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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 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 (p<0.001), with the SD also scoring lower than the bvFTD group (p<0.001). The control group had a higher prevalence of treatment with antihypertensives than the SD group (13/29 control, 1/20 SD, bvFTD 8/28, 3/21 AD) and the SD group had a higher prevalence of treatment with antidepressants than controls (10/20 SD, 2/29 control, bvFTD 9/28, 5/21 AD). As expected the AD group had a higher prevalence of treatment with a cholinesterase inhibitor (12/20 AD, 2/28 bvFTD and 2/20 SD).
Group differences were present (p<0.001) in the overall severity×frequency score for the ASQ. The bvFTD group had a higher score (mean=42.3) compared with the AD (mean=17.5, p=0.002) and control groups (mean=11.2, p<0.001). The SD group (mean=33.5) also scored higher than the control group (p<0.001). Results across the domains of autonomic function are shown in table 1.
Frequency of symptoms
A number of symptoms had increased prevalence in the bvFTD and SD groups. Highest reported prevalences in the bvFTD group related to changes in temperature regulation including reduced tolerance to cold (42.9%), change in sweating pattern (25%) and facial flushing (32.1%) as well as urinary symptoms including frequency (21.4%) and urinary incontinence (46.4%; see online supplementary table). The bvFTD group described a change in sweating pattern, which was typically experienced as increased body and facial sweating. The bvFTD group also reported increased symptoms of fatigue, weakness and tiredness suggesting orthostatic hypotension and swallowing difficulties suggesting gastrointestinal dysfunction. Patients with SD reported an increased prevalence of weakness, fatigue and pain around the neck and shoulders, which can indicate a postural drop in blood pressure and orthostatic hypotension. The SD group also reported increased symptoms of constipation, excessive fullness after a small meal, reduced tolerance to cold and tiredness during the day.
We found that patients with bvFTD had increased frequency and severity of symptoms across all domains of autonomic function when compared to control subjects, and in thermoregulatory/sweating, and urinary and sleep symptoms when compared to AD patients. Patients with SD had an increased frequency and severity of symptoms in the domains of blood pressure and cardiovascular functions compared to controls and patients with AD, and gastrointestinal functions and urinary and sleep symptoms compared to control subjects. Overall, the bvFTD group had increased autonomic abnormalities compared to the AD and control groups, and the SD group increased abnormalities when compared to the control group.
The autonomic nervous system involves both peripheral parasympathetic and sympathetic input as well as central cortical input.1 Many of the specific autonomic 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.
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.
Provenance and peer review Not commissioned; externally peer reviewed.
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