Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson’s Disease

Abstract

Background:

Orthostatic hypotension (OH) at an early stage of Parkinson’s disease (PD) predicts poor prognosis, which may suggest degeneration of dopaminergic neurons affects sympathetic function, causing OH.

Objective:

We tested the hypothesis that striatal dopaminergic depletion is associated with OH in PD.

Methods:

Out of 99 patients with newly diagnosed untreated PD, 81 patients were enrolled according to our selection criteria. All patients underwent head-up tilt-table testing and striatal ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (¹²³I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT). DaTQUANT software (GE Healthcare) was used as a semi-quantitative tool to analyze DAT-SPECT data. The association between hemodynamic changes and ¹²³I-FP-CIT uptake was examined.

Results:

¹²³I-FP-CIT uptake in the putamen, especially the anterior part and left side, was related not only to motor severity but also to OH. Change in systolic blood pressure correlated negatively with ¹²³I-FP-CIT uptake in bilateral anterior putamen (left: p < 0.01, right: p < 0.05) and left posterior putamen (p < 0.05). Patients with OH had more severe dopamine depletion in left anterior (p = 0.008) and posterior (p = 0.007) putamen at a similar motor severity than did patients without OH even though both groups have similar baseline characteristics. An analysis of asymmetry index showed patients with OH had symmetrically decreased dopamine levels in anterior putamen when compared to those without OH (p = 0.024).

Conclusion:

OH is closely related to striatal dopamine depletion in PD. This relation may help to account for the prognostic value of OH.

Keywords

Autonomic nervous system Parkinson’s disease single photon emission tomography (SPECT)orthostatic hypotension striatal dopamine depletion

INTRODUCTION

Symptoms of Parkinson’s disease (PD) include not only motor dysfunction but also non-motor symptoms. Sympathetic cardiovascular failure such as orthostatic hypotension (OH) is clinically important because it is present at the pre-motor phase and associated with future declines in motor and cognitive function and mortality [1 –4]. Nigrostriatal denervation reflected in ¹²³I-ioflupane dopamine transporter single photo emission computed tomography (DAT-SPECT) is also present at pre-motor phase in susceptible individuals who later develop PD [5]. In addition, a recent clustering-derived subtyping study has identified OH at an early stage of disease as a risk for rapidly progressive subtype (also named “diffuse malignant”) [6]. This finding suggests patients with OH would more likely have widespread alpha-synuclein involvement of both dopaminergic and sympathetic noradrenergic structures. However, it may also suggest that degeneration of dopaminergic neurons affects sympathetic function, causing OH. Direct evidence supporting this hypothesis is lacking.

Striatal dopamine depletion, particularly in anterior putamen, at an early stage of disease is associated with a higher risk for motor complication and dementia conversion [7]. We wondered if patients with OH already have dopamine depletion in such vulnerable striatal subregions at an early stage of PD.

We hypothesized that change in hemodynamics during orthostatic stress is associated with dopaminergic depletion in specific striatal subregions. We therefore investigated the relation between OH and striatal DAT uptake.

METHODS

Patients

A total of 99 patients with newly diagnosed un-treated PD were entered into a research database at The Jikei University School of Medicine from February 2014 through April 2019. PD was diagnosed according to the clinical diagnostic criteria of the UK Parkinson’s Disease Society Brain Bank [8], and we confirmed the presence of a PD drug response for longer than 1 year during the follow-up period. The clinical diagnosis was also supported by DAT-SPECT using ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (¹²³I-FP-CIT), which revealed that all patients had decreased dopamine transporter uptake in the striatum, mainly in the posterior putamen on visual analysis.

None of the patients had received levodopa, other anti-Parkinson drugs, or treatment for orthostatic hypotension (OH). The motor severity of PD was assessed according to the Unified Parkinson’s Dise-ase Rating Scale (UPDRS) part III scores. The pat-ients were divided into tremor-dominant type (TDT), akinetic-rigid type (ART), and mixed type (MXT) subgroups on the basis of the tremor and non-tremor scores, estimated with the use of part III of the UPDRS, as described by Spiegel and colleagues [9]. If patients were already receiving antihypertensive dr-ugs, such drugs were withdrawn at least 48 hours before orthostatic hypotension was evaluated. All pat-ients underwent evaluation of their olfactory function and Mini-Mental State Examination (MMSE). Olfactory function was assessed by the odor stick ide-ntification test for the Japanese (OSIT-J) (Daiichi Yakuhin Sangyo Co. Ltd., Tokyo, Japan) according to our previous report [10]. Symptom duration was measured from the onset of one of four hallmark symptoms of PD. This study was approved by the Ethics Committee of Jikei University School of Medicine, and all subjects gave written informed consent before enrollment.

We excluded 18 patients because they met any of the following exclusion criteria: 1) Patients who had lesions including atrophy on brain magnetic res-onance imaging of the striatum, brainstem, or cerebellum. 2) Patients with overt diabetes, cirrhosis, end-stage renal failure, anemia, dehydration on blood tests and relevant cardiac disease or any abnormalities on routine chest radiography or electrocardiography. 3) Patients with cognitive dysfunction as indicated by MMSE score less than 24. 4) Patients who were receiving medications known to interact with the striatal binding of ¹²³I-FP-CIT [11] and to affect autonomic function, such as beta-blockers and anticholinergic agents. 5) Patients aged less than 50 years and over 85 years.

Consequently, we retrospectively analyzed data from 81 patients with newly diagnosed untreated PD.

¹²³I-FP-CIT SPECT

SPECT was performed using a dual-head scintillation camera (Discovery NM 630; GE Healthcare) with a low energy-high resolution collimator, 4 h after a bolus injection of 167 MBq of ¹²³I-FP-CIT (DaTSCAN; Mediphysics, Tokyo, Japan). The imaging time was 32 min. The parameters of acquisition were as follows: rotation radius 15 cm, circular orbit; zoom 1.33; matrix size 128×128 pixels, pixel size 3.32 mm²; acquisition time 4 rotations, 8 m per rotation, 120 projections per rotation; and energy window 159 KeV±10%. Data were reconstructed by the ordered-subset expectation maximization (OSEM) method (iteration: 2, subset: 10) using a Butterworth filter setting with a critical frequency of 0.7 and a power of 10.0. Semi-quantitative calculations of str-iatal uptake were performed with the use of DaT-QUANT software (GE Healthcare). This software package calculated the patient’s uptake automatically. The volumes of interest (VOIs) of DaTQUANT fixed-size were semi-automatically placed over the right and left putamen and caudate nucleus in the transaxial slice showing the most intense tracer uptake and adjusted manually if necessary. Another VOI was placed over the occipital lobe representing cortical background. The software automatically placed the same VOIs in the adjacent previous and following slices so that data from three contiguous slices were used. Patient’s uptake was calculated for the posterior putamen (PP), anterior putamen (AP), and caudate nucleus (CA) by dividing the mean counts per pixel in the corresponding VOI by the mean count per pixel in the occipital lobe VOI. The software also pr-ovided a percent deviation of patient’s uptake from the age-matched, mean value of the normal database (118 healthy volunteers) that the patient’s measured value represents [12, 13]. Asymmetry index for the PP, AP, and CA was calculated according to the formula: [(a-b)/(a+b)]×2×100, where a and b represent the two different side [14].

Head-up tilt-table testing (HUT)

All subjects underwent HUT in a silent room, maintained at an ambient temperature of 23°C to 26°C. After an overnight fast, the subjects comme-nced the study between 9:00 am and 10:00 am. After 20 min of rest in the supine position, the subject was tilted to a 60° upright position within 15 s by means of a head-up tilt table. Brachial systolic and diastolic blood pressures were meaured with an automated sphygmomanometer after 20 min of rest in the supine position (SBP_supine, DBP_supine) and every 1 min after the subject was tilted for up to 10 min. The maximum falls in systolic blood pressure (⊿SBP), diastolic blood pressure (⊿DBP) and mean arterial pressure (MAP) defined as (SBP+2 x DBP)/3 in a tilt-up position were evaluated. Supine hypertension was defined as SBP_supine≥140 mmHg and/or DBP_supine≥90 mmHg. OH was defined as ⊿SBP≥20 mmHg and/or ⊿DBP≥10 mmHg in patients without supine hypertension, or as ⊿SBP≥30 mmHg in patients with supine hypertension [15 –17].

Cardiac MIBG scintigraphy

To evaluate cardiac sympathetic denervation, cardiac MIBG scintigraphy was performed. The ratio of the average pixel count in the heart (H) to that in the mediastinum (M) (H/M ratio) 15 min (early) and 3 hours after (delayed) of injection of 111 MBq ¹²³I-MIBG (FUJIFILM RI Pharma Co., Ltd. Tokyo, Japan) was calculated. The lower limit of normal ratio is 2.3 for early H/M and 2.1 for delayed H/M [18].

Statistical analyses

Statistical analyses were performed using a statistical data analysis system (Esumi Co., Ltd., Tokyo, Japan). One-way analyses of variance (with Bonferroni post hoc testing) were used to compare groups, and χ² tests were used to compare frequencies for categorical variables. Relations between sympathe-tic cardiovascular variables and ¹²³I-FP-CIT uptake were tested by Pearson product-moment. Associations of sympathetic cardiovascular variables with ¹²³I-FP-CIT uptake were also examined by multiple regression analysis or analysis of covariance with adjustment for covariables. p values of < 0.05 were considered to indicate statistical significance.

RESULTS

Baseline results

Among the 81 patients, 43 were men (53.1 %). Mean age (±SD) and symptom duration were 70.6±8.9 years and 1.5±1.5 years, respectively. UPDRS-III scores averaged 20.0±9.7. Sixty-one (75.3%) patients had ART PD. OSIT-J scores and MMSE averaged 4.8±2.8 and 28.4±1.9, respectively. Thirty-five patients had hypertension and were receiving antihypertensive drugs. Thirty-three patients had OH. Of these patients, 28 patients had OH within 3 min of upright tilt-table testing (classic-al OH) and 5 patients had OH beyond 3 min (delayed OH).

Clinical characteristics of patients with and without OH were summarized in Table 1. Age, sex, sym-ptom duration, motor subtype and MMSE in the two groups did not differ statistically. The two groups had similar UPDRS-III scores. Olfactory function and cardiac uptake of MIBG tended to be lower in patients with OH than in those without OH [olfactory function: 4.1±2.8 vs. 5.2±2.8, p = 0.108, cardiac uptake of MIBG (delayed): 1.35±0.33 vs. 1.48±0.41, p = 0.062].

Table 1

Comparison of clinical characteristics between PD patients with and without OH ^a

N = 81	No OH (n = 48)	OH (n = 33)	p	adjusted p^†
Age (years)	70.7±9.8	70.5±7.6	0.690
UPDRS-III scores	20.1±9.4	20.0±10.3	0.897
Motor subtype (ART/TDT or MT)	36/12	25/8	0.938
Men	22 (45.8%)	21 (63.6%)	0.115
Symptom duration (years)	1.5±1.4	1.5±0.9	0.576
HT	23 (47.9%)	12 (36.4%)	0.302
HbA1c(NGSP) (%)	5.8±0.5	5.9±0.7	0.854
Olfactory function (OSIT-J scores)	5.2±2.8	4.1±2.8	0.108
MMSE	28.5±1.8	28.2±1.9	0.563
SBP supine (mmHg)	127±22	130±21	0.551
DBP supine (mmHg)	74±12	77±13	0.265
⊿SBP (mmHg)	10±9	35±16	1.72x10^–12
⊿DBP (mmHg)	2±7	14±10	3.06x10^–6
MAP in a tilt-up position (mmHg)	87±15	74±14	3.89x10^–4
Cardiac uptake of MIBG early H/M	1.69±0.41	1.59±0.37	0.172
delayed H/M	1.48±0.41	1.35±0.33	0.062
Patient’s uptake
PP Right	0.34±0.21	0.27±0.17	0.136	0.103
PP Left	0.33±0.16	0.25±0.13	0.025	0.007
AP Right	0.66±0.28	0.55±0.22	0.063	0.064
AP Left	0.68±0.26	0.53±0.17	0.006	0.008
CA Right	1.11±0.34	0.97±0.38	0.055	0.077
CA Left	1.12±0.39	0.98±0.31	0.064	0.120
Percent deviation^*
PP Right	–71.28±16.95	–78.10±13.02	0.077	0.076
PP Left	–71.91±14.23	–80.72±9.49	0.008	0.002
AP Right	–62.40±15.17	–69.26±11.73	0.045	0.055
AP Left	–61.70±14.25	–71.30±8.60	0.001	0.002
CA Right	–45.79±15.55	–52.92±18.01	0.032	0.081
CA Left	–47.34±17.61	–54.69±14.05	0.041	0.088

PD, Parkinson’s disease; OH, orthostatic hypotension; UPDRS-III, Unified Parkinson’s Disease Rating Scale part III; HT, hypertension; NGSP, National Glycohemoglobin Standardization Program, BMI, body mass index; ART, akinetic-rigid type; TDT, tremor-dominant type; MT, mixed type; OSIT-J, odor stick identification test for the Japanese; MMSE, Mini-Mental State Examination; SBP, systolic blood pressure; DBP, diastolic blood pressure; ⊿SBP, difference in systolic blood pressure between two positions; ⊿DBP, difference in diastolic blood pressure between two positions; MAP, mean arterial pressure; MIBG, ¹²³I-metaiodobenzylguanidine; H/M, heart-to-mediastinum ratio. ^†Analyses were performed by analysis of covariance (ANCOVA) test controlling for age, sex, symptom duration, motor subtype, UPDRS-III scores and cardiac uptake of MIBG(delayed).

Differences in striatal ¹²³I-FP-CIT uptake between patients with and without OH

The comparison of striatal ¹²³I-FP-CIT uptake between patients with and without OH were also summarized in Table 1. Patients with OH had significantly lower 123I-FP-CIT uptake in left PP and AP than did those without OH after adjusting for age, sex, symptom duration, motor subtype, UPDRS-III score and cardiac uptake of MIBG (delayed) (Patient’s uptake: left PP; p = 0.007, left AP; p = 0.008, Percent deviation: left PP; p = 0.002, left AP; p = 0.002).

Correlations of ¹²³I-FP-CIT uptake in striatal subregions with hemodynamic changes during HUT

There was no correlation between supine blood pressure and ¹²³I-FP-CIT uptake in any striatal subregions (Table 2). In contrast, there was a significant correlation between the degree of OH and ¹²³I-FP-CIT striatal uptake.

Table 2

No correlation of striatal ¹²³I-FP-CIT uptake with supine blood pressure

N = 81	SBP_supine		DBP_supine
	r	adjusted p^†	r	adjusted p^†
Patient uptake
PP Right	0.114 c	0.121	0.160 ^c	0.536
PP Left	0.037 c	0.740	0.082 ^c	0.897
AP Right	0.030 c	0.215	0.162 ^c	0.677
AP Left	0.037 c	0.373	0.093 ^c	0.879
CA Right	–0.089 c	0.944	0.091 ^c	0.515
CA Left	–0.055 c	0.789	–0.004 ^c	0.196
Percent
deviation^*
PP Right	0.154 c	0.163	0.122 ^c	0.616
PP Left	0.084 c	0.764	0.050 ^c	0.917
AP Right	0.065 c	0.262	0.131 ^c	0.760
AP Left	0.089 c	0.369	0.074 ^c	0.938
CA Right	–0.066 c	0.952	0.060 ^c	0.453
CA Left	–0.020 c	0.798	–0.011 ^c	0.213

¹²³I-FP-CIT, ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane; SBP_supine, systolic blood pressure after 20 min of rest in the supine position; DBP_supine, diastolic blood pressure after 20 min of rest in the supine position; PP, posterior putamen, AP, anterior putamen; CA, caudate. ^*This value is percentage of deviation from age-matched, mean value of normal database from the Parkinson Progression Makers Initiative. ^c p > 0.05. ^† p value after adjusted for age, sex, symptom duration, motor subtype, UPDRS-III scores and cardiac uptake of MIBG (delayed).

Correlations of ¹²³I-FP-CIT uptake in striatal subregions with the changes in blood pressure during HUT are summarized in Table 3. ¹²³I-FP-CIT uptake in the putamen, especially anterior part and the left side, was negatively associated with ⊿SBP (Patient’s uptake: left PP; p = 0.013, left AP; p = 0.009, right AP; p = 0.048, Percent deviation: left PP; p = 0.006, left AP; p = 0.006, right AP; p =0.041) and ⊿DBP (Patient’s uptake: left PP; p =0.017, left AP; p = 0.007, Percent deviation: left PP; p = 0.022, left AP; p = 0.013), and positively associated with MAP in a tilt-up position (Patient’s uptake: left PP; p = 0.031, left AP; p = 0.015, right PP; p = 0.037, right AP; p = 0.032, Percent deviation: left PP; p = 0.028, left AP; p = 0.014, right PP; p = 0.041, right AP; p = 0.043) after adjustment for age, sex, symptom duration, motor subtype, UPDRS-III scores and cardiac uptake of MIBG (delayed) on multiple regression analysis. Multiple regression an-alysis also revealed that ¹²³I-FP-CIT uptake in all of these regions was associated with UPDRS-III scores as well as hemodynamic changes [Left PP: UPDRS-III scores; β=–0.255, p = 0.040, ⊿SBP; β=–0.285, p = 0.013, R² = 0.169, Left AP: UPDRS-III scores; β=–0.285, p = 0.015, ⊿SBP; β=–0.279, p = 0.009, R² = 0.270 (Fig. 1), Right AP: UPDRS-III scores; β=–0.269, p = 0.018, ⊿SBP; β=–0.206, p = 0.048, R² = 0.309].

Table 3

Correlation of striatal ¹²³I-FP-CIT uptake with change in hemodynamics during head-up tilt-table testing

N = 81	⊿SBP		⊿DBP		MAP in a tilt-up position
	r	adjusted p^†	r	adjusted p^†	r	adjusted p^†
Patient’s uptake
PP Right	–0.204	0.092	–0.140	0.328	0.274 ^a	0.037
PP Left	–0.251 ^a	0.013	–0.249 ^a	0.017	0.260 ^a	0.031
AP Right	–0.260 ^a	0.048	–0.186	0.152	0.276 ^a	0.032
AP Left	–0.325 ^b	0.009	–0.316 ^b	0.007	0.322 ^b	0.015
CA Right	–0.214	0.106	–0.205	0.095	0.174	0.314
CA Left	–0.203	0.190	–0.255 ^a	0.052	0.160	0.442
Percent deviation^*
PP Right	–0.225 ^a	0.062	–0.150	0.301	0.284 ^b	0.041
PP Left	–0.274 ^a	0.006	–0.240 ^a	0.022	0.270 ^a	0.028
AP Right	–0.278 ^a	0.041	–0.189	0.177	0.284 ^a	0.043
AP Left	–0.345 ^b	0.006	–0.309 ^b	0.013	0.341 ^b	0.014
CA Right	–0.222 ^a	0.113	–0.206	0.130	0.171	0.413
CA Left	–0.211	0.162	–0.250 ^a	0.065	0.169	0.436

¹²³I-FP-CIT, ¹²³I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl)nortropane; ⊿SBP, difference in systolic blood pressure between two positions; ⊿DBP, difference in diastolic blood pressure between two positions; MAP, mean arterial pressure; PP, posterior putamen, AP, anterior putamen; CA, caudate. ^*This value is percentage of deviation from age-matched, mean value of normal database from the Parkinson Progression Makers Initiative. ^†p value after adjusted for age, sex, symptom duration, motor subtype, UPDRS-III scores and cardiac uptake of MIBG(delayed). ^ap < 0.05; ^bp < 0.01.

Fig. 1

¹²³I-FP-CIT uptake in left anterior putamen correlated negatively with UPDRS-III scores (a), fall in systolic blood pressure (b) and that in diastolic blood pressure (c).

Analysis of covariance showed that patients with OH had more severe dopamine depletion in the left PP and AP at a similar UPDRS-III scores than did patients without OH after adjusting post hoc for age, sex, symptom duration, motor subtype, UPDRS-III score and cardiac uptake of MIBG [Patients’ uptake: left PP; p = 0.007, left AP; p = 0.008, Percent deviation; left PP; p = 0.002, left AP; p = 0.002 (Fig. 2a)]. Dopamine depletion in the right AP was marginally significant [Patients’ uptake: p = 0.064, Percent deviation; p = 0.055 (Fig. 2b)].

Fig. 2

Patients with OH had a significantly lower ¹²³I-FP-CIT SPECT uptake in left (a) and a marginally significant lower uptake in the right (b) anterior putamen at a similar UPDRS motor score than did patients without OH after controlling for age, sex, symptom duration, motor subtype, UPDRS-III scores and cardiac uptake of MIBG. a solid line, patients with OH; a dotted line, patients without OH.

However, the interaction effect between the presence of OH and UPDRS-III scores on ¹²³I-FP-CIT uptake or percent deviation in left PP and bilateral AP was not significant (left PP and bilateral AP: p > 0.05).

Effect of OH on asymmetry index in striatal subregions

The results were shown in Table 4. Asymmetry index of patient’s uptake in PP, AP and CA was not significantly different between patient with and without OH. However, AP asymmetry index of percent deviation from age-matched, mean value of normal database was significantly decreased in patients with OH than in those without OH after adjusted for age, sex, symptom duration, motor subtype, UPDRS-III score and cardiac uptake of MIBG (null p < 0.001, adjusted p = 0.024).

Table 4

The association of orthostatic hypotension with asymmetry index in striatal subregions

N = 81	no OH	OH	p	adjusted p^†
Patient uptake
PP asymmetry index (%)	46.92±41.52	60.7±64.6	0.693	0.464
AP asymmetry index (%)	26.91±19.64	20.2±14.9	0.068	0.123
CA asymmetry index (%)	19.58±15.92	14.5±11.9	0.171	0.223
Percent deviation^*
PP asymmetry index (%)	17.14±17.52	12.83±10.80	0.538	0.197
AP asymmetry index (%)	16.95±16.15	8.30±8.32	<0.001	0.024
CA asymmetry index (%)	28.33±45.66	15.50±19.95	0.007	0.259

OH, orthostatic hypotension; PP, posterior putamen; AP, anterior putamen; CA, caudate. ^*This value is percentage of deviation from age-matched, mean value of normal database from the Parkinson Progression Makers Initiative. ^†Analyses were performed by analysis of covariance (ANCOVA) test controlling for age, sex, symptom duration, motor subtype, UPDRS-III scores and cardiac uptake of MIBG (delayed).

DISCUSSION

To the best of our knowledge, this study is the first to demonstrate an association between OH and striatal dopamine depletion in untreated early-stage patients with PD. Patients with OH had more severe dopamine depletion in left PP and AP at a similar UPDRS-III scores than did patients without OH even though two groups have similar baseline characteristics such as age, UPDRS-III scores. Dopaminergic depletion in the putamen, especially the anterior part and left side and, was closely related not only to motor severity but also to hemodynamic changes during ort-hostatic stress, whereas it was not associated with the degree of SH. It correlated negatively with cha-nges in blood pressure during orthostatic stress. In addition, an analysis of asymmetry index showed pat-ients with OH had symmetrically decreased dopa-mine levels in AP when compared to those without OH.

OH is attributed to combined failure or dysregulation of both central and peripheral parts of the autonomic nervous system. As for central regions, the degeneration of noradrenergic periacqueductal ductal grey neurons, rostral ventrolateral medulla, dorsolateral vagal motor nucleus and nucleus ambiguus is, in particular, associated with OH. These structures connect with the anterior cingulate cortex, insular cortex, amygdala, hypothalamus and thalamus, and control heart rate and cardiac contractility under orthostatic or emotional stress [19 –22]. Increasing evidence also suggests that the putamen participates in autonomic activities along with other brain regions, such as the brainstem, accumbens, thalamus, amygdala, insula, and anterior cingulate cortex [23, 24]. One study reports that patients with OH had reduced brainstem functional connectivity to the putamen during Valsalva maneuvers [23], and another study reports the right and left putamen volume positively correlate with parasympathetic cardiac vagal tone [24]. These previous findings seem to support our findings that dopaminergic depletion in the putamen is associated with autonomic activity during orthostatic stress.

Recent studies have shown patients with PD exhibit an asymmetric nigrostriatal dysfunction [25]. Therefore, we examined whether the presence of OH contributes to this asymmetry of striatal dopamine depletion. Although patients with OH exhibited left-hemispheric predominance of dopamine depletion in the putamen, asymmetry index in PP was not different between patients with and without OH. On the contrary, asymmetry index in AP of percent deviation from age-matched, mean value of normal database was significantly decreased in patients with OH than in those without OH, suggesting patients with OH have a symmetrically decreased DAT availability in AP even at early stage of disease.

The AP is a part of associative striatum and is thought to be associated with cognition in patients with PD [27]. Although many studies have suggested dopamine loss in the CA as a candidate for future cognitive impairment, it has documented that selective dopamine loss in AP at early stage of PD is associated with a higher risk for dementia conversion and motor complication [7]. Therefore, symmetrically decreased dopamine level in AP in patients with OH seems to support the association between OH and diffuse malignant subtype of PD.

One possible explanation for why the AP is specifically affected is that this region is vulnerable to early deposition of amyloid-β (Aβ). A recent paper investigating DAT activity on dementia with Lewy bodies (DLB) with and without Aβ deposition, reported a lower DAT activity in AP and ventral striatum in the subgroup with Aβ deposition [26]. This result suggests that AP and ventral striatum are the most vulnerable regions and are involved early in amyloid deposition. DLB is one of Lewy body spectrum disorders having more severe autonomic failure and cognitive dysfunction than PD. Striatal pathological changes in PD with OH might be similar to those in DLB.

On the other hand, parkinsonism with OH at an early-stage of disease may suggest multiple system atrophy with predominant parkinsonism (MSA-P) as well as PD. We confirmed, therefore, all enrolled patients had a PD drug response for longer than 1 year, and all patients with PD and OH were hyposmic (OSIT-J score 4.1±2.8 is classified into severe hyposmia [10]), which is not generally observed in patients with MSA-P who have preserved olfactory function. It has documented OSIT-J score averages 8.7±2.2 in patients with MSA-P [28].

OH in PD often occurs beyond 3 min standing, which is clinically important because it could contribute to falls and increase morbidity [29]. We therefore examined hemodynamic changes after subject was tilted for up to 10 min. Decreased cardiac uptake of MIBG reflects cardiac sympathetic dysfunction [30] and is possibly involved in the pathophysiology of OH [31]. We include, therefore, its value in the independent factors to confirm significant association between OH and striatal dopamine depletion on multiple regression analysis.

The strength of this study is that we enrolled only patients with newly diagnosed, drug-naïve PD who had never taken any drugs affecting autonomic and dopaminergic function. We tried minimizing confounding biases by excluding patients with young and very old onset PD and squaring baseline characteristics. However, our study had several limitations: First, this study focused on one subject group. We evaluated, therefore, a percent deviation of patient’s uptake from age-matched, normal database provided by the DaTQUANT software. DaTQUANT software was created in 2013 as an adjunct processing tool with advanced quantitative uptake methods and a designated normal database from the Parkinson Progression Markers Initiative (PPMI), a comprehensive study of patients with diagnosed PD, to provide a more accurate assessment of a patient’s case. The software is over 95%accurate in automatic VOI placement, with the option of manual adjustments as needed. DaTQUANT can redirect any image automatically back to the optimal orientation of the anatomy within the images, which can remove the head-tilt artifact and is related to the potential problem of inaccurate VOI placement [12, 13]. Second, this was a relatively small study with a relatively homogeneous ethnic background. Further studies are needed in patients of different ethnic origins to be able to generalize to the overall population of patients with PD worldwide.

In conclusion, this is the first study to show that hemodynamic change during orthostatic stress is closely related to striatal dopamine depletion in pat-ients with PD. Our findings may deepen the knowledge on striatal role in the sympathetic pathway, underlying mechanisms and helping also to identify PD patients for whom the most rapid progression rate could be expected.

CONFLICT OF INTEREST

The authors have no conflict of interest to report.

Footnotes

ACKNOWLEDGMENTS

Special thanks to radiological technologist Takashi Oshita for his time and dedication to obtain ¹²³I-FP-CIT SPECT data.

References

Goldstein

(2006) Orthostatic hypotension as an early finding in Parkinson’s disease. Clin Auton Res 16, 46–54.

Goldstein

, Holmes

, Sharabi

, Wu

(2015) Survival in synucleinopathies: A prospective cohort study. Neurology 85, 1554–1561.

Melora

, Romagnolo

, Rosso

, Suri

, Berndt

, Maule

, Lopiano

, Espay

(2018) Autonomic dysfunction in Parkinson’s disease: A prospective cohort study. Mov Disord 33, 391–397.

De Pablo-Fernandez

, Tur

, Revesz

, Lees

, Holton

, Warner

(2017) Association of autonomic dysfunction with disease progression and survival in Parkinson disease. JAMA Neurol 74, 970–976.

Ponsen

, Stoffers

, Booij

, van Eck-Smit

, Wolters

Ech

, Berendse

(2004) Idiopathic hyposmia as a preclinical sign of Parkinson’s disease. Ann Neurol 56, 173–181.

Fereshtehnejad

, Romenets

, Anang

, Latreille

, Gagnon

, Postuma

(2015) New clinical subtypes of Parkinson disease and their longitudinal progression: A prospective cohort comparison with other phenotypes. JAMA Neurol 72, 863–873.

Chung

, Lee

, Yoo

, Lee

, Sohn

(2020) Patterns of striatal dopamine depletion in early Parkinson’s disease: Prognostic relevance. Neurology 95, e280–e290.

Hughes

, Daniel

, Kilford

, Lees

(1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. A clinico-pathological study of 100 cases. J Neurol Neurosurgery Psychiatry 55, 181–184.

Spiegel

, Hellwig

, Samnick

, Jost

, Möllers

, Fassbender

, Kirsch

, Dillmann

(2007) Striatal FP-CIT uptake differs in the subtypes of early Parkinson’s disease. J Neural Transm 114, 331–335.

10.

Umehara

, Oka

, Nakahara

, Matsuno

, Murakami

(2020) Differential leukocyte count is associated with clinical phenotype in Parkinson’s disease. J Neurol Sci 409, 116638.

11.

Kägi

, Bhatia

, Tolosa

(2010) The role of DAT-SPECT in movement disorders. J Neurol Neurosurg Psychiatry 81, 5–12.

12.

DaTQUANT^TM. GE Healthcare website. https://www.gehealthcare.com/products/nuclearimaging agents/datquant . Accessed January 24, 2019.

13.

Brogley

(2019) DaTQUANT: The future of diagnosing Parkinson disease. J Nucl Med Technol 47, 21–26.

14.

Zijlmans

, Evans

, Fontes

, Katzenschlager

, Gacinovic

, Lees

, Costa

(2007) [123I] FP-CIT spect study in vascular parkinsonism and Parkinson’s disease. Mov Disord 22, 1278–1285.

15.

Fanciulli

, Jordan

, Biaggioni

, Calandra-Buonaura

, Cheshire

, Cortelli

, Eschlboeck

, Grassi

, HilZ

, Kaufamnn

, Mancia

, Mayer

, Norcliffe-Kaufmann

, Pavy-Le Traon

, Raj

, Robertson

, Rocha

, Struhal

, Thijs

, Tsioufis

, vanDijk

, Wenning

(2018) Consensus statement on the definition of neurogenic supine hypertension in cardiovascular autonomic failure by the American Autonomic Society (AAS) and the European Federation of Autonomic Societies (EFAS): Endorsed by the European Academy of Neurology (EAN) and the European Society of Hypertension (ESH). Clin Auton Res 28, 355–362.

16.

Freeman

, Wieling

, Axelrod

, Benditt

, Benarocch

, Biaggioni

, Cheshire

, Chelimsky

, Cortelli

, Gibbons

, Goldstein

, Hainsworth

, Hilz

, Jacob

, Kaufmann

, Jordan

, Lipsitz

, Levine

, Low

, Mathias

, Raj

, Robertson

, Sandroni

, Schatz

, Schondorff

, Stewart

, Dijk

JGV

(2011) Consensus statement on the definition of orthostatic hypotension, neutrally mediated syncope and the postural tachycardia syndrome. Clin Auton Res 21, 69–72.

17.

Palma

, Gomez-Esteban

, Norcliffe-Kaufmann

, Martinez

, Tijero

, Berganzo

, Kaufmann

(2015) Orthostatic hypotension in Parkinson disease: How much you fall or how low you go? Mov Disord 30, 639–645.

18.

Nagamachi

, Wakamatsu

, Kiyohara

, Fujita

, Futami

, Tamura

, Nakazato

, Yamashita

, Arita

, Nishii

, Kawai

(2008) Usefulness of rCBF analysis in diagnosing Parkinson’s disease: Supplemental role with MIBG myocardial scintigraphy. Ann Nucl Med 22, 557–564.

19.

Cersosimo

, Benarroch

(2013) Central control of autonomic function and involvement in neurodegenerative disorders. Handb Clin Neurol 117, 45–57.

20.

Palma

, Benarroch

(2014) Neural control of the heart: Recent concepts and clinical correlations. Neurology 83, 261–271.

21.

Critchley

, Mathias

, Josephs

, O’Doherty

, Zanini

, Dewar

, Cipolotti

, Shallice

, Dolan

(2003) Human cingulate cortex and autonomic control: Converging neuroimaging and clinical evidence. Brain 126, 2139–2152.

22.

Papapetropoulos

, Mash

(2007) Insular pathology in Parkinson’s disease patients with orthostatic hypotension. Parkinsonism Relat Disord 13, 308–311.

23.

Baker

, Kimpinski

(2019) Reduced brainstem functional connectivity in patients with peripheral autonomic failure. Neuroimage Clin 23, 101924.

24.

Ruffle

, Coen

, Giampietro

, Williama

SCR

, Apkarian

, Farmer

, Aziz

(2018) Morphology of subcortical brain nuclei is associated with autonomic function in heathy humans. Hum Brain Mapp 39, 381–392.

25.

Garrido

, Iranzo

, Stefani

, Serradell

, Muñoz-Lopetegi

, Marrero

, Högl

, Gaig

, Santamaria

, Tolosa

, Poewe

, Sleep Innsbruck Barcelona (SINBAR) Group (2020) Lack of asymmetry of nigrostriatal dopaminergic function in healthy subjects. Mov Disord 35, 1072–1076.

26.

Hoo

, Lee

, Chung

, Lee

, Ye

, Sohn

, Yun

, Lee

(2020) Clinical and striatal dopamine transporter predictors of beta-amyloid in dementia with Lewy bodies. Neurology 94, e1344–1352.

27.

Chung

, Yoo

, Oh

, Kim

, Ye

, Sohn

, Lee

(2018) Effect of striatal dopamine depletion on cognition in de novo Parkinson’s disease. Parkinsonism Relat Disord 51, 43–48.

28.

Suzuki

, Hashimoto

, Yoshioka

, Murakami

, Kawasaki

, Urashima

(2011) The odor stick identification test for Japanese differentiates Parkinson’s disease from multiple system atrophy and progressive supranuclear palsy. BMC Neurol 11, 157.

29.

Jamnadas-Khoda

, Koshy

, Mathias

, Muthane

, Ragothaman

, Dodaballapur

(2009) Are current recommendations to diagnose orthostatic hypotension in Parkinson’s disease satisfactory? Mov Disord 24, 1747–1751.

30.

Oka

, Toyoda

, Yogo

, Mochio

(2011) Reduced cardiac 123I-MIBG uptake reflects cardiac sympathetic dysfunction in de novo Parkinson’s disease. J Neural Transm (Vienna) 118, 1323–1327.

31.

Nakamura

, Hirayama

, Hara

, Mizutani

, Suzuki

, Watanabe

, Sobue

(2014) Role of cardiac sympathetic nerves in preventing orthostatic hypotension in Parkinson’s disease. Parkinsonism Relat Disord 20, 409–414.

Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson’s Disease

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

INTRODUCTION

METHODS

Patients

123I-FP-CIT SPECT

Head-up tilt-table testing (HUT)

Cardiac MIBG scintigraphy

Statistical analyses

RESULTS

Baseline results

Differences in striatal 123I-FP-CIT uptake between patients with and without OH

Correlations of 123I-FP-CIT uptake in striatal subregions with hemodynamic changes during HUT

Effect of OH on asymmetry index in striatal subregions

DISCUSSION

CONFLICT OF INTEREST

Footnotes

ACKNOWLEDGMENTS

References

¹²³I-FP-CIT SPECT

Differences in striatal ¹²³I-FP-CIT uptake between patients with and without OH

Correlations of ¹²³I-FP-CIT uptake in striatal subregions with hemodynamic changes during HUT