Monthly Archives: February 2009

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

Improvement of gaze control after training/exercises

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This is a neat little study out of the Univ of Minnesota where 19 people with possible or probable PSP were part of a randomized controlled trial. Some received “balance training complemented with eye movement and visual awareness exercises” and others received balance training alone. Gaze control was assessed after week 1 and week 5. Gaze control significantly improved for the first group (who received the balance training and eye movement exercises). Presumably the goal is to combat downward gaze palsy that many with PSP have. An improvement in eye movement perhaps could lead to safer walking, easier reading, and an easier time finding food on one’s plate.
Robin

Archives of Physical Medicine & Rehabilitation. 2009 Feb;90(2):263-70.

Improvement of gaze control after balance and eye movement training in patients with progressive supranuclear palsy: a quasi-randomized controlled trial.

Zampieri C, Di Fabio RP.
Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN.

OBJECTIVE: One of the main oculomotor findings in progressive supranuclear palsy (PSP) is the inability to saccade downward. In addition, people with PSP have difficulty suppressing fixation, which may contribute to vertical gaze palsy. The objective was to investigate the effectiveness of a rehabilitation intervention tailored to enhance suppression of fixation and gaze shift in participants with PSP.

DESIGN: Controlled trial with a quasi-randomized design. Measures occurred at week 1 and 5. Researchers assessing participants were blind to the group assignments.

SETTING: Movement disorders assessment laboratory.

PARTICIPANTS: Nineteen adults with possible or probable PSP who were ambulatory for short distances and had far visual acuity of 20/80 and a Folstein Mini-Mental State score of more than 23.

INTERVENTIONS: Balance training complemented with eye movement and visual awareness exercises was compared with balance training alone.

MAIN OUTCOME MEASURES: Gaze control was assessed using a vertical Gaze Fixation Score and a Gaze Error Index.

RESULTS: Gaze control after the balance plus eye exercise significantly improved, whereas no significant improvement was observed for the group that received balance training alone.

CONCLUSIONS: These preliminary findings support the use of balance and eye movement exercises to improve gaze control in PSP.

PubMed ID#: 19236979

Improvement in gaze control after training/exercises in PSP

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This is a neat little study out of the University of Minnesota where 19 people with possible or probable progressive supranuclear palsy (PSP) were part of a randomized controlled trial.  Some received “balance training complemented with eye movement and visual awareness exercises” and others received balance training alone.  Gaze control was assessed after week 1 and week 5.  Gaze control significantly improved for the first group (who received the balance training and eye movement exercises).  Presumably the goal is to combat downward gaze palsy that many with PSP have.  An improvement in eye movement perhaps could lead to safer walking, easier reading, and an easier time finding food on one’s plate.
The abstract is copied below.
Robin
————————————–

Archives of Physical Medicine & Rehabilitation. 2009 Feb;90(2):263-70.

Improvement of gaze control after balance and eye movement training in patients with progressive supranuclear palsy: a quasi-randomized controlled trial.

Zampieri C, Di Fabio RP.
Department of Physical Medicine and Rehabilitation, University of Minnesota, Minneapolis, MN.

OBJECTIVE: One of the main oculomotor findings in progressive supranuclear palsy (PSP) is the inability to saccade downward. In addition, people with PSP have difficulty suppressing fixation, which may contribute to vertical gaze palsy. The objective was to investigate the effectiveness of a rehabilitation intervention tailored to enhance suppression of fixation and gaze shift in participants with PSP.

DESIGN: Controlled trial with a quasi-randomized design. Measures occurred at week 1 and 5. Researchers assessing participants were blind to the group assignments.

SETTING: Movement disorders assessment laboratory.

PARTICIPANTS: Nineteen adults with possible or probable PSP who were ambulatory for short distances and had far visual acuity of 20/80 and a Folstein Mini-Mental State score of more than 23.

INTERVENTIONS: Balance training complemented with eye movement and visual awareness exercises was compared with balance training alone.

MAIN OUTCOME MEASURES: Gaze control was assessed using a vertical Gaze Fixation Score and a Gaze Error Index.

RESULTS: Gaze control after the balance plus eye exercise significantly improved, whereas no significant improvement was observed for the group that received balance training alone.

CONCLUSIONS: These preliminary findings support the use of balance and eye movement exercises to improve gaze control in PSP.

PubMed ID#: 19236979  (see pubmed.gov for the abstract only)

“Core body temperature rhythm is altered” in PSP

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I don’t think this is a surprise to anyone. With the autonomic dysfunction that can come with PSP, body temperature regulation can malfunction as well. This research is out of Japan; the Japanese are world-class researchers of autonomic dysfunction.
Robin

Clinical Autonomic Research. 2009 Feb;19(1):65-68.

The core body temperature rhythm is altered in progressive supranuclear palsy.

Suzuki K, Miyamoto T, Miyamoto M, Hirata K.
Dept. of Neurology, Dokkyo Medical University, Tochigi, Japan.

We measured circadian rhythmicity in rectal temperature change and found that the amplitude of body temperature was significantly reduced in patients with progressive supranuclear palsy compared to those with Parkinson disease.

PubMed ID#: 19224326 (see pubmed.gov for this short abstract)

Using eye saccade velocity to distinguish PSP-P and PD

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This interesting research out of Germany looked at 12 cases of the RS (Richardson’s Syndrome) form of PSP, 5 cases of the PSP-P (PSP-Parkinsonism) form, 27 cases of Parkinson’s Disease, and 23 healthy controls. (It was just published on PubMed though the journal is dated Dec ’08 and the epub is dated 1/14/09.)

At the bottom of this post I’ve copied an abstract of an ’05 journal article explaining the terms RS and PSP-P. In short, “Cases of RS syndrome [make] up 54% of all cases, and [are] characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction.” “A second group of [32% are] characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson’s disease (PSP-P).”

Because PSP-P and PD are so similar in symptoms, clinicians need a way to differentiate the two disorders. The German researchers conclude that video-oculography (VOG) can be used because of the “clear-cut separation between PSP-P and [PD] obtained by measuring saccade velocity.” Typically, a neuro-ophthalmologist has the equipment to conduct a VOG.

It should be noted that none of the patients had pathologically-confirmed diagnoses, so the results may change based upon that.

Robin

Journal of Neurology. 2008 Dec;255(12):1916-1925. Epub 2009 Jan 14.

Differential diagnostic value of eye movement recording in PSP-parkinsonism, Richardson’s syndrome, and idiopathic Parkinson’s disease.

Pinkhardt EH, Jürgens R, Becker W, Valdarno F, Ludolph AC, Kassubek J.
Dept. of Neurology, University of Ulm, Ulm, Germany.

Vertical gaze palsy is a highly relevant clinical sign in parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is one of the core features in the diagnosis of this disease.

Recent studies have suggested a further differentiation of PSP in Richardson’s syndrome (RS) and PSP-parkinsonism (PSPP).

The aim of this study was to search for oculomotor abnormalities in the PSP-P subset of a sample of PSP patients and to compare these findings with those of (i) RS patients, (ii) patients with idiopathic Parkinson’s disease (IPD), and (iii) a control group. Twelve cases of RS, 5 cases of PSP-P, and 27 cases of IPD were examined by use of video-oculography (VOG) and compared to 23 healthy normal controls.

Both groups of PSP patients (RS, PSP-P) had significantly slower saccades than either IPD patients or controls, whereas no differences in saccadic eye peak velocity were found between the two PSP groups or in the comparison of IPD with controls.

RS and PSP-P were also similar to each other with regard to smooth pursuit eye movements (SPEM), with both groups having significantly lower gain than controls (except for downward pursuit); however, SPEM gain exhibited no consistent difference between PSP and IPD.

A correlation between eye movement data and clinical data (Hoehn & Yahr scale or disease duration) could not be observed.

As PSP-P patients were still in an early stage of the disease when a differentiation from IPD is difficult on clinical grounds, the clear-cut separation between PSP-P and IPD obtained by measuring saccade velocity suggests that VOG could contribute to the early differentiation between these patient groups.

PubMed ID#: 19224319 (see pubmed.gov for this same abstract)

Here’s an abstract of an important paper on PSP in 2005 that introduced the terminology RS and PSP-P:

Brain. 2005 Jun;128(Pt 6):1247-58. Epub 2005 Mar 23.

Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson’s syndrome and PSP-parkinsonism.

Williams DR, de Silva R, Paviour DC, Pittman A, Watt HC, Kilford L, Holton JL, Revesz T, Lees AJ.
The Queen Square Brain Bank for Neurological Disorders, University College London, UK.

The clinical diagnosis of progressive supranuclear palsy (PSP) relies on the identification of characteristic signs and symptoms. A proportion of pathologically diagnosed cases do not develop these classic features, prove difficult to diagnose during life and are considered as atypical PSP. The aim of this study was to examine the apparent clinical dichotomy between typical and atypical PSP, and to compare the biochemical and genetic characteristics of these groups. In 103 consecutive cases of pathologically confirmed PSP, we have identified two clinical phenotypes by factor analysis which we have named Richardson’s syndrome (RS) and PSP-parkinsonism (PSP-P). Cases of RS syndrome made up 54% of all cases, and were characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction. A second group of 33 (32%) were characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson’s disease (PSP-P). Fourteen cases (14%) could not be separated according to these criteria. In RS, two-thirds of cases were men, whereas the sex distribution in PSP-P was even. Disease duration in RS was significantly shorter (5.9 versus 9.1 years, P < 0.001) and age at death earlier (72.1 versus 75.5 years, P = 0.01) than in PSP-P. The isoform composition of insoluble tangle-tau isolated from the basal pons also differed significantly. In RS, the mean four-repeat:three-repeat tau ratio was 2.84 and in PSP-P it was 1.63 (P < 0.003). The effect of the H1,H1 PSP susceptibility genotype appeared stronger in RS than in PSP-P (odds ratio 13.2 versus 4.5). The difference in genotype frequencies between the clinical subgroups was not significant. There were no differences in apolipoprotein E genotypes. The classic clinical description of PSP, which includes supranuclear gaze palsy, early falls and dementia, does not adequately describe one-third of cases in this series of pathologically confirmed cases. We propose that PSP-P represents a second discrete clinical phenotype that needs to be clinically distinguished from classical PSP (RS). The different tau isoform deposition in the basal pons suggests that this may ultimately prove to be a discrete nosological entity.

PubMed ID#: 15788542 (see pubmed.gov for abstract only)

If you want to read the full paper published in Brain ’05, it’s available online for free here:
http://brain.oxfordjournals.org/cgi/reprint/128/6/1247
I have found that articles that are available for free are not always left online for free access. So if you want to save a copy of this article on your hard drive, do so now.