Neurodegenerative disease misclassified as psychiatric

This UCSF study says more about the behavioral variant of frontotemporal dementia than it does about PSP, CBD, or the other neurodegenerative diseases included in the research. The researchers’ conclusion makes a couple of points:

* “Neurodegenerative disease is often misclassified as psychiatric disease. …[When] patients with neurodegenerative disease are initially classified with psychiatric disease, the patient may receive delayed, inappropriate treatment and be subject to increased distress.”

* “Physicians should consider referring mid- to late-life patients with new-onset neuropsychiatric symptoms for neurodegenerative disease evaluation.”

Robin

Journal of Clinical Psychiatry. 2011 Feb;72(2):126-33.

The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease.

Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP.
UCSF, San Francisco, CA.

Abstract
OBJECTIVE: To identify rates of and risk factors for psychiatric diagnosis preceding the diagnosis of neurodegenerative disease.

METHOD: Systematic, retrospective, blinded chart review was performed of 252 patients with a neurodegenerative disease diagnosis seen in our specialty clinic between 1999 and 2008.

Neurodegenerative disease diagnoses included
* behavioral-variant frontotemporal dementia (n = 69),
* semantic dementia (n = 41), and
* progressive nonfluent aphasia (n = 17) (all meeting Neary research criteria);
* Alzheimer’s disease (n = 65) (National Institute of Neurologic and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association research criteria);
* corticobasal degeneration (n = 25) (Boxer research criteria);
* progressive supranuclear palsy (n = 15) (Litvan research criteria); and
* amyotrophic lateral sclerosis (n = 20) (El Escorial research criteria).

Reviewers remained blinded to each patient’s final neurodegenerative disease diagnosis while reviewing charts. Extensive caregiver interviews were conducted to ensure accurate and reliable diagnostic histories. For each patient, we recorded history of psychiatric diagnosis, family psychiatric and neurologic history, age at symptom onset, and demographic information.

RESULTS: A total of 28.2% of patients with a neurodegenerative disease received a prior psychiatric diagnosis. Depression was the most common psychiatric diagnosis in all groups.

Behavioral-variant frontotemporal dementia patients received a prior psychiatric diagnosis significantly more often (50.7%; P < .001) than patients with Alzheimer’s disease (23.1%), semantic dementia (24.4%), or progressive nonfluent aphasia (11.8%) and were more likely to receive diagnoses of bipolar disorder or schizophrenia than were patients with other neurodegenerative diseases (P < .001). Younger age (P < .001), higher education (P < .05), and a family history of psychiatric illness (P < .05) increased the rate of prior psychiatric diagnosis in patients with behavioral-variant frontotemporal dementia.

Cognitive, behavioral, and emotional characteristics did not distinguish patients who did or did not receive a prior psychiatric diagnosis.

CONCLUSIONS: Neurodegenerative disease is often misclassified as psychiatric disease, with behavioral-variant frontotemporal dementia patients at highest risk.

While this study cannot rule out the possibility that psychiatric disease is an independent risk factor for neurodegenerative disease, when patients with neurodegenerative disease are initially classified with psychiatric disease, the patient may receive delayed, inappropriate treatment and be subject to increased distress.

Physicians should consider referring mid- to late-life patients with new-onset neuropsychiatric symptoms for neurodegenerative disease evaluation.

© Copyright 2011 Physicians Postgraduate Press, Inc.

PubMed ID#: 21382304

Spectrum of Frontotemporal Degeneration – 3/2/11 Webinar Notes

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

[There were lots of examples of agrammatic speech. See the PDF for all of those.]

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.

[There was a slide on CSF biomarkers, different from the slide in the PDF.]

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!]

 

Acalculia in 2 autopsy-proven CBD cases

UPenn researchers recently got published a report of two cases of acalculia in autopsy-confirmed CBD. Acalculia is an impairment in the ability to calculate or performing simple mathematical tasks, such as adding or subtracting.

I don’t consider this particularly new information but the authors say that “While the original case descriptions mentioned acalculia, few studies have investigated this, and reports of acalculia in autopsy-proven CBD are very rare. We detail 2 autopsy-defined CBD cases with acalculia to emphasize that CBD compromises cognitive functioning due to disease that includes parietal cortex.”

This paragraph from the Discussion section is interesting: “In 15 patients with autopsy-proven CBD that included the 2 cases detailed here, acalculia was noted in 28.6%, although this was thought to be an underestimation since calculations were not often examined. … Patients with CBS have significant impairments estimating and comparing quantities, performing calculations with small numerosities, and using quantity knowledge to support word meaning. … MRI in CBS regularly shows parietal atrophy, including areas associated with number knowledge.”

I’ve copied the citation below.

Robin

Neurology. 2011 Feb 15;76(7 Suppl 2):S61-3.

Acalculia in autopsy-proven corticobasal degeneration.

Pantelyat A, Dreyfuss M, Moore P, Gross R, Schuck T, Irwin D, Trojanowski J, Grossman M.
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

FTD Webinar, Wed 3/2, noon CST, registration open

Editor’s note:  See our notes from the webinar here.

Sorry for the short notice on this. I just received an email on this webinar from the AFTD — which now stands for the Association for Frontotemporal Degeneration (rather than Dementia). The AFTD now has a new web address as well; you can find them online at theaftd.org. (ftd-picks.org re-routes you to theaftd.org.)

You are invited to participate in this webinar:

The Spectrum of Frontotemporal Degeneration
(tomorrow) Wednesday, March 2
noon to 1pm central time
speaker – Dr. Mario Mendez, Director of the FTD and Neurobehavior Clinic at UCLA
register here – http://cme.edocendo.com/

The registration page gives these objectives for the webinar:

“Those attending this presentation will receive information that should allow them to:
– Have a working knowledge of frontotemporal degeneration (FTD) and how to diagnosis these syndromes;
– Comprehend the major clinical syndromes of FTD: bvFTD, PPA, CBS, PSP;
– Learn principles of management of FTD, particularly addressing the unique burden on caregivers and family;
– Know where to find resources and when to refer patients with FTD.”

When you register, you first have to create an account, which requires entering a username and password. Then you fill out a form that asks for your name, last four digits of SSN, your degree, your company, your address, and your phone #. (There is no accuracy-checker.) You are then sent an email which tells you how to join the webinar tomorrow.

This webinar is sponsored by AFTD. Most of the audience will be physicians and other medical professionals. (CME — continuing medical education — credits are available for MDs.)

There’s a short 4-question pre-test on FTD you can take.* Based on that pre-test and other MD-oriented webinars I’ve attended, my guess is that most people here will be able to understand much of what is said.

Robin

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* The Spectrum of Frontotemporal Degeneration Pre-Test

The following test must be completed prior to participating in “The Spectrum of Frontotemporal Degeneration” CME activity. This test is required for you to receive your CME credit.

1. FTD has its usual onset in the elderly (>65 years of age)?
A. True
B. False

2. FTD is clinically indistinguishable from Alzheimer disease?
A. True
B. False

3. The diagnosis of FTD relies on clinical criteria rather than laboratory tests?
A. True
B. False

4. The most common presentations of FTD are personality changes or language problems?
A. True
B. False