Category Archives: Parkinson’s

Is Parkinson’s and parkinsonism on the increase?

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An interesting study was published in JAMA a couple of weeks ago. The authors, from Mayo Rochester, state: “Our study suggests that the incidence of parkinsonism and PD [Parkinson’s Disease] may have increased between 1976 and 2005, particularly in men 70 years and older. These trends may be associated with the dramatic changes in smoking behavior that took place in the second half of the 20th century or with other lifestyle or environmental changes. However, the trends could be spurious and need to be confirmed in other populations.”

If the increase in parkinsonism and PD were due to improved diagnosis, then we would likely see this effect in both men and women. But the researchers found an increased incidence in men especially.

There is research (albeit controversial), both in PD and in PSP (progressive supranuclear palsy), that smoking may suppress symptoms. Indeed, my father’s PSP symptoms began *after* he quit smoking. Another local support group member had the same experience. The rate of smoking has decreased more rapidly in men than women in the US.

Alzforum compares the rise of incidence in parkinsonism and PD with the opposite findings for dementia: “This finding is in stark contrast to a measurable decrease in Alzheimer’s disease in Europe and the United States, which researchers attribute to healthier lifestyles of late.”

Copied below is the link to the short Alzforum summary of the JAMA research paper and related papers, and the full Alzforum summary. And copied below is the link to the JAMA paper abstract.

See: www.alzforum.org/news/research-news/rising-tide-parkinsons

A Rising Tide of Parkinson’s?
Alzforum
July, 8 2016

Also see: www.ncbi.nlm.nih.gov/pubmed/27323276

JAMA Neurology. 2016 Jun 20.
Time Trends in the Incidence of Parkinson Disease
Savica R, Grossardt BR, Bower JH, Ahlskog JE, Rocca WA.
Mayo Clinic, Rochester, Minnesota.

Robin

“A Cautionary Tale of ‘Stem Cell Tourism'”

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Here’s a worrisome article from yesterday’s New York Times about the harm one person received from stem cell therapy in Mexico, China, and Argentina as a “treatment” for a stroke.  A neurosurgeon found a “huge mass with someone else’s cells growing aggressively in [the person’s] lower spine.”

Some in our local MSA support group have tried stem cell therapy in China and Germany.  In general, we’ve heard that this therapy was not helpful.  Perhaps their loved ones didn’t live long enough to experience these problems?

Find the full article here:  www.nytimes.com/2016/06/23/health/a-cautionary-tale-of-stem-cell-tourism.html

New York Times
Health
A Cautionary Tale of ‘Stem Cell Tourism’
By Gina Kolata
June 22, 2016

Robin

“Pimavanserin Nears Approval to Treat Psychosis in Parkinson’s”

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A new drug is coming on the market soon for psychosis (hallucinations, delusions) in Parkinson’s Disease — pimavanserin (brand name – Nuplazid). I imagine many with Lewy Body Dementia will be prescribed the medication as well, based on a neurologist’s willingness to prescribe a new medication. This is a good summary from Alzforum (alzforum.org) of the drug’s current status. And note Dr. Ian McKeith’s comment about prescribing this medication for those with DLB (dementia with Lewy bodies). He’s very concerned about “neuroleptic sensitivity” in the DLB population. Dr. McKeith is a DLB expert.

Robin

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www.alzforum.org/news/research-news/pimavanserin-nears-approval-treat-psychosis-parkinsons

Pimavanserin Nears Approval to Treat Psychosis in Parkinson’s
Alzforum
06 Apr 2016

Pimavanserin has cleared another hurdle on the road to becoming the first antipsychotic approved for use in any neurologic disease. A Food and Drug Administration committee voted 12 to two that the drug’s benefits outweigh its risks for Parkinson’s patients with psychosis. The drug’s maker, ACADIA Pharmaceuticals, announced the vote on March 29. The decision was covered by The Wall Street Journal and Business Wire. The FDA is expected to complete its review of pimavanserin, now trade named Nuplazid, by May 1.

The endorsement drew praise in the field. “Pimavanserin is a breakthrough agent,” Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, wrote to Alzforum. Cummings co-led a Phase 3 trial for the drug. “The trial and the approval process open the door to more neuropsychiatric drug development, and the availability of pimavanserin to our patients is a great stride forward,” Cummings added.

“This is definitely good news for patients with PD and psychosis,” wrote Dag Aarsland, Karolinska Institute, Stockholm. Daniel Weintraub, University of Pennsylvania, Philadelphia, agreed. “Given our recent research on increased mortality with [typical] antipsychotic use in PD patients, I am glad that a new option is likely to be available soon,” he wrote to Alzforum (see Weintraub et al., 2016). “There was good evidence for efficacy and short-term tolerability overall, and none of the current antipsychotics (except clozapine) have been shown to be efficacious,” he added.

Up to 40 percent of Parkinson’s patients develop frequent psychoses, according to the National Parkinson Foundation. No good drugs for this symptom currently exist, with older antipsychotics carrying a “black box” warning of increased mortality for dementia patients (see Oct 2005 news; Jan 2009 news; Feb 2011 news). Many of those drugs target dopaminergic systems, which are already perturbed in people with Parkinson’s. Pimavanserin, a serotonin inverse agonist, is a new class of drug, noted Jim Leverenz of the Cleveland Clinic. “The important clinical implication is that this is a fairly clean and effective drug that avoids the dopaminergic system and the motor side effects that can accompany treatment with typical antipsychotics.”

Pimavanserin diminished psychosis in a six-week Phase 3 trial of 199 Parkinson’s patients. In addition, participants reported better sleep and daytime alertness. The drug did not worsen motor function and was well-tolerated, with the most serious side effects being edema and confusion. Some participants have now taken the compound on an open-label basis for several years (see Apr 2013 news; Nov 2013 news).

The drug is under investigation for other neurodegenerative disorders as well, with a Phase 2 trial ongoing in Alzheimer’s. In a separate Phase 2 trial, clinicians are testing another serotonin inverse agonist, nelotanserin, for dementia with Lewy bodies. “Mechanisms for psychosis in patients with DLB would be similar to those in Parkinson’s patients, and one would hope they would respond similarly to treatment,” noted Leverenz. Even in AD, psychosis is often linked to the presence of Lewy bodies as well. Testing this new class of agent in different conditions would be a reasonable next step, Leverenz said. In the meantime, scientists agreed that should pimavanserin be approved for PD, then clinicians will likely begin prescribing it off-label for other conditions.

—Madolyn Bowman Rogers and Tom Fagan

Comment by:
Ian McKeith
Newcastle University, Institute for Ageing and Health
Posted: 07 Apr 2016

This development will be welcomed by people with PD and psychosis and their families, and by clinicians who struggle to manage such symptoms and who find themselves resorting to treatments of limited effectiveness but significant toxicity.

The question about using pimavanserin to treat DLB is interesting and important. If this drug is approved for use in PD psychosis, there will immediately be pressure to use it in people with DLB, who often have severe hallucinations and delusions but who are extremely hard to treat because of their severe neuroleptic sensitivity and because of possible increased susceptibility to confusion when treated with clozapine. However, PD psychosis to DLB isn’t a straightforward extrapolation. Although PD psychosis and DLB share some similarities clinically and pathologically, there are substantial differences, likely reflecting that they are underpinned by variable patterns of change in multiple neurotransmitter systems and circuits.

Patients with MMSE as low as 21 were included in the Acadia pimavanserin trial, and a third were on cholinesterase inhibitors (CHEIs) throughout, but since “patients with delirium” were excluded from entry few probably had the fluctuating pattern of symptoms that is typical of DLB. Elaine Perry published data on Newcastle brain bank cases as far back as the early 1990s showing that preservation of 5-HT2 receptors in the temporal cortex differentiated hallucinating from non-hallucinating DLB cases and suggested a hyper-serotinergic/hypo-cholinergic imbalance as a basis for visual hallucinations in particular. My feeling is that it is the fluctuating, cognitively impaired group who might benefit more than others. The combination of a compound like pimavanserin together with a cholinergic enhancer in DLB might have very significant positive effects upon attention and visual hallucinations, with secondary benefits in delusions and other neuropsychiatric symptoms such as anxiety. But the neurochemical volatility that might make these DLB patients more responsive to treatment could also lead to increased side effects, as we see with neuroleptics and to a lesser extent with CHEIs. So I would urge some careful early dose-finding work to establish safety in DLB, before hopefully moving quickly on to finding which patients and which symptoms benefit most.

Managing Orthostatic Hypotension (article for physicians)

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This post may be of interest to those who would like some ideas on dealing with orthostatic hypotension.

An article was published in late October 2015 in a managed care journal for MDs on how to treat neurogenic orthostatic hypotension that occurs in MSA, LBD, and Parkinson’s.  It’s a short article, and is available at no charge online.

www.ajmc.com/journals/supplement/2015/ACE0034_Oct15_NOH/ACE0034_Oct15_NOH_Isaacson_etal/

In particular, I like the list of non-pharmacologic physical “counter-maneuvers” that can be employed for orthostatic hypotension (OH).

Two websites are mentioned with video instructions and tutorials — www.syncopedia.org and www.stars.org.uk.

On the last page, you can find a link for the PDF of the full article.  Looking at the PDF seems to be the only way to view the tables.  There are two good tables — a list of drugs that cause OH (copied below), and details on three medications for OH (droxidopa, midodrine, and fludrocortisone).

Robin

Table 2. Drugs That Cause Orthostatic Hypotension

Alpha1-adrenergic antagonists
doxazosin, prazosin, terazosin

Antipsychotic drugs
clozapine, quetiapine, iloperiodone, chlorpromazine, thioridazine

Diuretics
furosemide, hydrochlorothiazide

Antidepressants
amitriptyline, clomipramine, imipramine, doxepin >6mg/day, trimipramine, trazodone

Calcium channel blockers
diltiazem, verapamil

Anti-Parkinson drugs
amantadine, levodopa, pramipexole, ropinirole, selegiline

Monoamine oxidase type A inhibitors
phenelzine, tranylcypromine

Nitrates
isosorbide dinitrate, nitroglycerin

 

Spinal fluid biomarker research – PSP v. MSA v. PD, and which PDers will develop LBD?

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There was an interesting – but hard to understand (at least for me!) – paper published a couple of weeks ago in JAMA Neurology, an important journal.  A lot of the worldwide research community is focused on biomarkers.  If we could give someone a blood test (or a spinal tap, in the case of this paper) to determine if the person had PD, PSP, or MSA, that would be groundbreaking.  And it might be helpful to know which of those who have PD will eventually develop dementia (or Lewy Body Dementia in particular).

In this paper, Swedish researchers looked at cerebrospinal fluid (CSF) of 128 people with Parkinson’s Disease (PD), Progressive Supranuclear Palsy (PSP), and Multiple System Atrophy (MSA) over a 5-9 year period.  None of the 128 had dementia.  CSF of 30 older healthy controls was also examined.

Here’s an (understandable) excerpt from a useful summary of the paper on Alzforum, posted last Friday:

“Scientists…report a combination of useful candidates in the cerebrospinal fluid (CSF) that may help [differentiate these diseases and predict who will decline cognitively]. One biomarker in particular, neurofilament light chain (NFL), a neuronal cytoskeleton protein, best distinguished PSP from PD. In helping predict which patients with PD would become demented, NFL joined two other proteins: Aβ42 and heart fatty acid–binding protein (HFABP), which helps carry fatty acids to the mitochondria for oxidization. All in all, the results propose useful diagnostic biomarkers for these diseases and may offer clues to their pathophysiology. … No single biomarker or combination separated MSA from PD.”

In the study, 35 percent of the PD patients developed dementia over the five to nine years of participation.  This seemed to be a high conversion rate to dementia for John Growdon, a neurologist at Mass General in Boston.  He said:

“‘To be able to predict with some certainty who’s on the path to dementia and who’s not is a very important finding,’ he told Alzforum. If these results can be reproduced, it could mean that Aβ-lowering therapeutics for Alzheimer’s disease (AD) will be applicable to the PDD group. It would be useful to compare these biomarkers in other disorders that might also cause diagnostic confusion, such as AD and dementia with Lewy bodies, he said.”

For what it’s worth, Dr. Growdon described this as a “very important study.”

Here’s a link to the Alzforum post, if you’d like to read more:

www.alzforum.org/news/research-news/biomarkers-differentiate-parkinsonian-diseases-and-forecast-decline

I’ve copied the abstract below.

Robin

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Abstract

JAMA Neurology. 2015 Aug 10.

Cerebrospinal Fluid Patterns and the Risk of Future Dementia in Early, Incident Parkinson Disease.
Bäckström DC, Eriksson Domellöf M, Linder J, Olsson B, Öhrfelt A, Trupp M, Zetterberg H, Blennow K, Forsgren L.

Importance:
Alterations in cerebrospinal fluid (CSF) have been found in Parkinson disease (PD) and in PD dementia (PDD), but the prognostic importance of such changes is not well known. In vivo biomarkers for disease processes in PD are important for future development of disease-modifying therapies.

Objective:
To assess the diagnostic and prognostic value of a panel of CSF biomarkers in patients with early PD and related disorders.

Design, Setting, and Participants:
Regional population-based, prospective cohort study of idiopathic parkinsonism that included patients diagnosed between January 1, 2004, and April 30, 2009, by a movement disorder team at a university hospital that represented the only neurology clinic in the region. Participants were 128 nondemented patients with new-onset parkinsonism (104 with PD, 11 with multiple system atrophy, and 13 with progressive supranuclear palsy) who were followed up for 5 to 9 years. At baseline, CSF from 30 healthy control participants was obtained for comparison.

Main Outcomes and Measures:
Cerebrospinal fluid concentrations of neurofilament light chain protein, Aβ1-42, total tau, phosphorylated tau, α-synuclein, and heart fatty acid-binding protein were quantified by 2 blinded measurements (at baseline and after 1 year). Follow-up included an extensive neuropsychological assessment. As PD outcome variables, mild cognitive impairment and incident PDD were diagnosed based on published criteria.

Results:
Among the 128 study participants, the 104 patients with early PD had a different CSF pattern compared with the 13 patients with progressive supranuclear palsy (baseline area under the receiver operating characteristic curve, 0.87; P < .0001) and the 30 control participants (baseline area under the receiver operating characteristic curve, 0.69; P = .0021). A CSF biomarker pattern associated with the development of PDD was observed. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein at baseline were related to future PDD as analyzed by Cox proportional hazards regression models. Combined, these early biomarkers predicted PDD with high accuracy (hazard ratio, 11.8; 95% CI, 3.3-42.1; P = .0001) after adjusting for possible confounders.

Conclusions and Relevance:
The analyzed CSF biomarkers have potential usefulness as a diagnostic tool in patients with parkinsonism. In PD, high neurofilament light chain protein, low Aβ1-42, and high heart fatty acid-binding protein were related to future PDD, providing new insights into the etiology of PDD.

PubMed ID#:  26258692