Objectives. RAIN Difficult Diagnosis 2014: A 75 year old woman with falls. Case History: First visit. Case History: First Visit
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1 Objectives 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 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) 1
2 Question 1: Which of the Following Diagnoses is Most Likely? Imaging 1. Idiopathic Parkinson s Disease 59% 2. Complications of Spine Surgery 3. Progressive Supranuclear Palsy 4. Frontotemporal Dementia 5. Multiple Sclerosis 22% 20% 0% 0% I d i o p a t h i c P a r... C o m p l i c a t i o n s... P r o g r e s s i v e S u... F r o n t o t e m p o r a l... M u l t i p l e S c l e r... 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
3 Case History: Second Visit Family History 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 65 bulbar Motor impairment did not respond to levodopa Family history of ALS 60 Motor Neuron Disease Cognitive/Behavioral Symptoms 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? 1. Lumbar Puncture 2. PET Brain Imaging 3. Genetic Testing 4. EMG L u m b a r P u n c t u r... 2% P E T B r a i n I m a g... 21% G e n e t i c T e s t i n... 66% 11% E M G 3
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 occasions and was normal Genetic Testing for C9ORF72 hexanucleotide expansion was positive 4
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 overall, 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,
6 FTD with C9ORF72 FTD with C9ORF72 bvftd with C9ORF72 bvftd - parkinsonism with C9ORF72 Akinetic/rigid, no rest tremor, none levodopa-responsive Also Sha et al,
7 Cognitive Features Imaging Features Impaired timed frontal/executive tasks Preserved reading 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 Conclusions C9ORF72 Negative Case C9ORF72 Positive Case P62/ubiquitin cytoplasmic inclusions 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 Cooper-Knock et al, 2013 Also 7
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) 8
! slow, progressive, permanent loss of neurologic function.
UBC ! slow, progressive, permanent loss of neurologic function.! cause unknown.! sporadic, familial or inherited.! degeneration of specific brain region! clinical syndrome.! pathology: abnormal accumulation
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