are preferred. Amounts used are small so systemic side effects are uncommon.
Botox trials underway
Try gum or hard candy to increase swallow and reduce drool.
MBSS (modified barium swallow study) shows 75-97% patients with PD have swallowing problems
Impaired swallow muscle control due to bradykinesia, etc.
Clinically, silent aspiration present in 15-33%. Choking or coughing may be a clue.
Why are there swallowing problems?
Other non-PD-related causes for swallowing: Zenker's diverticulum, gastroesophageal reflux disease, cervical osteophytes, cricopharyngeal bar. (Bad breath is another sign of Zenker's diverticulum.)
Tests of oropharyngeal dysfunction: MBSS, etc.
Tests of esophageal dysfunction: video fluoroscopy, etc.
Achalasia can only be seen with esophageal studies.
Dopaminergic therapy can improve dysphagia.
16% of PD patients feel nausea (that isn't tied to medication)
43% of PD patients experience bloating (that isn't tied to medication)
Could be gastroparesis
Gastroparesis may cause motor fluctuations (as the "on" time is delayed or doesn't occur)
Alpha-synuclein deposits are found in the enteric system (the gut) in those with PD. Changes are seen in the gut first.
Does PD move from the enteric nervous system to the central nervous system?
Changes are seen in the brain (substantia nigra) much later.
Domperidone (dopamine antagonist) is an effective med to treat gastroparesis but it's not available in the US.
Gastric pace maker could be an effective treatment of gastroparesis in PD. Need to study this.
Two aspects of bowel dysfunction: decreased bowel movement frequency (constipation) and decreased function (less emptying)
20-77% of those with PD suffer constipation. (Big range)
Is constipation related to decreased fluid intake? (Reduced intake could occur early in life.)
If you have one or fewer BM a day, you have a 4-fold increase in the chance to get PD.
Colon transit time occurs in 80% of those with PD. (19 hours for normal controls vs. 44 hours for those with PD)
Marked reduction of dopamine levels in colon in those with PD and constipation.
Order of medication treatment of constipation: 1. fiber, 2. stool softener, 3. Miralax, 4. osmotic laxatives, 5. enema
In normal defection, some muscles contract and some relax.
The most frequent urinary problem in PD is frequent urination (irritative urinary symptoms).
Newer anticholinergics don't get into brain: Sanctura, Enablex, etc.
Obstructive urinary symptoms are second most common urinary problem in PD.
Don't treat with anticholinergics.
Sphincter bradykinesia can be a problem here.
Treatment is catherization.
Sexual dysfunction can be either reduced/impaired or excessive.
Be careful using Viagra because of the problem of inducing hypotension.
Upper airway obstruction can occur in PD.
Stridor can occur in PD though it is associated with MSA.
PD patients can breathe more shallowly and rapidly.
Question: is fecal incontinence a problem in PD?
Answer: this is rare. Make sure there's no other explanation for it. If there is not, Imodium might be useful but it is likely to aggravate constipation. There's not a good treatment for this.
Comment: patient in the audience does 20-minutes of steam and this helps the voice and swallowing.
Answer: never heard this before. There is no danger in this so it's worth a try.
Pain and Other Sensory Abnormalities in PD- Blair Ford, M.D.
Columbia University's Neurological Institute of NY (cumc.columbia.edu/dept/neurology)
Pain = unpleasant sensory or emotional experience associated with the actual or potential damage to tissue
Pain is a disorder of movement
Pain is an underappreciated cause of suffering in PD.
1/3 to 1/2 of PD patients will experience pain, sometimes chronic pain.
Complexity to causes of pain.
Treatment of pain is challenging.
Close link between pain and motor fluctuations.
Pain in PD was known from the beginning about this disorder. Dr. Parkinson described pain in two patients.
UPDRS (Unified Parkinson's Disease Rating Scale) only has one question on pain.
Snider, 1976: 29% cramping/aching, 43% tingling/numbness, 11% burning
Goetz, 1996: akathisia, etc.
Painful sensations in PD:
Musculoskeletal: aching muscles and joints
Ridicular/neuropathic (pinched nerve): numbness, tingling
Dystonic: pain associated with dystonic postures and movement (related to medical/motor fluctuations)
Central/primary: burning, tingling, formication (very hard to treat; occupies the mind)
Akathisia: restless; felt everywhere (not just in legs as with RLS)
Musculoskeletal pain associated with rigidity, akinesia, mechanical stresses.
Contractures due to immobility.
Muscle pains and fibromyalgia. (Fibromyalgia common in PD.)
43% of patients had frozen shoulder before the development of PD!
Exercise/movement can help with dystonia.
Painful dystonia can occur during off-periods in PD.
Treatment of dystonia: reduce off-periods; use agonists or amantadine; botox for focal dystonia; stereotactic neurosurgery (DBS).
Witjce paper on "Nonmotor fluctuations in PD," Neurology '02.
Patients can experience extreme anxiety when their medications run out.
Autonomic symptoms can also occur.
Very complex: pain/sensory - cognitive/psychiatric - autonomic
Does pain in PD arrive from the brain itself (rather than from a muscle, eg)?
Two pain pathways - lateral pathway (neurologists know about this) and medial pathway (paleospinalxxx pathway).
Central pain is presumed abnormal processing of somatosensory info
Central pain is inferred.
Central pain is not abolished by a peripheral nerve block.
Medial pain system - autonomic
Case #1 with severe abdominal pain during wearing off periods.
Case #2 with oral pain (right hand side of mouth only).
Patient had a little bit of parkinsonism on his right side.
Akathisia affects 25% of patients. Most commonly affects legs. Restlessness.
Often related to timing of medication.
Most patients with RLS do not develop PD.
Those with RLS can experience relief with dopamine agents.
PD patients rarely describe headaches.
Persistent headaches can be related to depression and anxiety.
There is a relationship between PD, pain, and depression.
40% of PD patients are depressed.
Pain and sleep disturbance more common in PD patients who are depressed.
Musculosketal problems can be effectively addressed by pain medication (NSAIDs), etc.
Living with Nonmotor Complications in PD #1 - Julie Carter, R.N., ANP
Oregon Health and Science University, Professor of Neurology
Growing recognition that non-motor symptoms have greater impact on life than motor symptoms.
Depression is the most common non-motor problem in PD.
Under-recognized by clinicians and patients.
Depression in PD is really a spectrum disorder of mood and may not fit into the DSM-IV criteria for major depression.
There's not a well-recognized instrument for screening for depression in PD.
PD symptoms can be confused with the motor and cognitive symptoms of depression.
Schrag article, Journal of the Neurological Sciences '06 article
Depression is the main factor that correlates with poor health-related quality of life. It also correlates with worse disability.
Depression is a risk factor in cognitive impairment.
Ravina article, Neurology '07
Depression correlates with increased caregiver strain.
Depression has biological and psychological basis.
Inflammation and PD Pathogenesis- Serge Przedborski, M.D., Ph.D.
Columbia Univ's PD Research Center, Dept of Neurology, Pathology, and Cell Biology
Toxin models show that inflammation could contribute to the neurodegenerative process in PD
Optimal protective strategy in PD includes anti-inflammatory agents
His research shows that vaccinations are worth pursuing. We must move cautiously.
Their test was a vaccination of nitrated synuclein. (??not sure about this??)
He would vaccinate with PARKIN or C-able.
He doesn't believe in getting behavioral data from mice.
PD: Epidemiology Update- Caroline Tanner, M.D., Ph.D.
The Parkinson's Institute's Director of Clinical Research
PD incidence increases with age.
Honolulu Asian Aging Study seems to indicate that PD starts in mid-life.
Mid-life obesity predicts PD.
Have toxicants come into the body through the nose or the GI tract? Is that why PD seems to begin there?
PD prevalence is higher in Inuits in Greenland. Is this due to PCB exposure? Is there a common genetic cause?
Is PD passed on in families in PD in genetic code? Yes.
Are all cases of PD purely genetic? No. Only 10% or fewer cases are due to genetic causes only.
Mostly likely it's the combined effect of factors (risk and protective factors) that determine whether you get PD.
Inverse associations - protective factors: cigarette smoking, increased uric acid, early life exercise, coffee drinking, anti-inflammatory drug use
Direct associations - risk factors: family history; occupation; etc.
Honolulu Asian Aging Study looked at combined protection of smoking and risk of another factor.
Are some people more vulnerable to environmental toxicants? This is part of your genetic make-up.
Pesticides and PD, Elbaz '04 showed genetic make-up and exposure were both important.
Dawson & Dawson '04 showed that there are many causes leading to common mechanisms of neuronal injury in PD.
Is PD part of a clinical and neuropathological continuum?
AD - DLB - PDD - PD - MSA
Risk factors in MSA include: pesticide exposure, head injury, etc.
Dementia frequency is much higher for those with PD as they get older.
Question: do you think pesticides should be banned?
Answer: it's too soon for that. It might help if you use protective equipment when administering pesticides when (hobby) gardening.