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 Simulated brain biopsy vs. autopsy-confirmed diagnoses 
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Joined: Fri Aug 11, 2006 1:46 pm
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Post Simulated brain biopsy vs. autopsy-confirmed diagnoses
Years ago I remember hearing that someone in Boston arranged for her mother to have a brain biopsy -- this is where a small piece of brain tissue is removed while the patient is alive. It was done for the purpose of diagnosing what sort of dementia the mother had. Lewy bodies were found in the part of the brain examined. It was never clear to me why anyone would allow a loved one's brain to be biopsied in this manner, given the risks of this procedure. Was the treatment going to change based upon the findings of the biopsy? Nor was it clear how good a picture the biopsy gave of the pathologies in the brain. For example, if Lewy bodies were in that part of the brain, did that mean that the mother had Parkinson's Disease (a Lewy body disease) or Lewy Body Dementia (also a Lewy body disease). And, did that mean that the mother did not have Alzheimer's pathology? Could a biopsy reveal if the mother had vascular dementia? (I doubt it.) Were tests run for the many rare disorders that cause parkinsonism and dementia, such as FTLD-TDP? (I doubt it.) Most of the neuropathology reports that I see indicate that a brain donor has multiple pathologies, not just one.

An abstract published yesterday by researchers at UPenn addresses some of these questions. Researchers removed tissue from 73 cases where the patient's brain was donated upon death. (This research is only possible if families donate the brains of their loved ones upon death.) The 73 cases included Alzheimer's disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration-TDP43 (FTLD-TDP), multiple system atrophy (MSA), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). Again, "LBD" in this article refers to Lewy body disease, which includes both Parkinson's Disease and Lewy Body Dementia.

Tissue was removed from four brain regions -- frontal cortex, temporal cortex, parietal cortex, and the basal ganglia, which controls movement. (I'm curious as to whether it's even more dangerous to biopsy tissue from the basal ganglia as compared to the cortex, which is the outer part of the brain.)

"Brain biopsy was simulated in a blinded manner by masking each slide with opaque tape except for an area measuring 10 mm in diameter."

"Diagnoses obtained from frontal cortex only or all 4-brain regions were then compared with autopsy diagnoses." Researchers found:

* "Diagnostic sensitivity in frontal cortex was highest in FTLD-TDP (88%), AD (80%) and LBD (79%); intermediate for MSA (71%), CBD (66%) and PiD (66%) and lowest for PSP (0%) (average 64%). Specificity was 43%."

* "Sensitivities were enhanced with all 4-brain regions: FTLD-TDP (100%), AD (80%), LBD (100%), MSA (100%), CBD (83%), PiD (100%) and PSP (88%) (average 92%). Specificity was 71%."

What does this mean? When tissue from all four brain regions was tested and compared to the confirmed pathological diagnosis, *all* of the cases that had LBD and MSA were detected via the brain biopsy approach. 88% of the PSP cases were detected, and 83% of the CBD cases were detected.

Those percentages for LBD, MSA, and CBD don't come close to the diagnostic accuracy of a clinical diagnosis. For one type of PSP, Richardson syndrome, the accuracy of the clinical diagnosis is 86%; so, 88% isn't a big difference.

The four brain region biopsy simulation was accurate 71% of the time on average in identifying correctly the people who did NOT have the various disorders.

The researchers conclude: "These data could inform efforts to establish criteria for biopsy diagnosis of neurodegenerative disorders to guide care of individuals who undergo biopsy for enigmatic causes of cognitive impairment or when evidence of an underlying neurodegenerative disease may influence future therapy."

Robin




Acta Neuropathologica. 2011 Sep 30. [Epub ahead of print]

Simulated brain biopsy for diagnosing neurodegeneration using autopsy-confirmed cases.

Venneti S, Robinson JL, Roy S, White MT, Baccon J, Xie SX, Trojanowski JQ.
Division of Neuropathology, Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Abstract
Risks associated with brain biopsy limit availability of tissues and the role of brain biopsy in diagnosing neurodegeneration is unclear.

We developed a simulated brain biopsy paradigm to comprehensively evaluate potential accuracy of detecting neurodegeneration in biopsies. Postmortem tissue from the frontal, temporal and parietal cortices and basal ganglia from 73 cases including Alzheimer's disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration-TDP43 (FTLD-TDP), multiple system atrophy (MSA), Pick's disease (PiD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were evaluated using H&E and immunostains.

Brain biopsy was simulated in a blinded manner by masking each slide with opaque tape except for an area measuring 10 mm in diameter.

Diagnoses obtained from frontal cortex only or all 4-brain regions were then compared with autopsy diagnoses. Diagnostic sensitivity in frontal cortex was highest in FTLD-TDP (88%), AD (80%) and LBD (79%); intermediate for MSA (71%), CBD (66%) and PiD (66%) and lowest for PSP (0%) (average 64%). Specificity was 43%. Sensitivities were enhanced with all 4-brain regions: FTLD-TDP (100%), AD (80%), LBD (100%), MSA (100%), CBD (83%), PiD (100%) and PSP (88%) (average 92%). Specificity was 71%.

Simulated brain biopsy addressed limitations of standard brain biopsies such as tissue availability and lack of autopsy confirmation of diagnoses. These data could inform efforts to establish criteria for biopsy diagnosis of neurodegenerative disorders to guide care of individuals who undergo biopsy for enigmatic causes of cognitive impairment or when evidence of an underlying neurodegenerative disease may influence future therapy.

PubMed ID#: 21959586 (see pubmed.gov for this abstract only)


Sun Oct 02, 2011 4:29 pm
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
What were the risks and how many involved in the biopsy suffered adverse effects, do you know?

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Pat [68] married to Derek [84] for 38 years; husband dx PDD/LBD 2005, probably began 2002 or earlier; late stage and in a SNF as of January 2011. Hospitalized 11/2/2013 and discharged to home Hospice. Passed away at home on 11/9/2013.


Sun Oct 02, 2011 5:22 pm
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
As for risks, I assume a biopsy of the brain is considered brain surgery though presumably it's done on an out-patient basis.

Don't know about adverse effects as I've only read the abstract.


Sun Oct 02, 2011 6:08 pm
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Joined: Thu Apr 21, 2011 9:07 pm
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
No one in this study suffered any ill effects because these were not "real" biopsies - they used only brains donated after death, and took samples that would be similar to what you would get if you did a biopsy and could only get a tiny little bit of tissue.

It is very rare to do a brain biopsy, as there really are risks, everything from infection to bleeding to brain damage. (Not common, but high risk for a procedure that may not offer a lot of added clinical benefit beyond just a really good clinician and some brain scans, as we improve the imaging techniques.) I have seen some studies where people analyzed data from brain biopsies that were done for other reasons, eg brain cancer, to get more information about Alzheimer's, for example. The reason for using these samples is that it would be unethical at this point to do a biopsy in living patients for diagnosis of dementia (at least that's my reasonably informed opinion.)

This study is interesting but I don't think it suggests that biopsies are really worthwhile at this point for any clinical purposes. I will try to take a look at the paper in next few days. My impression, though, is that it is really trying to point toward techniques that may be useful someday in the future, not for quite a while. (I do talk to the senior author every 2 weeks on conference call, so if it is not obvious from reading paper, I can ask him.)

Laurel

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Laurel - mother (97) diagnosed April, 2011, with LBD; died May, 2014.


Tue Oct 04, 2011 1:23 am
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
OK, Laurel, now it makes sense. Perhaps it would be possible to derive the necessary diagnosis post mortem without removing the brain.

_________________
Pat [68] married to Derek [84] for 38 years; husband dx PDD/LBD 2005, probably began 2002 or earlier; late stage and in a SNF as of January 2011. Hospitalized 11/2/2013 and discharged to home Hospice. Passed away at home on 11/9/2013.


Tue Oct 04, 2011 9:38 am
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
I wondered what "simulated" brain biopsy meant. Thanks, Laurel.

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Jeanne, 68 cared for husband Coy, 86. RBD for 30+ years; LDB since 2003, Coy at home, in early stage, until death in 2012


Tue Oct 04, 2011 10:16 am
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
I don't think it would make sense to do post-mortem tissue samples as that would likely require a pathologist to take the tissue from the correct areas, and then send the tissue off some place for testing. It might then be hard to find a neuropathologist to test the tissue samples.

We aren't told in the abstract the accuracy of the cases where there is mixed dementia. And, I still don't think vascular disease can be detected through these small samples.


Tue Oct 04, 2011 10:28 am
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Post Re: Simulated brain biopsy vs. autopsy-confirmed diagnoses
Yes, Laurel, brain biopsies are very rare. The only one I've heard of to diagnose dementia is the Boston case I mentioned above. And there's no diagnostic criteria for a brain biopsy for DLB so we don't really know for sure what disorder the woman had.


Tue Oct 04, 2011 10:29 am
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