Orthostatic hypotension and cognitive impairment: a dangerous association?

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Neurological SciencesOfficial Journal of the ItalianNeurological Society ISSN 1590-1874 Neurol SciDOI 10.1007/s10072-014-1686-8

Orthostatic hypotension and cognitiveimpairment: a dangerous association?

Luisa Sambati, Giovanna Calandra-Buonaura, Roberto Poda, PietroGuaraldi & Pietro Cortelli

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REVIEW ARTICLE

Orthostatic hypotension and cognitive impairment: a dangerousassociation?

Luisa Sambati • Giovanna Calandra-Buonaura •

Roberto Poda • Pietro Guaraldi • Pietro Cortelli

Received: 5 August 2013 / Accepted: 12 February 2014

� Springer-Verlag Italia 2014

Abstract Many studies have addressed the relation

between orthostatic hypotension (OH) and cognitive

impairment (CI) in the elderly, in mild cognitive impair-

ment, vascular and neurodegenerative dementias and

movement disorders, such as Parkinson’s disease. How-

ever, results concerning both the increased coexistence of

the two conditions and their causal relationship remain

controversial. According to the literature three hypotheses

can be formulated on the relation between OH and CI. In

neurodegenerative disease, OH and CI may result from a

common pathological process which affects areas involved

in both cognition and cardiovascular autonomic control.

Alternatively, OH may lead to cerebral hypoperfusion

which is supposed to play a role in the development of CI.

Finally, recent data suggest that CI should probably be

considered more a transient symptom of OH than a chronic

effect. This study reviews the literature reports on the

relationship between OH and CI, and emphasises the need

for longitudinal studies designed to investigate this topic.

Keywords Orthostatic hypotension � Cognitive

impairment � Elderly � Dementia � Movement disorders

Introduction

Several terms have been used to describe an intermediate

stage of cognitive decline. Among the others Mild

Cognitive Impairment (MCI) is used to recognise a path-

ological condition leading to dementia and a clinical entity

with discussed diagnostic criteria [1].

Similarly the term cognitive impairment (CI) lacks a

clear-cut definition, and generally refers to an indefinite state

between normality and dementia resulting in progressively

reduced cognitive performance. Degrees of CI have been

described in a multitude of diseases, varying across defini-

tions and in the different settings (i.e. community, specialty

clinical and research programs). In addition, normal ageing

is associated with cognitive decline and the prevalence of CI

increases even in advanced age reaching 68.3 % people in

individuals 95 years and above [1].

Orthostatic hypotension (OH) is common especially in the

elderly, with a prevalence between 5 % and 30 % depending

on the definition, segment (age range; institutions) and

composition (healthy population versus select groups) of the

population evaluated, the role of medications and the level of

orthostatic stress. In 2011, the Consensus Statement defined

OH as a clinical sign related to a sustained reduction in

systolic blood pressure (SBP) of at least 20 mmHg or, in

diastolic BP (DBP) of at least 10 mmHg, within 3 min of

standing up or head-up tilt to at least 60� on a tilt-table [2].

Orthostatic hypotension can be caused by vascular, phar-

macological or neurogenic factors; the latter is defined as

neurogenic OH (nOH). Neurogenic orthostatic hypotension

can be related to preganglionic neurodegenerative disease,

i.e. multiple system atrophy (MSA), or to neurodegenerative

postganglionic disease, i.e. Parkinson’s disease (PD), pure

autonomic failure (PAF), autoimmune autonomic gangli-

onopathy (AAG) associated with antiacetylcholine receptor

antibodies (AchR) or to metabolic disease.

Considering that several disorders occur with OH, CI or

both, regardless of the aetiology, many studies have been

conducted in order to define the increased coexistence of

L. Sambati (&) � G. Calandra-Buonaura � R. Poda �P. Guaraldi � P. Cortelli

IRCCS Istituto delle Scienze Neurologiche di Bologna e

Dipartimento di Scienze Biomediche e NeuroMotorie,

Alma Mater Studiorum, Universita di Bologna, Bologna, Italy

e-mail: [email protected]

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DOI 10.1007/s10072-014-1686-8

Author's personal copy

the two conditions and their causal relationship. Although

their identification could be relevant for diagnostic, prog-

nostic and therapeutic outcomes, the results of these studies

remain controversial.

This study reviews the literature describing the possible

link between progressive CI and OH.

Method

Research criteria

We searched PubMed for English language articles pub-

lished from 1992 to 1st May 2013 containing the terms

‘‘orthostatic hypotension’’ in conjunction with other key

terms, including ‘‘cognitive impairment’’, ‘‘dementia’’, and

‘‘neuropsychological impairment’’.

Results

Fifty-eight studies addressed the relation between OH and

CI in the elderly, in vascular and neurodegenerative

dementias, MCI and movement disorders, especially PD.

Except for three studies [3–5] assessing CI in nOH, the

others did not determine the aetiology of OH, in particular

they did not distinguish between primary nOH, secondary

OH, i.e. drug-related OH, OH induced by cardiovascular

dysfunction, etc.

Orthostatic hypotension and cognitive impairment

in the elderly

Orthostatic hypotension is common in older people, due to

ageing of the arterial and autonomic nervous system and a

decline in baroreceptor sensitivity [6]. The frequency of

OH increases with age [6] with a prevalence between 4 and

33 % depending on the methodology used and differences

in population. It is more common in institutionalised (up to

70 %) than community-dwelling elderly (6 %) [2]. Further,

as ageing is related to reduced cerebral autoregulation, any

abrupt change in BP resulting in a rapid and significant

change in cerebral blood flow can be assumed to cause or

exacerbate cognitive dysfunction [7]. The literature

addressing the relationship between OH and CI in the

elderly found no significant association between the two

[8–12] (Table 1). A longitudinal study by Yap et al. con-

sidering 2,294 community-living older adults identified

OH, defined according to the Consensus Committee of the

American Autonomic Society and the American Academy

of Neurology [13], in 16.6 % of subjects. Overall, there

was no significant association of OH with CI, corre-

sponding to Mini Mental State Examination (MMSE)

scores of 23 or less. Patients with OH were significantly

older and less educated than patients without OH. The

authors repeated the evaluation after 1 year of follow-up

finding no significant longitudinal association of OH with

cognitive decline and incident CI [9]. Similarly, Viramo

et al. tested people for OH and cognitive capacity in a

community-based setting in northern Finland [12]. Mean

MMSE (±Standard Deviation, SD) score was 21.6 (±3.98)

for persons with OH and 21.1 (±4.08) for non-OH persons.

Cognitive capacity was reassessed on 651 subjects who had

participated in the first examination. Orthostatic hypoten-

sion did not predict cognitive decline during a 2-year fol-

low-up; the only predictors of CI were old age and low

level of formal education [12]. The other studies [8, 10, 11]

failed to disclose any association (Table 1). The Athero-

sclerosis Risk in Communities Study included data from

12,702 participants [8]. Orthostatic hypotension was

defined as a drop in SBP [ 20 mmHg or

DPB [ 10 mmHg, upon two minute standing. Cognitive

function was evaluated by the Delayed Word Recall Test,

Digit Substitution Test and Word Fluency Test. After

adjustment for socio-demographic and cardiovascular risk

Table 1 Cognitive impairment and orthostatic hypotension in the elderly

Ref N Sex (M/F) Age Educationa MMSE Cognitiveimpairment

OH OH- OH OH- OH OH- OH OH- OH OH- OH OH-

9 381 1,913 122/259 664/1,249 66.6 ± 8.5 65.3 ± 7.1* 59.1 % 49.9 %*** 26.7 ± 3.5 27.3 ± 3.2* 16.6 % 9.9 %**

12 931 228 339/592 n.r. 76.0 ± 4.93 76.0 ± 5.10 n.r. n.r. 21.6 ± 3.98 21.1 ± 4.08 n.r. n.r.

8 652 12,050 288/364 1249/10,801 57.3 53.9 32.4 % 22.4 % n.r. n.r. n.r. n.r.

10 9 27 26/10 80.5 ± 6.2 n.r. n.r. 21.3 ± 4.8 n.r. n.r.

11 70 n.r. n.r. 72 ± 4 n.r. n.r. n.r. n.r. n.r. n.r.

Ref references, N numerosity, M male, F female, MMSE mini mental state examination, OH group of patients with orthostatic hypotension, OH- group ofpatients without orthostatic hypotension, n.r. not reported

* P = 0.003, ** P = 0.07, *** P = 0.002a The studies report the percentage of patients with \6 years of schooling

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factors, the association between OH and CI was not sig-

nificant. Bendini et al. [10] selected a group of 36 subjects

older than 65 years and found no relation between cogni-

tive status and OH. Kuo et al. evaluated orthostatic BP in

70 healthy persons administering neuropsychological tests

to assess short-term and long-term verbal and visual

memory, visuospatial skills, and frontal-executive func-

tions [11]. Participants were considered impaired in spe-

cific cognitive performance if their scores fell below the

25th percentile of the study population. There was no

significant association between cognitive function and

orthostatic BP decline (Table 1).

All these studies did not report a cut-off score and did

not include a control group so we do not know if the results

of cognitive evaluation are in the range of normality or not.

Another important consideration related to three of these

studies [9, 10, 12] is that elderly people with CI were not

classified as demented patients, or at least as patients with

MCI, giving rise to possible misunderstanding. In addition,

these studies reported MMSE cut-off scores consistent with

a diagnosis of both MCI and dementia (Table 1).

Orthostatic hypotension and cognitive impairment

in dementia syndromes

Autonomic dysfunction (cardiovascular, urinary, gastroin-

testinal and sudomotor) is common in all forms of

dementia (i.e. vascular dementia, VAD; Alzheimer disease,

AD; frontotemporal dementia, FTD; dementia with Lewy

bodies, DLB, and PD dementia, PDD) [14]. Furthermore,

the anatomical structures that degenerate in dementia

syndrome are also involved in autonomic functions’ con-

trol and this observation makes the hypothesis of a relation

between CI and OH reliable [14]. A higher prevalence of

OH was found in demented patients with respect to con-

trols [6, 16–19], but no study defined the causal relation

between OH and CI in the different forms of dementia and

only one [6] reported a significant relationship between the

two. Meharabian et al. described OH, defined according to

the Consensus Committee of the American Autonomic

Society and the American Academy of Neurology [13], in

69/495 patients (mean age ± SD: 76 ± 8 years) com-

plaining of memory loss at a geriatric memory clinic [6]. A

significant relation was observed between OH and cogni-

tive function (Cognitive Efficiency Profile score ± SD:

50 ± 24 in patients with OH vs. 56 ± 22 in patients

without OH, p \ 0.05). Further, a significant gradient

(p \ 0.01 for overall test) was found in the level of cog-

nitive function in relation to OH (Table 2). This relation

persisted after adjustment for age, education, seated SBP

and DBP, weight and antihypertensive drugs. However,

although cognitive function was assessed with a

comprehensive battery of neuropsychological tests, the

final result of the battery and the single results of the dif-

ferent tasks were not reported [6], so we cannot conclude

that these patients were cognitively impaired or suffered a

subjective reduction in cognitive performance within nor-

mal range. The other studies only evaluated a general score

of global cognitive function (generally MMSE) (Table 2).

In particular, Schoon et al. evaluated 184 patients (mean

age ± SD: 80.2 ? 6.8 years) referred to a centre for cog-

nitive deterioration; 104/184 patients had OH, defined as a

decrease of at least 20 mm Hg in SBP, recorded at any of

the 10-min averages after the first 60 s of standing. Patients

with dementia were older, weighed less and had a higher

baseline heart rate compared to patients with MCI and

patients without CI (Table 2). No differences were reported

in CI, evaluated by MMSE and Cambridge Examination

for Mental Disorders in the Elderly, between patients with

and without OH [15]. Andersson et al. considered OH and

CI in DLB and AD patients. They found no differences in

Table 2 Cognitive impairment and orthostatic hypotension in

dementia syndromes

Diagnosis Ref N Age MMSE OH (n) OH (%)

MCI 6 139 n.r. n.r. 19 13

15 44 80.5 ± 7.1 24.6 23 55

AD 6 233 n.r. n.r. 37 16

16 235 76 21 99 42

17 39 79 ± 6 n.r. 13 33

18 46 78 n.r. 18 39

19 128 75.6 ± 7.7 23,8 52 41

VAD 6 34 n.r. n.r. 9 23

17 30 80 ± 6 n.r. 10 33

18 77 63 n.r. 40 52

FTLD 18 28 80 n.r. 13 46

DLB 16 52 77 22 36 69

17 30 75 ± 7 n.r. 14 46

19 39 78.1 ± 8.2 23.7 16 42

PDD 17 40 72 ± 7 n.r. 18 45

19 11 73.4 ± 8.8 25.7 6 55

Dementia 15 35 83 ± 6.4 19.4 23 68

19 18 74.7 ± 7.6 23.5 6 31

Controls 6 89 n.r. n.r. 4 4

15 104 79.1 ± 6.6 27.2 58 57

16 62 73 29 8 13

17 38 76 ± 7 n.r. 5 13

19 81 75.6 ± 3.9 n.r. 11 14

Ref references, N numerosity, MMSE mini mental state examination,

OH orthostatic hypotension, OH- group of patients without ortho-

static hypotension, MCI mild cognitive impairment, AD alzheimer

disease, VAD vascular associated dementia, FTLD frontotemporal

lobar degeneration, DLB lewy body dementia, PDD Parkinson’s

disease dementia, n.r. not reported

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mean MMSE score between the two groups, but only with

respect to controls (p \ 0.001) (Table 2). Considering OH,

they demonstrated a higher prevalence of OH in the group

of DLB patients with respect to AD (Table 2) and a more

significant and prolonged drop of SBP in DLB patients

compared to AD and controls (p = 0.001) [16].

Allan et al. compared different demented patients with

OH, reporting no differences in CI among the different

types of dementia. Sustained OH was more prevalent in all

patient groups than in controls (p \ 0.005) [17]. Passant

et al., comparing AD, FTD and VAD patients, reported

OH, defined as a SBP decrease of more than 20 mmHg

when standing from supine position, as a common clinical

finding [18]. Sonnesyn et al. reported no differences in the

mean MMSE score of patients with PDD, DLB, AD and

other dementias (VAD, FTD, alcoholic dementia) but a

prevalence of OH patients, defined according to the Con-

sensus Committee of the American Autonomic Society and

the American Academy of Neurology [13], in AD and PDD

groups with respect to controls (p = 0.000) (Table 2), and

lower SBP values in PDD and DLB patients than AD and

controls (p = 0.01) were observed [19].

Orthostatic hypotension and cognitive impairment

in movement disorder

Orthostatic hypotension has been reported in 43–58 % of

PD patients, but the results of a recent meta-analysis

reported a prevalence of 30 % [20]. These differences are

probably due to different definitions of OH, different

methods used to measure postural blood pressure changes

and variation in timing of recordings. Further, these studies

were conducted in hospital PD clinics and may not be

representative of the PD community as a whole.

Cognitive impairment in PD is common, with a mean

prevalence of 27 % [21], and is associated with ageing,

disease duration and severity [22]. In general, studies on

the relation between CI and OH in PD patients reported no

differences in global function but significant differences in

single tasks, especially executive tasks. As reported for

elderly and demented patients, PD patients with OH were

generally older than patients without [23, 25, 26] and this

may contribute to a decline in cognitive function. Despite

different disease duration and motor disability, the MMSE

scores were similar in PD patients with and without OH

(Table 3), but none of the studies explained the aetiology

of OH.

A community-based study [23] recorded OH in 47 % of

PD patients. These patients with OH were older and were

taking more hypotensive drugs in addition to levodopa, but

the impact of levodopa/dopamine agonist treatment on OH

could not be calculated. No differences were reported in

cognitive function or in behavioural examination evaluated

only on the basis of MMSE, Geriatric Depression Score

and Montgomery Assessment Depression Rating Scale

between patients with and without OH.

Idiaquez et al. compared 40 consecutive PD patients

with controls (Table 3) and considered the relationship

between OH, defined according to the Consensus State-

ment on the diagnosis of multiple system atrophy of 1999

[25], and CI, finding the same incidence of OH in PD

patients and controls [24]. Eleven of 40 PD patients had a

diagnosis of PDD but there were no differences in OH

incidence between PD and PDD patients and no significant

correlation between OH and any of the cognitive or

behavioural scores (MMSE, Frontal Assessment Battery or

Blessed Score).

Allock et al. evaluated the relationship between clinical

phenotype of subjects with PD and OH, defined according

to the Consensus Committee of the American Autonomic

Society and the American Academy of Neurology [13].

Eighty of 159 patients with PD had OH, but there were no

differences in the mean MMSE score compared with

Table 3 Cognitive impairment and orthostatic hypotension in Parkinson’s disease

Ref N Age Sex (M/F) Disease duration (years) UPDRS MMSE

OH OH- OH OH- OH OH- OH OH- OH OH- OH OH-

26 80 79 72.10 69.10 56/24 41/38 3.00 5.00 19.00 17.00 25.50 26.00

27 87 88 72.40 69.20 63/24 46/42 3.50 5.00 18.50 17.00 25.00 26.00

28 23 25 64.96 65.60 13/10 15/10 11.48 11.76 37.83 37.36 25.10 24.72

30 32 55 68.60 66.80 17/14 18/37 1.70 1.80 21.50 22.90 25.40 26.00

23 42 47 72.6 ± 8.1 68.2 ± 9.6 n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r.

29 7 11 n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r.

24 5 35 n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r.

31 n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r. n.r.

Ref references, N numerosity, MMSE mini mental state examination, OH orthostatic hypotension, OH- group of patients without orthostatic

hypotension, UPDRS unified Parkinson’s disease rating scale, n.r. not reported

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patients without OH [26]. In a further study, they evaluated

a group of 175 PD patients for OH (drop in SBP after

standing, greater than or equal to 20 mmHg or a SBP of

\90 mm Hg after standing): 87 of the PD patients had OH

and were significantly more impaired in sustained attention

and visual episodic memory [27].

A recent study evaluated 48 patients with PD who

underwent a tilt-table test to disclose OH, defined accord-

ing to the Consensus Statement of 2011 [2], were further

investigated with a complete neuropsychological battery

[28]. At tilt test, 23 patients presented OH. There were no

differences in demographic parameters, disease duration or

UPDRS score in patients with and without OH, but OH

patients showed worse cognitive performances in sustained

attention, visuospatial and verbal memory when compared

to patients without OH [28].

Two studies [29, 30] evaluated the differences in cog-

nitive function between PD and PDD patients with or

without OH, reporting conflicting results. Peralta et al.

investigated the differences in cognitive performance dur-

ing tilt test on Test of Everyday Attention (TEA) and Word

Fluency Test in a group of ten PD patients compared to

eight PDD patients [29]. Orthostatic hypotension, defined

according to the Consensus Committee of the American

Autonomic Society and the American Academy of Neu-

rology [13], was present in five PDD and two PD patients

without significant differences. They also reported a greater

attentional deficit upon standing in PDD compared to PD

patients, correlated with SBP drop. Another study [30]

investigated 87 Korean drug-free patients with a diagnosis

of early Parkinson’s disease using tilt-table testing and

neuropsychological tests. Orthostatic hypotension was

diagnosed according to the Consensus Committee of the

American Autonomic Society and the American Academy

of Neurology [13]. There were no differences in demo-

graphic characteristics between patients with and without

OH, but the OH group had more severe impairment in

immediate and delayed memory. Further, OH and non-OH

patients differed in the prevalence of cognitive impairment

and dementia (5 normal cognition, 17 MCI, 10 PDD in the

OH group vs 20, 31 and 4 respectively in non-OH group)

and patients with dementia had a marked progressive

reduction in blood pressure during orthostasis compared

with the other groups [30].

Oh et al. considered the relationship between autonomic

dysfunction, evaluated by SCOPA-aut questionnaire

results, cognitive deterioration, through MMSE, and dis-

ease progression, through Hoen and Yahr scale, in a group

of 63 PD patients at different stages of disease. They found

a progressive deterioration of cognitive and autonomic

function following disease progression [31].

No studies have evaluated the relationship between CI

and OH in multiple system atrophy.

Cognitive impairment in neurogenic orthostatic

hypotension

Only three studies [3–5] assessed cognitive function in

patients with nOH, reporting transient or stable CI,

especially in executive functions. Globally impaired

cognitive function was never reported. Cognitive function

assessed with a comprehensive battery of neuropsycho-

logical tests [3] in seated position in a group of 14

patients with PAF disclosed CI in only six patients, with a

prominent deficit in speed, attention and executive func-

tions. Another interesting study evaluated ten patients

with postganglionic nOH on tilt-table while supine and

during head-up tilt (HUT) to an angle able to cause a fall

in SBP fulfilling OH criteria of the Consensus Committee

of the American Autonomic Society and the American

Academy of Neurology [4, 13]. Patients’ cognitive status

was investigated with the Brief Mental Deterioration

Battery. Patients did not have pathological scores in the

final result of the battery, but cognitive function was

significantly worse during HUT compared to the supine

position (p \ 0.005). The worsening was also reported in

different subtests of the battery exploring executive

functioning [4]. Recently, Gibbons et al. assessed three

patients with AAG in the seated and standing position

over a 1-year period before and/or after cycles of plasma

exchange [5]. Postural hypotension in the presence of

high nicotinic AChR antibody levels prior to plasma

exchange resulted in deficits in executive function, sus-

tained attention and working memory both in the sitting

and orthostatic positions; CI resolved with improved OH

after plasma exchange.

Discussion

Cognitive impairment and OH are common conditions and

their prevalence increases with ageing [1, 2]. However, the

review of different studies [8–12] addressing the question

of the relationship between CI and OH in the elderly dis-

closed no association between the two.

Many studies have addressed the relation between OH

and CI in different diseases, but results remain inconclu-

sive. In particular, OH is reported to be more prevalent in

the different types of dementia, especially in DLB, with a

gradient related to the level of cognitive function [6, 16–

19] but no association with CI is reported. Considering PD,

only two of eight studies [27, 28] reported a greater

impairment in sustained attention and visuospatial memory

in PD patients with OH. Two more studies [29, 30] con-

sidered PD and PDD patients and, as for demented patients,

showed a greater prevalence of OH, associated with a

gradient related to the level of cognitive function.

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Three studies [3–5] assessing cognitive function in

patients with nOH reported that these patients showed a

transient worsening of the executive functions which

resolved in the lying position [4] or after plasmaferesis [5].

Discrepancies probably depend on the methods used,

including different selection and diagnostic criteria, the

settings of recruitment and the analysis of small cohorts

of patients. Further, these studies did not report cut-off

scores of normality; several did not compare patients with

control groups and do not discuss the role of confounding

factors such as comorbidities, drugs and disease

characteristics.

In order to establish the causal relation between OH and

CI studies with longer periods of observation starting from

early stage of diseases are needed, as neither those on pure

peripheral disorder [3–5] nor those on central nervous

system diseases [6, 8–12, 14–19, 26–31] were designed to

answer this question.

Considering the current state of the art, three hypotheses

can be formulated on the relation between OH and CI.

First, the same cerebral areas involved in the neurode-

generative process leading to dementia syndromes are

devoted to the autonomic control of the cardiovascular

system, so that neurodegeneration can be the cause of both

CI and OH [14].

Another hypothesis is that OH may result in cerebral

hypoperfusion which is supposed to play a role in the

development of CI. Frontal lobe hypoperfusion during OH

has been reported, regardless of the underlying disease,

both in dementia syndromes and pure peripheral disorder

[34, 35]. Orthostatic hypotension can, therefore, contribute

to frontal brain changes, exacerbate the underlying disease

and lead to impaired executive functions [3–5, 8–11, 28–

30]. However, previous studies in OH patients demon-

strated an expansion of the autoregulated cerebral perfu-

sion range at both the upper and lower limits, so that

cerebral perfusion remained relatively constant with the

patient in the supine position (when supine hypertension

might be present) and in response to standing (when OH

occurs), not explaining a true reduction in cerebral perfu-

sion [33].

The third hypothesis on the relationship between CI and

OH indicates that CI should probably be considered more a

transient symptom of OH than a chronic effect.

In patients with PAF the orthostatic challenge induces a

significant worsening of executive function reversible in

the supine position [3, 4] and in patients with AAG the

treatment with plasma exchange improves both OH and CI

[5]. Moreover, recently, Basile et al. demonstrated, in

normal subjects engaged in a visuospatial attention task,

that an autonomic perturbation increases the reaction times

of response and induced activation of the fronto-parietal

attention network [36].

Conclusion and future directions

In conclusion, it should be demonstrated that patients

presenting chronic OH became demented in the absence of

any other cause. On the other hand, OH should be con-

sidered in patients presenting cognitive dysfunction, and

standardised orthostatic measurements should be under-

taken into routine physical examinations to identify a

possible influence on CI. The investigation of the effect of

a direct stimulation of the ANS on the brain functioning

in vivo could also be promising for applications in clinical

conditions [36].

Future longitudinal studies must adopt standardised

criteria to identify OH patients possibly developing CI, and

CI patients possibly developing OH to establish if OH is

the cause of CI or the two conditions are simply the

expression of the same neurodegenerative process.

Acknowledgments We thank Professor Paolo Barone for his

valuable suggestions and Dr. Anne Collins for the careful editing of

the manuscript.

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