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 During the last months of his life, he began to become more rigid in his personality and more socially withdrawn.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.)