SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 7 NUMBER 4 • NOVEMBER 2010
147
a long-acting dihydropyridine protects against dementia in older
patients with systolic hypertension.
47
SheP was conducted over an average of five years’ follow-up
involving 4 736 elderly persons with isolated elevated systolic BP.
Participants on antihypertensive treatment showed a slight positive,
but non-significant effect on cognitive function.
48
The SCoPe trial in
4 964 participants assessed whether candesartan therapy in mildly
to moderately hypertensive elderly patients reduced cognitive
decline. The result was non-significant as mean MMSe score fell
from 28.5 to 28.0 in the candesartan group and from 28.5 to 27.9
in the control group (
p
=
0.20).
49
PRogReSS included 6 105 people with prior stroke or transient
ischaemic attack who received either perindopril plus indapamide
or matching placebo. After nearly four years, cognitive decline
occurred more often in the actively treated group, but in the
absence of recurrent stroke, no clear effect on either dementia
or cognitive decline was detected.
50
hYVeT-Cog assigned 3 336
elderly patients either indapamide (plus perindopril, if necessary)
or placebo. After two years, no significant difference between
treatment and placebo groups was detected.
51
Altogether, four studies showed no protective effect,
45,48,49,51
whereas two studies demonstrated some positive effect.
46,50
The
latest Cochrane review included four of these trials with 15 936
hypertensive subjects without any history of cerebrovascular
disease, average age of 75.4 years and mean BP at entry of 171/86
mmHg. The combined result of incidence of dementia indicated
no significant difference between treatment and placebo (oR 0.89;
95% CI 0.74–1.07).
52
On the other hand, a meta-analysis of the
combined data of hYVeT, Syst-Eur, SheP and PRogReSS showed a
borderline pooled ratio favouring treatment (hR 0.87; 0.76–1.00,
p
=
0.045).
51
Limitations
Several limitations, even of these ‘gold standard’ randomised
placebo-controlled studies restrict their interpretation or
generalisation. For example, the proportion of placebo patients
given active treatment was 27% in Syst-Eur,
46
44% in SheP
48
and
even 84% in SCoPe.
49
In PRogReSS, only a selected study population
(prior cerebrovascular disease) was assessed.
50
The inclusion criteria,
hypertension, varied between isolated systolic hypertension
46–48
and
hypertension with different thresholds.
45,49,51
The observation period
of two years for the assessment of cognitive decline was very short
in Syst-Eur and hYVeT-Cog.
46,51
Furthermore, differences within
the antihypertensive drugs may explain the divergent results:
53
data
from animal studies indicate that an ARB (olmesartan) prevents beta-
amyloid-induced vascular dysregulation and partially attenuates the
impairment of hippocampal synaptic plasticity.
54
The Cardiovascular
Health Study Cognition Substudy revealed that centrally active ACe
inhibitors (those that cross the blood–brain barrier, e.g. captopril
or ramipril) were associated with a highly significantly reduced
cognitive decline compared with other antihypertensive drugs.
55
In
addition, the methods of assessing cognitive function varied among
the studies; for example, in the MRC trial, cognitive function was
tested by the rate of change in paired-associate learning test and
trail-making test scores over time,
45
whereas Syst-Eur and SCoPe
used the MMSe.
46
Considering the complex relationship between
BP and cognitive function, the need for various assessments for
evaluating cognitive impairment of differing aetiologies has been
suggested
56
and the diverse results shown in both epidemiological
and interventional studies may in part be explained by the use of a
variety of cognitive instruments.
Summary
There exists an age-dependent relationship between BP and
cognitive impairment. Midlife hypertension is associated with
an increased risk of developing cognitive decline, whereas
hypertension later in life does not carry the same risk.
57
Evidence
for a protective effect of antihypertensive treatment on cognitive
deterioration remains controversial, although this therapy is in any
case mandatory for its well-proven cardiovascular benefit. Further
open questions include the extent of antihypertensive treatment
as current guidelines recommend a target BP of 140/90 mm Hg.
The duration of BP-lowering therapy medication is not known but
apparently for persons aged
≤
75 years there exists an increasing
benefit per year of treatment.
58
Finally, the latency of a protective
effect remains unclear and may carry potential risks as BP sometimes
spontaneously declines in the years before dementia onset.
59
Conclusion
Though there are many hints for a causal association between
diabetes and the development of cognitive decline, a definitive
proof for a protective effect of antidiabetic treatment by controlled
or even randomised placebo-controlled studies is required.
Abi-directional association exists between hypercholesterolaemia
and cognitive function. In midlife, elevated cholesterol levels
comprise a risk factor for cognitive decline. In elderly subjects,
cholesterol levels decline and are not clearly associatedwith cognitive
impairment. The evidence for treatment of hypercholesterolaemia
by statins solely for prevention of cognitive decline remains unclear.
An age-dependent relationship is found between BP and
cognitive impairment. Midlife hypertension is associated with an
increased risk of developing cognitive decline, whereas hypertension
later in life does not carry the same risk. Cardiovascular benefit
of antihypertensive treatment is well proven, while its efficacy
regarding cognitive performance remains controversial.
Key messages
• Mild cognitive impairment can be caused by treatable
somatic factors
• Diabetes mellitus has a causal relationship in the
development of cognitive decline and there are indirect
hints for a possible benefit of antidiabetic therapy
• Hypercholesterolaemia in midlife is a risk factor for
cognitive decline
• In elderly subjects, cholesterol levels decline and are not
clearly associated with cognitive impairment
• The role of statin treatment of hypercholesterolaemia in
the prevention of cognitive decline remains unclear
• Midlife hypertension is associated with an increased risk
of developing cognitive decline and antihypertensive
treatment may be beneficial
• Hypertension later in life does not carry the same risk of
cognitive dysfunction
