Some of the most severe forms of dysautonomia appear in neurodegenerative diseases. Aggregation of misfolded protein is a common characteristic of many neurodegenerative disorders, with considerable interaction between pathologic/toxic proteins and neurodegeneration. Dysautonomia is common in the synucleinopathies, a group of disorders characterized by intracellular cytoplasmic inclusions of abnormal accumulation of misfolded α-synuclein protein. Synucleinopathies include Lewy body disorders (Parkinson disease [PD], dementia with Lewy bodies [DLB], and pure autonomic failure [PAF]), as well as multiple system atrophy (MSA). Lewy body disorders are characterized by Lewy bodies and Lewy neurite aggregates, which mainly consist of α-synuclein assembled into fibrillar inclusions that stain with periodic acid–Schiff and ubiquitin [2, 3]. In addition, most of these neurodegenerative diseases, as well as others such as some tauopathies (characterized by accumulation of tau protein as a major constituent of neurofibrillary tangles, e.g. corticobasal degeneration [CBD] and progressive supranuclear palsy [PSP]), present with parkinsonian movement disorders, and some also present with dementia. The pathologic interaction among different neurodegenerative processes also includes the amyloidopathies, which also may present with dementia (e.g., Alzheimer disease [AD]). LBs Lewy bodies, OH orthostatic hypotension, PDD Parkinson disease dementia.

The overlapping of pathophysiologic and clinical features among different neurodegenerative diseases often makes the differential diagnosis difficult, especially in the early stages or in patients with atypical symptoms, resulting in an initial misdiagnosis in nearly 25 % of patients with parkinsonism. Cardiac sympathetic imaging helps in this differential diagnosis, as can be seen here. The decreased cardiac ¹²³I-MIBG uptake reflects the extensive distribution of Lewy aggregates through the nervous system (in both the central and peripheral nervous systems in PD and DLB, and in the peripheral nervous system in PAF), including the postganglionic sympathetic and intrinsic neurons in the heart (Adapted from Kashihara et al. [4]).

In a study including 391 outpatients with parkinsonian symptoms and 10 healthy control individuals of similar age, ¹²³I-MIBG was decreased in most patients with PD. However, more than half the patients without PD also exhibited low uptake, resulting in a sensitivity of 87.7 % and specificity of 37.4 % for detecting PD (H/M ratio cutoff value >2 standard deviations below the control mean), indicating that cardiac sympathetic denervation is not specific for PD. CVD cardiovascular disease, SDAT senile dementia of Alzheimer type (Adapted from Nagayama et al. [5]).

Planar images of the thorax in the anterior view acquired at 15 minutes and 4 h after ¹²³I-MIBG injection in a patient with PD (a) and a patient with MSA (b). Cardiac ¹²³I-MIBG uptake is extremely reduced in the patient with PD, but only mildly reduced in the patient with MSA.

Dopamine transporter (DAT) imaging by means of brain single-photon emission computed tomography (SPECT) with ¹²³I- fluoropropyl (FP)-β-carbomethoxy-3 β-(4-iodophenyltropane) (CIT) usually is abnormal in patients with parkinsonian movement disorders, who show reduced striatal ¹²³I-FP-CIT uptake. (a), This abnormality is seen in this patient with DLB, who also shows impairment of cardiac sympathetic innervation, as reflected by extremely reduced cardiac ¹²³I-MIBG uptake. (b), Planar images of the thorax at 15 min and 4 h of ¹²³I-MIBG injection.

In patients older than 65 years with cognitive decline, DLB is the second most common neurodegenerative dementia after AD, accounting for 10 % of all dementias [6–8]. Differential diagnosis between DLB and AD has important therapy implications, as DLB may benefit from treatment with cholinesterase inhibitors and carbidopa–levodopa, whereas it may worsen from treatment with anticholinergics and certain neuroleptic medications. Predominance of deficits in attention and visual perception over deterioration of memory and naming; psychiatric features, such as fluctuating cognition and recurrent visual hallucinations; parkinsonism; REM sleep behavior disorder; and dysautonomia are more common in DLB, but distinguishing DLB from AD is clinically challenging, especially in the early disease stages [6]. Among the different imaging techniques used in the diagnosis of DLB, DAT imaging has had the greatest effect so far. Exhibition of reduced DAT uptake in the basal ganglia is listed as one of the suggestive features of DLB [9]. However, cardiac ¹²³I-MIBG imaging also has been advocated as useful in this setting because of the similarities between PD and DLB (Fig. 9.1) [10, 11]. Decreased cardiac ¹²³I-MIBG uptake in DLB has been reported, whereas uptake is normal or near normal in AD. In a direct comparison between cardiac ¹²³I-MIBG imaging and ¹²³I-FP-CIT SPECT in the same cohort of DLB patients, Camacho et al. [12] found that all patients with reduced cardiac ¹²³I-MIBG uptake (23 of 28 patients with a clinical diagnosis of DLB) also showed reduced striatal ¹²³I-FP-CIT uptake (orange dots in the figure). Interestingly, the five patients with normal cardiac ¹²³I-MIBG uptake (green dots in the figure) also showed normal striatal ¹²³I-FP-CIT uptake. In addition, H/M ratio correlated positively with striatal ¹²³I-FP-CIT uptake ratios (R = 0.6; P < 0.05). Horizontal and vertical lines in the figure reflect normal values for H/M ratio (1.56) and ¹²³I-FP-CIT binding in basal ganglia (2.51). The severity of parkinsonism was highly correlated with striatal ¹²³I-FP-CIT uptake but not with cardiac ¹²³I-MIBG uptake. Other studies have shown that reduced cardiac ¹²³I-MIBG uptake in DLB is not related to autonomic failure or parkinsonism [4, 11], but patients with DLB and orthostatic hypotension (OI) have lower ¹²³I-MIBG uptake than patients with DLB without OI [13]. An advantage of cardiac ¹²³I-MIBG over DAT imaging is the short acquisition time and comfortable planar imaging, which is appreciated by patients and their caregivers [14]. Current guidelines include abnormal cardiac ¹²³I-MIBG imaging as one of the supportive features commonly present in DLB but not proven to have diagnostic specificity [9]. Debate is ongoing regarding whether abnormal cardiac ¹²³I-MIBG scintigraphy should be upgraded in the guidelines as a feature suggestive of DLB, but evidence is still lacking and further studies are warranted [15] (Adapted from Camacho et al. [12]).

Diabetes mellitus (DM) is the most common identifiable cause of neuropathy. Approximately 50 % of patients with type 1 (T1DM) or type 2 DM (T2DM) will develop diabetic neuropathy, which is a serious complication involving variable multiple organ involvement, principally of the cardiovascular system but also of the gastrointestinal and urogenital tracts. Cardiovascular autonomic diabetic neuropathy (CADN) is the primary disorder of diabetic neuropathy, and it is defined as the impairment of cardiovascular autonomic control in patients with established DM after the exclusion of other causes [16]. CADN likely has a multifactorial pathogenesis, as shown here, leading to neuronal ischemia and/or direct neuronal death or dysfunction, as well as left ventricular (LV) dysfunction. It probably is the most common form of autonomic dysfunction worldwide, and its prevalence varies between 1 and 90 % in patients with T1DM and 20 and 73 % in those with T2DM. Such wide variation is a result of the discrepancy in the criteria used to diagnose CADN and differences in the study populations in relation to CADN risk factors (conventional cardiovascular risk factors, glycemic control, and DM duration) [17]. AGE advanced glycation end products, BP blood pressure, Catechol catecholamine, FFA free fatty acids, Glu glucose, PARP poly (ADP-ribose) polymerase; PKC protein kinase C, RAAS renin–angiotensin–aldosterone system, RAGE receptor for advanced glycation end products, ROS reactive oxygen species, SNS sympathetic nervous system, Vc vasoconstriction.

(a), CADN may result in disabling clinical and functional manifestations, with an associated increased mortality risk. A meta-analysis showed that the pooled estimated relative mortality risk for DM patients with CADN was 2.14 (95 % CI, 1.83–2.51) [18]. In addition, among other risk factors, CADN has the strongest association with mortality [19]. (b), CADN remains a significant predictor of death after adjustment for conventional cardiovascular risk factors [20, 21], and CADN appears to be associated with major cardiovascular events [22]. Despite normal myocardial perfusion imaging in DM patients predicting an improved prognosis [23], the presence of CADN increases cardiovascular risk by mechanisms that are not fully understood [21]. CADN also is associated with a higher mortality risk in DM patients after a first myocardial infarction, which suggests that screening for CADN in these patients might be used for risk stratification [24].