Best Post of September 2018: A Case of Posterior Cortical Atrophy

The next in our "Best of the Month" series is from September 7, 2018:

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterised by progressive decline in visuospatial, visuoperceptual, literacy, and praxic skills. The progressive neurodegeneration affecting parietal, occipital, and occipitotemporal cortices that underlies PCA is attributable to Alzheimer's disease in most patients. However, alternative underlying causes, including dementia with Lewy bodies, corticobasal degeneration, and prion disease, have also been identified, and not all patients with PCA have atrophy on clinical imaging. (Crutch, S. J., Lehmann, M., Schott, J. M., Rabinovici, G. D., Rossor, M. N., & Fox, N. C. (2012). Posterior cortical atrophy. Lancet Neurology, 11(2), 170-178)

This is a case of a 60-year-old female with PCA:

Although there is diffuse neocortical atrophy, note the prominent occipital lobe atrophy

Tau stain of temporal lobe section highlights Alzheimer pathology

Pallor of the substantia nigra was noted, and Lewy bodies noted microscopically (see inset)

Alpha-synuclein staining showed neocortical Lewy bodies (here in the frontal lobe)

The final diagnosis was Alzheimer disease and Diffuse Neocortical Lewy Body Disease in the setting of Posterior Cortical Atrophy.

“Rising Star Award” in Neurodegenerative Research: Call for Submissions

The Mahoney Institute for Neurosciences (MINS) at the  University of Pennsylvania is has announced a call for submissions for its annual Rising Star Award in neuroscience research. To highlight the “Year of Neurodegenerative Research” on Penn’s campus, the award honors a young researcher for outstanding contributions to neurodegenerative research with a $10,000 personal honorarium at the MINS 35^th Annual Retreat and Symposium on April 3, 2019.

Dr. Virginia Lee

“Neurodegenerative disorders are major health problems for the elderly, and there are currently no treatments for any of these diseases,” said Virginia Lee, PhD, director of Penn’s Center for Neurodegenerative Disease and a MINS faculty member. “I am proud that there is a large research community at Penn, including MINS, at the forefront of research elucidating the etiology and pathogenesis of these devastating disorders. We look forward to honoring and facilitating a young researcher to enhance our understanding of age-related neurodegeneration and to advance future therapies.”

In addition, the 2019 award recipient will present a research seminar at the symposium and, before the seminar, a separate introductory lecture on neurodegeneration. Also at the symposium, Prof. Pietro De Camilli, Yale School of Medicine, will give the Sprague Lecture, and Prof. Beth Stevens, Harvard Medical School, will give the Adler Lecture.

Researchers who received their first advanced degree, such as the PhD, in 2005 or more recently are invited to submit a one-page description of their contributions to neurodegenerative research, full curricula vitae, and names of three references in a single PDF file by December 1, 2018, to MINSRisingStarAward@lists.upenn.edu. More information can be found at www.med.upenn.edu/ins.

A case of posterior cortical atrophy

Posterior cortical atrophy (PCA) is a neurodegenerative syndrome that is characterised by progressive decline in visuospatial, visuoperceptual, literacy, and praxic skills. The progressive neurodegeneration affecting parietal, occipital, and occipitotemporal cortices that underlies PCA is attributable to Alzheimer's disease in most patients. However, alternative underlying causes, including dementia with Lewy bodies, corticobasal degeneration, and prion disease, have also been identified, and not all patients with PCA have atrophy on clinical imaging. (Crutch, S. J., Lehmann, M., Schott, J. M., Rabinovici, G. D., Rossor, M. N., & Fox, N. C. (2012). Posterior cortical atrophy. Lancet Neurology, 11(2), 170-178)

This is a case of a 60-year-old female with PCA:

Although there is diffuse neocortical atrophy, note the prominent occipital lobe atrophy

Tau stain of temporal lobe section highlights Alzheimer pathology

Pallor of the substantia nigra was noted, and Lewy bodies noted microscopically (see inset)

Alpha-synuclein staining showed neocortical Lewy bodies (here in the frontal lobe)

The final diagnosis was Alzheimer disease and Diffuse Neocortical Lewy Body Disease in the setting of Posterior Cortical Atrophy.

A case of Alexander disease

Alexander disease is a progressive and often fatal leukodystrophy wherein innumerable Rosenthal fibers form. Caused by mutation in the gene encoding GFAP, Alexander disease can be inherited in an autosomal dominant manner, but typically arises de novo.

Cerebrum

Cerebrum

Cerebellum

Cerebellar dentate neuron undergoing grumose degeneration in a case of progressive supranuclear palsy

Bodian stain

An inquiry for the neuropathology community from two illustrious German neurologists regarding possible olivary dysgenesis

Prof. Dr. Gunther Deuschl

Prof. Dr. Olaf Jansen

 

 

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The following is an inquiry received from Prof. Dr. Günther Deuschl, Chairman of the Department of Neurology, UKSH, Christian-Albrechts University, Kiel, Germany. Please post your ideas on this case in the comments section:

Dear friends,

I have a patient presenting with  different noises: one subjectively in the thyroid region (nothing objectively), one in the region of the ear (coming erratically in groups, some resemblance to earclicks, again nothing objectively), one pulse synchronous noise (with a known neuroradiologically confirmed and treated fistula carotis to sinus cavernosus). I would have considered her to have only the latter clinical problem. All the other complaints seemed to be due to enhanced introspection without definite psychiatric diagnosis. Then the neuroradiologist (Prof. O. Jansen, Kiel University, Germany) made an MRI scan and found this curious ‘Tic-sign’ of the brain stem (you will understand when you look at the images below, which you can click on to enlarge). It shows definite circumscribed regional and bilateral atrophy of the inferior olive. Interestingly there seems to be some ‘white matter’ remaining. . Indeed an olivary agenesis or dysgenesis is one of the possibilities. The lady has no cerebellar signs as you see this sometimes (but not always) after olivary destruction.

I wonder if anybody has ever seen something like this and have an insights on a diagnosis?

Best regards for taking your time to read and see this.

Best regards,
Guenther

 

 

Primary progressive aphasia (non-fluent/agrammatic variant) in a patient with Pick disease

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.