I listened to yesterday’s AFTD (Association for Frontotemporal Degeneration) webinar on the spectrum of frontotemporal degeneration, thinking it was truly about the “spectrum.” It was NOT about the spectrum in that the speaker announced early on that he would be ignoring PSP and CBS (two movement types of FTD), and concentrating on the three other types of FTDs – bvFTD, PNFA, and SD. So my notes may not be of much interest to the PSP and CBD communities.
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Notes by Robin Riddle about
The Spectrum of Frontotemporal Degeneration
AFTD webinar
Wednesday, March 2, 2011
Speaker – Mario Mendez, MD, PhD, Director of the FTD and Neurobehavior Clinic, UCLA
Organization of Talk
1. What is frontotemporal degeneration (FTD)?
2. What are the clinical syndromes of FTD?
3. Principles of Management
4. Resources and Referral
Brief History of FTD Syndromes
1892: Arnold Pick described 6 patients with FTD
1911: Alzheimer describes the neuropathology
DARK AGES
1993+: Renaissance: Epidemiology, Clinical Criteria
1997: Age of Tauopathy: FTDP-17, abnormal tau
2006: Age of TDP43 protein and progranulin gene
2009+: NEW AGE OF EXPLORATION, THERAPY
Epidemiology of FTD Syndromes
1. 5-8% of dementias; 13.5-15% if onset < 65
AD, VaD, and DLB are more common than FTD
Second most common dementia among young people
2. Prevalence/Incidence in 45-64 yr age group: 15/100,000 and 1-2/100,000
3. Usual onset in 50’s (mean onset 57-58)
Strikes people in their prime
Devastating time to develop a dementia: raising a family; making an income
4. Slightly more men than women
5. Duration shorter than AD (mean 8 years)
There are different series with different means and members.
Mean duration of about 7.6 years makes the most sense to him.
Semantic Dementia may be longer (9 years).
Three Key Points on FTD
1. Variable phenotypes and syndromes:
Behavioral variant FTD (bvFTD) involves social brain
Progressive nonfluent aphasia (PNFA)
Semantic dementia (SD)
Others: FTD-MND (10%), CBS (asymmetric motor findings; ideomotor apraxia), PSP
CBS and PSP are related syndromes. They are movement disorders. This talk will focus on the main syndromes.
2. Variable neuropathology: misfolded protein. The most common abnormal inclusions (clumps of protein) are with TDP-43 (45%), tau (40%), and FUS.
3. 15% autosomal dominant genetic mutations: in MAPT, PRGN, VCP, FUS, CHMP2B, TARDBP (this last one is with TDP-43).
Variable phenotypes and syndromes: Some people are very frustrated by this!
FTD Common Syndromes:
1. bvFTD: behavioral variant ~ 50%
A. often present with apathy, abulia, or detachment. MDs commonly diagnose these people as depressed when, in fact, these people are developing problems in the frontal lobe. Need to screen for depression.
B. Disinhibition or impulsivity. People violate social boundaries. Causes distress in families. He calls this “Private behaviors in public.”
C. FTD-MND (motor neuron disease)
2. Language predominant variants
A. PNFA: Progressive non-fluent aphasia ~ 25%
B. SD: Semantic dementia ~25%
3. CBS or PSP: parkinsonism symptoms
The FTD Spectrum With 5-Year UCLA FTD Clinic Experience:
FTD (behavioral variant), n=118
Primary Progressive Aphasia (non-fluent), n=48
Semantic Dementia, n=19
Corticobasal syndrome, n=11
Progressive supranuclear palsy, n=9
(Literature: MND in about 15%)
Frontotemporal Degenerations
Frontotemporal Dementia: 56.7%; Age at Onset 57.5 (9.7); Male sex 63.5%; Initial MMSE 22.7 (6.6)
Progressive Nonfluent Aphasia: 18.7%; Age at Onset 59.3 (8.2); Male sex 66.7%; Initial MMSE 21.5 (7.08)
Semantic Dementia: 24.6%; Age at Onset 63.0 (9.7); Male sex 39.1%; Initial MMSE 22.5 (7.0)
From Johnson et al, Arch Neurol 2005;62:925-30
bvFTD – Core diagnostic features
A. Insidious onset and gradual progression
B. Early decline in social interpersonal conduct
C. Early impairment regulation of personal conduct
D. Early emotional blunting: Acting as if they don’t care. Not caring about others.
E. Early loss of insight: No acceptance that anything is wrong.
From: Neary et al, Neurology 1998;51:1546-51;
SE 85%, SP 99% among 34 patients in Knopman et al, 2005
These diagnostic criteria are difficult to operationalize! How do you assess “early decline in social interpersonal conduct”?
Symptoms in 53 bvFTD Patients – at onset and after 2 years:
Decline in social conduct: 39.6% onset; 83% 2 years
Impaired personal regulation: 69.8% onset; 88.7% 2 years
Emotional blunting: 35.8% onset; 94.3% 2 years
Lack of insight: 58.5% onset; 100% 2 years
Compulsive-like behaviors: 45.3% onset; 88.7% 2 years
Logopenia and anomia: 41.5% onset; 96.2% 2 years
Hyperorality (other KBS) 0% onset; 20.8% 2 years
From Mendez & Perryman, 2002
Results of 134 referrals to the UCLA FTD & Neurobehavior Clinic for possible bvFTD:
23 (17.2%) initially met criteria for bvFTD
40 converted to bvFTD by two year f/up
36 had psychiatric disorder
17 had Alzheimer’s disease
9 had another neurological disorder [Anoxic encephalopathy (2), prion disease (2), Hashimoto’s encephalopathy, neurosarcoidosis, NPH, paraneoplasticsyndrome, sleep apnea syndrome]
9 without final diagnosis
Note how few met the criteria for bvFTD!
International Consensus Criteria for bvFTD
I. Neurodegenerative Disease: progressive deterioration behavior and/or cognition
II. Possible bvFTD (3 of A-F present…so 3 out of 6)
A. Early behavioral disinhibition (1 or more)
1. Socially inappropriate behavior
2. Loss of manners or decorum
3. Impulsive, rash or careless actions
B. Early apathy or inertia
C. Early loss of sympathy or empathy (1 or more)
1. Diminished response to others people’s
needs and feelings
2. Diminished social interest, interrelatedness
or personal warmth
D. Early perseverative, stereotyped or compulsive/ritualistic behavior
1. Simple repetitive movements
2. Complex, compulsive or ritualistic
3. Stereotypy of speech
E. Hyperorality and dietary changes (1 or more)
1. Altered food preferences
2. Binge eating, increased consumption of alcohol or cigarettes
3. Oral exploration or consumption of inedible objects
F. Neuropsychological profile (all 3 present)
1. Deficits in executive tasks
2. Relative sparing of episodic memory
3. Relative sparing of visuospatial skills
These are much better. They will be approved soon.
C: has some similarities with autistic spectrum disorders.
The clinical diagnosis should be corroborated with neuro-imaging. Scan shows disproportionate frontal lobe hypometabolism. The imaging is getting better and better.
UCLA uses the FDDNP ligand. FDDNP-PET shows different distribution of cortical pathology in AD and FTD.
The disease often begins in the “social brain.”
How does FTD affect social behavior?
1. Acquired sociopathy (Mendez et al, 2003; Miller et al, 1997)
2. Reduced understanding of social concepts (Zahn et al, 2009)
3. Reduced self-referential emotions (Sturm et al, 2006)
4. Reduced recognition of facial emotions (Rosen et al, 2005)
5. Reduced empathy (cognitive-OF, emotional-TL; Rankin et al, 2005)
6. Reduced theory of mind (Gregory et al, 2002; Lough et al, 2006)
7. Reduced recognition of humanness (Mendez et al, 2005,2006)
Sociopathy in 16 FTD Patients seen at UCLA:
3 Unsolicited sexual approach or touching
3 Traffic violations including hit-and-run accidents
2 Physical assaults
1 Shoplifting
1 Deliberate non-payment of bills
1 Pedophilia
1 Indecent exposure in public
1 Urination in inappropriate public places (eg, on neighbor’s lawn)
1 Stealing food
1 Eating food in grocery store stalls
1 Breaking and entering into others’ homes (eg, in order to play the piano)
Phineas Gage: famous patient; iron rod damaged his frontal lobe. He illustrates the disinhibited subtype.
International Guidelines for the Diagnosis of Primary Progressive Aphasia – Workgroup Results
Three main variants:
• PNFA progressive non-fluent aphasia: Now nonfluent/agrammatic variant PPA
• SD semantic dementia: Now semantic variant PPA
• PLA- progressive logopenic aphasia: Now logopenic variant PP. This is often AD.
Progressive NF Aphasia
• Grammatical difficulty in language production
• Reduced motor speech — effortful, hesitant, phonemic abnormality
• Apraxia of speech frequently present
• Reduced comprehension of syntactically complex sentences
• Spared word comprehension and object recognition
• Atrophy inferior left frontal-anterior insula region
Semantic Dementia
• Multimodal semantic deficits (modality-specific)
• Semantic anomia – decreased category fluency & decreased word comprehension
• Abnormal person and object recognition
• Surface dyslexia and regularization, typicalization errors
• Decreased specificity, general (superordinate) word preference
• Bizarre food choices or fads and rigidity
• Atrophy of temp polar, perirhinal “recognition” cortex
He calls this the “what is” disease as patients ask “what is a bottle?,” “what is this?”
Pyramids and palm trees test.
Drawings become more generic. Drawing of peacock becomes more generic.
Logopenic Variant PPA: Not discussing today as this is typically AD.
Evolution of FTD’s (2-5 yrs)
• FTDbv: 1/2 become PNFA; 1/4 become CBS/PSP
• PNFA: 1/2 become FTDbv; 1/3 become CBS/PSP
• CBS/PSP: 1/2 become FTDbv; 1/2 become PNFA
• SD: 3/4 become FTDbv
• Differences still persist at end of life
From Kertesz et al, 2007; Snowden et al, 2007
MAPT and PRGN
• 6% Microtubule-associated tau gene (C’17) mutations
• Progranulingene (C’17) mutations in 10%; TAR-DNA-binding protein-43 (TDP-43) in ubi+ inclusions
Good review in the journal Neurology about genetic testing with genetic counseling.
Most people don’t benefit from genetic testing.
There is genetic testing for MAPT and PRGN.
His management approach:
Primarily symptomatic
SSRIs helpful for disinhibition and repetitive or compulsive behaviors
Trazodone for more disruptive behaviors
Methylphenydate useful in activating some who lack initiation or are apathetic
AchI used in AD can make things worse in FTD (disinhibition, repetitive behaviors)
Long list of drugs tested in FTD
Caregiver support is extremely important:
* Behavioral, functional, financial, and legal counseling
* Provide an “external executive”
* Use AFTD (theaftd.org) and Alzheimer’s Association resources
* Speech, occupational, physical therapy
* Establish dedicated support groups
* Daycare, respite care and nursing care
Conclusions
* FTD is common in those <65 who develop changes in social behavior or language
* The clinical syndromes vary and overlap. The main syndromes are bvFTD, PNFA, and SD. Others are FTD-MND, CBS, and PSP.
* The neuropathology varies.
* 15% are genetic and include MAPT, PRGN, FUS, valosin, and TARBP genes. Must provide genetic counseling for the entire family.
* Management is primarily symptomatic. Focus on treating disruptive behaviors with a limited psychoactive agents such as SSRIs.
* Contact AFTD
Questions and Answers:
Q: Is there a standard evaluation?
A: We have standard scales we use, including neuropsychological tests. UCLA has its own MRI sequence or series.
Q: Once diagnosed, do you declare them incapacitated?
A: Yes/No. Capacity is state-dependent. The communication to the patient and family: “the patient is incapacitated.” Patients are more incapacitated than their neuropsychological tests will tell you. The patient is at risk for poor decision-making.
Q: Is there a correlation with traumatic brain injury?
A: TBI is not an established risk factor for FTD.
Many with TBI are injured in their frontal lobes so some of the symptoms may be the same.
Q: Neuropathological differences?
A: [didn’t understand question or answer!]