Category Archives: LBD

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

Exercise and dementia (research updates from Alzforum)

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This post may be of general interest since many of us are dealing with dementia or will be dealing with dementia at some point in our lives.

At the recent Alzheimer’s Association International Conference in Washington DC (mid-July), a lot of research was presented on exercise.  The Alzforum has two good summaries of the research.

The first summary is here:

alzforum.org/news/conference-coverage/exercise-boosts-cognition-symptomatic-disease

The first summary examines research into whether Alzheimer’s disease can be tempered by aerobic exercise and whether dementia can be avoided through exercise:

“Speakers…presented new evidence that regular aerobic exercise can help people in prodromal disease stages maintain their cognition, while for those with full-blown dementia it relieves neuropsychiatric symptoms. Some studies provided hints that exercise can also hone thinking at the dementia stage, but only if the participants reach moderate intensity heart rates during their workout. Exactly how exercise helps the brain is still not known, but several talks reported better cerebral blood flow and improved structural and functional connectivity in exercisers, and even some signs that six months or more of physical activity can slow pathology.  Researchers agreed that the duration and intensity of an exercise intervention are crucial to determining its effects. For aerobic exercise in particular, the field is standardizing methods and narrowing in on the appropriate dose to prescribe. Some believe supervised exercise classes could become part of the standard of care for people with cognitive problems. … Researchers have few doubts now that exercise protects normal older adults against brain decline.”

(prodromal = before symptoms appear)

The second summary is here:

alzforum.org/news/conference-coverage/can-exercise-slow-progression-alzheimers-pathology

The second summary explores research into whether exercise can slow the progression of a neurodegenerative process:

“Overall, the findings indicated that working out enhances vascular brain health and connectivity, implying a direct benefit to brain structure and function. Data were mixed on whether exercise slows the progression of underlying Alzheimer’s pathology, however. One six-month study of moderate aerobic exercise reported a drop in cerebrospinal fluid tau in cognitively impaired people, but a shorter intervention failed to budge brain amyloid in people with AD. In general, speakers agreed that the cognitive boost from exercise likely comes from diverse benefits on several different aspects of brain function, something that would be hard to match pharmacologically.”

Both summaries are worth reading if exercise research is of interest.

While this may be a good day to go to the gym, this is probably not a good day to exercise outdoors.

Stay cool,
Robin

Falls and Dysphagia (new publication co-authored by BSN)

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This post will be of interest to those dealing with falls and/or dysphagia (swallowing difficulty).

Local support group member Phil Myers and I co-authored a case study on falls and dysphagia in the latest issue of the Association of Frontotemporal Degeneration (AFTD) newsletter.  The case study is about “Jackie Riddle” — a composite of my father’s PSP symptoms (confirmed through brain donation) and Phil’s wife Jackie’s PSP symptoms (also autopsy-confirmed).  Though “Jackie Riddle” had PSP, since the focus of the case study is on falls and dysphagia, all of our BSN group members, regardless of diagnosis, will find something of value here.

The newsletter is written for healthcare professionals but I’m fairly certain the language is understandable.  We assumed that healthcare professionals are completely un-knowledgeable about PSP, fall prevention, and treatment of dysphagia.

There are also sections in the newsletter specifically for healthcare professionals working at care facilities.  So if any of you has a loved one in a care facility, those sections may be particularly helpful for staff.

The last two pages of the newsletter are my ideas for practical things that can be done about falls and dysphagia.  Again, though it’s titled “in PSP,” these ideas apply to all four disorders in our BSN group.

Check it out; it’s hot off the presses:

www.theaftd.org/wp-content/uploads/2015/07/PinFTDcare_Newsletter_summer_2015.pdf

Robin

“Could a vitamin or mineral deficiency be behind your fatigue?” (short article, Harvard)

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Fatigue can be a symptom in all of the disorders in our local support group.  Today’s Healthbeat email from the Harvard Medical School points to one mineral and two vitamin deficiencies that may cause fatigue.  It might be worth having an MD check one’s vitamin levels to rule these out as problems if fatigue is present.

Robin

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Excerpts from

Could a vitamin or mineral deficiency be behind your fatigue?

Healthbeat
Harvard Medical School
August 1, 2015

The world moves at a hectic pace these days. If you feel like you’re constantly running on empty, you’re not alone. Many people say that they just don’t have the energy they need to accomplish all they need to. Sometimes the cause of fatigue is obvious — for example, getting over the flu or falling short on sleep. Sometimes a vitamin deficiency is part of the problem. It might be worth asking your doctor to check a few vitamin levels, such as the three we’ve listed below.

* Iron. Anemia occurs when there aren’t enough red blood cells to meet the body’s need for oxygen, or when these cells don’t carry enough of an important protein called hemoglobin. Fatigue is usually the first sign of anemia. A blood test to measure the number of red blood cells and amount of hemoglobin can tell if you have anemia. The first step in shoring up your body’s iron supply is with iron-rich foods (such as red meat, eggs, rice, and beans) or, with your doctor’s okay, over-the-counter supplements.

* Vitamin B12. Your body needs sufficient vitamin B12 in order to produce healthy red blood cells.  So a deficiency in this vitamin can also cause anemia. The main sources of B12 are meat and dairy products, so many people get enough through diet alone. However, it becomes harder for the body to absorb B12 as you get older, and some illnesses (for example, inflammatory bowel disease) can also impair absorption. Many vegetarians and vegans become deficient in B12 because they don’t eat meat or dairy. When B12 deficiency is diet-related, oral supplements and dietary changes to increase B12 intake usually do the trick. Other causes of B12 deficiency are usually treated with regular injections of vitamin B12.

* Vitamin D. A deficit of this vitamin can sap bone and muscle strength. This vitamin is unique in that your body can produce it when your skin is exposed to sunlight, but there also aren’t many natural food sources of it. You can find it in some types of fish (such as tuna and salmon) and in fortified products such as milk, orange juice, and breakfast cereals. Supplements are another way to ensure you’re getting enough vitamin D (note that the D3 form is easier to absorb than other forms of vitamin D).

“When DLB, PD, and PSP masquerade as MSA” (Mayo autopsy study)

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We’ve been waiting for this sort of article to be published for a long time.  And we need similar articles for all the disorders in our group, not just MSA.  The article calls into question diagnostic criteria (for PD and PSP) and calls into question assumptions made by clinicians (for MSA and PD).

A fascinating article was published in the journal Neurology this week.  It’s from Mayo researchers and focuses on 134 patients who had clinical diagnoses of MSA and donated their brains between 1998 and 2014.  As you may know, Brain Support Network helps people nationally donate a loved one’s brain. We were responsible for about 25% of those 134 (clinical) MSA brain donations!

Of the 134, 125 had adequate medical records to review.  (It’s so important to provide complete medical records when you are donating a loved one’s brain!  Sadly, not everyone does.)  Of the 134 patients, only 62% actually had MSA upon brain autopsy!  The most common misdiagnosis was DLB (37% – wow!), followed by PSP (29%) and Parkinson’s Disease (15%).  (18% had other diagnoses including CBD and vascular parkinsonism.)

Those who actually had DLB and PD, not MSA, had autonomic failure — which is what led the clinicians astray in their diagnosis.  (According to the PD diagnostic criteria, severe dysautonomia in early stages is an exclusionary criteria.)

Those who actually had PSP, not MSA, had cerebellar ataxia — which is what led the clinicians astray in their diagnosis.  (According to the PSP diagnostic criteria, cerebellar ataxia is an exclusionary criteria.)  Apparently, there is an atypical form of PSP called PSP-cerebellar.  The authors note that a recent study “has shown that older onset, early falls, and vertical gaze palsy without dysautonomia may differentiate PSP-C from MSA-C.”

We have certainly seen this in our local support group — people diagnosed with MSA but it turns out they have DLB, PD, or PSP.  Happens all the time.  In our local sample, the diagnostic accuracy is closer to 50%.  Clinicians do not seem to understand that:

(a) autonomic failure can occur in DLB,

(b) hallucinations and dementia do not occur in MSA, and

(c) poor tolerance of levodopa is not the same thing as poor response to levodopa.

The diagnostic accuracy was not different between general neurologists and movement disorder specialists.

Retrospectively, the 125 patients with clinical records were diagnosed with probable MSA, possible MSA, or unknown.  49 patients met the criteria for probable MSA, 35 for possible MSA, and the remaining 41 were not assigned due to lack of clinical information (such as whether the patient was responsive to levodopa).  Of those with probable MSA or possible MSA, the diagnostic accuracy was 71% and only 60% respectively.

The authors note that “Correctly diagnosed patients with MSA had a younger age at onset and age at death than patients with PD or PSP.”  Duration of symptoms wasn’t different.

The authors looked at frequency of clinical features among the various confirmed diagnoses.

“Comparing MSA and DLB, urinary incontinence, limb ataxia, nystagmus, and pyramidal signs were more frequent in MSA. Cognitive impairment and visual hallucinations were more frequent in DLB. Comparing MSA and PD, urinary incontinence was less frequent and visual hallucinations were more frequent in PD. Comparing MSA and PSP, urinary incontinence, constipation, orthostatic hypotension, and RBD were more frequent in MSA. Vertical gaze palsy was more frequent in PSP. Frequency of levodopa responsiveness and average Mini-Mental State Examination score were not different among the groups.”

This aspect of “levodopa responsiveness” is interesting to me because we are always told that one symptom of MSA, PSP, DLB, and CBD is that there’s either no or a poor response to levodopa, as compared to PD.  I asked Dr. Neng Huang, BSN’s medical advisor, about this recently as we have a local group member whose husband was diagnosed with MSA during life but PD on brain autopsy.  Dr. Huang pointed out that “poor tolerance” of levodopa is not the same thing as “poor response.”  Many people have side effects when taking levodopa and want to discontinue it.  This seems to be viewed in the movement disorder specialist’s mind as being non-responsive rather than poor-tolerance.

The abstract makes an interesting statement about DLB.  Apparently not everyone with DLB confirmed through autopsy had dementia during life!  If someone doesn’t have dementia, they don’t qualify for a DLB diagnosis during life.  The authors wonder if the cognitive impairment was overlooked because few of the DLB-masquerading-as-MSA patients had neuropsychological evaluations.

The researchers point out that a 62% diagnostic accuracy isn’t adequate for either patient care or MSA research.  Obviously, we won’t have success with MSA research if only 62% of the participants actually have MSA!

Those are the highlights.  The abstract is copied below.  You can now find the full paper for free online:

www.ncbi.nlm.nih.gov/pmc/articles/PMC4534078/

Robin

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Here’s the abstract:

Neurology. 2015 Jul 2.  [Epub ahead of print]

When DLB, PD, and PSP masquerade as MSA: An autopsy study of 134 patients.

Koga S, Aoki N, Uitti RJ, van Gerpen JA, Cheshire WP, Josephs KA, Wszolek ZK, Langston JW, Dickson DW.

OBJECTIVE:
To determine ways to improve diagnostic accuracy of multiple system atrophy (MSA), we assessed the diagnostic process in patients who came to autopsy with antemortem diagnosis of MSA by comparing clinical and pathologic features between those who proved to have MSA and those who did not. We focus on likely explanations for misdiagnosis.

METHODS:
This is a retrospective review of 134 consecutive patients with an antemortem clinical diagnosis of MSA who came to autopsy with neuropathologic evaluation of the brain. Of the 134 patients, 125 had adequate medical records for review. Clinical and pathologic features were compared between patients with autopsy-confirmed MSA and those with other pathologic diagnoses, including dementia with Lewy bodies (DLB), Parkinson disease (PD), and progressive supranuclear palsy (PSP).

RESULTS:
Of the 134 patients with clinically diagnosed MSA, 83 (62%) had the correct diagnosis at autopsy. Pathologically confirmed DLB was the most common misdiagnosis, followed by PSP and PD. Despite meeting pathologic criteria for intermediate to high likelihood of DLB, several patients with DLB did not have dementia and none had significant Alzheimer-type pathology. Autonomic failure was the leading cause of misdiagnosis in DLB and PD, and cerebellar ataxia was the leading cause of misdiagnosis in PSP.

CONCLUSIONS:
The diagnostic accuracy for MSA was suboptimal in this autopsy study. Pathologically confirmed DLB, PD, and PSP were the most common diseases to masquerade as MSA. This has significant implications not only for patient care, but also for research studies in MSA cases that do not have pathologic confirmation.

© 2015 American Academy of Neurology.
PMID: 26138942