2010 MEETING, PHILADELPHIA AMERICAN ASSOCIATION OF NEUROPATHOLOGISTS DSS CASE # 11 J-M BILBAO, B YOUNG and N LIU SUNNYBR

1. 2010 MEETING, PHILADELPHIA AMERICAN ASSOCIATION OF NEUROPATHOLOGISTS DSS CASE # 11 J-M BILBAO, B YOUNG and N LIU SUNNYBROOK HOSPITAL UNIVERSITY OF TORONTO

2. This male patient died after an episode of cardio-respiratory failure during a swallowing evaluation on June 17, 2009 In 2005 at the age of 56 years he experienced the onset of partial complex seizures. MRI showed asymmetry of mesial temporal lobes, and a cerebellar hemangioblastoma. Born in Austria he had an Engineering degree and ran his own business. His mother had died of ALS. There was no history of alcoholism. A long and progressive neurological-psychiatric history began to evolve including insomnia, passive suicidal ideation, panic attacks, tremors, agitation, unsteady gait, urinary incontinence, decreased social interaction, decrease of interest, obsessions (writing down what he eats and how much he sleeps), weight loss attributed to compulsive exercising with no loss of appetite, and low sex drive. Seizure activity was difficult to control with a variety of drugs A vast number of hematological, biochemical and radiological studies were undertaken with negative results.

3. May 2009: “he can not function without his wife, has major memory problems and was cognitively impaired and unable to drive”. Patient did not show lack of inhibition. His speech remained fluent and there were no abnormal movements or Parkinsonism. Beginning on June 2009 he began to suffer choking episodes. During a swallowing assessment he had a cardiac arrest and died on June 2009 aged 61 years. At autopsy the brain weighted 1550 grams. No significant atrophy was demonstrable. A cyst measuring 3.5 X 3 cm was found in one cerebellar hemisphere with an attached nodule having the histological appearance of hemangioblastoma

4. tau, AT8 IMMUNOSTAINS AND GALLYAS Ag IMPREGNATION: • INCIPIENT AgG DISEASE • ALPHA SYNUCLEIN IMMUNOSTAIN: • SIGNIFICANT LEWY PATHOLOGY IN NIGRA WITH EARLY • LIMBIC INVOLVEMENT • TDP-43 IMMUNOSTAIN: • PROTEINOPATHY IN HIPPOCAMPUS, ENTORHINAL AREA • AND AMYGDALA • **NO POSITIVITY FOR tau, ALPHA-SYNUCLEIN, FUS, INTERNEXIN • AND TDP-43 WAS OBSERVED IN CEREBRAL NEOCORTEX.

6. PRETANGLES

7. Highly branched (bush-like) Astrocytes; non Ag

10. tau, AT8 IMMUNOSTAINS AND GALLYAS Ag IMPREGNATION: • INCIPIENT AgG DISEASE • ALPHA SYNUCLEIN IMMUNOSTAIN: • SIGNIFICANT LEWY PATHOLOGY IN NIGRA WITH EARLY • LIMBIC INVOLVEMENT • TDP-43 IMMUNOSTAIN: • PROTEINOPATHY IN HIPPOCAMPUS, ENTORHINAL AREA • AND AMYGDALA • **NO POSITIVITY FOR tau, ALPHA-SYNUCLEIN, FUS, INTERNEXIN • AND TDP-43 WAS OBSERVED IN CEREBRAL NEOCORTEX.

11. ADDITIONAL IMMUNOSTAIN UNVEILED THE PRESENCE OF A FOURTH DEGENERATIVE PROCESS: WIDESPREAD IN NEOCORTEX, CEREBELLUM AND HIPPOCAMPUS AND TO A LESSER DEGREE IN THALAMUS AND BASAL GANGLIA QUESTIONS COMMENTS

13. Sensory-motor

15. gyrus

21. Specific pathological changes associated with most frontotemporal lobar degenerations (FTLD) consist of protein aggregates that can be characterized by IHC in neurons and occasionally glial cells. FTLD with tau or TDP-43 or FUS pathology are designated as FTLD-tau, FTLD-TDP and FTLD-FUS, respectively. A small number of FTLD cases with inclusions of a protein that can not be identified and that can only be unveiled by immunostaining against the proteins of the ubiquitin proteasome system (UPS) are classified as FTLD-UPS. ** Negativity for INTERNEXIN and FUS immunostains rules NEURONAL INTERMEDIATE FILAMENT INCLUSION DISEASE AND BASOPHILIC INCLUSION BODY DISEASE Dx: FRONTO TEMPORAL LOBAR DEGENERATION (UPS) WITH CEREBELLAR INVOLVEMENT * Non-argyrophilic, tau negative, TDP-43 negative, Internexin negative and FUS negative.

22. Neuropathology of FTD other *aFTLD-UPS *DLDH *CHMP2B ● aFTLD-U ● NIFID ● BIBD FTLD-FUS FTLD: tau ●PiD ●CBD ●PSP ●AGD ●MSTD ●MAPT FTLD:TDP-43 FTLD-U (type 1, 2, 3)●FTD+ALS ●GRN ●VCP ●chrom 9p α-synucleopathy Mackenzie 2010

23. KING A, AL-SRRAJ S AND SHAW C. FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUINATED TAU-NEGATIVE INCLUSIONS AND ADDITIONAL α-SYNUCLEIN PATHOLOGY BUT ALSO UNUSUAL CEREBELLAR UBIQUITINATED p62-POSITIVE, TDP-43 NEGATIVE INCLUSIONS NEUROPATHOLOGY 2009; 29, 466-471 PIKKARAINEN M, HARTIKAINEN P AND ALAFUZOFF I. NEUROPATHOLOGICAL FEATURES OF FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONS VISUALIZED WITH UBIQUITIN-BINDING PROTEIN p62 IMMUNOHISTOCHEMISTRY J NEUROPATHOL EXP NEUROL 2008, pp280-298 LETTER TO THE EDITOR (PIKKARAINEN, HARTIKAINEN ALAFUZOFF) UBIQUINATED p62-POSITIVE, TDP-43-NEGATIVE INCLUSIONS IN THE CEREBELLUM IN FTLD WITH TAR DNA BINDING PROTEIN 43 NEUROPATHOLOGY 2010; 30, 197-199