Peripheral immune profile in drug-naïve dementia with Lewy bodies.

BACKGROUND: Accumulating evidence suggests that peripheral inflammation is associated with the pathogenesis of Parkinson's disease (PD). We examined peripheral immune profiles and their association with clinical characteristics in patients with DLB and compared these with values in patients with PD. METHODS: We analyzed peripheral blood from 93 participants (drug-naïve DLB, 31; drug-naïve PD, 31; controls, 31). Absolute leukocyte counts, absolute counts of leukocyte subpopulations, and peripheral blood inflammatory indices such as neutrophil-to-lymphocyte ratio were examined. Associations with clinical characteristics, cardiac sympathetic denervation, and striatal 123I-2-carbomethoxy-3-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) binding were also examined. RESULTS: Patients with DLB had lower absolute lymphocyte and basophil counts than did age-matched controls (both; p < 0.005). Higher basophil counts were marginally associated with higher global cognition (p = 0.054) and were significantly associated with milder motor severity (p = 0.020) and higher striatal 123I-FP-CIT binding (p = 0.038). By contrast, higher basophil counts were associated with more advanced PD characterized by decreased global cognition and severe cardiac sympathetic denervation. Although lower lymphocyte counts had relevance to more advanced PD, they had little relevance to clinical characteristics in patients with DLB. Higher peripheral blood inflammatory indices were associated with lower body mass index in both DLB and PD. CONCLUSIONS: As in patients with PD, the peripheral immune profile is altered in patients with DLB. Some peripheral immune cell counts and inflammatory indices reflect the degree of disease progression. These findings may deepen our knowledge on the role of peripheral inflammation in the pathogenesis of DLB.

Specific vulnerability of iPSC-derived motor neurons with TDP-43 gene mutation to oxidative stress.

Amyotrophic lateral sclerosis (ALS) is a disease that affects motor neurons and has a poor prognosis. We focused on TAR DNA-binding protein 43 kDa (TDP-43), which is a common component of neuronal inclusions in many ALS patients. To analyze the contribution of TDP-43 mutations to ALS in human cells, we first introduced TDP-43 mutations into healthy human iPSCs using CRISPR/Cas9 gene editing technology, induced the differentiation of these cells into motor and sensory neurons, and analyzed factors that are assumed to be altered in or associated with ALS (cell morphology, TDP-43 localization and aggregate formation, cell death, TDP-43 splicing function, etc.). We aimed to clarify the pathological alterations caused solely by TDP-43 mutation, i.e., the changes in human iPSC-derived neurons with TDP-43 mutation compared with those with the same genetic background except TDP-43 mutation. Oxidative stress induced by hydrogen peroxide administration caused the death of TDP-43 mutant-expressing motor neurons but not in sensory neurons, indicating the specific vulnerability of human iPSC-derived motor neurons with TDP-43 mutation to oxidative stress. In our model, we observed aggregate formation in a small fraction of TDP-43 mutant-expressing motor neurons, suggesting that aggregate formation seems to be related to ALS pathology but not the direct cause of cell death. This study provides basic knowledge for elucidating the pathogenesis of ALS and developing treatments for the disease.

Weak gluteus maximus and weak iliopsoas with normal gluteus maximus: Two complementary new signs to diagnose lower limb functional weakness.

BACKGROUND AND PURPOSE: The diagnosis of functional neurological disorder should be actively made based on the neurological signs. We described two new complementary signs to diagnose functional weakness of the lower limb, "weak gluteus maximus (weak GM)" and "weak Iliopsoas with normal gluteus maximus (weak iliopsoas with normal GM)," and tested their validity. METHODS: The tests comprised Medical Research Council (MRC) examinations of the iliopsoas and GM in the supine position. We retrospectively enrolled patients with functional weakness (FW) or structural weakness (SW) who presented with weakness of either iliopsoas or GM, or both. Weak GM means that the MRC score of GM is 4 or less. Its complementary sign, weak ilopsoas with normal GM, means that the MRC score of ilopsoas is 4 or less, whereas that of GM is 5. RESULTS: Thirty-one patients with FW and 72 patients with SW were enrolled. The weak GM sign was positive in all 31 patients with FW and in 11 patients with SW, that is, 100% sensitivity and 85% specificity. Therefore, the complementary sign, weak iliopsoas with normal GM, was 100% specific for SW. DISCUSSION: Although 100% should be discounted considering limitations of this study, these signs will likely be helpful in differentiating between FW and SW in the general neurology setting. Downward pressing of the lower limb to the bed in the supine position is interpreted by the patient as an active movement exerted with an effort and might be preferentially impaired in FW.

Clinical features of organizing pneumonia in anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders.

BACKGROUND: Anti-aquaporin-4 (AQP4) antibody is an autoantibody marker often observed in patients with neuromyelitis optica spectrum disorder (NMOSD). The pathological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD remains unclear. We aimed to assess the clinical and histological relevance of complicated pulmonary disorders in anti-AQP4 antibody-positive NMOSD. METHODS: We retrospectively reviewed the medical records of 52 patients with anti-AQP4 antibody-positive NMOSD and conducted immunohistochemical evaluations of the lung biopsy specimens. RESULTS: Among 52 patients with anti-AQP4 antibody-positive NMOSD, 4 patients showed pulmonary involvement with a diagnosis of organizing pneumonia (OP). The proportion of males was larger (75% vs. 12.5%; p = 0.013) and creatine kinase levels were higher (458.3 U/L vs. 83.9 U/L; p = 0.003) in patients with OP than in those without OP. OP development preceded or coincided with the NMOSD symptoms. Chest computed tomography findings were consistent with OP in all four patients. Bronchoalveolar lavage fluid predominantly contained lymphocytes. Transbronchial lung biopsy revealed intraluminal plugs of inflammatory debris within the alveoli. Alveolar epithelial cells covering the OP lesions exhibited AQP4 loss, immunoglobulin G deposition, and complement activation. Corticosteroid treatment resulted in clinical improvement of OP. CONCLUSION: OP may be considered a pulmonary manifestation of anti-AQP4 antibody-positive NMOSD beyond the central nervous system. Complement-dependent cytotoxicity of the lung epithelial cells caused by anti-AQP4 antibody is at least partly involved in OP development. When diagnosing NMOSD, the possibility of OP should be carefully evaluated based on the detailed history and chest imaging findings.

Frontal lobe dysfunction is associated with reduced DAT-SPECT accumulation in Lewy body disease.

INTRODUCTION: Lewy body disease (LBD) causes olfactory or cognitive dysfunction even before motor symptoms emerge. Recent reports indicate that the dopamine transporter (DAT), which can be imaged using single-photon emission computed tomography (123I-ioflupane SPECT), is related to olfactory and cognitive dysfunction in LBD patients. We suspected that decreased cerebral blood flow (CBF) in the frontal lobe might be involved in these relationships. If so, then the results of these examinations may be useful in assessing the pathological progression of Lewy bodies. METHODS: We retrospectively analyzed the data of 139 de novo consecutive patients with LBD. We used the Odor Stick Identification Test for Japanese (OSIT-J) and the Frontal Assessment Battery (FAB) to evaluate olfactory and frontal lobe dysfunction, respectively. Among the 139 patients, ultimately 84 patients were analyzed and underwent 123I-ioflupane SPECT within 3 months (before or after) of the OSIT-J and FAB. We categorized patients on the basis of whether frontal lobe CBF was reduced (n = 28) or normal (n = 56). RESULTS: The average OSIT-J and FAB scores were 4.0 and 14.1, respectively, and the scores on the two tests were significantly correlated. Furthermore, OSIT-J scores were significantly correlated with the specific binding ratio (SBR) in both groups. The SBR was correlated with FAB scores in patients with reduced CBF in the frontal lobe, but not in those with normal CBF. CONCLUSION: Frontal lobe dysfunction and striatum dysfunction are correlated in LBD patients only after CBF has declined. Also, there is a time lag in the appearance of olfactory dysfunction and frontal lobe dysfunction in LBD patients. As with pathological development, olfaction is impaired earliest, followed by striatal, and then frontal lobe dysfunction.

Association between heart rate variability and striatal dopamine depletion in Parkinson's disease.

Striatal dopamine depletion is associated with not only motor symptom but also non-motor symptoms in patients with Parkinson's disease (PD). The purpose is to elucidate the relation between heart rate variability (HRV) and dopaminergic depletion in specific striatal subregions. The subjects were 84 patients with newly diagnosed untreated PD. All patients underwent striatal 123I-2ß-carbomethoxy-3ß-(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. Association of HRV with dopaminergic depletion in specific striatal subregions was examined. HRV was related to dopamine depletion in the caudate and anterior putamen, especially the left side, after controlling for age, hemoglobin A1c level, disease duration, motor severity and global cognition on multiple regression analysis (left caudate p = 0.012). HRV was closely related to striatal dopamine depletion, especially in the left associative striatum, in patients with PD.

Clinical and neuroendocrinological characteristics of delayed orthostatic hypotension in Parkinson's disease.

PURPOSE: Delayed orthostatic hypotension (DOH), a fall in blood pressure after a 3-min cutoff, is clinically meaningful. The aim of this study was to elucidate the clinical and neuroendocrinological characteristics of DOH in patients with Parkinson's disease (PD). METHODS: A total of 132 patients with newly diagnosed PD were enrolled. Baseline clinical characteristics, including olfactory function, and changes in norepinephrine (NE) and vasopressin (ADH) concentrations during the head-up tilt test (HUT), were examined. RESULTS: Fifty-five patients (42%) had classical orthostatic hypotension (COH), and 19 patients (14%) had DOH. Patients with COH and DOH tended to have more severe hyposmia than patients without OH. A multivariate linear regression model showed that hyposmia was associated with DOH and COH. The increase of heart rate against the fall in blood pressure was significantly lower in patients with COH and DOH than those without OH. The NE levels at supine rest and after upright tilting were lower in the COH group than in the PD without OH and DOH groups. The levels of ADH were higher in the DOH group than in the COH group at supine rest and higher than in the PD without OH group after upright tilting. There was no significant difference in the cardiac 123I-MIBG scintigraphy between the COH and DOH groups. CONCLUSION: Compared with patients without OH, patients with DOH had severe hyposmia. Relatively preserved peripheral sympathetic nervous system function in patients with DOH suggests that DOH might be an early and milder form of OH in PD.

Dopaminergic Correlates of Orthostatic Hypotension in de novo Parkinson's Disease.

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-2ß-carbomethoxy-3ß-(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.

Comparisons of cardiovascular dysautonomia and cognitive impairment between de novo Parkinson's disease and de novo dementia with Lewy bodies.

BACKGROUND: Cognitive impairment may be correlated with cardiovascular dysautonomia, including blood pressure (BP) dysregulation, in Parkinson's disease (PD), but the association between these factors in dementia with Lewy bodies (DLB) is uncertain. This study aimed to clarify whether cardiovascular dysautonomia had an influence on cognitive function in Lewy body disease or not. METHODS: Ninty-nine patients with de novo PD (n = 75) and DLB (n = 24) were evaluated using the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy, orthostatic hypotension (OH), supine hypertension (SH), postprandial hypotension (PPH), nocturnal BP fall in 24-h ambulatory blood pressure monitoring (ABPM) and constipation were estimated. Associations of these factors with cognitive and executive dysfunction were examined. RESULTS: In DLB, MIBG uptake was reduced and OH, PPH and SH were severely disturbed, compared to PD. The nocturnal BP fall in ABPM was lower in DLB, and the failure of nocturnal BP fall in PD was associated with MMSE, after adjustment for other clinical features. FAB was significantly associated nocturnal BP fall, age and SH in PD, but no significant correlations among factors were found for DLB. CONCLUSION: The significant association between nocturnal BP dysregulation and cognitive or executive decline in PD might be due to impaired microvascular circulation or invasion of α-synuclein in the CNS. The lack of a correlation of BP insufficiency with cognitive impairment in DLB suggests initial involvement of Lewy body pathology in the neocortex, regardless of Lewy body invasion of the autonomic nervous system.

Sympathetic nervous activity and hemoglobin levels in de novo Parkinson's disease.

PURPOSE: Sympathetic nervous denervation may be associated with the development of anemia. We aimed to investigate the association between sympathetic nervous denervation and hemoglobin levels in patients with Parkinson's disease (PD). METHODS: As indices of sympathetic nervous denervation, we investigated resting norepinephrine levels, increased norepinephrine levels after tilt-up, cardiac uptake of 123I-metaiodobenzylguanidine, supine blood pressure, and the degree of orthostatic hypotension in 132 patients with de novo PD. RESULTS: Older age, female sex, severe motor dysfunction, and lower body mass index were associated with decreased hemoglobin levels. After adjustment for these covariables, resting norepinephrine levels were negatively associated with hemoglobin levels. Hemoglobin levels were not associated with cardiac sympathetic denervation or orthostatic intolerance. CONCLUSION: Hemoglobin levels in PD seem to be closely related to noradrenergic nervous activity and nigrostriatal dopaminergic degeneration. In contrast to expectations, decreased hemoglobin levels were associated with increased whole-body sympathetic nervous activity in PD.

Differential leukocyte count is associated with clinical phenotype in Parkinson's disease.

INTRODUCTION: Elevated proinflammatory cytokines are associated with disease progression in patients with Parkinson's disease (PD). The aim of study is to investigate whether components of peripheral blood leukocyte are associated with clinical symptoms in patients with de novo PD. METHODS: We analyzed data from 123 newly diagnosed de novo patients who had no focal and systemic inflammatory diseases. Associations between clinical symptoms and differential leukocyte count (DLC) or DLC associated peripheral inflammatory biomarkers were examined. RESULTS: Altered DLC and DLC associated peripheral inflammatory biomarkers were associated with PD related symptoms even though there was no sign of clinical inflammation. After controlling for covariables, olfaction and body mass index (BMI) were inversely associated with percentage of neutrophil, neutrophil to lymphocyte ratio, derived neutrophil to lymphocyte ratio, and positively associated with percentage of lymphocyte, lymphocyte to monocyte ratio. Patients with tremor-dominant or mixed type had lower peripheral inflammatory indices than those with akinetic rigid type. CONCLUSION: Components of peripheral blood leukocytes reflect some clinical symptoms of PD. Patients with normosmia, tremor-dominant or mixed type, and patients without low BMI have low peripheral inflammatory indices. Relative mild peripheral inflammation may play one of major roles in developing mild disease phenotype in these patients.

Nerve Ultrasound, Electrophysiological, and Clinical Changes in Treatment-Naive Chronic Inflammatory Demyelinating Polyneuropathy: A Case Report.

We report the case of a 74-year-old woman with treatment-naive chronic inflammatory demyelinating polyneuropathy evaluated by both nerve conduction studies and nerve ultrasound (NUS) before and after initial treatment. Performing both nerve conduction study and NUS before and after initial treatment seems rare for treatment-naive chronic inflammatory demyelinating polyneuropathy. This case yielded two major findings. First, improvement of nerve swelling as evaluated by NUS correlated well with the improvement of neurological symptoms. Second, NUS improvements were seen right after treatment, whereas electrophysiological improvements were not. Nerve ultrasound might thus allow for judgment of curative effects much more immediately and sensitively than nerve conduction study in treatment-naive chronic inflammatory demyelinating polyneuropathy.

High norepinephrinergic orthostatic hypotension in early Parkinson's disease.

INTRODUCTION: Plasma norepinephrine concentration reflects lesions causing OH. We investigate whether patients with high norepinephrinergic orthostatic hypotension (OH) whose supine plasma norepinephrine concentration (NEsupine) is above the mean value in all patients with Parkinson's disease (PD) have central sympathetic denervation. METHODS: We analyzed data from 110 non-demented patients with early de novo PD who underwent cardiovascular examinations. We divided the patients into three groups according to the presence or absence of orthostatic hypotension and NEsupine: patients without OH, patients with OH+high NEsupine, and patients with OH+low NEsupine. RESULTS: The mean NEsupine in all patients was 251.6 pg/ml. Twelve patients (10.9%) had OH+high NEsupine (≥251.6 pg/ml), and 45 patients (40.9%) had OH+low NEsupine (<251.6 pg/ml). OH was more pronounced in patients with OH+high NEsupine than in those with OH+low NEsupine (p = 0.024). Vasopressin release and percent increase of NE after orthostatic stress were well preserved in patients with OH+low NEsupine, but not in patients with OH+high NEsupine. Cognition was lower in patients with OH+high NEsupine than in patients with OH+low NEsupine (p = 0.019) and was associated with vasopressin release during orthostatic stress on multiple regression analysis. The degree of cardiac sympathetic denervation did not differ between two groups with OH. CONCLUSIONS: Patient with PD and high norepinephrinergic OH are a subset of patients who have early cognitive decline and impaired vasopressin release. Vasopressin release after orthostatic stress was closely related to global cognition in PD.

Thrombotic Microangiopathy Presenting with Intestinal Involvement Following Long-term Interferon-ß1b Treatment for Multiple Sclerosis.

Thrombotic microangiopathies (TMAs) are systemic microvascular occlusive disorders. The present report describes a patient with relapsing-remitting multiple sclerosis who had been treated with interferon (IFN)-ß1b therapy for eight years and developed TMA. The patient presented with headache, thrombocytopenia, renal dysfunction, severe hypertension, posterior reversible encephalopathy syndrome, and gastrointestinal involvement. After discontinuation of the medication and initiation of antihypertensive treatment, the patient rapidly improved. This is the first report of TMA with gastrointestinal involvement (intestinal TMA) induced by IFN-ß. The new onset of hypertension or headache requires careful attention in cases of long-term administration of IFN-ß1b.

Common Carotid Artery Stump Syndrome Due to Mobile Thrombus Detected by Carotid Duplex Ultrasonography.

Carotid stump syndrome is a cause of recurrent embolic stroke following occlusion of the ipsilateral internal carotid artery. The present report describes a case of recurrent cerebral embolism ipsilateral to a chronically occluded left common carotid artery (CCA), i.e., "CCA stump syndrome." Doppler color flow imaging showed anterograde flow in the left internal and external carotid arteries, which were supplied by collateral flow from the superior thyroid artery inflowing just proximal to the left carotid bifurcation. According to carotid duplex ultrasonography (CDU), a low-echoic mobile thrombus was noted at the distal stump of the occluded CCA, which presumably caused distal embolism. The low-echoic mobile thrombus dramatically changed to a homogenously high-echoic thrombus, and there was no recurrence of stroke after antiplatelet and anticoagulant therapy. This is the first report to demonstrate a CDU-verified temporal change in the thrombus at the stump in CCA stump syndrome. CDU is a noninvasive and useful technique to characterize hemodynamics, thrombus morphology, and the response to therapy.

Predictors of postprandial hypotension in elderly patients with de novo Parkinson's disease.

Postprandial hypotension is one of the most important autonomic disorders in Parkinson's disease. However, its predictors remain unclear. We investigated which variable(s) predict the presence of postprandial hypotension in elderly patients with Parkinson's disease. The subjects were 64 patients with de novo Parkinson's disease who were 70 years or older. Postprandial hypotension was evaluated on a 75-g oral glucose tolerance test. Olfactory function, constipation, cardiac sympathetic or parasympathetic denervation, orthostatic intolerance on head-up tilt table testing, and other baseline characteristics were evaluated. The results showed the presence of postprandial hypotension was associated with severe dysosmia, constipation, orthostatic hypotension (a decrease in systolic blood pressure ≥30 mmHg) and preprandial hypertension at rest. On multiple logistic regression analyses adjusted for age, sex, symptom duration, disease severity, and motor subtype, the odds ratio was 4.02 for severe dysosmia (p = 0.027), 9.99 for constipation (p = 0.006), 6.42 for orthostatic hypotension with alternative definition (p = 0.004) and 7.90 for preprandial hypertension at rest (p = 0.001). Each multiple logistic regression analysis revealed that female sex was also a risk factor for postprandial hypotension. The variables with the highest sensitivity and specificity for postprandial hypotension were constipation (89.6 %) and preprandial hypertension at rest or orthostatic hypotension with alternative definition (both 77.1 %), respectively. Our results suggest that these variables predict the presence of postprandial hypotension in elderly patients with Parkinson's disease, suggesting that postprandial hypotension shares etiologic factors with these potential predictors.

Cerebral venous sinus thrombosis and dural arteriovenous fistula in a 75-year-old man primarily presenting with repeated transient visual obscurations.

A 75-year-old man was admitted to our hospital because of repeated transient visual obscurations of greying vision. The transient visual obscurations were caused by rotating his neck or the Valsalva manoeuver, and they recovered in about 30 seconds. A few weeks later, pulsatile tinnitus of the right ear and a dull headache developed. Both ocular fundi showed papilledema, and there was significant intracranial hypertension on cerebrospinal fluid examination. He was diagnosed as having right sigmoid sinus thrombosis and a dural arteriovenous fistula with a rapid arteriovenous shunt from the right ascending pharyngeal artery and the right occipital artery to the right transverse sinus. Anticoagulant therapy was started, and coil embolization was performed. The transient visual obscurations, headache, and tinnitus improved dramatically after the procedure. We hypothesized that the transient visual obscurations were triggered by rotating the neck or performing the Valsalva manoeuver as they both increase the pressure of cerebrospinal fluid, inducing transient optic nerve ischemia and visual obscurations under mild intracranial hypertension. Transient visual obscurations are an important initial symptom of intracranial hypertension.

Clinical characteristics of supine hypertension in de novo Parkinson disease.

PURPOSE: Supine hypertension is frequently associated with autonomic failure. However, its clinical characteristics in patients with Parkinson disease (PD) remain unclear. The present study aimed to clarify the characteristics of supine hypertension in patients with de novo PD. METHODS: The subjects were 72 patients with de novo PD. We studied blood pressure and plasma norepinephrine levels after the patients rested for 20 min in the supine position. Changes in blood pressure were also examined on head-up tilt-table testing. RESULTS: The disease duration was 1.7 ± 1.6 years (average ± SD). Thirty-three (45.8 %) patients had supine hypertension (defined as a blood pressure of ≥140/90 mmHg). Supine blood pressure positively correlated with the degree of orthostatic hypotension. Age and the proportion of patients with akinetic-rigid motor subtype or preexisting hypertension were higher among patients with supine hypertension than among those without supine hypertension. The Mini-Mental State Examination score was lower in patients with supine hypertension than in those without supine hypertension. Sex, disease duration, disease severity, and peripheral sympathetic nervous activity as evaluated by the cardiac uptake of (123)I-metaiodobenzylguanidine and the plasma norepinephrine level did not differ between patients with and those without supine hypertension. CONCLUSION: Older age, akinetic-rigid motor subtype, and preexisting hypertension are independent risk factors for supine hypertension. Supine hypertension alone may be associated with milder peripheral sympathetic nervous denervation than orthostatic hypotension alone. As for global cognitive decline, supine hypertension is a far riskier comorbidity of early-stage PD than is orthostatic hypotension.