30 Sep 2016

As frontotemporal dementia researchers gear up for trials, high up on their wish lists are better clinical outcome measures to detect change over time more sensitively than standard cognitive tests do. At the 10th International Conference on Frontotemporal Dementias, held August 31-September 2 in Munich, researchers discussed possibilities, including an old informant-based test of social cognition and a new social cognition battery. Both are being evaluated in ongoing cohort studies. Other presenters discussed innovations in measuring the functional deficits that are specific to FTD, often done in combination with structural or functional imaging that ties a deficit to degeneration and connectivity loss in particular brain regions. Attendees were excited about the potential of these tests to flag common behavioral deficits of FTD.

“Hopefully we can start to use social cognition measures. Right now we’re missing key aspects of the disease,” said Edward Huey of Columbia University, New York City.

Currently, most FTD trials use cognitive or functional measures such as the MMSE, CDR, and the ADCS-CGIC. However, these were designed for Alzheimer’s disease, with its primary features of impaired executive function and memory. That is inadequate because the primary symptoms of FTD are behavioral or affect different cognitive domains than AD does. In fact, Everard Vijverberg of VU University Medical Center, Amsterdam, reported in Munich that bvFTD patients perform better than psychiatric patients in tests of executive function and verbal and working memory.

Many researchers are exploring measures of social cognition as more specific outcome markers for FTD. In early FTD, personality changes above all else. FTD patients typically lose social skills and become insensitive to other people’s emotions. They can become unfiltered, speak rudely to strangers, or miss social cues and the meaning of jokes. 

Katherine Rankin of UCSF reminded the audience of one measure to quantify changes of this sort, the Revised Self-Monitoring Scale (RSMS) developed more than 30 years ago (see Lennox and Wolfe, 1984). On this 13-item questionnaire, an informant rates a person’s ability to modulate his or her behavior in various social situations. Rankin said this questionnaire performs well, with a normal distribution and a wide range of scores suggesting it is unlikely to be hobbled by floor or ceiling effects. Scores on the RSMS start to dip in asymptomatic mutation carriers and drop steadily throughout the course of FTD, Rankin said.

Worsening scores also predict a loss of connectivity in the salience network. The longitudinal studies GENFI, ARTFL, LEFFTDS, and the National Alzheimer’s Coordinating Center’s FTLD Module are currently evaluating the RSMS using their respective data sets. Other researchers were cautiously optimistic about it, but said it needs further validation.

In the long run, a battery of tests may perform better than any single one, several researchers said. “It’s unlikely there will be one magic bullet,” Jonathan Rohrer of University College London told Alzforum. Bruno Dubois of Pierre and Marie Curie University, Paris, developed a battery of five subtests to evaluate prefrontal functions. Called Social Cognition and Emotional Assessment, or SEA, this battery in initial testing separated FTD patients from AD patients and controls with a specificity of 89 percent (see Funkiewiez et al., 2011). GENFI, ARTFL, and LEFFDTS use a shorter version of it, the mini-SEA, which includes only the tests of facial emotion recognition and the ability to recognize a social faux pas (see Bertoux et al., 2012). The cohort studies will gather data on how well the battery performs longitudinally, said Brad Boeve of the Mayo Clinic in Rochester, Minnesota.

Numerous other talks discussed exploratory clinical measures. David Perry of UCSF reported that people with bvFTD show less aversion to unpleasant smells than controls do. This behavioral deficit reflects atrophy in the insula and amygdala, not the anosmia known to occur early in AD, PD, and DLB. People with FTD do smell the garbage left out in the heat—they are simply less bothered by it. Charles Marshall of University College London described dulled reaction to facial emotions in people with bvFTD compared with controls, as measured by facial electromyography. This characteristic correlated with atrophy of several brain regions, particularly the supplementary motor cortex. Other speakers presented evidence that tests of social cognition can distinguish between bvFTD patients and those with semantic dementia, or between people with MAPT mutations and GRN mutations.

Some researchers are thinking further afield in their search for ways to measure FTD. Jason Warren of UCL reviewed measures that can flag disruption of specific processes (see Nov 2014 conference news). For example, people with bvFTD can seem quite impervious to pain, heat, and cold, while people with semantic dementia appear more sensitive (see Fletcher et al., 2015). People with bvFTD respond less than controls to pictures evoking emotion, as measured by skin conductance and heart rate (see Balconi et al., 2015). 

Electrophysiological measures, such as transcranial magnetic stimulation, reveal impaired cortical inhibition and plasticity in people with FTD, in some cases before symptoms develop (see Burrell et al., 2011; Benussi et al., 2016). Task fMRI uncovers differences in how FTD patients process music and think about moral dilemmas (see Agustus et al., 2015; Chiong et al., 2013). 

All these data are preliminary. While researchers sounded excited about the potential of these measures, they emphasized that work remains to develop and validate them. Warren noted that these potential markers should be evaluated in large longitudinal cohorts to figure out which ones are both useful and robust for widespread use.—Madolyn Bowman Rogers

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References

News Citations

1. Too Hot, Too Cold, or Just Wrong? Physiology Links Behavior to Circuits in FTD 13 Nov 2014

Paper Citations

1. Lennox RD, Wolfe RN. Revision of the self-monitoring scale. J Pers Soc Psychol. 1984 Jun;46(6):1349-64. PubMed.
2. Funkiewiez A, Bertoux M, de Souza LC, Lévy R, Dubois B. The SEA (social cognition and emotional assessment): A clinical neuropsychological tool for early diagnosis of frontal variant of frontotemporal lobar degeneration. Neuropsychology. 2011 Sep 5; PubMed.
3. Bertoux M, Delavest M, de Souza LC, Funkiewiez A, Lépine JP, Fossati P, Dubois B, Sarazin M. Social Cognition and Emotional Assessment differentiates frontotemporal dementia from depression. J Neurol Neurosurg Psychiatry. 2012 Apr;83(4):411-6. PubMed.
4. Fletcher PD, Downey LE, Golden HL, Clark CN, Slattery CF, Paterson RW, Rohrer JD, Schott JM, Rossor MN, Warren JD. Pain and temperature processing in dementia: a clinical and neuroanatomical analysis. Brain. 2015 Nov;138(Pt 11):3360-72. Epub 2015 Oct 12 PubMed.
5. Balconi M, Cotelli M, Brambilla M, Manenti R, Cosseddu M, Premi E, Gasparotti R, Zanetti O, Padovani A, Borroni B. Understanding Emotions in Frontotemporal Dementia: The Explicit and Implicit Emotional Cue Mismatch. J Alzheimers Dis. 2015 Mar 10; PubMed.
6. Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotemporal dementia. Brain. 2011 Sep;134(Pt 9):2582-94. PubMed.
7. Benussi A, Cosseddu M, Filareto I, Dell'Era V, Archetti S, Sofia Cotelli M, Micheli A, Padovani A, Borroni B. Impaired long-term potentiation-like cortical plasticity in presymptomatic genetic frontotemporal dementia. Ann Neurol. 2016 Sep;80(3):472-6. Epub 2016 Aug 10 PubMed.
8. Agustus JL, Mahoney CJ, Downey LE, Omar R, Cohen M, White MJ, Scott SK, Mancini L, Warren JD. Functional MRI of music emotion processing in frontotemporal dementia. Ann N Y Acad Sci. 2015 Mar;1337:232-40. PubMed.

External Citations

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Further Reading

News

1. When Frontotemporal Dementia Leads to Crime—Prosecution or Protection? 13 Jan 2015