PREVENTING COGNITIVE DECLINE/ESSENTIAL ARTICLES
From American College of Physicians’ Washington Chapter Scientific Meeting
| PREVENTION OF COGNITIVE DECLINE —Henry J. Williams, MD, Geriatrician, Internal Medicine, and
Medical Director, Bellevue Senior Health Center, Overlake Hospital, Bellevue, WA
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| Normal aging: decreased ability to—take timed cognitive tests; learn new word definitions; multitask; immediately
recall proper nouns and names
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| Abnormal aging: mild cognitive impairment—deteriorates to Alzheimer’s disease (AD) at rate of 15% to 20% per
year; impairment of one area of cognition (usually memory) greater than expected for patient’s age (66% perform
better); consider in patients who forget birthdays of children, or unable to calculate age of child when given birth
date; no other findings of dementia, and no deterioration in behavior or function; dementia—significant memory
impairment present early in AD; apraxia (eg, inability to operate household appliances); agnosia (inability to recognize
familiar objects); aphasia (loss of ability to use language); functional or behavioral deterioration
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Causes of Cognitive Decline in AD-type Dementia
| Age: cognitive impairment present in 1% to 2% at 60 yr of age; percentage doubles every 5 yr after age 60 yr;
≈50% of people >85 yr of age have some form of cognitive impairment
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 | <60 yr of age: only ≈3% develop AD; caused by defect on chromosome 14 (γ-secretase [presenilin 1]); amyloid
precursor protein in brain—important for structural integrity and repair of synapses and cells; recycled when
cut by secretase; α-secretase cleaves amyloid precursor protein at amyloid- β 38 (normal); β-secretase and γ-
secretase cleave amyloid precursor protein at different site, making amyloid- β 40 and amyloid- β 42 (highly
inflammatory)
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| >65 yr of age: 30% to 40% of people who develop AD at >65 yr of age have defect on chromosome 19 (apolipoprotein
E [Apo E]) receptor; patients have increased production of cholesterol, and brain neurons unable to move
low-density lipoprotein (LDL) from extracellular space and cell membrane into cell (γ-secretase located in cell
membranes); people with double allele of Apo Ee4 have higher risk for AD
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| Risk factors for cognitive decline: hypertension most significant risk factor for stroke, heart attack, and cognitive
decline at >65 yr of age; elevated blood glucose; hyperlipidemia (higher amount of LDL in serum, greater amount
of amyloid β 42 in brain); smoking (highly inflammatory; increases blood pressure); metabolic syndrome; sedentary
lifestyle
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| Central nervous system (CNS) inflammation: anything that increases inflammation in brain increases risk of AD;
causes of inflammation—transient ischemic attack (TIA) or stroke (dead cells highly inflammatory); vasculitis;
poorly controlled diabetes; hyperlipidemia; any other cause of elevated amyloid β 40 or β 42
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| “Type 3 diabetes”: term appears in geriatric literature; brain of patients with AD has decreased insulin, insulin receptors,
and insulin-like growth factors 1 and 2; these continue to decrease as AD progresses, leading to inability to take
up and metabolize glucose, which leads to cell death and inflammation; thiazolidinediones (TZDs) decrease triglycerides,
increase high-density lipoprotein (HDL), decrease insulin resistance, and turn off expression of amyloid- β gene
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| Vascular dementia: ischemic cell death provokes release of inflammatory cytokines, increasing amyloid precursor
protein, amyloid- β 42, neurofibrillary tangles, amyloid plaques, and cell death
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Prevention
| Nonpharmacologic methods: minimize risk factors for atherosclerotic vascular disease; mental exercise—
increasing attention through such activities as solving crossword puzzles; physical exercise—people >65 yr of age
who walked 2 miles daily had 38% decrease in risk for cognitive decline; stress reduction—decrease stress hormones;
cortisol raises blood pressure (BP) and appears to decrease uptake of glucose by hippocampus (responsible
for learning and short-term memory); relieve stress through daily exercise, tai chi, meditation and yoga; diet—
decrease free radicals with low-fat diet and exercise; increase antioxidants with fruits, vegetables, omega-3 fatty
acids (in fatty fish, eg, salmon)
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| Nonsteroidal anti-inflammatory drugs (NSAIDs): prevent cleavage of amyloid precursor protein at abnormal site; review
of 17 epidemiologic studies showed 50% reduction in incidence of AD after long-term use of NSAIDs; people
>55 yr of age taking ibuprofen ≥200 mg 1 to 3 times daily for many years had 80% lower AD risk (relative risk
[RR] 0.2); ibuprofen shown to decrease amyloid- β 42, cytokines, neurofibrillary tangles, and amyloid plaque; flurbiprofen,
indomethacin, and probably sulindac also useful; benefit not result of anti-inflammatory properties; 2003
study (JAMA) found naproxen and rofecoxib (withdrawn from market, 2004) did not decrease AD risk and worsened
existing AD; use of NSAIDs does not improve existing AD (once started, inflammatory cascade cannot be
stopped); NSAIDs useful in reducing amyloid- β 42 ≈10 yr before onset of AD; NSAIDs not recommended to prevent
AD in patients ≥65 yr of age because of potential peptic ulcer, renal, and hepatic problems; flurbiprofen
(Ansaid)—does not cause ulcer or renal problems; 400 to 800 mg tid produced improvement in patients with AD;
may be useful in future to prevent dementia
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| Statins: decrease serum cholesterol, reduce amyloid- β 42; stimulate α-secretase (normal secretase); clinical studies
found ≥70% reduction in risk of AD
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| Vitamins: 500 mg of vitamin C and 400 units of vitamin E daily lowered risk of cognitive impairment, according to
reported data; ginkgo biloba increases risk of bleeding while failing to show striking improvement in AD or risk
of AD
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| Estrogen: hormone replacement therapy (HRT) delayed development of AD 7.5 yr when given 3 to 4 yr during
menopause (48 to 52 yr of age); hot flushes appear to result from failure of glucose to pass through blood-brain
barrier into hippocampus; increases risk of stroke in women ≥65 yr of age
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| Testosterone: decreased level associated with increased cognitive decline, but no evidence testosterone therapy
useful
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| Homocysteine: high levels associated with risk of atherosclerotic disease and dementia; no proof drug therapy beneficial
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| Summary of recommendations: exercise, diet, and maintaining optimal body weight; statins potentially useful at
early age in patients with strong family history of AD; ibuprofen (200 mg tid) and r-flurbiprofen may be considered
in patients in fifth decade with strong family history of AD; 1 mg of vitamin B12 po recommended for gastric
achlorhydria; strict BP control (possibly with angiotensin-converting enzyme [ACE] inhibitor or angiotensin-receptor
blocker [ARB] for effect on endothelium); strict glucose control; evidence of benefits from TZDs anticipated
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| TEN ARTICLES THAT CAN CHANGE YOUR PRACTICE —Douglas S. Paauw, MD, Professor of Medicine,
University of Washington School of Medicine, Seattle
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| Prednisolone for cellulitis: placebo-controlled study of 112 patients hospitalized for cellulitis and treated with 8
days of prednisolone in addition to antibiotics; median healing time 5 days in prednisolone group vs 6 days in placebo
group; time to 90% healing in prednisolone group 10 days, 14.6 days in placebo group; hospital stay 1 day
shorter in prednisolone group; no difference in side effects between groups; no recurrence at 6 mo
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| Community-acquired Clostridium difficile: now common; in 2005, Centers for Disease Control and Prevention
(CDC) reported C difficile disease in 33 otherwise healthy patients; 23 cases community-acquired and 10 peripartum;
65% of community-acquired and 90% of peripartum cases had antimicrobial therapy in previous 3 mo; most
common antibiotic clindamycin; 33% of community-acquired and no peripartum cases had recent contact with diarrheal
disease; incidence of bloody diarrhea higher (24% of cases) than usual (5%-10%); 33% required hospitalization,
with several deaths and fetal demise; health care workers at high risk; bottom line—consider C difficile in
community patients with diarrhea; bloody diarrhea more common than in hospital-acquired C difficile; manage aggressively
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| Pulmonary embolism (PE) in chronic obstructive pulmonary disease (COPD) exacerbations: 211 consecutive
patients admitted to hospital with unexplained “COPD exacerbation”; PE found in 49 (25%) patients; most useful
markers history of previous PE (RR 2.43) and cancer (RR 1.82); bottom line—consider PE as cause of worsening
dyspnea in patient with COPD exacerbation severe enough to require hospitalization
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| Hyperaldosteronism in refractory hypertension: 157 patients evaluated (BP >90 mm Hg diastolic or >140 mm
Hg systolic, aldosterone to renin ratio >25, and plasma aldosterone level >12 ng/dL); 58 had idiopathic hyperaldosteronism;
91 had high aldosterone but did not meet criteria for hyperaldosteronism, so classified as aldosterone-associated
hypertension; during 22-mo follow-up, BP goals reached in 41% of patients with idiopathic
hyperaldosteronism, 38.5% with aldosterone-associated hypertension, and 54% with essential hypertension; bottom
line—consider hyperaldosteronism in patients with refractory hypertension; possible treatment with aldosterone-blocker
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| C difficile and unexplained leukocytosis: prospective study of 60 hospitalized patients with unexplained leukocytosis
(leukocyte count >15 000/µL) found 35 (58%) had positive stool culture for C difficile; responded to metronidazole;
patients had little or no diarrhea; bottom line—consider C difficile in hospitalized patients with
unexplained leukocytosis and without diarrhea
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| Another cause of thyroxine malabsorption: 248 patients receiving thyroxine for goiter suppression; 20% to 30%
higher daily dose of thyroxine needed to suppress thyroid-stimulating hormone (TSH) in patients with Helicobacter-pylori
–related atrophic or nonatrophic gastritis or both; average of 37% increase in thyroxine dose needed to
suppress TSH in patients treated with omeprazole; thyroxine absorption also affected by iron, calcium, proton
pump inhibitors (PPIs), H2 -blockers, achlorhydria, and sprue; bottom line—consider decreased gastric acidity as
cause of thyroxine malabsorption
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| Can sutures get wet? 870 patients undergoing minor skin excisions randomized to early removal of dressing, and
either allowing skin to get wet or keeping skin dry and covered for 48 hr; wound infections occurred in 8.4% patients
in wet group and 8.9% in dry group; bottom line—no need to keep simple excisions dry
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| No need to suture punch biopsies: study found no cosmetic difference between sites ≤8 mm in group sutured and
group not sutured; biopsies limited to back and other cosmetically nonsensitive areas
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| Auscultatory percussion for pleural effusions: 118 patients with radiographic evidence of pleural effusion randomized
in prospective blinded study of auscultatory percussion; 113 patients had demonstrable fluid level above
last rib that shifted with decubitus position (sensitivity 95.8%, specificity 100%); none had pleural effusion detected
on standard admission examination; bottom line—auscultatory percussion useful as simple test for pleural
effusion
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| Homocysteine and vascular disease: design—multinational randomized double-blind placebo-controlled trial;
5522 adults ≥55 yr of age with established vascular disease or diabetes randomized to pill containing folic acid (2.5
mg), vitamin B6 (50 mg), and vitamin B12 (1 mg) or placebo and followed for 5 yr;results—homocysteine levels
lowered 20%; no significant difference in primary outcome (cardiovascular death, MI, or stroke) in placebo group;
risk of stroke significantly lower (1.3%) in vitamin group; hospitalizations for unstable angina more common in vitamin
supplement group; patients in highest quintile of homocysteine levels had no benefit from folate
supplementation; bottom line—no benefit from folate supplementation; small reduction of stroke with vitamin B6
and B12 supplementation
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| Vitamin E and statins do not mix: 160 patients with coronary artery disease (CAD), low HDL, and normal LDL randomized
to simvastatin and niacin, to antioxidants alone, or to simvastatin, niacin, and antioxidants, or placebo
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| Results: average stenosis increased—3.9% with placebo; 1.8% with antioxidants; 0.7% with simvastatin, niacin, and
antioxidants; average stenosis regressed—0.4% with simvastatin and niacin; cardiovascular events—24% with
placebo; 21% with antioxidants; 14% with simvastatin, niacin, and antioxidants; 3% with simvastatin and niacin;
bottom line—do not give vitamin E with statins; other studies show lack of cardioprotection with vitamin E
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| Benefits of vitamins: vitamin C—little benefit; vitamin E—no cardiac benefit; worse outcomes with statins;
folate—no CAD benefit; vitamin D—lowers fracture risk
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| Role of HRT: indicated for prevention of hot flushes; results of Womens’ Health Initiative (WHI) distorted in
media; led to changes in clinical practice not indicated by evidence; estrogen and progestin—coronary heart
disease (CHD; 7 more events per 10,000; RR 1.29); breast CA (8 more; RR 1.26); cardiovascular disease (8
more; RR 1.41); PE (8 more; RR 2.13); colon cancer (6 fewer; RR 0.63); hip fracture (6 fewer; RR 0.66); death
(increase not significant; RR 0.92); estrogen only—CHD (5 fewer events for 10,000; RR 0.91) breast CA (7
fewer; RR 0.77); cardiovascular disease (12 more; RR 1.41); PE (7 more; RR 1.34); hip fracture (6 fewer; RR
0.61); death (increase not significant; RR 1.04); bottom line—HRT indicated to relieve hot flushes; risks of
HRT exaggerated
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Suggested Reading
Albrich WC et al: Clostridium difficile: association with thrombocytosis and leukocytosis. South Med J 100:149,
2007; Bergmann C et al: Cardiac risk factors and potential treatments in Alzheimer's disease. Neurol Res 28:595,
2006; Brown BG et al: Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary
disease. N Engl J Med 345:1583, 2001; Centanni M et al: Thyroxine in goiter, Helicobacter pylori infection,
and chronic gastritis. N Engl J Med 354:1787, 2006; Flicker L et al: Healthy mental ageing. J Br Menopause Soc
12:92, 2006; Guarino JR et al: Auscultatory percussion: a simple method to detect pleural effusion. J Gen Intern
Med 9:71, 1994; Heal C et al: Can sutures get wet? Prospective randomised controlled trial of wound management
in general practice. BMJ 332:1053, 2006; Kang JH et al: A randomized trial of vitamin E supplementation and cognitive
function in women. Arch Intern Med 166:2462, 2006; Krakoff LR: Are elevated aldosterone levels associated
with refractory hypertension? Nat Clin Pract Endocrinol Metab 2:604, 2006; Lonn E et al: Homocysteine lowering
with folic acid and B vitamins in vascular disease. N Engl J Med 354:1567, 2006; Milgram NW et al: Neuroprotective
effects of cognitive enrichment. Ageing Res Rev 5:354, 2006; Smith AD: Prevention of dementia: a role for B vitamins?
Nutr Health18:225, 2006; Srikanth VK et al: Long-term cognitive transitions, rates of cognitive change,
and predictors of incident dementia in a population-based first-ever stroke cohort. Stroke 37:2479, 2006; Stampfer
MJ: Cardiovascular disease and Alzheimer's disease: common links. J Intern Med 260:211, 2006; Vance DE et al:
Wedzicha JA et al: Chronic obstructive pulmonary disease exacerbation and risk of pulmonary embolism. Thorax
62:103, 2007; Willis SL et al: Long-term effects of cognitive training on everyday functional outcomes in older
adults. JAMA 296:2805, 2006.
Educational Objectives
| The goal of this program is to encourage internists to consider the measures for preventing cognitive decline and for
making improvements in clinical practice that are currently being discussed in the medical literature. After hearing and
assimilating this program, the clinician will be better able to:
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| 1. Diagnose cognitive decline.
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| 2. Counsel patients on possible means to prevent cognitive decline.
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| 3. Consider using prednisolone in treating cellulitis.
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| 4. Identify Clostridium difficile as a cause of diarrhea in community dwelling patients.
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| 5. Suspect pulmonary embolism as a cause of dyspnea in patients with chronic obstructive pulmonary disease exacerbations.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members to disclose
relevant financial relationships within the past 12 months that might create any personal conflicts of interest. Any
identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty reported nothing to disclose.
Acknowledgements
Drs. Williams and Paauw were recorded at the American College of Physicians’ Washington Chapter Scientific
Meeting held November 2-4, 2006, in Seattle, WA. The Audio-Digest Foundation thanks the speakers and the meeting
sponsor for their cooperation in the production of this program.
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