RB Clincopathologic Conference (CPC) 3/18/2016 Thomas Shoemaker, MD Ronald Hamilton, MD

History 2008: I saw RB for her problem with imbalance. As you know, the patient is a 74-year-old woman who indicates that while in Hawaii for winter and spring she suffered a fall without obvious provocation. Since that time, the patient has had a fear of falling. There has been minimal dizziness, but there has been a tendency to fall with veering of gait more so to the left than to the right. The patient notes no hearing loss, tinnitus, or ear fullness aside from her baseline which includes hearing loss on the right. The patient does not complain of double vision, blurred vision, blindness, numbness, clumsiness, confusion, loss of consciousness, nor difficulty with speech or swallowing. – Dx: Fear of falling..

History 2010: Seen for abnormal gait and falls. She has difficulty walking and getting out of a chair, also having problems getting dressed – The patient was started on Sinemet regular 25/100, and she has titrated this up to 1 tablet 3 times a day. She states that she had no benefit from this medication.. – Ddx: Question vascular parkinsonism. There is also a possibility of atypical Parkinson disease. 2011: Worsened after d/c of sinement, placed back on.. ? of LE parkinsonism 2014: Dyskinesias

History Past Medical History dementia Parkinson's HTN hyperlipidemia depression Past Surgical History eye surgery (cataracts/glaucoma) cochlear implant

History Family History mother deceased 77 MI father deceased 57 MI sister polio (childhood, since recovered) Social History resident of The Atria (assisted living facility) past 2 years tobacco never EtOH none +walker married, 3 children (living in HI, NY, TX)

FTD? 5/21/2012: NeuroPsych Battery Testing Within normal limits: Geriatric Depression Scale: 3/15 MMSE: 28/30 Go/No Go HVLT Delayed Recall: 11/12 HVLT Recognition (true positives:11/12)

FTD? 5/21/2012: NeuroPsych Battery Abnormal Testing Peaks and Plateaus: 2 errors Trail Making Trails A (>2 standard deviations (SD) below the norm for age and education level.) Trail Making Trails B (>2 standard deviations (SD) below the norm for age and education level.) Both her trails A and B demonstrate signs of executive dysfunction. Clock Drawing: 5/8 (>2standard deviations (SD) below the norm for age and education level.)

FTD? 5/21/2012: NeuroPsych Battery Summary: She is exhibiting signs that are more consistent with a frontotemporal dementia. Further, she does not have signs of major depression at this time.

Psychic Abilities? 10/26/2012: The patient comes in for her appt today. She is not accompanied by her husband, who had an appt of his own, although he did drive her into the office. She remains quite interested in politics and is worried about an announcement Donald Trump will be making today about President Obama.

Examination Mental Status: (performed only by PM&R, 6/28/2015) – No aphasia or dysarthria. However noted to by hypophonic – Following multi step commands. Concentration intact and fluid. – 3 object identification intact to pen, glasses, stethoscope – recall of 3/3 at 5 minutes though patient admits to normally having difficulty with this test with doctors, particular at the end of the day

Examination There was mild facial masking. Blink frequency was decreased. Voice was mildly hypophonic. Muscle strength was 5/5 bilaterally in upper extremities. She has 4/5 hip flexors/extensors, knee extensors, 3/5 knee flexors. Examination of tone revealed mild to moderately increased in the bilateral upper and lower extremities. Adventitious movements: without dyskinesia. resting tremor - none appreciated action tremor - none appreciated Postural in outstretched and wingbeating positions - none appreciated

Examination Finger taps were decreased in speed and amplitude. Foot taps were decreased amplitude. +palmomental reflex Rapid alternating movements were slowed and without dysmetria. Posture was mildly stooped

Radiology MRI ETC:

Differential Diagnosis Progressive Supranuclear Palsy Vascular Parkinsonism Parkinson’s Disease Fronto-temporal Demetria Alzheimer’s Disease Parkinson’s Disease Dementia

Predicted Pathology- PSP GROSS: Atrophy of subthalamic nucleus, midbrain tectum and the superior cerebellar peduncle. – Substantia nigra may show loss of pigment corresponding to nigrostriatal dopaminergic degeneration. Microscopic: Neuronal loss, gliosis and neurofibrillary tangles in basal ganglia, diencephalon and brainstem. – Characteristic tau pathology is also found in glia

Predicted Pathology- FTD Predicted Gross pathology: Decreased brain weight with varying degrees of mesial temporal lobe and frontotemporal atrophy with corresponding lateral ventricular enlargement. Predicted Micro pathology: – Pick bodies (argyrophilic intracytoplasmic inclusions) – Neuronal and glial tau deposits

Histopathology Slide A – H&E H&E – Abeta Abeta – Bielschowsky Bielschowsky – P-Tau P-Tau – Alpha synuclein Alpha synuclein Slide B – H&E H&E

Histopathology Slide G – H&E H&E – P-Tau P-Tau – Alpha Synuclein Alpha Synuclein Slide E – H&E H&E – TDP43 TDP43 – P-Tau P-Tau – Alpha Synuclein Alpha Synuclein

Histopathology Slide J – H&E H&E – Alpha Synuclein Alpha Synuclein Slide H – H&E H&E – Alpha Synuclein Alpha Synuclein Slide I – H&E H&E

Diagnostic comment the decedent’s husband, indicates that the cognitive difficulties appeared before the Parkinsonian symptoms. With this history, then, the presence of alpha-synuclein aggregates in the amygdala, hippocampus and frontal lobe are diagnostic of Dementia With Lewy Bodies (DLB). Parkinson’s disease must have extra-pyramidal motor symptoms for over a year prior to the emergence of cognitive difficulties and neuropathologically would show severe loss of neurons in the substantia nigra along with much greater alpha-synuclein aggregation in the rest of the brainstem than seen here. Alpha-synuclein aggregates outside of the brainstem are usually not present until end-stage Parkinson’s disease. Many cases of DLB are accompanied by varying degrees of Alzheimer’s Disease pathology. In this case, neocortical beta-amyloid deposits were not present and there was only mild amyloid angiopathy. A Bielschowsky silver stain confirmed that there were no neocortical neuritic plaques or neurofibrillary tangles. A few neurofibrillary tangles were noted in the mesial temporal lobe structures (primarily hippocampus) but these are very common at this age and without neocortical neuritic plaques, do not indicate Alzheimer’s Disease. Finally, the possibility of a frontotemporal dementia (FTD) was mentioned during clinical evaluations and additional history of head trauma (concussion) was revealed. However, tau immunostains do not show any evidence of a Chronic Traumatic Encephalopathy and no residual injury was seen by gross examination or microscopic evaluation. There is no evidence of a tau-related frontotemporal dementia (e.g., Pick’s disease) and TDP-43 stains are negative, excluding that type of frontotemporal dementia.