Downloaded from on July 21, 2015 - Published by

JNNP Online First, published on December 30, 2014 as 10.1136/jnnp-2014-309424 PostScript


Autonomic dysregulation in frontotemporal dementia INTRODUCTION Autonomic symptoms are associated with a number of neurodegenerative conditions.1 Cerebral structures mediating these symptoms include the anterior cingulate cortex, insular, amygdala, hypothalamus and brainstem.1 2 Of the cerebral structures implicated in autonomic control, the hypothalamus3 and insula4 undergo pathological changes in frontotemporal dementia (FTD). Given the locus of the pathology, it is likely that other hypothalamic functions such as blood pressure control, thermoregulation and urinary control may be affected in FTD through the process of autonomic dysfunction. Cardiac dysfunction,5 urinary dysfunction6 and thermoregulatory dysfunction7 have been previously reported in FTD; features which were included in the original 1998 diagnostic criteria.8 Despite these reports, investigations into the integrity of the autonomic system and whether dysfunction results in clinically significant symptoms have been limited. Carers of 69 patients with dementia: 28 behavioural-variant FTD (bvFTD; 10 female (F), 18 male (M)), 20 semantic dementia (SD; 9 F, 11 M), 21 Alzheimer’s disease (AD; 10 F, 11 M) from the FTD clinic at Neuroscience Research Australia, completed the Autonomic Symptoms Questionnaire (ASQ), which comprises 44 questions that examine physical symptoms related to autonomic functions including blood pressure/cardiovascular function, gastrointestinal, temperature regulation and sweating, urinary symptoms and sleep. The survey was validated in the Autonomic unit at the National Hospital for Neurology and Neurosurgery, London (see online supplementary file S1). Carers were asked to rate the frequency of autonomic symptoms on a five-point Likert

Table 1

scale, ranging from 0 (never) to 4 (daily or continuously) and the severity on a 3-point scale, ranging from 0 (not applicable) to 2 (marked) for each symptom over the previous 6 months. A composite score of frequency×severity was calculated for each question. All patients met the current clinical diagnostic criteria for probable bvFTD, SD or AD and underwent cognitive testing and MRI to confirm their diagnosis. In addition, 29 age-matched, and education-matched healthy controls (14 F, 15 M) were also recruited. Medications were recorded including those that may affect the autonomic nervous system (antihypertensives, antidepressants, cholinesterase inhibitors). Groups were matched for demographic characteristics: age (years, mean±SD), bvFTD 66±9.4, SD 66±6.1, AD 67±7.7, controls 70±4.8; and disease duration (years): bvFTD 6.4±4.2, SD 6.6±2.6, AD 5.5±2.7. As expected, the control group scored higher than the patient groups on the ACE-R, a measure of global cognition ( pC,


High scores denote increased abnormal features. For the ASQ, the overall score reflect the combination of frequency and severity of each relevant feature investigated by the questionnaire. AD, Alzheimer’s disease; ASQ, Autonomic Symptoms Questionnaire; bvFTD, behavioural-variant frontotemporal dementia; SD, semantic dementia.

J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0

Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd under licence.


Downloaded from on July 21, 2015 - Published by

PostScript domains relate to specific cortical structures, including the insula and hypothalamus which regulate heart rate and blood pressure,2 and the hypothalamus and limbic areas that integrate thermoregulatory and sweating responses.1 Given the known involvement of the hypothalamus3 and insula4 in FTD, it is perhaps not surprising that such patients exhibit autonomic symptoms. A number of interesting behavioural phenomena and somatic sensations reported may implicate autonomic dysfunction in FTD via pathology in the insula, hypothalamus and thalamus, which are known to be involved in the perception of pain and temperature.9 Patients with bvFTD, particularly those with the c9orf72 repeat expansion, describe somatic symptoms, including increased sensitivity to temperature and pain. The present study supports the concept of FTD as a network disease, causing degeneration of multiple systems, cognitive as well as physiological. Further research, including autonomic function testing, is required to ascertain the physiological markers of autonomic dysfunction and how this correlates with survival and disease progression in FTD. Finally, many of the symptoms elicited in our survey cause significant distress to patients and their carers, and may be overlooked. Patients with FTD should be questioned about autonomic disturbance and advice given to manage and reduce the discomfort related to these symptoms. R M Ahmed,1,2,3 V Iodice,4 N Daveson,1 M C Kiernan,1,5 O Piguet,1,3,6 J R Hodges1,3,6



Neuroscience Research Australia, Sydney, New South Wales, Australia 2 Prince of Wales Clinical School, Sydney, New South Wales, Australia 3 ARC Centre of Excellence in Cognition and its Disorders, the University of New South Wales, Sydney, New South Wales, Australia 4 Department of Autonomic Medicine, National Hospital for Neurology and Neurosurgery, London, UK 5 Sydney Medical School, Brain and Mind Research Institute, University of Sydney, Sydney, New South Wales, Australia 6 School of Medical Sciences, the University of New South Wales, Sydney, New South Wales, Australia Correspondence to Dr R M Ahmed, Neuroscience Research Australia, Barker St, Randwick, NSW 2031, Australia; [email protected]

To cite Ahmed RM, Iodice V, Daveson N, et al. J Neurol Neurosurg Psychiatry Published Online First: [ please include Day Month Year] doi:10.1136/jnnp2014-309424 Received 5 September 2014 Revised 24 November 2014 Accepted 8 December 2014 J Neurol Neurosurg Psychiatry 2014;0:1–2. doi:10.1136/jnnp-2014-309424



Contributors RMA was involved in study concept, data collection, statistical analyses, manuscript writing and preparation. VI, MCK and OP were involved in study concept, manuscript writing and preparation. ND was involved in data collection, manuscript writing and preparation. JRH was involved in study concept, manuscript writing and preparation; and study supervision.


Funding This work was supported by funding to Forefront, a collaborative research group dedicated to the study of frontotemporal dementia and motor neurone disease, from the National Health and Medical Research Council of Australia (NHMRC) programme grant (#1037746) and the Australian Research Council Centre of Excellence in Cognition and its Disorders Memory Node (#CE110001021) and other grants/ sources (NHMRC project grant #1003139). RMA is a Royal Australasian College of Physicians PhD scholar and MND Australia PhD scholar. OP is an NHMRC Career Development Research Fellow (#1022684).


Competing interests None. Ethics approval University of NSW HREC committee.






Idiaquez J, Roman GC. Autonomic dysfunction in neurodegenerative dementias. J Neurol Sci 2011;305:22–7. Jones SE. Imaging for autonomic dysfunction. Cleve Clin J Med 2011;78(Suppl 1):S69–74. Piguet O, Petersen A, Yin Ka Lam B, et al. Eating and hypothalamus changes in behavioral-variant frontotemporal dementia. Ann Neurol 2011;69:312–19. Seeley WW. Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct 2010;214:465–75. Robles Bayon A, Gude Sampedro F, Torregrosa Quesada JM. Bradycardia in frontotemporal dementia. Neurologia 2014;29:76–85. Perneczky R, Diehl-Schmid J, Forstl H, et al. Urinary incontinence and its functional anatomy in frontotemporal lobar degenerations. Eur J Nucl Med Mol Imaging 2008;35:605–10. Snowden JS, Bathgate D, Varma A, et al. Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry 2001;70:323–32. Neary D, Snowden JS, Gustafson L, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–54. Davis KD, Kwan CL, Crawley AP, et al. Functional MRI study of thalamic and cortical activations evoked by cutaneous heat, cold, and tactile stimuli. J Neurophysiol 1998;80:1533–46.

Provenance and peer review Not commissioned; externally peer reviewed. ▸ Additional material is published online only. To view please visit the journal online ( 1136/jnnp-2014-309424).

J Neurol Neurosurg Psychiatry Month 2014 Vol 0 No 0

Downloaded from on July 21, 2015 - Published by

Autonomic dysregulation in frontotemporal dementia R M Ahmed, V Iodice, N Daveson, M C Kiernan, O Piguet and J R Hodges J Neurol Neurosurg Psychiatry published online December 30, 2014

Updated information and services can be found at:

These include:

Supplementary Supplementary material can be found at: Material html


This article cites 9 articles, 3 of which you can access for free at:

Email alerting service

Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.


To request permissions go to: To order reprints go to: To subscribe to BMJ go to:

Autonomic dysregulation in frontotemporal dementia.

Autonomic dysregulation in frontotemporal dementia. - PDF Download Free
126KB Sizes 0 Downloads 15 Views