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1.  Dementia with Lewy Bodies versus Alzheimer's Disease and Parkinson's Disease Dementia: A Comparison of Cognitive Profiles 
Background and Purpose
It is particularly difficult to differentiate dementia with Lewy bodies (DLB) from the related dementias of Alzheimer's disease (AD) and Parkinson's disease dementia (PDD). Few studies have been designed to comparatively analyze detailed neuropsychological assessments of DLB patients and patients with AD and PDD.
Three groups of patients participated in this study: 10 with DLB, 76 with AD, and 17 with PDD, who had been diagnosed as probable DLB, AD, and PDD, respectively, according to the clinical criteria of the consortium on DLB, National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorder Association, and the clinical diagnostic criteria for PDD. All patients were evaluated by careful neurological examination with detailed neuropsychological testing.
Significant differences among the three groups were found for attention, memory, and executive function, which included tasks of backward digit span, three-word recall, verbal delayed recall, and the Stroop test. Post hoc analysis revealed that the deficiencies of attention on the digit span task were greater in the DLB group than in the AD and PDD groups. The scores for episodic verbal memory tasks were significantly lower in the DLB and AD groups than in the PDD group. The performance in frontal executive function, as indicated by the Stroop test, was significantly worse in the DLB and PDD groups than in the AD group.
The results of the present study show that the pattern of cognitive dysfunction, in terms of attention, episodic memory, and executive functions, differ between patients with DLB and patients with AD and PDD.
PMCID: PMC3079155  PMID: 21519522
dementia with lewy bodies; Alzheimer's disease; Parkinson's disease dementia; cognition; neuropsychology
2.  Autonomic Mechanisms and Therapeutic Implications of Postural Diabetic Cardiovascular Abnormalities 
Cardiovascular autonomic neuropathy (CAN) is a disorder of progressive autonomic dysfunction (AD) associated with diabetes and other chronic diseases. Orthostatic hypotension (OH) is one of the most incapacitating symptoms of CAN and AD. AD in OH can include sympathetic withdrawal (SW). To detect and diagnose SW, parasympathetic and sympathetic changes must be clearly differentiated from each other. This is accomplished by means of the novel autonomic nervous system (ANS) method based on the simultaneous spectral analyses of respiratory activity (RA) and heart rate variability (HRV).
We performed autonomic profiling of 184 (142 females) consecutive, arrhythmia-free patients with type 2 diabetes using the ANX-3.0 autonomic monitoring system. The patient cohort included 86 (64 female) patients for whom an α1-agonist was the only drug changed and increased from one test to the next; 37 (33 female) for whom the α1-agonist was discontinued; and 61 (45 female) who were on an α1-agonist, but for whom no drug changes were made. The tests averaged 3.1 ± 1.4 months apart; midodrine (ProAmatine) was the α1-agonist prescribed. Of the group, 99 patients also had hypertension and 47 also had cardiovascular disease. No patient had supine hypertension.
Changes in parameters from the HRV (without respiration) and ANS methods were compared with changes in heart rate and blood pressure (BP) as measured from one test (test N) to the next (test N + 1). SW with a BP drop of less than the clinical definition may be a trend that can be an early indicator of orthostasis. In this study, patients were treated with low-dose, short-term α1-agonist (vasopressor) therapy, which tended to correct the abnormal trend of SW with a drop in BP. Included in the findings was a systolic BP trend in response to vasopressor therapy of an (expected) initial increase in BP followed by an eventual decrease in systolic BP as SW was reversed.
The ANS method enables quantitative assessment of CAN by independently and simultaneously quantifying the two branches of the ANS, sympathetic and parasympathetic. The ANS method modifies standard spectral analysis of HRV (without RA analysis) by incorporating spectral analysis of RA.
The ANS method appears to model the normal and abnormal responses to upright posture and changes in vasopressor therapy with greater fidelity than the HRV method. Independent, simultaneous assessment of progressive parasympathetic and sympathetic dysfunction, autonomic imbalance, and responses of the two ANS branches to therapy seems to enable early detection and early intervention. Orthostasis, by way of example, illustrates that frequent, sensitive assessments of both ANS branches can improve the negative outcomes associated with CAN.
PMCID: PMC2769753  PMID: 19885241
autonomic nervous system; cardiovascular autonomic neuropathy; orthostatic hypotension; postural orthostatic tachycardia syndrome; respiratory activity analysis; vasopressor
3.  Pupillary autonomic denervation with increasing duration of diabetes mellitus 
The British Journal of Ophthalmology  2001;85(10):1225-1230.
BACKGROUND/AIMS—The autonomic pupillary changes in type I and II diabetic patients without clinical evidence of diabetic autonomic neuropathy (DAN) were compared with age matched controls. The relation between pupillary and cardiovascular autonomic function was assessed in the diabetic patients.
METHODS—A case-control study was performed with diabetics grouped according to type and duration of diabetes. Static infrared pupillography was used to compare mean dark adapted pupil size and mean percentage changes in pupil size with pilocarpine 0.1% and cocaine 4% in the diabetic and control groups. All diabetic patients underwent cardiovascular autonomic function assessment using the Valsalva ratio, the 30:15 ratio, and testing for orthostatic hypotension.
RESULTS—In total, 72 type I and 69 type II diabetic patients were compared with 120 controls. Mean dark adapted pupil size was significantly smaller in diabetic groups than controls. Except for type I diabetics with disease for less than 5 years, all patient groups had significantly greater mean percentage constriction in pupil size in response to dilute pilocarpine than controls. There was no significant difference between the mean percentage dilatation in response to cocaine 4% in diabetics and controls. A high proportion of patients had normal cardiovascular autonomic function particularly when this was assessed with the Valsalva ratio.
CONCLUSIONS—Denervation hypersensitivity to dilute pilocarpine is a result of damage to the pupillary parasympathetic supply of diabetic patients. This occurs before the pupillary sympathetic pathway is affected, it can be detected early in the disease, and it may be a possible explanation for the small pupil size seen in diabetic patients. Pupillary autonomic dysfunction occurs before cardiovascular autonomic changes and detection of pupil denervation hypersensitivity to dilute pilocarpine is an inexpensive way to detect early DAN.

PMCID: PMC1723745  PMID: 11567969
4.  A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer's-type and dementia with Lewy bodies 
OBJECTIVE—Scintigraphy with [123I]metaiodobenzyl guanidine ([123I]MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Recently, myocardial [123I]MIBG scintigraphy has been found to be useful in distinguishing Parkinson's disease, a Lewy body disease, from other akinetic rigid syndromes. Some patients initially diagnosed with dementia of the Alzheimer's type (DAT) are discovered to have an alternative disease such as dementia with Lewy bodies (DLB), despite the application of stringent diagnostic criteria. In the present study, examinations were performed to clarify the usefulness of myocardial [123I]MIBG scintigraphy in improving the differential diagnosis between patients with DLB and DAT.
METHODS—Fourteen patients with DLB and 14 patients with DAT underwent scintigraphy with [123I]MIBG, combined with orthostatic tests and cardiac examinations.
RESULTS—In all patients with DLB, the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in both early and delayed images, independently of the duration of disease and autonomic failure. All patients with DAT had successful MIBG uptake in the heart regardless of duration of disease and autonomic failure. Orthostatic hypotension was seen in four patients with DAT and 13 patients with DLB.
CONCLUSIONS—[123I]MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in DLB and might provide useful diagnostic information to discriminate DLB from DAT. The distinction between DLB and DAT may be improved by greater emphasis on cardiac sympathetic disturbances.

PMCID: PMC1737586  PMID: 11606666
5.  Treatment induced diabetic neuropathy– a reversible painful autonomic neuropathy 
Annals of neurology  2010;67(4):534-541.
To describe the natural history, clinical, neurophysiological and histological features and outcomes of diabetic patients presenting with acute painful neuropathy associated with glycemic control, also referred to as ‘insulin neuritis’.
Sixteen subjects, presenting with acute painful neuropathy had neurological and retinal examinations, laboratory studies, autonomic testing and pain assessments over 18 months. Eight subjects had skin biopsies for evaluation of intra-epidermal nerve fiber density.
All subjects developed severe pain within 8 weeks of intensive glucose control. There was a high prevalence of autonomic cardiovascular, gastrointestinal, genitourinary, and sudomotor symptoms in all subjects. Orthostatic hypotension and parasympathetic dysfunction were seen in 69% of subjects. Retinopathy worsened in all subjects. Reduced intra-epidermal nerve fiber density (IENFD) was seen in all tested subjects. After 18 months of glycemic control, there were substantial improvements in pain, autonomic symptoms, autonomic test results and IENFD. Greater improvements were seen after 18 months in type 1 vs. type 2 diabetic subjects in autonomic symptoms (cardiovascular p<0.01; gastrointestinal p<0.01; genitourinary p<0.01) and autonomic function tests (p<0.01, sympathetic and parasympathetic function tests).
Treatment induced neuropathy is characterized by acute, severe pain, peripheral nerve degeneration and autonomic dysfunction after intensive glycemic control. The neuropathy occurred in parallel with worsening diabetic retinopathy suggesting a common underlying pathophysiological mechanism. Clinical features and objective measures of small myelinated and unmyelinated nerve fibers can improve in these diabetic patients despite a prolonged history of poor glucose control, with greater improvement seen in patients with type 1 diabetes.
PMCID: PMC3057039  PMID: 20437589
diabetic neuropathy; painful neuropathy; autonomic neuropathy
6.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
PMCID: PMC2637553  PMID: 18794492
7.  Demography, diagnostics, and medication in dementia with Lewy bodies and Parkinson’s disease with dementia: data from the Swedish Dementia Quality Registry (SveDem) 
Whether dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) should be considered as one entity or two distinct conditions is a matter of controversy. The aim of this study was to compare the characteristics of DLB and PDD patients using data from the Swedish Dementia Quality Registry (SveDem).
SveDem is a national Web-based quality registry initiated to improve the quality of diagnostic workup, treatment, and care of patients with dementia across Sweden. Patients with newly diagnosed dementia of various types were registered in SveDem during the years 2007–2011. The current cross-sectional report is based on DLB (n = 487) and PDD (n = 297) patients. Demographic characteristics, diagnostic workup, Mini-Mental State Examination (MMSE) score, and medications were compared between DLB and PDD groups.
No gender differences were observed between the two study groups (P = 0.706). PDD patients were significantly younger than DLB patients at the time of diagnosis (74.8 versus 76.8 years, respectively; P < 0.001). A significantly higher prevalence of patients with MMSE score ≤24 were found in the PDD group (75.2% versus 67.6%; P = 0.030). The mean number of performed diagnostic modalities was significantly higher in the DLB group (4.9 ± 1.7) than in the PDD group (4.1 ± 1.6; P < 0.001). DLB patients were more likely than PDD patients to be treated with cholinesterase inhibitors (odds ratio = 2.5, 95% confidence interval = 1.8–3.5), whereas the use of memantine, antidepressants, and antipsychotics did not differ between the groups.
This study demonstrates several differences in the dementia work-up between DLB and PDD. The onset of dementia was significantly earlier in PDD, while treatment with cholinesterase inhibitors was more common in DLB patients. Severe cognitive impairment (MMSE score ≤24) was more frequent in the PDD group, whereas more diagnostic tests were used to confirm a DLB diagnosis. Some similarities also were found, such as gender distribution and use of memantine, antidepressants, and antipsychotics drugs. Further follow-up cost-effectiveness studies are needed to provide more evidence for workup and treatment guidelines of DLB and PDD.
PMCID: PMC3700781  PMID: 23847419
dementia with Lewy bodies; Parkinson’s disease with dementia; age; diagnostic approach; medication; Mini-Mental State Examination
8.  Primary Sjögrens syndrome is associated with impaired autonomic response to orthostasis and sympathetic failure 
Background: Symptoms in keeping with autonomic dysfunction are commonly described by primary Sjögrens syndrome patients (pSS); whether objective abnormalities of autonomic function occur is unclear. This study set out to explore dynamic cardiovascular autonomic responses in pSS and their relationship with symptoms and quality of life.
Methods: Twenty-one people from the UK pSS registry, 21 community controls and 21 patients with the autoimmune liver disease primary biliary cirrhosis (PBC) (matched case-wise for age and sex) attended for assessment of autonomic responses to orthostasis and Valsalva manoeuvre (VM). pSS patients also completed EULAR Sjögrens Syndrome patient-reported index (ESSPRI), EULAR Sjögren’s syndrome disease activity index (ESSDAI), fatigue impact scale and EURO-QOL 5-dimension (EQ-5D).
Results: Compared with controls, pSS patients had significantly lower baseline systolic blood pressure (SBP) (114 ± 13 vs. 127 ± 20; P = 0.02), which dropped to a significantly lower value (98 ± 22 vs. 119 ± 24, P = 0.009). When area under the curve (AUC) was calculated for when the SBP was below baseline this was significantly greater in pSS compared to both control groups (pSS vs. control vs. PBC: 153 ± 236 vs. 92 ± 85 vs. 1.2 ± 0.3, P = 0.005). Peak phase IV SBP during the VM was significantly lower in pSS (P = 0.007) indicating early sympathetic failure. Increased heart rate associated with fatigue (P = 0.02; r2 = 0.2) and EQ-5D. A shift in sympathetic-vagal balance associated with overall symptom burden (ESSPRI) (P = 0.04, r2 = 0.3) and EULAR sicca score (P = 0.016; r2 = 0.3), the latter also correlated with baroreceptor effectiveness (P = 0.03; r2 = 0.2) and diastolic blood pressure variability (P = 0.003; r2 = 0.4).
Conclusion: pSS patients have impaired blood pressure response to standing. Dysautonomia correlates with PSS-associated symptoms and quality of life.
PMCID: PMC3508582  PMID: 22976617
9.  Incidence and Prediction of Falls in Dementia: A Prospective Study in Older People 
PLoS ONE  2009;4(5):e5521.
Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia.
Methods and Findings
179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer's disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson's disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11–18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11–5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52–4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19–3.80), autonomic symptom score (HR per point 0–36: 1.055, 1.012–1.099), and Cornell depression score (HR per point 0–40: 1.053, 1.01–1.099). Higher levels of physical activity were protective (HR per point 0–9: 0.827, 0.716–0.956).
The management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority.
PMCID: PMC2677107  PMID: 19436724
10.  Cardiovascular autonomic functions & cerebral autoregulation in patients with orthostatic hypotension 
Background & objectives:
Patients of orthostatic hypotension may or may not have symptoms of the cerebral hypoperfusion despite fall in the blood pressure. The present study was done to quantify autonomic functions and cerebral autoregulation in patients of orthostatic hypotension with or without symptoms.
The study was conducted in 15 patients of orthostatic hypotension and 15 age, sex matched control subjects. The sympathetic reactivity was measured by diastolic blood pressure response to handgrip test (ΔDBP in HGT) and cold pressor test (ΔDBP in CPT). The parasympathetic reactivity was measured by E:I ratio during deep breathing test (DBT) and Valsalva ratio (VR) during Valsalva maneuver. The cerebral autoregulation was computed from the changes in the cerebral blood flow, cerebrovascular conductance and blood pressure measured during different time points during head-up tilt (HUT).
The sympathetic reactivity was lower in patients as compared to controls [ΔDBP in HGT: 10 (4 - 16) vs 18 (12 - 22) mmHg, P<0.01; ΔDBP in CPT : 10 (4-12) vs 16 (10-20) mmHg, P<0.01]. The parasympathetic reactivity was also lower in patients as compared to controls. The sympathetic and parasympathetic reactivity was comparable in the symptomatic and asymptomatic patients. The maximum fall in blood pressure during HUT was comparable between symptomatic and asymptomatic patients (29.14 ± 10.94 vs 29.50 ± 6.39 mmHg), however, the percentage fall in the cerebral blood flow was significantly higher in the symptomatic (P<0.05) compared to asymptomatics.
Interpretation & conclusions:
Patients with orthostatic hypotension had deficits in sympathetic and parasympathetic control of cardiovascular system. Cerebral autoregulation was present in asymptomatic patients (increase in cerebrovascular conductance) during HUT while it was lost in symptomatic patients.
PMCID: PMC3237244  PMID: 22089608
Autonomic function test; cerebral autoregulation; cerebrovascular conductance; orthostatic hypotension
11.  Association of anosmia with autonomic failure in Parkinson disease 
Neurology  2010;74(3):245-251.
Olfactory dysfunction and autonomic failure are gaining recognition as nonmotor manifestations of Parkinson disease (PD). This observational study assessed whether in PD anosmia and autonomic failure are related to each other or to neuroimaging evidence of striatal dopamine deficiency.
Olfactory function was assessed by the University of Pennsylvania Smell Identification Test (UPSIT) in 23 patients with sporadic PD. Baroreflex-cardiovagal gain was quantified from the relationship between cardiac interbeat interval and systolic pressure during the Valsalva maneuver and baroreflex-sympathoneural function by responses of systolic pressure to the Valsalva maneuver and of hemodynamics and plasma norepinephrine (NE) and dihydroxyphenylglycol (DHPG) levels to orthostasis. 6-[18F]Fluorodopamine PET and plasma and skeletal muscle microdialysate NE and DHPG were used to indicate cardiac and extracardiac noradrenergic innervation and brain 6-[18F]fluorodopa PET to indicate striatal dopaminergic innervation. Parkinsonism was assessed by UPDRS scores.
Compared to patients with PD and normal to moderately decreased sense of smell, patients with anosmic PD had lower mean baroreflex-cardiovagal gain (p = 0.04), larger falls in systolic pressure during the Valsalva maneuver and orthostasis (p = 0.04, p = 0.02), smaller orthostatic increments in plasma NE and DHPG (p = 0.003, p = 0.03), lower cardiac septal:hepatic and renal cortical:hepatic ratios of 6-[18F]fluorodopamine-derived radioactivity (p = 0.01, p = 0.06), and lower microdialysate NE and DHPG (p = 0.01; p = 0.006). Neither clinical severity of parkinsonism nor the putamen:occipital cortex ratio of 6-[18F]fluorodopa-derived radioactivity was related to the UPSIT category.
In Parkinson disease, anosmia is associated with baroreflex failure and cardiac and organ-selective extracardiac noradrenergic denervation, independently of parkinsonism or striatal dopaminergic denervation.
= dihydroxyphenylglycol;
= least significant difference;
= norepinephrine;
= orthostatic hypotension;
= Parkinson disease;
= quantitative sudomotor axon reflex test;
= Unified Parkinson's Disease Rating Scale;
= University of Pennsylvania Smell Identification Test.
PMCID: PMC2809034  PMID: 20083801
12.  Autonomic Dysfunctions in Parkinsonian Disorders 
Journal of Movement Disorders  2009;2(2):72-77.
Background and Purpose:
Symptoms of autonomic dysfunctions are common in the patients with parkinsonian disorders. Because clinical features of autonomic dysfunctions are diverse, the comprehensive evaluation is essential for the appropriate management. For the appreciation of autonomic dysfunctions and the identification of differences, patients with degenerative parkinsonisms are evaluated using structured questionnaire for autonomic dysfunction (ADQ).
Total 259 patients, including 192 patients with [idiopathic Parkinson’s disease (IPD, age 64.6 ± 9.6 years)], 37 with [multiple system atrophy (MSA, 62.8 ± 9.1)], 9 with [dementia with Lewy body (DLB, 73.9 ± 4.3)], and 21 with [progressive supranuclear palsy (PSP, 69.4 ± 9.6)]. The ADQ was structured for evaluation of the presence of symptoms and its severity due to autonomic dysfunction, covering gastrointestinal, urinary, sexual, cardiovascular and thermoregulatory domains. Patients were also evaluated for the orthostatic hypotension.
Although dementia with Lewy body (DLB) patients were oldest and duration of disease was longest in IPD, total ADQ scores of MSA and PSP (23.9 ± 12.6 and 21.1 ± 7.8) were significantly increased than that of IPD (15.1 ± 10.6). Urinary and cardiovascular symptom scores of MSA and gastrointestinal symptom score of PSP were significantly worse than those of IPD. The ratio of patient with orthostatic hypotension in IPD was 31.2% and not differed between groups (35.1% in MSA, 33.3% in DLB and 33.3% in PSP). But the systolic blood pressure dropped drastically after standing in patients with MSA and DLB than in patients with IPD and PSP.
Patients with degenerative parkinsonism showed widespread symptoms of autonomic dysfunctions. The severity of those symptoms in patients with PSP were comparing to that of MSA patients and worse than that of IPD.
PMCID: PMC4027718  PMID: 24868361
Parkinsonism; Autonomic dysfunction; Orthostatic hypotension
13.  REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century(e–Pub ahead of print)(CME) 
Neurology  2010;75(6):494-499.
Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]).
We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome.
Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients.
These cases illustrate that the α-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.
= dementia with Lewy bodies;
= mild cognitive impairment;
= multiple system atrophy;
= Parkinson disease;
= PD with associated mild cognitive impairment;
= Parkinson disease dementia;
= polysomnogram;
= REM sleep behavior disorder.
PMCID: PMC2918473  PMID: 20668263
14.  Verbal Learning and Memory in Patients with Dementia with Lewy Bodies or Parkinson's Disease with Dementia 
This study compared verbal learning and memory in patients with autopsy-confirmed dementia with Lewy Bodies (DLB) and patients with Parkinson's disease with dementia (PDD). Twenty-four DLB patients, 24 PDD patients, and 24 normal comparison participants were administered the California Verbal Learning Test. The three groups were matched on demographic variables and the two patient groups were matched on the Mattis Dementia Rating Scale. The results indicated that DLB patients recalled less information than PDD patients on all but one recall measure and displayed a more rapid rate of forgetting. In contrast, the PDD patients committed a greater percent of perseveration errors than the DLB patients. The two groups did not differ in the percentage of recall intrusion errors or any measures of recognition. A discriminant function analysis (DFA) using short delay cued recall, percent perseveration errors, and list b recall, differentiated the DLB and PDD groups with 81.3% accuracy. The application of the DFA algorithm to another sample of 42 PDD patients resulted in a 78.6% correct classification rate. The results suggest that, despite equivalent levels of general cognitive impairment, patients with DLB or PDD exhibit a different pattern of verbal learning and memory deficits.
PMCID: PMC2935683  PMID: 19221922
15.  Differences in autonomic nerve function in patients with silent and symptomatic myocardial ischaemia. 
British Heart Journal  1994;71(1):22-29.
BACKGROUND--Autonomic neuropathy provides a mechanism for the absence of symptoms in silent myocardial ischaemia, but characterisation of the type of neuropathy is lacking. AIM--To characterise and compare autonomic nerve function in patients with silent and symptomatic myocardial ischaemia. METHODS AND RESULTS--The Valsalva manoeuvre, heart rate variation (HRV) in response to deep breathing and standing, lower body negative pressure, isometric handgrip, and the cold pressor test were performed by patients with silent (n = 25) and symptomatic (n = 25) ambulatory ischaemia and by controls (n = 21). No difference in parasympathetic efferent function between patients with silent and symptomatic ischaemia was recorded, but both had significantly less HRV in response to standing than the controls (p < 0.005 for silent and p < 0.01 for symptomatic). Patients with silent ischaemia showed an increased propensity for peripheral vasodilatation compared with symptomatic patients (p < 0.02) and controls (p < 0.04). Impaired sympathetic function was found in patients with pure silent ischaemia (n = 4) compared with the remaining patients with silent ischaemia whose pain pathways were presumed to be intact. CONCLUSIONS--Patients with silent ischaemia and pain pathways presumed to be intact have an enhanced peripheral vasodilator response, and if this applied to the coronary vasculature it could provide a mechanism for limiting ischaemia to below the pain threshold. Patients with pure silent ischaemia have evidence of sympathetic autonomic dysfunction.
PMCID: PMC483603  PMID: 8297687
16.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
PMCID: PMC2637553  PMID: 18794492
17.  Brain amyloid and cognition in Lewy body diseases 
Many patients with Parkinson disease (PD) develop dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account in part for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases.
29 cognitively normal PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and PiB imaging with PET. Apolipoprotein (APOE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference.
PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the APOEε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition.
DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.
PMCID: PMC3725259  PMID: 22693110
dementia; Lewy; Parkinson; amyloid; PiB
18.  Vascular dysfunctions following spinal cord injury  
Journal of Medicine and Life  2010;3(3):275-285.
The aim of this article is to analyze the vascular dysfunctions occurring after spinal cord injury (SCI). Vascular dysfunctions are common complications of SCI. Cardiovascular disturbances are the leading causes of morbidity and mortality in both acute and chronic stages of SCI.
Neuroanatomy and physiology of autonomic nervous system, sympathetic and parasympathetic, is reviewed. SCI implies disruption of descendent pathways from central centers to spinal sympathetic neurons, originating in intermediolateral nuclei of T1–L2 cord segments. Loss of supraspinal control over sympathetic nervous system results in reduced overall sympathetic activity below the level of injury and unopposed parasympathetic outflow through intact vagal nerve.
SCI associates significant vascular dysfunction. Spinal shock occurs during the acute phase following SCI and it is a transitory suspension of function and reflexes below the level of the injury. Neurogenic shock, part of spinal shock, consists of severe arterial hypotension and bradycardia. Autonomic dysreflexia appears during the chronic phase, after spinal shock resolution, and it is a life–threatening syndrome of massive imbalanced reflex sympathetic discharge occurring in patients with SCI above the splanchnic sympathetic outflow (T5–T6). Arterial hypotension with orthostatic hypotension occurs in both acute and chronic phases. The etiology is multifactorial. We described a few factors influencing the orthostatic hypotension occurrence in SCI: sympathetic nervous system dysfunction, low plasma catecholamine levels, rennin–angiotensin–aldosterone activity, peripheral alpha–adrenoceptor hyperresponsiveness, impaired function of baroreceptors, hyponatremia and low plasmatic volume, cardiovascular deconditioning, morphologic changes in sympathetic neurons, plasticity within spinal circuits, and motor deficit leading to loss of skeletal muscle pumping activity. Additional associated cardiovascular concerns in SCI, such as deep vein thrombosis and long–term risk for coronary heart disease and systemic atherosclerosis are also described.
Proper prophylaxis, including non–pharmacologic and pharmacological strategies, diminishes the occurrence of the vascular dysfunction following SCI. Each vascular disturbance requires a specific treatment.
PMCID: PMC3019008  PMID: 20945818
spinal shock; neurogenic shock; orthostatic hypotension; autonomic dysreflexia; deep vein thrombosis; coronary heart disease
19.  Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease 
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
PMCID: PMC1738667  PMID: 12933921
20.  Autonomic Ganglia: Target and Novel Therapeutic Tool 
Neurology  2008;70(20):1926-1932.
Nicotinic acetylcholine receptors (AChR) are ligand-gated cation channels that are present throughout the nervous system. The muscle AChR mediates transmission at the neuromuscular junction; antibodies against the muscle AChR are the cause of myasthenia gravis. The ganglionic (α3-type) neuronal AChR mediates fast synaptic transmission in sympathetic, parasympathetic, and enteric autonomic ganglia. Impaired cholinergic ganglionic synaptic transmission is one important cause of autonomic failure. Pharmacological enhancement of ganglionic synaptic transmission may be a novel way to improve autonomic function.
Ganglionic AChR antibodies are found in patients with autoimmune autonomic ganglionopathy (AAG). Patients with AAG typically present with rapid onset of severe autonomic failure. Major clinical features include orthostatic hypotension, gastrointestinal dysmotility, anhidrosis, bladder dysfunction, and sicca symptoms. Impaired pupillary light reflex is often seen. Like myasthenia, AAG is an antibody-mediated neurological disorder. The disease can be reproduced in experimental animals by active immunization or passive antibody transfer. Patient may improve with plasma exchange treatment or other immunomodulatory treatment. Antibodies from patients with AAG inhibit ganglionic AChR currents.
Other phenotypes of AAG are now recognized based on the results of antibody testing. These other presentations are generally associated with lower levels of ganglionic AChR antibodies. A chronic progressive form of AAG may resemble pure autonomic failure. Milder forms of dysautonomia, such as postural tachycardia syndrome, are associated with ganglionic AChR in 10–15% of cases. Since ganglionic synaptic transmission is a common pathway for all autonomic traffic, enhancement of autonomic function through inhibition of acetylcholinesterase is a potential specific therapeutic strategy for autonomic disorders. Increasing the strength of ganglionic transmission can ameliorate neurogenic orthostatic hypotension without aggravating supine hypertension. Recent evidence also suggests a potential role for acetylcholinesterase inhibitors in the treatment of postural tachycardia syndrome.
PMCID: PMC2637993  PMID: 18474849
autonomic neuropathy; thymoma; gastrointestinal dysmotility; orthostatic hypotension
21.  Autonomic neuropathy in Fabry disease: a prospective study using the Autonomic Symptom Profile and cardiovascular autonomic function tests 
BMC Neurology  2010;10:38.
Fabry patients have symptoms and signs compatible with autonomic dysfunction. These symptoms and signs are considered to be due to impairment of the peripheral nervous system, but findings indicative of autonomic neuropathy in other diseases, such as orthostatic intolerance and male sexual dysfunction, are infrequently reported in Fabry disease. The aim of our study was to investigate autonomic symptoms and cardiovascular autonomic function in a large cohort of male and female Fabry patients.
Forty-eight Fabry patients (15 male, 30 treated with enzyme replacement therapy) and 48 sex- and age-matched controls completed a questionnaire on autonomic symptoms (the Autonomic Symptom Profile). Thirty-six Fabry patients underwent cardiovascular function tests.
The Autonomic Symptom Profile revealed a significantly higher sum score in Fabry patients than in healthy control subjects (22 versus 12), but a relatively low score compared to patients with proven autonomic neuropathy. Fabry patients scored worse than healthy controls in the orthostatic intolerance domain. Scores in the male sexual dysfunction domain were comparable between healthy controls and male Fabry patients. The cardiovascular autonomic function tests revealed only mild abnormalities in seven patients. None of these seven patients showed more than one abnormal test result. Enzyme replacement therapy was not associated with less severe disease, lower ASP scores or less frequent abnormal cardiovascular function test results.
Male sexual function and autonomic control of the cardiovascular system are nearly normal in Fabry patients, which cast doubt on the general accepted assumption that autonomic neuropathy is the main cause of symptoms and signs compatible with autonomic dysfunction in Fabry disease. Possibly, end-organ damage plays a key role in the development of symptoms and signs in Fabry patients. An exceptional kind of autonomic neuropathy is another but less likely explanation.
PMCID: PMC2892441  PMID: 20529242
22.  Dysphagia in Lewy body dementia - a clinical observational study of swallowing function by videofluoroscopic examination 
BMC Neurology  2013;13:140.
Dysphagia, which can result in aspiration pneumonia and death, is a well-known problem in patients with dementia and Parkinson’s disease. There are few studies on dysphagia in patients with dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), especially studies objectively documenting the type of swallowing dysfunction. The aim of this study was therefore to investigate the prevalence, and define the actual swallowing dysfunction according to a videofluoroscopic swallowing examination (VFSE) in patients with DLB and PDD.
Eighty-two consecutive patients with DLB or PDD in a clinical follow-up program were asked about symptoms of dysphagia. Those experiencing dysphagia were examined with VFSE. Prevalence and type of swallowing dysfunction was recorded.
Twenty-six patients (32%) reported symptoms of dysphagia such as swallowing difficulties or coughing. Twenty-four (92%) of these had a documented swallowing dysfunction on VFSE. Eighty-eight percent suffered from pharyngeal dysfunction.
Almost all DLB or PDD patients with subjective signs of dysphagia had pathologic results on VFSE, the majority of pharyngeal type. This type of dysphagia has not been reported in DLB before. The results have clinical implications and highlight the importance of asking for and examining swallowing function to prevent complications such as aspiration.
PMCID: PMC4126015  PMID: 24099488
Dementia with Lewy bodies; Parkinson’s disease dementia; Dysphagia; Videofluoroscopy
23.  There is No Association between Cardiovascular Autonomic Dysfunction and Peripheral Neuropathy in Chronic Hemodialysis Patients 
Background and Purpose
The potential association between the severity of autonomic dysfunction and peripheral neuropathy has not been extensively investigated, with the few studies yielding inconsistent results. We evaluated the relationship between autonomic dysfunction and peripheral neuropathy in chronic hemodialysis patients in a cross-sectional study.
Cardiovascular autonomic function was assessed in 42 consecutive patients with chronic renal failure treated by hemodialysis, using a standardized battery of 5 cardiovascular reflex tests. Symptoms of autonomic dysfunction and of peripheral neuropathy were evaluated using the Autonomic Neuropathy Symptom Score (ANSS) and the Neuropathy Symptoms Score. Neurological deficits were assessed using the Neuropathy Disability Score. Conduction velocities along the sensory and motor fibers of the sural and peroneal nerves were measured. Thermal thresholds were documented using a standardized psychophysical technique.
Parasympathetic and sympathetic dysfunction was prevalent in 50% and 28% of cases, respectively. Peripheral neuropathy was identified in 25 cases (60%). The prevalence of peripheral neuropathy did not differ between patients with impaired (55%) and normal (75%) autonomic function (p=0.297; Fisher's exact test). The electrophysiological parameters for peripheral nerve function, neuropathic symptoms, abnormal thermal thresholds, age, gender, and duration of dialysis did not differ significantly between patients with and without autonomic dysfunction. Patients with autonomic dysfunction were more likely to have an abnormal ANSS (p=0.048). The severity of autonomic dysfunction on electrophysiological testing was positively correlated with ANSS (r=0.213, p=0.036).
The present data indicate that although cardiovascular autonomic dysfunction is prevalent among patients with chronic renal failure, it is not associated with the incidence of peripheral neuropathy.
PMCID: PMC2950919  PMID: 20944815
autonomic dysfunction; hemodialysis; neuropathy; cardiovascular reflexes
24.  Parasympathetic failure does not contribute to ocular dryness in primary Sjögren's syndrome 
Annals of the Rheumatic Diseases  1999;58(12):746-750.
OBJECTIVE—To investigate the sympathetic and parasympathetic cardiovascular function in primary Sjögren's syndrome (SS) and to investigate the possible relation with ocular dryness.
METHODS—41 (40 women) patients with primary SS, mean age 50 years (range 20-80) with a mean disease duration of eight years (range 1-30), were studied. In each patient direct arterial blood pressure (BP), heart rate (HR) and respiration were measured continuously for two hours. The function of the autonomic circulatory regulation was evaluated by measuring the heart rate response to deep breathing (6 cycles/min) and by means of the Valsalva manoeuvre and the responses of BP, HR and plasma noradrenaline (norepinephrine) concentrations to a 10 minute 60 degree head up tilt test. Pupillography was done to evaluate ocular autonomic function.
RESULTS—The HR-Valsalva ratio was abnormal in 24% of the patients, and the HR variability during forced respiration was abnormal in 56% of the patients. The HR responses to both the Valsalva manoeuvre and deep breathing, as indicators of parasympathetic function, were abnormally low in 6 of 41 (15%) patients. In only two patients the decrease in systolic BP in response to the head up tilt test, as indicator of sympathetic function, was more than 20 mm Hg. However, increment of plasma noradrenaline concentration during head up tilt test and the overshoot of BP in phase IV of the Valsalva manoeuvre, as indicators of sympathetic function, were normal in both patients. Thus, no evidence for sympathetic dysfunction was found, whereas evidence for parasympathetic failure occurred sometimes. Autonomic pupillary function in patients with primary SS and healthy controls, as well as the Schirmer test in patients with or without evidence for parasympathetic dysfunction as based on the results of the Valsalva and deep breathing tests, were not significantly different.
CONCLUSION—Parasympathetic, but not sympathetic dysfunction seems to occur in a subgroup of primary SS. Results show that this does not necessarily contribute to the typical ocular dryness in this condition.

PMCID: PMC1752817  PMID: 10577960
25.  Sympathetic skin response and heart rate variability as diagnostic tools for the differential diagnosis of Lewy body dementia and Alzheimer's disease: a diagnostic test study 
BMJ Open  2013;3(3):e001796.
The purpose of this study is to investigate the usefulness of sympathetic skin response (SSR) and heart rate variability (HRV) for the differential diagnosis of patients with dementia with Lewy bodies (DLB).
A diagnostic test study.
Single centre in Japan.
We examined 20 patients with probable Alzheimer's disease (AD) diagnosed with NINCDS-ADRDA criteria and 20 with probable DLB diagnosed with the criteria of the third international DLB workshop.
For the SSR measurement, surface electrodes were used: the active recording electrode was placed on the palm of the hand and the reference electrode was placed on the dorsum of the same hand. SSR was induced by a median nerve electrical stimulation at an amplitude of 20 mA. For the HRV measurement, the A–A intervals were measured twice for 2 min with an interval of 5 min in a sitting position after a rest of 5 min. From the low-frequency power (LF; 0.02–0.15 Hz) and high-frequency power (HF; 0.15–0.50 Hz), the ratio of LF to HF power (LF/HF) was calculated using the maximal entropy method.
SSR and HRV could detect the abnormality of autonomic function in patients with DLB at sensitivities of 85% and 90%, respectively. On the other hand, SSR and HRV detected an abnormality of autonomic function in patients with AD at sensitivities of 15% and 25% (p<0.05). The combination of the SSR and the HRV (double-positive) indicated abnormal autonomic function was recorded in only 1 of 20 patients (5%) with AD. In contrast, this combination indicated autonomic abnormality in 15 of 20 patients with DLB by our criteria (75%).
SSR and HRV can be applied to differentiate DLB from AD.
PMCID: PMC3612799  PMID: 23457321
Dementia < Neurology; Neurophysiology < Neurology; Clinical Physiology; Geriatric Medicine; Neurology < Internal Medicine

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