Best Post of May 2014: Primary Progressive Aphasia (non-fluent/agrammatic variant) in a patient with Pick disease

The next in our "Best of the Month" series is from May 14, 2014:

I recently performed an autopsy on a 67-year-old man had a seven-year history of progressive difficulty with halting speech. His wife described him as seeming to be “groping for words”. Three years after initial presentation, he demonstrated profound difficulty both initiating and finishing sentences. His verbal communication was marked by jumbled grammatical errors in which he put words in the wrong order and tense. For example, when asked by his neurologist to recount his activities over the day, he responded: “Go I… the grocery store… to.” He had no difficulty with naming objects or understanding their use. He had only mild amnestic deficits and no visuospatial difficulties. During the last months of his life, he began to become more rigid in his personality and more socially withdrawn. 
 
The clinical diagnosis in this patient is primary progressive aphasia, non-fluent/agrammatic variant. The pathologic diagnosis is frontotemporal lobar degeneration with 3R tau inclusions (FTLD-tau), commonly known as Pick disease.  The clinical presentation of FTLD can be divided into two types: the behavioral variant (bvFTLD) and primary progressive aphasia (PPA). Neurologists subclassify PPA into three subtypes: semantic variant (sv-PPA), non-fluent/agrammatic variant (na-PPA), and logopenic/phonologic variant (lv-PPA). While sv-PPA and na-PPA generally correspond to FTLD pathology, lv-PPA typically corresponds to Alzheimer disease (AD) pathology (and is accordingly referred to as the “language variant” of AD).  The syndrome of na-PPA is characterized by predominant language dysfunction in which there is a disordering of words in sentences, an inability to repeat complex words (e.g., saying “castaphory” when asked to repeat back the word “catastrophe”), inability to construct complex sentences, and other deficits in grammar and phonology.  In contrast, a diagnosis of sv-PPA is given to patients who exhibit a general deficit in their ability to understand word and object meaning. Patients with sv-PPA also show difficulty in naming objects and understanding what they are used for. A diagnosis of bvFTLD is ruled out as this patient only showed behavioral changes only late in the disease course

Pick disease was demonstrated pathologically by the presence of 3R tau positive Pick bodies (see photomicrograph) in the frontal and temporal lobes as well as the dentate fascia of the hippocampus, cornu Ammonis of the hippocampus, presubiculum, cingulate gyrus, insula, and inferior parietal lobe.

3R tau positive Pick body in the inferior temporal gyrus

For the practicing neuropathologist, FTLD’s are not yet classified on a molecular basis (although some day they surely will be),  but rather according to the particular protein aggregation which is detected using immunohistochemistry. The five possible FTLD subtypes, based on specific associated protein aggregations, are represented in the following table: 

FTLD type	Associated Protein Aggregation
FTLD-tau	Tau (can be further subclassified into 3-repeat [3R], 4-repeat [4R], or 3R+4R tau)
FTLD-TDP	Transactive response DNA-binding protein of 43 kDa (TDP-43)
FTLD-FUS	Fused in sarcoma (FUS)
FTLD-UPS	Ubiquitin (with UPS standing for ubiquitin-proteasome system)
FTLD-ni	No immunoreactivity

 
In 80% of cases of sv-PPA, the underlying histopathology is that of FTLD-TDP; while in the majority of na-PPA cases, the pathologic substrate is FTLD-tau.  Although not denoting a specific clinical syndrome, the term “Pick disease” has come to denote FTLD-tau, particularly referring to aggregation of the tau isoform in which there are three repeats (3R) of the phosphate-binding domain.

References:

Sieben A, Van Langenhove T, Engelborghs S, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol. 2012;124(3):353-372.

Zdenek R, Matej R. Current Concepts in the Classification and Diagnosis of Frontotemporal Lobar Degenerations: A Practical Approach. Arch Pathol Lab Med. 2014;138:132-138.

35-year-old woman who died after a presumed seizure episode

A 35-year-old woman died after a witness saw her "foaming at the mouth". A seizure was presumed to have occurred by emergency personnel. At autopsy, there was mild dilatation of the lateral and third ventricles:

This translucent mass was identified in the third ventricle:

Histological examination of the cyst contents revealed:

Although no ciliated epithelium was identified within the specimen, there were columnar cells with a pseudostratified configuration:

However, the majority of the cyst lining was flattened, simple epithelium:

Diagnosis?  (Please post to comments)
 

Dr. Peter Cummings Challenges Neuropathologists to Ice Bucket Challenge

Peter Cummings, MD

Dr. Peter Cummings has challenged his neuropathology colleagues to take the ALS ice bucket challenge. The good doctor dumps a bucket of ice water on his head in this video. If you are unfamiliar with the viral phenomenon of the ice bucket challenge, here's a New York Times article describing it. Now, grab a bucket!

Best Post of April 2014: Nobel Laureate Prusiner Tells His Story

The next in our  "Best of the Month" series is from April 8, 2014:

Just published by Yale University Press: Stanley Prusiner's new book, Madness and Memory: The Discovery of Prions - A New Biological Principle of Disease, is now available for purchase. Although I am not personally a big fan of Dr. Oliver Sacks's work, his blurb on Prusiner's book is worth reading: “Stanley Prusiner is a brilliant scientist whose boldness and tenacity enabled him, against all odds and despite near-universal skepticism, to discover and prove the importance of a new class of disease-producing agents—prions—a discovery as fundamental as that of bacteria and viruses. Prions, by subverting the brain’s own proteins, may play a crucial role in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases—and perhaps afford a clue to their prevention. Madness and Memory is the story of one of the most important discoveries in recent medical history, and it is also a vivid and compelling portrait of a life in science." Special thanks to Dr. Mark Cohen for alerting me to the publication of this new account of a seminal discovery in biological science.

The bookish Dr. Mark Cohen

Best of March 2014: Vulnerability of Glioblastoma Cells to Catastrophic Vacuolization and Death Induced by a Small Molecule

The next in our "Best of the Month" series is from March 21, 2014:

Researchers at the Karolinska Institute in Sweden have introduced what could possibly be a revolution in glioblasoma treatment. In a recent article in Cell, researchers found that molecules known as vacquinols "reliably and selectively compromised" neoplastic cell viability. Vacquinols stimulate cell death by membrane ruffling, vacuolization, and -- ultimately -- cytoplasmic membrane rupture. Although in vivo testing has been restricted to mice thus far, this paper may prove to be the beginning of a new avenue of research into the selective killing of glioblastoma cells in patients.

Best Post of February 2014: Seizing Control of Brain Seizures

The next in our Best of the Month series comes from February 27, 2014:

How can trauma lead to chronic seizures? Berkeley researcher Daniela Kaufer found that only when albumin in the blood breaches the blood-brain barrier does the likelihood of post-traumatic epilepsy go up. Accelerated signaling between neurons results from this exposure, leaduing to seizures. “We were surprised, even a little disappointed, that it was such a common component of the blood  – nothing exotic at all  – that led to epilepsy,” recalls Kaufer, associate professor of integrative biology. She and colleagues went on to

Daniela Kaufer in the lab

show that albumin interacts with a ubiquitous cell protein TGF-Beta receptor to cause the damage. In the healthy brain, TGF-Beta signaling affects activity of astrocytes, which normally limit neuron-to-neuron firing signals across the synapse. But when albumin stimulates TGF-Beta receptors, astrocytes lose some of their control. Neuron signaling then spike dangerously, and promote the development of epileptic seizures. As luck would have it, statin drugs block TGF-Beta signaling.  Kaufer is now carrying out research to confirm that blocking abnormal TGF-Beta activity can prevent epilepsy from a range of insults. “Right now, if someone comes to the emergency room with traumatic brain injury, they have a 10 to 50 percent chance of developing epilepsy. But you don’t know which ones, nor do you have a way of preventing it. And epilepsy from brain injuries is the type most unresponsive to drugs." says Kaufer. “I’m very hopeful and that our research can spare these patients the added trauma of epilepsy.”

(Thanks to Dr. Doug "Scout" Shevlin for alerting me to this potentially groundbreaking research.)

Best Post of January 2014 -- The Alzheimer Conundrum: New Book Challenges Long-Held Assumptions

Margaret Lock, PhD

The next in our Best of the Month series comes from January 16, 2014: 
Professor Margaret Lock supplies an ethnographic account of Alzheimer disease in her recent book, The Alzheimer Conundrum. Lock furnishes a comprehensive description of the events leading up to the recasting of the phenomenon of Alzheimer’s as a condition to be prevented. The author challenges traditional assumptions and statistics about Alzheimer’s and takes us on a journey from the disease’s original clinical case through the vacillations in the science world and the media regarding possible causes, diagnostics, biomarkers, genetics and cures. She questions prevalence estimates for the impending “Alzheimer’s epidemic” that has been forecast with great assurance by some interest groups. Lock raises provocative questions that extend beyond the realm of Alzheimer disease, such as: When is a disease not a disease? When is pathology normal? When does a natural entity become pathological? Worth a read for those of us who are charged with the responsibility of ultimately diagnosing Alzheimer disease at autopsy.

"In a decade, the only people who are still playing football will be African-Americans and working class people." - Sociologist Harry Edwards

Harry Edwards, PhD

The public health policy debate (in which neuropathologists are inevitably enmeshed by virtue their involvement in the diagnosis of chronic traumatic encephalopathy) has taken on a new socio-economic ramification. I was reading an article this morning about NFL-player DeSean Jackson in the July 7th issue of ESPN The Magazine when I came across a provocative insight from sociologist Harry Edwards based on recent studies showing that white families and wealthier families are more informed about football-related concussions than their non-white and poor counterparts. Edwards had this to say about the changing demographics of football: "In a decade, the only people who are still playing football will be African-Americans and working class people."  Just as boxing was once embraced by Ivy League athletes but in recent decades dismissed as barbaric, football will one day be relegated to the underclass and only appreciated as a spectator sport among middle-class white people. Unsettling, isn't it?

Best Post of December 2013: What Happened to Neuropathology in 1946

The next in our 'Best of the Month' series is from December 3, 2013. Since posting, three readers posted comments speculating as to what indeed did happen to neuropathology in 1946. See comments after the post below:

What happened to neuropathology in 1946?

The esteemed Dr. Jim Mandell and his son were recently playing with the amazing Google Books Ngram Viewer. Google Ngram searches a huge corpus of books for the mention of a particular search term. It then graphs the frequency with which that term appears over time. On a whim, the Mandell's entered the search term "neuropathologist". Here's the resulting graph:

I couldn't fit the y-axis label in the picture, but it ranges from 0% up to 0.00000300%. Dr. Mandell challenges his neuropathology colleagues to explain the sharp spike in the usage of "neuropathologist" around 1946-47. Please enter your speculations in the comment section. Dr. Mandell also points out the lamentable fact that it "appears we are past our peak".
______________

Gabrielle Yeaney said...

Not sure if I'm on to something but ...in 1946--certification in pathology was formally recognized, CAP was founded and in 1947--first stereotactic neurosurgical procedure performed. In the early 1940s, AMA recognized pathology as practice of medicine (1943);first neurosurgical training programs and American board of Neurological surgery established. Bernd Scheithauer was born in 1946. Maybe he started publishing at a very early age :) Thanks for the blog

jd said...

JNEN began in 1942.

shipcolldoc said...

It is likely just because WW II was over and a lot of medicine-related terminology other than war trauma would have come to the fore.

3D print of white matter "captures a sense of delicate complexity that evokes a sense of wonder about the brain"

Creating an accurate 3D model of the brain's white matter for Philadelphia's Franklin Institute was a project no 3D printing company would tackle -- until 3D Systems (Rock Hill, SC) agreed to take it on. Here is an image of the finished project, which took about 210 hours to print out:

Interviewed for the tech website CNET, Franklin Institute chief bioscientist and lead exhibit developer Dr Jayatri Das said that the model "has really become one of the iconic pieces of the exhibit. Its sheer aesthetic beauty takes your breath away and transforms the exhibit space," said . "The fact that it comes from real data adds a level of authenticity to the science that we are presenting. But even if you don't quite understand what it shows, it captures a sense of delicate complexity that evokes a sense of wonder about the brain."

Thanks to the illustrious Dr. Doug Shevlin for informing me of this remarkable feat of engineering which, in his words, sits at "the intersection of neuroscience, computers and 3D printing".

2nd Edition of "Biopsy Diagnosis of Peripheral Neuropathy" to be released August 31, 2014

The second edition of Biopsy Diagnosis of Peripheral Neuropathy by Drs. Juan M. Bilbao and Robert E. Schmidt is set to come out on August 31, 2014. The is from the book's description from amazon.com:
"This book presents a simple, logical method for constructing a differential diagnosis based on pathology and clinical presentation. It also provides advice on the selection of ancillary molecular, immunohistochemical and genetic techniques to establish a definitive diagnosis. Clear, authoritative guidance is offered on diagnosis of the full range of neuropathies with the aid of a wealth of high-quality color photomicrographs and electron micrographs. The pathologist will benefit greatly from the identification of a variety of artifacts and normal structures occasionally encountered in nerve biopsies that need to be distinguished from specific pathologic alterations"

The first edition, also co-authored by Bilbao, was released back in 1995. Given the advent of new diagnoses and techniques of analysis and the impact of molecular genetics, there is without doubt a dire need for this book, which is authored by well-established authorities in the field.

Thanks to the inimitable Dr. Mark Cohen for alerting me to the imminent release of this text.