This is the first controlled study of autonomic function in AD, VAD, DLB and PDD in comparison with healthy controls. The findings, based on a range of clinical autonomic tests and sensitive research tools, emphasise the importance of autonomic dysfunction in dementia. There were significant differences in severity of cardiovascular autonomic dysfunction between the four types of dementia. PDD and DLB had considerable dysfunction. VAD showed limited evidence of autonomic dysfunction and, in AD, apart from orthostatic hypotension, autonomic functions were relatively unimpaired. The prevalence of autonomic neuropathy, as measured by the Ewing criteria, was more common in all of the dementia subtypes than in controls, but was especially prominent in PDD.
PDD and DLB cases both showed evidence of parasympathetic dysfunction on clinical testing and, apart from the Valsalva ratio, the degree of impairment was similar. However, on sympathetic testing, patients with PDD were more impaired than patients with DLB, although there was some evidence of sympathetic dysfunction in DLB in multivariate analyses. Both AD and VAD patients had a higher prevalence of sustained orthostatic hypotension and autonomic neuropathy than controls, but in other group comparisons did not differ from controls.
There has been considerable debate about the diagnostic concepts of PDD and DLB. It has been suggested that in PD, Lewy body pathology begins in the brainstem and progresses to the neocortex.25
However, there may be a different pattern of evolution in DLB, with some studies suggesting that cerebrocortical pathology predominates in DLB,26,27
although prominent Lewy body pathology is still evident in the brainstem, including the dorsal vagal nucleus.28
In our study the profile of parasympathetic abnormalities in PDD and DLB suggests that there is significant central autonomic involvement of the dorsal vagal nucleus in both conditions. Inevitably, patients with PDD were taking a higher dose of levodopa, reflecting the duration of their disease. In comparisons between PDD and DLB, use of levodopa and dose are not constantly correlated, but the correlation is strong. Adjustment for levodopa use or dose in the multivariate analyses comparing PDD and DLB would therefore result in the significant differences being lost. However, this does not necessarily mean that differences between PDD and DLB were solely due to the pharmacological effect of levodopa. It is more likely that they are measuring a similar variable, namely the extent of brainstem disease, as opposed to cortical disease.
The origin of sympathetic dysfunction in Lewy body diseases has been thought to be mainly a result of peripheral sympathetic denervation.29
I‐meta‐iodobenzylguanidine scintigraphy and neuropathological studies have found evidence of cardiac sympathetic denervation in PD and DLB.30,31
Lewy body pathology can also be found in medullary regions controlling preganglionic sympathetic neurons, but with relative preservation of catecholaminergic neuronal populations.32
Our findings suggest that sympathetic dysfunction is present in PDD and DLB, but less marked in DLB patients. This raises the possibility that there may a differential susceptibility and order of involvement of central and peripheral autonomic neurons to Lewy body pathology in DLB and PDD. This needs to be addressed in comparative neuropathological studies of the autonomic nervous system, but highlights a potentially important pathological difference between the two conditions.
The increased frequency of autonomic neuropathy in all dementias emphasises the importance of these conditions in all people with dementia. Their impact on key symptoms such as dizziness, syncope, falls, constipation and incontinence needs to be investigated. Specifically, the current study identifies an increased prevalence of orthostatic hypotension in all dementias. Although orthostatic blood pressure responses can be impaired for a number of reasons, including medications, endothelial dysfunction and age related orthostatic hypotension, our findings remained significant after adjusting for age, sex, duration of dementia, hypertension, diabetes and cardiovascular medications, suggesting that autonomic dysfunction was possibly an attributable cause of orthostatic hypotension in these patients. No studies have compared the effects of sustained orthostatic hypotension on the risk of falls in different types of dementia. Our findings highlight the importance of orthostatic hypotension in all patients with dementia and the need for further research into sustained orthostatic hypotension as a modifiable risk factor for falls. In elderly people without cognitive impairment, simple measures such as adequate hydration, support hosiery and pharmacological treatments such as fludrocortisone and midodrine can be used to manage orthostatic hypotension, as part of a multifactorial intervention to reduce the risk of falls.33
Trials of multifactorial falls interventions for people with mild to moderate dementia are a priority.
Cholinergic dysfunction has been discussed as a potential cause of autonomic failure in patients with dementia, and may be particularly important in PDD and DLB, where cholinergic deficits are especially pronounced, and where the disease pathology involves the dorsal vagal nucleus. In this context, it will be important to determine the impact of cholinesterase inhibitor therapy in patients with dementia with autonomic impairment. Preliminary reports suggest an adverse effect of donepezil on autonomic function, leading to carotid sinus hypersensitivity and falls in some individuals.34
The general impact of cholinesterase inhibitors on autonomic function is difficult to determine from the existing clinical trial literature, given the selected nature of the patient populations, but will be important to establish for clinical practice where patients are more frail and more likely to have autonomic symptoms.
The study included an appropriately aged control group, which is of importance because autonomic function declines with age.35
Although the controls were slightly older than the PDD group (mean difference 3.9 (1.4) years), this strengthens the finding that dysautonomia is most impaired in PDD, as it is likely that even greater differences would have been found if the PDD cases were compared with younger controls. Unfortunately, the VAD group were slightly older than the control group (mean difference 3.9 (1.6) years), and this leads to some uncertainty with respect to the findings in this group. The abnormalities in the heart rate responses to standing and Valsalva manoeuvre may not have been present if comparisons had been made with an older control group. In addition, some of the responses to the Ewing tests might not have been classified as abnormal or borderline if they were compared with a more closely age matched control group, with the result that the prevalence of autonomic neuropathy could have been overestimated. Nevertheless, the number of abnormal findings in our VAD group was few, and therefore we are able to conclude that there is no substantial dysautonomia in VAD, and that comparison with an older control group would be likely to improve the strength of this finding.
We conclude that autonomic dysfunction can occur in all common dementias in older people, but is a particularly common feature of DLB and PDD. The high prevalence of autonomic neuropathy and sustained orthostatic hypotension in dementia has potentially important implications for patient management.