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 During the last months of his life, he began to become more rigid in his personality and more socially withdrawn.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

The International Society for Frontotemporal Dementias has been founded

The following is an email sent out this week from Bernardino Ghetti, MD, neuropathologist at Indiana University:

Dear Friends,

Bernardino Ghetti, MD

In October 2010, I had the distinct privilege to host the 7^th International Conference on Frontotemporal Dementias in Indianapolis, Indiana.  Hundreds of you from around the world participated in this exciting meeting.

While the social relevance of frontotemporal dementia (FTD) is recognized, we have lacked a scientific international society devoted to the exchange of knowledge on FTD, facilitation of scientific cooperation, promotion of education, and planning of logistics and financial support.  As you may remember, the idea of organizing an international scientific society of FTD researchers was launched during the 7^th International Conference.  This concept obtained an enthusiastic response.

Since that time, many of you have been asking about the status of the society.  I am happy to announce that the legal documents have been filed and the International Society for Frontotemporal Dementias has been founded.  The current board of directors is composed of the following scientists:

Arne Brun MD, PhD                David Knopman MD

Emanuele Buratti PhD             Ian Mackenzie MD

Bernardino Ghetti MD             Marsel Mesulam MD

Murray Grossman MD             Bruce Miller MD

Lars Gustafson MD, PhD         Manuela Neumann MD

John Hodges MD, PhD            Rosa Rademakers PhD

Andrew Kertesz MD                Julie Snowden PhD

                                                                         John van Swieten MD

There is still work to be done, but the society is taking shape and we are currently looking for funding to support a website.  The society will facilitate scientific exchanges between researchers involved in all areas of clinical and basic neuroscience related to frontotemporal dementias and promote scientific discoveries.  As we prepare to open the society for membership, our hope is to reach all of you who have been an active part of the progress for the understanding of FTD and the care of people affected by this devastating disease. Our next step is to develop a website and facilitate the application for membership.  The membership fee will be $200.  Please let us know if you are interested in being a part of the International Society for Frontotemporal Dementias, or would also be interested in serving as part of a committee. 

I am truly convinced that this is a necessary step for the advancement of our knowledge of FTD.  I look forward to working with you in the future.

Regards,

Bernardino Ghetti, MD

For the Board of the International Society for Frontotemporal Dementias

The International Society for Frontotemporal Dementias can be reached at isftd.org@gmail.com

Attractive Neuropathology Postdoc Position in Neurodegenerative Disease Now Available at UCSF

Lea T. Grinberg, MD, PhD.

I recently received an email from Lea T. Grinberg, MD, PhD, a neuropathologist originally from Sao Paulo, Brazil now working at UCSF. She is recruiting a postdoc to work with her. Dr. Grinberg specializes in aging and neurodegenerative diseases and was recently awarded an R01 grant to study early stages of AD and FTLD-TDP in postmortem human tissue. She has access to a large brain bank associated with the Brazilian Aging Brain Study Group as well as the UCSF Memory and Aging Center brain bank. The postdoc will learn state-of-the-art methods for studying human post mortem brains, such as stereology, immunohistochemistry and fluorescence, computer assisted 3D reconstruction, and whole brain processing. She writes of the UCSF Memory and Aging Center: "We are a team of 150 individuals and the division promotes weekly grand rounds, journal clubs, lab meetings and regular CPC sessions. I believe it is an excellent opportunity for a young neuropathologist aiming to have a career in neurodegenerative disease."

I would say so! Here's the official job listing:

Post Doctoral Position in Neurodegenerative Diseases

NIH-supported post-doctoral position is immediately available for a qualified and highly motivated researcher to study early stages of neurodegenerative disease in human postmortem tissue

The fellow will pursue a series of related experiments regarding brain areas involved in very early clinical stages of Alzheimer’s disease and frontotemporal dementia. The successful candidate will have access to very difficult to get tissue belonging to cognitively normal elderly who already showed neurodegenerative changes in the brain. In addition, the fellow will be trained in state-of-the-art neuropathological/neuroanatomical processing and sophisticated graphic and reconstruction software. The fellow will have the opportunity of further participate in ongoing experimental studies.

Preferred Qualifications
Strong interest in neurodegenerative disease

Training in quantitative neuropathology or neuropathology is a plus.

This project is part of a close collaboration with other groups; therefore, candidates must have the ability to work in an international team, show organizational skills, and be driven by an interest in a multidisciplinary research setting

Applicants should possess a recent (within last three years) MD or PhD degree in the neuropathology/neuroanatomy/ neurosiciences with strong experience in stereology.

Applicants should send a CV and 3 letters of recommendation to Dr. Grinberg lea.grinberg@ucsf.edu

A Snapshot of the people behind the brains we autopsy

A Rhode Island patient with frontotemporal dementia.

Best Post of August '08: Loss of von Economo neurons may be associated with frontotemporal dementia

And now for another in my occasional “Best of the Month” series, where I march through the past months choosing only the very best blog posts. Since publishing this post, I have been looking for von Economo neurons in my autopsy cases. I believe that I have come upon three in a row, as depicted in the following photomicrograph from the the right anterior cingulate gyrus of an Alzheimer patient. As you can see, von Economo neurons are huge spindle-shaped neurons. (Compare their size to nearby pyramidal neurons):

With that update, I now present my "Best of the Month" post for August '08:

On Wednesday [Aug 6 '08], I wrote about the fact that the brains of gorillas weigh only about 40% as much as human brains. There is, however, one way in which our brains are similar to simians: the presence of the von Economo neuron (VEN).

Constantin von Economo demonstrated in the 1920’s that these neurons are present only in the anterior cingulate and insular cortices (layer Vb). It was later determined that VENs are only present in hominids (humans and great apes), and that they are more numerous on the right side of the brain. Also referred to as spindle neurons because of their spindle-shaped cell bodies, VENs are larger than pyramidal neurons and tend to cluster parallel to small arterioles (pictured on right as compared to pyramidal neuron). More recently, it was found that VENs are also present in various species of whales and in elephants. The common theme here is that VENs are present in social animals with large brains. Since the VEN-populated areas of the brain are preferentially affected in frontotemporal dementia (FTD), it is thought that perhaps loss of these neurons may be related to the aberrant social functioning seen in FTD patients.

Loss of von Economo neurons may be associated with frontotemporal dementia

On Wednesday, I wrote about the fact that the brains of gorillas weigh only about 40% as much as human brains. There is, however, one way in which our brains are similar to simians: the presence of the von Economo neuron (VEN).

Constantin von Economo demonstrated in the 1920’s that these neurons are present only in the anterior cingulate and insular cortices (layer Vb). It was later determined that VENs are only present in hominids (humans and great apes), and that they are more numerous on the right side of the brain. Also referred to as spindle neurons because of their spindle-shaped cell bodies, VENs are larger than pyramidal neurons and tend to cluster parallel to small arterioles (pictured on right as compared to pyramidal neuron). More recently, it was found that VENs are also present in various species of whales and in elephants. The common theme here is that VENs are present in social animals with large brains. Since the VEN-populated areas of the brain are preferentially affected in frontotemporal dementia (FTD), it is thought that perhaps loss of these neurons may be related to the aberrant social functioning seen in FTD patients.

Wednesday: My last day at the AAN annual meeting

I'm currently at an evening conference entitled: "Case Studies in Dementia". This will be my last engagement at the meeting. My family and I leave tomorrow morning for a 3+ hour train ride back to Springfield, IL. Tonight's program features: Dr. Richard Caselli of the Mayo Clinic Scottsdale; Dr. Jody Corey-Bloom from UCSD; and Dr. Ronald Petersen of the Mayo Clinic Rochester. Cory-Bloom started off with a case of a 33 yo female with a one year history of cognitive difficulty. Her boyfriend described reduced speech alternating at other times with incessant speech. The Boston Naming Test showed difficulty with word finding. There was no deficit in memory. Brain MRI showed mild frontal atrophy. Two years later, the patient is now almost mute, with echolalia. She is very oral, and very disinhibited, and paces incessantly. She is also compulsive about routines. Dr. Corey-Bloom feels that the patient has frontotemporal lobar degeneration (the behavioral variant). The other two types of frontotemporal lobar degeneration, as described by Neary, are progressive nonfluent aphasia and semantic dementia. (Semantic dementia is where the patient has fluent speech with loss of meaning. They can also have mental rigidity and a cold affect.) Corey-Bloom went on to talk about FTDP-17, and the recent discovery of the two genetic subtypes: MAPT mutation and Progranulin mutation. Corey-Bloom says that the only treatment for FTLD is aimed at the behavioral symptoms (SSRIs and anti-psychotics).

Dr. Caselli presented a case of a 46 yo woman with a five-month personality change with increased libido, increased wine consumption, chain smoking, erratic sleep patterns, and a fixation on consuming candy mints. She had five seizures witnessed by her physician husband. MRI showed no frontal atrophy and was essentially normal. I raised my hand when there was a call for differential diagnosis, I suggested a low-grade brain tumor. Other people suggested various encephalitides. Brain biopsy showed Nonvasculitic Autoimmune Inflammatory Meningoencephalitis (Caselli doesn't like the term Hashimoto's Encephalitis since these patients don't have serum anti-thyroid antibodies). What was unusual here was that the diffuse process caused a focal (frontal) clinical presentation.

Dr. Petersen presented a case of a patient with a clinical picture of FTLD who, upon imaging for amyloid using PET scanning for Pittsburgh compound B (PiB) caused Petersen to decide that the diagnosis was more consistent with Alzheimer disease.

Frontal lobe metastases cause Phinaes Gage syndrome

I got this email from my esteemed colleague and friend, Dr. Gerald Colvin:

"Hi Brian,
Here is an addition to your blog from your esteemed colleague and friend. This patient has metastatic non-small cell lung carcinoma and presented to us with mental status changes. He was found to have bilateral frontal lobe tumors causing significant edema. What is interesting about this case was that he has personality changes reminded me of those of Phineas P. Gage was reported to have. Gage's remains I believe are housed in Boston. I did see something on display in a London museum when I was there a million years ago
Ger-"

Most of us know the story of the railroad construction foreman Phineas Gage, who, in 1848, suffered an accident on the job which resulted in a 13-pound iron rod shooting through the front of his brain. Gage survived the accident, and lived 11 years more. But he was never the same. His physician, Dr. Harlow, describes Phineas some time after the accident as “fitful, irreverent, indulging at times in the grossest profanity (which was not previously his custom), manifesting but little deference for his fellows, impatient of restraint or advice when it conflicts with his desires.” (Reference: Phineas Gage: A Gruesome But True Story About Brain Science by John Fleischman, HMCo Children’s Books, 2004).

The Ice Pick Lobotomy

My wife, Jennifer, and I recently watched a PBS documentary called “The Lobotomist”, which explores the background of the procedure popularization during the 1940’s through the ‘60’s of the prefrontal lobotomy. The neurologist Walter J. Freeman of Washington, DC was primarily responsible for the widespread performance of this surgery in the United States by developing the 10-minute, outpatient “ice pick lobotomy”. Quite literally, an ice pick was inserted beneath the eyelid and over the eyeball of a patient who was rendered temporarily unconscious by electroshock. When the instrument hit the thin orbital plate of the frontal bone, a few taps with a mallet would allow entrance into the intracranial cavity. The ice pick was then advanced upward, after which it was swept back and forth like a windshield wiper blade. The instrument was then extracted and the procedure was repeated on the opposite side. Approximately 30,000 of these procedures were performed before the medical establishment decided that it was ill-advised.

These procedures were designed to sever the connections of the brain with the prefrontal cortex (the anterior-most portion of the frontal lobes, not including the motor and premotor gyri, which does not cause movements when stimulated by electodes). Patients were left with varying degrees of abulia, but with no motor deficits.