2010 MEETING, PHILADELPHIA
AMERICAN ASSOCIATION OF
NEUROPATHOLOGISTS
DSS CASE # 11
J-M BILBAO, B YOUNG and N LIU
SUNNYBROOK HOSPITAL
UNIVERSITY OF TORONTO
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.
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
•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.
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 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.
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
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 FTLDFUS, 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.
Neuropathology of FTD
●
aFTLD-U
●
NIFID
●
BIBD
FTLDFUS
*aFTLD-UPS
FTLD: tau
●PiD
FTLD:TDP-43
FTLD-U
(type 1, 2, 3)
●FTD+ALS
●GRN
●VCP
●
chrom 9p
Mackenzie 2010
other
*DLDH
*CHMP2B
●CBD
●PSP
●AGD
●MSTD
●MAPT
α-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 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