Objectives Recognize important clinical features of patients who - - PowerPoint PPT Presentation

2/14/2014 1

RAIN Difficult Diagnosis 2014: A 75 year old woman with falls

Alexandra Nelson MD, PhD UCSF Memory and Aging Center/Gladstone Institute of Neurological Disease

Objectives

• Recognize important clinical features of

patients who have a combination of motor and cognitive dysfunction

• Identify common syndromes of parkinsonism

with cognitive impairment

• Identify clinical features where parkinsonism

with cognitive impairment may suggest a particular syndrome

Case History: First Visit

• 75 year old woman referred to Spine Center with a

history of lumbar spinal stenosis, two prior lumbar spine surgeries and several recent falls

• Following her back surgery 9 months previously, she

made slow progress in physical therapy and falls began, culminating in a fall while pivoting her closet, with hip fracture, and subsequent slow recovery

• Recent labile mood and mild cognitive symptoms were

reported by family

• Past Medical History: hypothyroidism
• Medications: synthroid

Case History: First visit

• Examination significant for MMSE of 29/30,

normal eye movements and speech, normal strength and sensation, no tremor, but mild bilateral bradykinesia with cogwheeling rigidity in the arms, and slowed gait with decreased arm swing and retropulsion

• Laboratory tests (complete blood count,

electrolytes, renal and kidney function, thyroid function, vitamin B12 are normal)

2/14/2014 2

Question 1: Which of the Following Diagnoses is Most Likely?

I d i

• p

a t h i c P a r . . . C

• m

p l i c a t i

• n

s . . . P r

• g

r e s s i v e S u . . . F r

• n

t

• t

e m p

• r

a l . . . M u l t i p l e S c l e r . . .

59% 0% 0% 20% 22%

• 1. Idiopathic Parkinson’s Disease
• 2. Complications of Spine Surgery
• 3. Progressive Supranuclear Palsy
• 4. Frontotemporal Dementia
• 5. Multiple Sclerosis

Imaging Imaging

Parkinsonism + Cognitive Impairment

• Parkinson’s Disease
• Lewy Body Dementia
• Progressive Supranuclear Palsy
• Corticobasal Degeneration
• Multiple System Atrophy
• Vascular Disease
• Frontotemporal Dementia – Parkinsonism
• Alzheimer’s Disease +/- PD

2/14/2014 3

Case History: Second Visit

• Additional history obtained from family, including

progressive gait disorder for 2-3 years, progressive cognitive symptoms (disorganization, word finding problems), longstanding “sharp tongue” but increased argumentativeness, irritability, obsessive criticism of family members

• Motor impairment did not respond to levodopa
• Family history of ALS

Family History

Motor Neuron Disease Cognitive/Behavioral Symptoms bulbar 56 65 89 49 90 75 80 60

Cognitive Evaluation

• MMSE 27/30
• Verbal learning and memory: impaired but

improved with cueing (CVLT 9 item)

• Visuospatial memory: impaired (Figure drawing

OK, but poor recall

• Frontal/Executive: Working memory WNL. Set

switching/sequencing severely impaired (Modified Trails Test)

• Language: Reading WNL. Phonemic and category

verbal fluency impaired

Question 2: Which of the Following Studies Would You Choose Next?

L u m b a r P u n c t u r . . . P E T B r a i n I m a g . . . G e n e t i c T e s t i n . . . E M G

2% 11% 66% 21%

• 1. Lumbar Puncture
• 2. PET Brain Imaging
• 3. Genetic Testing
• 4. EMG

2/14/2014 4

Behavioral Variant Frontotemporal Dementia

• Behavioral phenotype: loss of social graces,

compulsive behaviors (eating, hoarding), irritability

• Cognitive phenotype: frontal/executive (loss of

ability to multitask, plan; poor processing speed, sequencing, verbal fluency)

• Other FTD clinical phenotypes include aphasias

(progressive nonfluent aphasia, semantic dementia), corticobasal syndrome, FTD-ALS

• Can include parkinsonism in a subset of cases

FTD with Parkinsonism

• Relatively common feature of FTD
• Akinetic-rigid subtype predominant
• Can manifest as corticobasal syndrome
• Variable severity

Genetic Correlates of bvFTD and/or ALS

• GRN (progranulin) – uncommon ALS
• MAPT
• CHMP2B
• FUS – rarely FTD
• C9ORF72 – FTD, ALS, and FTD-ALS
• SOD1 – uncommon FTD
• TARDBP – uncommon FTD

Genetic Testing

• About 10 years previous, patient had

participated in ALS research and none of the ALS-related genes known at that time were identified in her sample

• EMG had also been performed on 2 prior
• ccasions and was normal
• Genetic Testing for C9ORF72 hexanucleotide

expansion was positive

2/14/2014 5

C9ORF72

• Originally identified in families with ALS

and/or FTD

• Non-coding region, hexanucleotide repeat

(>30 deemed pathologic)

• Autosomal dominant inheritance but may not

be 100% penetrance, and variety of phenotypes, even in the same family

C9ORF72 Hexanucleotide Expansion

• ALS: about 10% overall of cases have family

history; of these large portion are associated with C9ORF72, though also TARDBP, FUS, SOD1

• ALS clinical spectrum in C9 similar to ALS
• verall, though more often other neurological

symptoms present (dementia, parkinsonism)

• NOT a common cause of idiopathic PD

(3/1446 patients in one large study)

C9ORF72 Hexanucleotide Expansion

• FTD: Patients have family history in approaching

half of cases, but about 10-15% have clear autosomal dominant inheritance

• Many familial FTD caused by C9ORF72; other

genes include MAPT, GRN, CHMP2B, TARDBP, VCP, FUS

• 3-4% of sporadic cases of FTD also associated

with C9

• C9/FTD clinical features similar to FTD overall, but

favors FTD-ALS, bvFTD, more commonly presenting with psychosis, rarely language

• C9 Carriers can also have pure psychiatric disease

FTD with C9ORF72

Devenney et al, 2014

2/14/2014 6

FTD with C9ORF72

Boeve et al, 2012

FTD with C9ORF72

Boeve et al, 2012

bvFTD with C9ORF72

Boeve et al, 2012

bvFTD - parkinsonism with C9ORF72

Boeve et al, 2012 Also Sha et al, 2012 Akinetic/rigid, no rest tremor, none levodopa-responsive

2/14/2014 7

Cognitive Features

Boeve et al, 2012 Impaired timed frontal/executive tasks Preserved reading

Imaging Features

• Heterogeneous; similar to

FTD overall

• Tends to be symmetric
• Thalamic and cerebellar

atrophy noted (connections to frontal cortex?)

• Cortical and subcortical

atrophy, ALS with C9>ALS without C9

• Dorsolateral PFC, insula

common locations

Mahoney et al, 2012; Sha et al, 2012

Pathological Features in SNc

C9ORF72 Negative Case C9ORF72 Positive Case P62/ubiquitin cytoplasmic inclusions Cooper-Knock et al, 2013 Also Boeve et al, 2012

Conclusions

• Progressive parkinsonism + cognitive

impairment can be caused by several atypical parkinsonian disorders, and this should also include FTD variants

• Behavioral variant FTD, ALS, and FTD-ALS can

are commonly accompanied by parkinsonism

• C9ORF72 is the most common cause of

inherited FTD, ALS, and FTD-ALS

2/14/2014 8

Conclusions

• C9ORF72 is inherited in an autosomal dominant

fashion, but can be present in sporadic cases

• C9ORF72 positive cases have typical onset in the

50s, survival 5-10 years

• C9ORF72 clinical features: often psychosis

(delusions), often parkinsonism; rare primary language variants

• C9ORF72 has TDP-43 neuropathology, and

includes substantia nigra pathology in both parkinsonian and nonparkinsonian cases

Acknowledgements

• Maggie Waung (UCSF Neurology)
• John Engstrom (UCSF Neurology)
• Jamie Fong (UCSF Memory and Aging Center,

Genetic Counselor)

• Cindy Barton (UCSF Memory and Aging

Center, Geriatric Nurse Practitioner)