2010 MEETING, PHILADELPHIA

AMERICAN ASSOCIATION OFNEUROPATHOLOGISTS

DSS CASE # 11

J-M BILBAO, B YOUNG and N LIU

SUNNYBROOK HOSPITALUNIVERSITY OF TORONTO

This male patient died after an episode of cardio-respiratoryfailure 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 cerebellarhemangioblastoma.

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 includinginsomnia, passive suicidal ideation, panic attacks, tremors, agitation, unsteady gait, urinary incontinence, decreased social interaction, decrease ofinterest, obsessions (writing down what he eats and how much he sleeps), weightloss 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 radiologicalstudies were undertaken with negative results.

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 arrestand died on June 2009 aged 61 years.

At autopsy the brain weighted 1550 grams. No significant atrophy wasdemonstrable. A cyst measuring 3.5 X 3 cm was found in one cerebellarhemisphere with an attached nodule having the histological appearanceof hemangioblastoma

•tau, AT8 IMMUNOSTAINS AND GALLYAS Ag IMPREGNATION:INCIPIENT AgG DISEASE

•ALPHA SYNUCLEIN IMMUNOSTAIN: SIGNIFICANT LEWY PATHOLOGY IN NIGRA WITH EARLYLIMBIC INVOLVEMENT

•TDP-43 IMMUNOSTAIN:PROTEINOPATHY IN HIPPOCAMPUS, ENTORHINAL AREAAND AMYGDALA

**NO POSITIVITY FOR tau, ALPHA-SYNUCLEIN, FUS, INTERNEXINAND TDP-43 WAS OBSERVED IN CEREBRAL NEOCORTEX.

PRETANGLES

Highly branched (bush-like)

Astrocytes; non Ag

•tau, AT8 IMMUNOSTAINS AND GALLYAS Ag IMPREGNATION:INCIPIENT AgG DISEASE

•ALPHA SYNUCLEIN IMMUNOSTAIN: SIGNIFICANT LEWY PATHOLOGY IN NIGRA WITH EARLYLIMBIC INVOLVEMENT

•TDP-43 IMMUNOSTAIN:PROTEINOPATHY IN HIPPOCAMPUS, ENTORHINAL AREAAND AMYGDALA

**NO POSITIVITY FOR tau, ALPHA-SYNUCLEIN, FUS, INTERNEXINAND TDP-43 WAS OBSERVED IN CEREBRAL NEOCORTEX.

ADDITIONAL IMMUNOSTAIN UNVEILED THE PRESENCE OF AFOURTH DEGENERATIVE PROCESS: WIDESPREAD INNEOCORTEX, CEREBELLUM AND HIPPOCAMPUS AND TO A LESSERDEGREE IN THALAMUS AND BASAL GANGLIA

QUESTIONS

COMMENTS

Sensory-motor

gyrus

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 INCLUSIONBODY DISEASE

Dx: FRONTO TEMPORAL LOBAR DEGENERATION (UPS) WITHCEREBELLAR INVOLVEMENT

* Non-argyrophilic, tau negative, TDP-43 negative, Internexin negative and FUS negative.

Neuropathology of FTD

FTLD:TDP-43

FTLD: tau

FTLD-FUS

FTLD-U (type 1, 2,

3) ●FTD+ALS ●GRN ●VCP ● chrom 9p

● aFTLD-U

● NIFID

● BIBD●PiD ●CBD ●PSP ●AGD ●MSTD ●MAPT

other

*aFTLD-UPS

*DLDH *CHMP2B

Mackenzie 2010α-synucleopathy

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 INCLUSIONSNEUROPATHOLOGY 2009; 29, 466-471

PIKKARAINEN M, HARTIKAINEN P AND ALAFUZOFF I.NEUROPATHOLOGICAL FEATURES OF FRONTOTEMPORAL LOBAR DEGENERATION WITH UBIQUITIN-POSITIVE INCLUSIONSVISUALIZED WITH UBIQUITIN-BINDING PROTEIN p62IMMUNOHISTOCHEMISTRYJ NEUROPATHOL EXP NEUROL 2008, pp280-298

LETTER TO THE EDITOR (PIKKARAINEN, HARTIKAINEN ALAFUZOFF)

UBIQUINATED p62-POSITIVE, TDP-43-NEGATIVE INCLUSIONS IN THECEREBELLUM IN FTLD WITH TAR DNA BINDING PROTEIN 43NEUROPATHOLOGY 2010; 30, 197-199