(Stroke. 1997;28:1351-1356.)
© 1997 American Heart Association, Inc.
Articles |
Impaired Calcium Regulation in Subcortical Vascular Encephalopathy
From the Departments of Psychopharmacology (A.E., W.E.M.) and Psychiatry (H.F.), Central Institute of Mental Health, and the Department of Neurology (M.O., M.H.), Klinikum Mannheim of the University of Heidelberg, Mannheim, Germany.
Correspondence to Prof Dr Walter E. Müller, Department of Pharmacology, University of Frankfurt, Biocenter, Geb N260, D-60439 Frankfurt, Germany. E-mail psymail{at}as200.zimannheim.de
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Abstract |
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Background and Purpose A number of clinical observations and first in vitro findings indicate that chronic cerebral ischemia influences immunologic status, such as the proliferative response of T lymphocytes. The purpose of the present report was to assess (1) whether changes of immune function are likewise detectable in patients with progressive subcortical vascular encephalopathy (SVE) by investigating the [Ca2+]i homeostasis of lymphocytes and (2) whether differences exist in calcium regulation between lymphocytes from SVE patients and from Alzheimer's disease (AD) patients. This is of great interest, since specific changes have been reported recently in AD patients.
Methods [Ca2+]i was recorded in 26 patients with SVE, 26 age-matched nondemented control subjects, and 26 age-matched patients with AD. Basal [Ca2+]i and [Ca2+]i after lymphocyte activation with the mitogen phytohemagglutinin (PHA) were measured with the fura 2 method. In addition, modulation of the Ca2+ signaling by the peptide ß-amyloid and the potassium channel blocker tetraethylammonium was studied.
Results Basal [Ca2+]i was not different between patients and control subjects. After stimulation with PHA, however, a significant reduction of the Ca2+ response could be observed in lymphocytes of SVE patients compared with control subjects and with AD patients, providing evidence that the Ca2+ homeostasis of lymphocytes is impaired in SVE. The effect of the peptide ß-amyloid, the major constituent of senile plaques in AD brain, on Ca2+ signaling was similar in SVE patients and nondemented control subjects but typically reduced in cells of AD patients. Potassium channels were not involved in the impaired Ca2+ response of SVE lymphocytes after cell activation.
Conclusions [Ca2+]i is not only one of the most important second messengers in signal transduction of many cells but also an early event in the signal cascade of cell proliferation as a reaction to antigen recognition. This mechanism seems to be impaired in SVE. These findings may result in new insights regarding the pathogenesis of this disease and the possible involvement of inflammatory or immunologic disturbances.
Key Words: calcium • cerebrovascular disorders • dementia • lymphocytes • encephalopathy
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Vascular dementia is the second most common cause of dementia in the western world, after AD.1 2 3 4 Very little evidence is available regarding possible implications of immunologic dysfunction in the pathogenesis of this disease. Some early findings in patients indicate that immunologic status underlies alterations during stroke. Thus, stroke seems to trigger systemic memory T cells.5 In the early stages, the proliferative responses to the mitogens PHA or concanavalin A and to tuberculin were reduced in T lymphocytes from stroke patients compared with control subjects.6 Furthermore, markers for systemic leukocyte activation, eg, proinflammatory cytokines, were higher in plasma7 and brains8 of patients with acute ischemic cerebrovascular disease than in control subjects. On the basis of these data, it seems possible to speculate that after several ischemic insults during cerebrovascular disease or vascular dementia, similar or related alterations may be present. Furthermore, it has been emphasized that the immunologic response plays an important role in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage.9 Even a lymphocyte infiltration in ischemic lesions of the rat cortex and an intensive accumulation of polymorphonuclear lymphocytes in the regions of cerebral infarction of patients with ischemic stroke have been reported.10 11
Free [Ca2+]i is elevated by several second messenger generating systems. Because of its broad and crucial role in signal transduction pathways, [Ca2+]i has attracted specific attention. In lymphocytes, [Ca2+]i represents an early event in the intracellular signal cascade of cell proliferation and cytokine activation.12 Therefore, measurement of [Ca2+]i appears to be a valuable tool to detect early disturbances in the immunologic function of these cells.
The goal of the present study was to assess specific changes of [Ca2+]i regulation in a large group of patients with SVE13 and to distinguish between SVE, AD, and nondemented control subjects.
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Subjects and Methods |
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Subjects
The experiments were performed with the use of blood cells from 26 patients (14 men and 12 women) with SVE13 14 15 following the diagnostic criteria for research studies (NINDS-AIREN).16 Patients underwent a structured medical and neurological examination as well as neuropsychological interviews following a research protocol with particular emphasis on the presence of motor and gait disturbances, urinary incontinence, memory and attention disorders, frontal release signs, and spontaneous episodes. All patients recruited showed evidence of memory impairment with at least one deficit in cognitive domains (eg, abstract thinking, language, orientation, flexibility, personality changes) or isolated functional impairment unrelated to physical deficits. Furthermore, dementia was diagnosed only on the basis of combined information from the initial and follow-up studies. All patients who entered this study had repeated follow-ups, with confirmation of the entry diagnosis for at least a 2-year period. Several standardized test procedures, including the Structured Interview for the Diagnosis of Dementia, Brief Assessment Interview, and Nürnberg Ageing Inventory, were used to exclude patients with other psychopathological diseases, in particular a significant mood disorder and degenerative dementia diseases. Moreover, care was taken to avoid inclusion of patients with mixed forms of dementia by strict adherence to the NINDS-AIREN and NINCDS-ADRDA criteria.16 17 Essential differences consisted of focal neurological findings, stepwise versus progressive decline of cognitive functions, presence or absence of lacunar cortical infarction, and white matter lesions on MRI scans. The mean age was 72±6.2 years (range, 59 to 84 years; median, 71 years).
Blood cells from 26 patients (14 men and 12 women) with "probable" or "possible" AD according to the NINCDS-ADRDA criteria17 were used as a second demented group to elucidate differences in pathogenesis. Patients were recruited from an ongoing longitudinal study.18 These patients were also followed for at least a 2-year period, and confirmation of the diagnosis was established before entry into the present study. With regard to the aforementioned criteria, particular care was taken to separate vascular from degenerative dementia disorders and to exclude patients with mixed diseases. The mean age was 68±8.6 years (range, 51 to 86 years; median, 68 years).
Blood cells from 26 nondemented individuals of similar age (mean age, 69±6.7 years; median, 70 years; range, 56 to 84 years; 14 men and 12 women) were used as controls. These subjects also underwent standardized neurological and neuropsychological examinations, as previously mentioned, and brain imaging disclosed cerebral infarction, brain atrophy, or significant white matter lesions.
Approximately half of the AD patients, half of the aged control subjects, and most of the SVE patients were taking cardiovascular and antidiabetic drugs. Nine SVE patients were taking calcium antagonists. None of the drugs used are known to interfere with [Ca2+]i homeostasis in lymphocytes. This is also the case for calcium antagonists, since lymphocytes do not express L-type Ca2+ channels.19
Cell Separation
Peripheral blood lymphocytes were separated from
heparinized blood by centrifugation with Ficoll-Hypaque
at 400g for 40 minutes, as previously
described,20 according to the method of
Boyum.21
[Ca2+]i Measurements
Fura 2-AM (3 µmol/L) loading and measurements of
[Ca2+]i were performed as described
previously.22 Freshly prepared lymphocytes were stimulated
with PHA (Sigma) at a final concentration of 15 µg/mL.
[Ca2+]i was calculated according to the
method of Grynkiewicz et al.23 To investigate the
involvement of potassium channels in PHA-induced Ca2+
response, cells were exposed for 2 minutes to TEA (50 mmol/L)
before stimulation. To study the effects of preaggregated ßA25-35
(1 µmol/L; Sigma) on PHA-induced increases in
[Ca2+]i, freshly prepared lymphocytes were
preincubated with ßA25-35 for 60 seconds.20 22
Ca2+ responses to PHA in the presence or absence of
ßA25-35 are expressed as 
Ca2+, which is the maximal
increase in [Ca2+]i over baseline.
Ca2+ßA25-35 is the ßA-induced increase in
[Ca2+]i over maximal stimulation by PHA.
Statistical Analysis
Significance was tested with ANOVA (SAS Institute), Student's
t test, or the paired t test.
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Results |
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Alterations of [Ca2+]i were investigated in freshly prepared peripheral lymphocytes of 26 SVE patients, 26 age- and sex-matched elderly nondemented control subjects, and 26 AD patients (Table
). Fig 1 shows
the time course of PHA-induced increase in
[Ca2+]i over baseline
[Ca2+]i (Ca2+) after PHA (15
µg/mL) stimulation in lymphocytes from aged control subjects and SVE
patients. The maximum Ca2+ signal was reached after 1
minute in both groups (Fig 1). However, comparison of the time courses
revealed a significantly impaired PHA-induced Ca2+ response
in cells from SVE patients compared with control subjects (ANOVA,
P=.002, F=10.64; Fig 1). The difference in
[Ca2+]i mobilization between both groups was
mainly pronounced in the initial phase of the Ca2+ response
(ANOVA, P<.001 for the time points within the first 60
seconds), which is dominated by a Ca2+ release from
intracellular stores.24 25
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In contrast, the PHA-induced Ca2+ increase was not
different between AD patients and control subjects (Fig 2 inset,
Table
), confirming previous findings.26 27 28 29
Moreover, measurement of basal [Ca2+]i in
lymphocytes revealed no difference among the three groups (Table).
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Approximately half of the AD patients and half of the aged control
subjects were taking drugs, mainly for cardiovascular
diseases, but none were taking calcium antagonists. For
each group, the basal [Ca2+]i and the
PHA-induced Ca2+ increase in lymphocytes of individuals on
drugs versus the drug-free individuals were not significantly different
(basal [Ca2+]i: control subjects, 107.7±19.4
versus 95.8±19.1 nmol/L; patients, 107.7±11.3 versus 99.0±18.6
nmol/L; Ca2+: control subjects, 84.5±22.3 versus
102.8±15.7 nmol/L; patients, 106.7±27.1 versus 99.0±26.3 nmol/L,
respectively). The majority of the SVE patients were taking drugs for
cardiovascular diseases, and 9 of 26 patients were
taking calcium antagonists. There was no difference in
basal [Ca2+]i levels or in PHA-induced
Ca2+ increase between patients taking calcium
antagonists and calcium antagonist–free
individuals (basal [Ca2+]i: 97.2±12.0 versus
101.9±14.3 nmol/L; Ca2+: 82.1±25.6 versus 83.7±25.1
nmol/L, respectively), which is in agreement with the report that
peripheral human lymphocytes do not express functional
voltage-gated L-type Ca2+ channels.19
Moreover, there was no significant difference in Ca2+ to
PHA in lymphocytes of SVE patients with normotonus, mostly after
medication, compared with SVE patients with either hypotonus or
hypertonus. Furthermore, plasma cholesterol levels did not
differ among the three groups (Table).
The time to reach the maximum Ca2+ peak after stimulation
with PHA was unaltered between SVE patients and age-matched control
subjects (control subjects: 68.1±26.6 seconds; SVE patients:
76.7±29.8 seconds) (Fig 3). In contrast, the time to
reach the maximum Ca2+ peak was significantly delayed
(P<.01) in lymphocytes of AD patients compared with control
subjects (AD: 96.4±42.4 seconds; control subjects: 68.1±26.6 seconds)
(Fig 3 inset) by unaltered Ca2+ response between both
groups (Fig 2 inset), confirming our previous
findings.28
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As previously described,20 the Ca2+-amplifying
effect of ß-amyloid is not restricted to neuronal cells but could
likewise be demonstrated on the PHA-induced Ca2+ increase
in lymphocytes. Preincubation of freshly prepared lymphocytes obtained
from aged nondemented control subjects with the ß-amyloid fragment
25-35 (ßA25-35) (1 µmol/L) resulted in a significant
amplification (Ca2+ ßA25-35: 13.4±9.4 nmol/L, the
difference between the Ca2+ response to PHA alone and the
Ca2+ response to PHA in the presence of ßA25-35) (Fig 4). A similar amplification of the PHA-induced
Ca2+ increase was observed in lymphocytes from SVE patients
after exposure to ßA25-35 (Ca2+ ßA25-35: 8.3±10.5
nmol/L) (Fig 4). In contrast, ßA25-35 amplification was absent in
lymphocytes from AD patients (0.6±5.9 nmol/L; P<.001
compared with the Ca2+ ßA25-35 values of the aged
control subjects, P<.01 compared with the
Ca2+ ßA25-35 values of the SVE patients) (Fig 4 inset,
Table), confirming our previous findings about the marker function of
this effect in AD.22 30 31 The effect of ßA25-35 on
PHA-induced Ca2+ increase in lymphocytes was not different
between SVE patients taking calcium antagonists and calcium
antagonist–free individuals (Ca2+
ßA25-35: 10.3±8.8 versus 7.2±11.4 nmol/L, respectively).
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.001, Student's t
test.
Furthermore, we investigated the effect of the potassium channel
blocker TEA on the PHA-induced Ca2+ increase in
lymphocytes. Preincubation of lymphocytes with TEA depolarizes the
membrane potential, which reduces the Ca2+ current into the
cell after PHA stimulation. Preincubation of cells with TEA (50
mmol/L) for 2 minutes caused a similar inhibition of the
Ca2+ increase in lymphocytes of nondemented control
subjects and SVE patients (51.9±9.9% inhibition versus 48.3±12.4%
inhibition, respectively) (Fig 5). Lymphocytes of AD
patients, however, showed a tendency toward diminished effects of TEA
(42.2±14.6% inhibition) compared with nondemented control subjects
(Fig 5 inset), supporting the assumption of a pure AD-specific
potassium channel dysfunction.32 33 34
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Discussion |
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The present results clearly indicate that the Ca2+ increase after cell activation with the mitogen PHA is markedly reduced in lymphocytes from SVE patients compared with nondemented control subjects. Only very few data presently provide detailed information about specific changes of [Ca2+]i in patients with cerebrovascular disease or dementia. Two investigators studied [Ca2+]i regulation in lymphocytes of patients with MID and compared them with aged control subjects and AD patients.29 35 Consistent with our data, neither observed any difference in basal [Ca2+]i levels among the three groups. However, they did not observe differences after PHA stimulation in lymphocytes from MID patients compared with aged control subjects or AD patients. One explanation for the inconsistency of the results might be the higher PHA concentrations used by Adunsky et al35 and Bondy et al29 (PHA 25 µg/mL and 100 µg/mL), thereby superimposing the possibly impaired initial Ca2+ release from intracellular stores by intense Ca2+ influx through the plasma membrane into the cell during the plateau phase of the Ca2+ response. Moreover, a different subgroup of patients was investigated in our study. The SVE patients represent a well-characterized group of patients with white matter lesions particularly in the frontal regions,13 14 whereas the diagnosis of MID may represent a less precisely defined group of patients.36 With respect to the heterogeneity of our findings in PHA-induced Ca2+ response in lymphocytes from SVE patients compared with other groups, the divergent type of subgroup and the small number of patients investigated by Adunsky et al35 (MID patients, n=6) and by Bondy et al29 (MID patients, n=6) have to be considered. The impaired PHA-induced Ca2+ response in lymphocytes of SVE patients during the entire period of stimulation seems to be associated with a reduced Ca2+ mobilization from [Ca2+]i organelles, which mainly dominates the initial Ca2+ increase after cell activation,25 whereas impaired Ca2+ influx mechanisms seem to be involved in the delayed time of the maximum Ca2+ response in lymphocytes of AD patients.28
On the other hand, SVE patients could be distinguished from AD patients in two experiments that appear to determine AD-specific alterations. In agreement with our previous findings22 28 30 and those of others,31 the lymphocyte sensitivity for the Ca2+-amplifying effect of ß-amyloid is strongly reduced in AD patients compared with nondemented control subjects and compared with SVE patients. The specific reduction of the effect of ß-amyloid on [Ca2+]i and even the complete absence of the Ca2+-amplifying effect are striking and represent an important peripheral marker of AD.22 28 30 37
One possible explanation for the impaired ß-amyloid sensitivity of lymphocytes in AD might be a potassium channel dysfunction, as previously described by Etcheberrigaray et al32 33 from skin fibroblasts of AD patients. The authors demonstrated that the effect of ß-amyloid on potassium channel function and the subsequent modulation of [Ca2+]i were reduced in skin fibroblasts of AD patients as a result of the absence of TEA-sensitive potassium channels in AD fibroblasts.33 A similar reduction of the effects of TEA has been in lymphocytes from AD.19 29 By blocking potassium channels, TEA is also able to indirectly influence the Ca2+ influx into lymphocytes. Preincubation of lymphocytes with TEA depolarizes the membrane potential, which reduces the Ca2+ influx into the cell after PHA stimulation.38 Consistent with our data19 and those of others,29 lymphocytes from AD patients showed a tendency to diminished effects of TEA compared with control subjects. This mechanism was unaltered in lymphocytes from SVE patients compared with control subjects. Therefore, K+ channels appear not to be involved in the impaired Ca2+ response of lymphocytes from SVE patients after PHA stimulation. Whether this potassium channel alteration can be linked to the reduced ß-amyloid sensitivity of AD lymphocytes is currently under investigation.
In lymphocytes, an increase in [Ca2+]i represents an early event in the intracellular signal cascade of cell proliferation after PHA stimulation.12 Very importantly, Tarkowski et al6 demonstrated that during stroke the proliferative responses of T lymphocytes to the mitogens PHA and concanavalin A were reduced compared with healthy control subjects. Therefore, we can assume that findings of an impaired Ca2+ activation in SVE lymphocytes are in accordance with these data and provide new insights into the pathogenesis of SVE with respect to a probably altered immunologic function. The nervous system and the immune system are known to communicate with soluble factors such as cytokines and interact at various levels. The cytokines are upregulated in patients with ischemic stroke and suggest an early inflammatory response in human cerebrovascular disease.7 8 Thus, modulators of cell-mediated immunity may alter T lymphocyte and macrophage invasion or function, as seen after vasospasm of superficial cerebral arteries and cerebral injury.10 11 The cellular invasion characterized by the alteration of the CD4+/CD8+ ratio in cerebral tissues is seen in many forms of inflammation. Even in AD an increase in CD8+ cytotoxic/suppressor T cells has been found,39 probably initiating an activation of brain microglia40 ; in addition, overexpression of two cytokines may be involved in HIV neuropathogenesis with similarities to the neuronal cell loss in AD.41
In conclusion, our results show that [Ca2+]i regulation was specifically impaired after cell activation during SVE. This effect was detected in circulating peripheral lymphocytes obtained from these patients. There was some overlap between the SVE and the AD groups. Several of the SVE patients showed low responses to the Ca2+-amplifying effect of ß-amyloid and after TEA treatment, as occurred in lymphocytes from AD patients. When one considers the difficulties of differentiating between vascular disease and the coexistence of vascular and degenerative dementia,4 overlap of some results between patient groups should be expected. Nonetheless, our work offers a new approach to partially discriminate between two different groups of patients with either cerebrovascular disease or AD.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by grants from the Deutsche Forschungsgemeinschaft, SFB 258, projects K2 and K5, and the Forschungsfond Fakultät Mannheim.
Received February 5, 1997; revision received April 21, 1997; accepted April 21, 1997.
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