Category Archives: LBD

Can olfactory bulb biopsy distinguish PSP – MSA – PD?

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The last line of this abstract caught my eye: “It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.” In the article, the authors indicate that one of their concerns is that MSAers, misdiagnosed as having PD, will get deep brain stimulation and will be harmed by that. They say:

“It has been reported that patients with multiple system atrophy (MSA) misdiagnosed as PD have undergone placement of deep brain stimulators and have not had a lasting benefit. As the characteristic glial cytoplasmic synuclein-immunoreactive inclusions of MSA are also present and diagnostic in the olfactory bulb, as reported by Kovacs et al. (we have confirmed this finding in five MSA cases), olfactory bulb biopsy would differentiate between PD and MSA. Olfactory bulb biopsy might therefore be useful for the evaluation of candidates for surgical therapy of PD, where the risks of biopsy might be justified if it would spare non-PD subjects the greater risks associated with pallidotomy, thalamotomy, deep brain stimulation or neural transplantation.”

In one of the response letters, scientists asked specifically about PSP and MSA. The authors of the main article reply:

“The authors question whether olfactory bulb biopsy could distinguish PD from MSA or PSP, especially since Lewy bodies may be present in sparse numbers in both of the latter two conditions. We have utilized olfactory bulb alpha-synuclein stains in six MSA cases, and found all had numerous and characteristic flame-shaped glial cytoplasmic inclusions, unambiguously identifying these as MSA. It may be more difficult to distinguish PD from PSP. Our data show that 15 of 45 PSP cases had olfactory bulb Lewy bodies. Of these 15, the majority also had Lewy bodies in the brainstem and limbic region, suggesting that these subjects had both PD and PSP. Whether or not these subjects would differ in surgical outcome from those with pure PD or pure PSP is not known at this time. We are currently testing methods for detecting glial tauopathy to determine whether these might positively identify PSP subjects from olfactory bulb material.”

So an olfactory bulb biopsy — which is a relatively minor surgical procedure done while someone is alive — would differentiate PD from MSA but not PD from PSP. To increase the success rate of deep brain stimulation going forward, it sounds like researchers may require an olfactory bulb biopsy to weed out the MSAers.

And I thought the part about “testing methods for detecting glial tauopathy to determine whether these might positively identify PSP subjects from olfactory bulb material” was interesting too.

Probably not many of you will want to read the abstract (or the full paper). But if you do and you pick up a different facet, please share!

Robin

Acta Neuropatholpgica. 2009 Feb;117(2):169-74. Epub 2008 Nov 4.

Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders.

Beach TG, White CL 3rd, Hladik CL, Sabbagh MN, Connor DJ, Shill HA, Sue LI, Sasse J, Bachalakuri J, Henry-Watson J, Akiyama H, Adler CH; Arizona Parkinson’s Disease Consortium.
Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ.

Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson’s disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer’s disease with LTS (ADLS), Alzheimer’s disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson’s Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

PubMed ID#: 18982334

The comments are:

Acta Neuropathologica. 2009 Feb;117(2):213-4; author reply 217-8. Epub 2008 Nov 25.
Can olfactory bulb biopsy be justified for the diagnosis of Parkinson’s disease?
Parkkinen L, Silveira-Moriyama L, Holton JL, Lees AJ, Revesz T.
Queen Square Brain Bank for Neurological Disorders, Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK.
PubMed ID#: 19031077

Acta Neuropathologica. 2009 Feb;117(2):215-6; author reply 217-8. Epub 2008 Nov 5.
Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders.
Jellinger KA.
Institute of Clinical Neurobiology, Vienna, Austria.
PubMed ID#: 18985364

PSP/CBD Update – Diagnosis, Genetics, Treatment (Litvan ’07)

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Larry in southern California (whose wife has PSP) emailed several of the Yahoo!Groups yesterday about this August ’07 Irene Litvan article, asking if anyone knew anything about “transcranial sonography (TCS),” which is a diagnostic method mentioned in the article. Turns out that only a short paragraph of the Litvan article was on TCS. Dr. Irene Litvan is one of the top experts in the world on PSP. She’s written quite a bit on CBD and MSA as well.

This review article is an update for neurologists as to what advancements have been made in the area of diagnostic tools, genetics, and treatments for PSP, CBD, and MSA. The rest of this post is a summary of what I learned from the article. If you want more details, read the abstracts of the articles on PubMed (pubmed.gov – enter in the ID#). (A few of the full articles are available online for free. It’s mostly the harder-to-comprehend papers that are free!)

Dr. Litvan, writing in August ’07, concludes the article by saying that the field of atypical Parkinsonian disorders — diagnostic tools, genetics, and treatment — has “significantly advanced over the past year.” From a patient/family perspective, it is hard to agree with her.

DIAGNOSIS. From the article, I learned about recent studies of four diagnostic methods using “ancillary tools”:

1. TCS (transcranial sonography): TCS may help distinguish PD vs. atypicals, PD vs. MSA/PSP, MSA/PSP vs. CBD, and perhaps PSP vs. CBD, if I’m reading this correctly. PSP can be differentiated from CBD because the dilation of the third ventricule of the brain has so far only been described in PSP. This TCS study was done in Europe. TCS cannot be performed in up to 20% of patients. The study had nothing to say about LBD or about differentiating MSA from PSP. Of all the papers referenced in her review article, this is the only one labeled as “of outstanding interest” by Dr. Litvan. (PubMed ID#17189043)

2. Diffusion-weighted MRI: This method may help distinguish PSP and MSA-P. (PubMed ID#17089396)

3. T2-weighted MRI: This method may help differentiate MSA and PD. (PubMed ID#17361340)

4. Saccade tasks: This sort of diagnostic test (of saccade latencies and directional errors) would be performed by a neuro-ophthalmologist. This test may help distinguish PSP vs. CBD/PD. (PubMed ID#17124191)

GENETICS. From the article, I learned some things about genetics that I was unaware of:

* The location of a second genetic risk for PSP was identified in 2007. (This utilized brain tissue at the Mayo Jax PSP Brain Bank. PubMed ID#17357082; very challenging reading)

* The LRRK2 genetic mutation, which can be a factor in PD and DLB, is “not associated with MSA or with sporadic PSP.” (This is the genetic mutation that was discussed in the Frontline program last week on PD, “My Father, My Brother, and Me.”)

TREATMENT. And here’s what I learned about treatment:

* Because of the success (“significant gait and postural balance benefits”) of an Italian study of DBS in two locations of the brain in advanced PD patients, Dr. Litvan believes that DBS of the pedunculopontine nucleus (PPN) “may be useful in treating the balance and gait disorder in the atypical parkinsonian disorders, particularly in patients with PSP and MSA.” In fact, CurePSP is funding a study of DBS of the PPN in those with PSP in Toronto. (PubMed ID#17251240)

* Mayo Rochester is studying respiratory dysfunction in MSA. (PubMed ID#17235127; very challenging reading)

* Transgenic mice models are being developed for PSP, CBD, and MSA.

What follows are the abstract of the article.

Robin

Current Opinion in Neurology. 2007 Aug;20(4):434-7.

Update of atypical Parkinsonian disorders.

Litvan I.
Department of Neurology, University of Louisville, Louisville, Kentucky.

PURPOSE OF REVIEW: This timely update discusses novel diagnostic approaches, recently identified genes, and innovative experimental symptomatic treatments for these devastating disorders.

RECENT FINDINGS: Differential patterns in the basal ganglia transcranial sonography, magnetic resonance diffusion-weighted imaging regional apparent diffusion coefficients in the brainstem, basal ganglia T2-weighted gradient echo sequences combined with fluid attenuated inversion recovery, or saccades error rates in single and mixed-task blocks could help differentiate the various parkinsonian disorders. In addition to the familial tauopathies (frontotemporal dementia associated with chromosome 17) presenting with an atypical parkinsonian phenotype, ‘TDP-43opathies’ and ‘tataboxbinding or ataxinopathies’, depending on the protein deposited in the brain, widen the scope of the familial atypical parkinsonian disorders. Recent identification of novel deep brain stimulation targets such as the pedunculopontine nucleus may help treat the balance and gait disorder in atypical parkinsonian disorders in the near future.

SUMMARY: These new findings are important for diagnosis, help better understanding of the nosology of these disorders, and will likely in the near future impact our clinical practice.

PubMed ID#: 17620879 (see pubmed.gov for abstract only)

Bak article on cognitive profiles – AD, PSP, CBD, MSA, DLB

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Thomas Bak from the UK wrote a great article in Nov/Dec ’06 providing the cognitive profiles of those with AD, PSP, CBD, MSA, and DLB, based upon the subtests of ACE (Addenbrooke’s Cognitive Examination).

You can find it for free online here:
http://www.acnr.co.uk/NO06/ND06_review_cog.pdf

In that article, he says:

“There are two serious problems connected with the use of MMSE in this patient group [with parkinsonian syndromes]. Firstly, MMSE has been demonstrated to be particularly insensitive to frontal-executive dysfunction, which, as will be shown below, constitutes the most common cognitive deficit in basal ganglia diseases. Secondly, based on the unitary concept of dementia, it does not examine different cognitive domains but confines itself to one global ‘dementia score’. It is, therefore, unable to determine qualitative differences between diseases.”

He advocates the use of other tests besides or in addition to the MMSE. In particular, he likes Addenbrooke’s Cognitive Examination (ACE) test, which includes verbal fluency among other cognitive batteries. He says this test “has been validated in PSP, CBD
and MSA.”

Check out Figure 1 of his short, two-page article. Figure 1 shows the impairment levels of those with (clinical diagnoses of) AD, PSP, CBD, MSA, and DLB on the various ACE subtests of Orientation, Attention, Memory, Verbal Fluencies, Language, and Visuospatial functions.

I have referred to this article in other posts but I think it deserves it’s own topic!

Dr. Gott: Seroquel not advised for elderly

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I know some of you read Dr. Gott. Here’s another MD’s opinion about Seroquel (quetiapine). Of course your MD’s opinion may be different!

http://www.montereyherald.com/health/ci_11525837

Ask Dr. Gott: Seroquel not advised for elderly
Peter Gott
Updated: 01/22/2009

Dear Dr. Gott: Please give your opinion on Seroquel being prescribed to a patient with dementia. I’ve heard it is a dangerous drug when given to the elderly, as it can cause death. Should this drug be given long term?

Dear Reader: Seroquel is a medication used to treat conditions such as bipolar disorder. It is not approved for behavioral problems related to dementia. Black-box warnings for elderly patients with a dementia-related psychosis indicate an increased risk of serious side effects, including pneumonia, heart attack, stroke and death.

The product is available in doses from 25 milligram to 300 milligram tablets or capsules by prescription only. When the drug is prescribed for the elderly, the recommended initial dose is 25 milligrams daily. Contraindications are noted for people with a history of hypertension, stroke, thyroid disorder, diabetes, high cholesterol, seizures or heart attack.

Side effects include fever, sweating, uncontrolled muscle movements, severe headaches, visual and gait disturbances, and more. Be sure to speak to the prescribing physician should any symptoms occur.

Seroquel XR extended-release tablets contain black-box warnings because of an increased mortality rate in elderly patients with dementia. XR is indicated for treatment of schizophrenia, a name given to a group of mental disorders in which a patient loses touch with reality and is unable to think or act in a rational manner. The condition is often treated with tranquilizers and specific drugs to lessen the degree of depression.

Extended-release tabs are not recommended for the elderly. Adverse reactions include dry mouth, dizziness, orthostatic hypotension, constipation, a feeling of sedation and more.

There are a number of interactions with this drug. Be sure to advise your physician of medications you are taking to ensure there will not be a negative response should he or she choose to prescribe Seroquel XR.

The long-term effectiveness (more than six weeks) has not been fully evaluated. All prescribing physicians should re-evaluate patients on a regular basis.

You are correct that the drug can be dangerous for elderly patients with dementia. I can only hope the prescribing physician fully researched all the options before prescribing it and that the dose is a reasonable one.

All patients regardless of age who are treated with antidepressants or antipsychotics for any condition should be monitored carefully for negative alterations in behavior, especially during the early stages of a new medication. Family and caregivers must be observant and should report those changes accordingly.

If you continue to have unanswered questions and have the legal right to be involved with the care of the individual in question, return to the prescribing physician with a list and request answers. If you are dissatisfied, seek a second opinion.

To give you related information, I am sending you a copy of my Health Report “Consumer Tips on Medicines.” Other readers who would like a copy should send a self-addressed, stamped No. 10 envelope and $2 to Newsletter, PO Box 167, Wickliffe, OH 44092. Be sure to mention the title.

Write to Dr. Gott c/o United Media, 200 Madison Ave., 4th fl., New York, N.Y. 10016.

LBD- Clinical; PSP- Pathological

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Curiously there were two brain donation cases I was involved in this year where the clinical DX was Lewy Body Dementia but the pathological diagnosis was PSP (with nary a Lewy body to be found).

Actually, one case was PSP + AgD (similar to Ed’s wife Rose), and the other was AD + PSP.

Neither of these patients had hallucinations, which are not required for LBD but you have to have either hallucinations or fluctuating cognition.

In the PSP + AgD case, I know the diagnosing neurologist well and am very surprised. Her reply: “humbling.”

Of course this made no difference for the treatment but always leaves people reeling in terms of expectations.