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Dementia Spotlight
Dementia and cognitive disturbances have become topics of increasing worldwide concern and interest to patients, medical practitioners, and researchers. It is noteworthy that the May 2015 issue of the Annals of Long-Term Care: Clinical Care and Aging® contains four abstracted summaries related to this topic. These reviews variously address diet, complications, quality of life and side effects of pharmacologic therapy.
The pathophysiology of the direct and indirect effects of antihypertensive therapy on cerebral function is still poorly understood and in a state of flux. A recent report by Mossello et al.1 discusses the effects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs. With the inherent limitations noted by the authors, the study was performed solely to determine the possible adverse effects of antihypertensives on cerebral function as associated with a specified range of blood pressure measurements—the lower parameters having the greater demonstrable cognitive impairment. The medical literature is replete with articles (positive, negative, and contradictory) concerning the effects of hypertension, low blood pressure, and pharmacologic therapy on brain function. The most confounding factor of importance is the direct effect that the antihypertensive drugs themselves may have on cerebral function—cellular, synaptic and vascular. These effects must be evaluated not only by drug classification but also by the age of the patients at the time of initiation of drug therapy, by the duration of therapy, and by the eventual conclusion regarding temporary versus possible permanency of these critically important pathophysiologic results.
A meaningful commentary by Sabayan and Westendorp2 properly addressed the necessity of such studies. Heckbert et al.3 correlated the presence of greater white matter hyperintensity on MRI and worse performance on modified mini-mental state examination in patients taking calcium channel blockers or loop diuretics, with lesser effects from beta-blockers. Nine years prior to that study, Callender4 concluded that patients on atenolol were found to have significant impairment on tests of short-term memory than did those patients on enalapril. In a previous study, he reported significant impairments on tests of non-verbal memory in patients receiving nicardipine and propranolol.5 A significant case report of severe forgetfulness caused by methyldopa in a 36-year-old nurse was published nearly four decades ago.6
The most disconcerting and frequently encountered cerebral side effect of antihypertensive therapy is diminished rapid recall. More often than not, the physician must appropriately observe and inquire as to the possibility of its presence. It is most notable in patients with professions that require mental acuity, recall, and thought-pattern formulation (eg, physicians, lawyers, accountants, teachers, etc).7 The rapid recall deficit includes recent and past memory. These individuals complain of having to take minutes to hours to recall something that has previously been quite easily and quickly remembered.
The question remains, of our ~100 billion brain cells, how many could we be losing permanently to antihypertensive drug therapy in spite of the apparent reversibility of symptoms on temporary discontinuance of the medication? It appears to involve all classes of antihypertensive drugs, with beta-blockers being foremost, followed by calcium channel blockers, ACE inhibitors, and diuretics.
If the above supposition is correct, it would not be surprising that progression of cognitive dysfunction is greatest in the elderly, especially those with dementia, for they already have a deficit in the total number of normal functioning brain cells. It brings to mind quite vividly the number of times during our “rounding days” we were told that each episode of binge drinking (alcohol) results in the permanent loss of an undisclosed but highly significant number of brain cells that cannot be replaced or rejuvenated. Is there a pathophysiologically similar effect secondary to antihypertensive drug administration? After all is said and done, we must still deal with age, duration, and dose.
Basil M. RuDusky MD, FACA, FASA, FACP, FCCP, FACC, FACFE, FAGS (emeritus) Wilkes-Barre, PA
References:
1. Mossello E, Pieraccioli M, Nesti N, et al. Effects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs. JAMA Intern Med. 2015;175 (4):578-585.
2. Sabayan B, Westendorp R. Blood pressure control and cognitive impairment—why low is not always better. JAMA Intern Med. 2015;175(4):586-587.
3. Heckbert SR, Longstreth WT, Psaty BM, et al. The association of antihypertensive agents with MRI white matter findings and with modified mini-mental state examination in older adults. J Am Geriatr Soc. 1997;45:1423-1433.
4. Callender JS. Evaluation of the cerebral effects of antihypertensive medication. Eur Heart J. 1988;9(suppl G):59-63.
5. Callender JS, Medley IR. Robertson JIS. Psychological effects of nicardipine and propranolol on hypertensive patients. Br J Clin Pharmacol. 1986;22:2678-2728.
6. Ghosh SK. Methyldopa and forgetfulness. Lancet 1976;1(7952):202-203.
7. RuDusky BM. Unappreciated side effects of antihypertensive therapy. J Am Geriatr Soc. 2013;61(10):1848.
A response from Lillian Min, MD, MSHS, Assistant Professor, Internal Medicine, University of Michigan Geriatrics, Ann Arbor, MI:
Dr. RuDusky’s letter discussing the recent article by Mossello et al.1 serves as an important reminder to clinicians who provide care to older individuals that a one-size-fits-all approach to treating common conditions can result in less-reported side effects that are prioritized highly by some individuals. Mossello et al. highlighted potential unintended cognitive decline among a small sample of patients with dementia and mild cognitive impairment who were prescribed antihypertensive medications and treated to very low blood pressures (<127 mmHg).1 Dr. RuDusky further alludes to his concern that his patients with preserved cognitive function report subtle cognitive changes with any treatment, regardless of the degree of blood pressure control.
In both of these examples—patients with dementia and those with preserved cognitive functioning—prospective trials specifically designed for these very different populations are needed. The trials will need to be designed to detect subtle clinical and patient-reported outcomes to disentangle major confounding factors in both patients with and without dementia, such as whether or not the changes are due to pre-existing microvascular disease. Without such trials, the current literature (which consists of studies that have largely been performed in healthy adults) suggests the opposite: a strong meta-analysis of 19 trials and 11 observation studies2 of blood pressure treatment demonstrated that dementia incidence was reduced by 9% (95% CI: 6–11%). These results continue to support at least modest blood pressure control. A strong cohort study that prospectively administered cognitive tests to older participants from the Cardiovascular Health Study suggests that treatment with centrally-acting angiotensin-converting enzyme inhibitors (ACEIs; eg, lisinopril) reduced progression of cognitive decline by 65% in comparison to non-ACEI classes.3
Dr. RuDusky’s concerns are also timely. No other condition is more commonly treated by prescribing medications than hypertension. As the population ages, control of blood pressure among older patients is better than ever, with increasing implementation of guidelines and performance measures to determine which patients receive blood pressure medications for hypertension and other conditions,4 and a landmark trial supporting the clinical benefit (primarily stroke reduction) of modest blood pressure control in even very old adults.5 However, a recent report from the National Health and Examination Surveys (NHANES)6 suggests not only an improvement in modest control of systolic blood pressure over the past two decades but also concerning indicators of over-control: the proportion of octogenarians taking three classes of antihypertensive medication increased from 7.0% to 30.9%, and the proportion with a diastolic blood pressure <60 mmHg has increased from 16% to 49%. I believe that older individuals, even if cognitively impaired, would choose modest blood pressure reduction to prevent a major stroke as being worthwhile in relation to potential side effects—especially in light of further measurable cognitive decline that occurs post-stroke.7 However, whether or not there are any benefits of over-control, as identified in NHANES and the VA Health System,4 has yet to be determined. Particularly relevant for the readership of Annals of Long-Term Care: Clinical Care and Aging® is a very large study of nursing homes in France, the Predictive Values of Blood Pressure and Arterial Stiffness in Institutionalized Very Aged Population (PARTAGE) study, that found that the combination of blood pressure medications and achievement of low blood pressure was also associated with increased mortality, another important clinical outcome.8 As in Mossello et al., whether or not the relationship observed in PARTAGE is biased by preexisting cardiovascular comorbidity must be seriously considered. The harms of over-control identified by Mossello et al.1 and PARTAGE suggest that certain subgroups of patients who are especially vulnerable to those harms need to be studied more carefully in further prospective trials in order to weigh the risks in relation to the potential benefits.
References
1. Mossello E, Pieraccioli M, Nesti N, et al. Effects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs. JAMA Intern Med. 2015;175(4):578-585.
2. Levi Marpillat N, Macquin-Mavier I, Tropeano AI, Bachoud-Levi AC, Maison P. Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis. J Hypertens. 2013;31(6):1073-1082.
3. Sink KM, Leng X, Williamson J, et al. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the Cardiovascular Health Study. Arch Intern Med. 2009;169(13):1195-1202.
4. Kerr EA, Lucatorto MA, Holleman R, Hogan MM, Klamerus ML, Hofer TP. Monitoring performance for blood pressure management among patients with diabetes mellitus: too much of a good thing? Arch Intern Med. 2012;172(12):938-945.
5. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-1898.
6. Bromfield SG, Bowling CB, Tanner RM, et al. Trends in hypertension prevalence, awareness, treatment, and control among US adults 80 years and older, 1988-2010. J Clin Hypertens (Greenwich). 2014;16(4):270-276.
7. Levine DA, Galecki AT, Langa KM, et al. Trajectory of cognitive decline after incident stroke. JAMA. 2015;314(1):41-51.
8. Benetos A, Labat C, Rossignol P, et al. Treatment with multiple blood pressure medications, achieved blood pressure, and mortality in older nursing home residents: the PARTAGE Study. JAMA Intern Med. doi:10.1001/jamainternmed.2014.8012. Published online February 16, 2015.
