DEMENTIA


See also under "Hormone Replacement Therapy" re: postmenopausal hormone replacement & risk of Alzheimer's

Prevention of Dementia

Screening for Dementia

Undifferentiated Dementias

Alzheimer's Disease

Lewy Body Disease

Parkinson's-Associated Dementias

Vascular Dementia

Treatment of Behavioral Disturbances in Dementia

 

I. Prevention of Dementia

  1. Prevention of dementia through treatment of Hyperhomocyteinemia if present
    1. In a study in 276 pts > 65yo with elevated plasma homocysteine levels (> 13 umol/L) randomized to treatment with oral vitamin supplementation intended to reduce homocysteine levels (vit. B6 10mg, vit. B12 500 ug, and folate 1g), at 2y, there were no sig. differences in the groups in changes from baseline cognitive scores. (NEJM 354:2764, 2006--JW)
    2. In a study in about 6,400 women > 65yo randomized to ASA 100mg QOD vs. placebo, over 4y f/u, there was no sig. diff. in rate of decline of cognitive performance in the overall cohort, but there was in the subgroup who were smokers or had dyslipidemias at randomization. (Women's Health Study, BMJ 334:987, 2007--JW)
    3. In a study in 299 men > 75yo and Folstein Mini-Mental status scores of > 24, no depression, and with hypertension randomized to (vitamin B6 25mg/d, folate 2mg/d, and vitamin B12 400 mcg/d) vs. placebo, over 2y f/u, there weere no sig. differences in cognitive function between the two groups, even after adjustment for potential confounders (Neurol. 75:1540, 2010-AFP)
  2. Antioxidants for prevention of dementia
    1. In a study in 5,845 in women > 65yo randomized to vitamin E 600 IU QD vs. placebo, over mean 9.6y f/u, there were no sig. differences in measures of change in cognitive function over time (Arch. Int. Med. 166:2462, 2006--AFP)
    2. In a study in 4,052 adult men randomized to beta carotene 50mg QOD vs. placebo x 18y, the beta carotene group had sig. better mean global scores of cognitive function ("Physicians Health Study II", Arch. Int. Med. 167:2184, 2007--JW)

II. Screening for dementia

III. Undifferentiated dementias

  1. Risk factors for undifferentiated dementias
    1. In a prospective study of 12,480 women 70-81yo at intake, over 2y observation, moderate alcohol consumption (average 0-1 drinks/day) was ass'd with RR 0.85 for substantial cognitive decline c/w nondrinkers, after adjustment for possible confounders (NEJM 352:245, 2005--JW)
    2. In an observational study in 7,123 pts > 65yo, over mean 3.5y f/u, pts who continually used anticholinergic drugs during the study period had sig. increased risk for dementia (HR 1.65) but pts who used anticholinergic drugs and stopped them prior to f/u did not (Arch> Int. Med. 169:1317, 2009-JW)
  2. Diagnostic studies to consider in workup for dementia: ESR. CBC, lytes, glucose, creatinine, LFT's, TSH, Folate, B12, RPR, noncontrast head CT, testosterone (in men).
  3. Treatment of undiagnosed or undifferentiated Dementias
    1. Mild cognitive impairment
      1. Used to describe mild impairment in one or more cognitive domains without meeting criteria for other dementias
      2. In a randomized trial in 270 pts with MCI randomized to donepezil 10mg/d or less vs. placebo, over 24wks, no sig. diff. in measures of memory or global assessment of function (Neurol. 63:651, 2004--JW)
      3. In a study in 821 pts with amnestic mild cognitive impairment randomized to donepezil vs. placebo x 48wks, there was only minimal difference in change in cognitive scores on one of the two measures used, and no sig. diff. in the other (Neurol. 72:1555, 2009-JW)
    2. Gingko Biloba for unspecified dementias:
      1. G. biloba contains various ingredients that have anti-oxidant properties
      2. JAMA 278:1327, 1997
        1. 309 pts, avg. age 69y, 54% women, avg. Folstein MMS 21, with mild-severe Alzheimer's (70%) or multi-infarct dementia (30%) who were otherwise w/o sig. physical or sychiatric illness, average age
        2. Randomized to EGb761 (a standardized extract of G. biloba made by Murdock in Springville, UT, containing 24% Gonkgo-flavoneglycosides and 6% terpenelactones) 40mg TID before meals vs. placebo x 1y; eval at 26, 39, and 52 wks; avg. f/u 38 wks
        3. Measurements used:
        1. Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) to measure cognitive impairment
        2. Geriatric Evaluation by Relative's Rating Instrument (GERRI) to measure daily living and social behavior
        3. Clinical Global Impression of Change (CGIC) to measure general psychopathology, evaluated by clinician
        1. Intention-to-treat analysis showed:
        2. Sig. less deterioration from baseline ADAS-Cog w/EGb
        3. Slight improvement form baseline in GERRI c/w slight deterioration w/placebo; sig. diff.
        4. No sig. diff. seen in CGIC change from baseline in either group
        5. In subset of Alzheimer's pts, EGb group showed slight improvement in both ADAS-Cog and GERRI c/w deterioration w/placebo; sig. differences
        6. No sig. diff. between drug and placebo groups in frequency or severity of adverse effects
  1. In a trial of 214 pts with mild-mod dementia (Alzheimer's or vascular) or age-ass'd memory impairment randomized to EGb 761 160-240mg/d vs. placebo; no sig. diff's found in various measures of cognition, behavior, and affect (J. Am. Geriat. Soc. 48:1183, 2000--JW)
IV. Lewy Body Disease
  1. Pathophysiology
    1. May represent more than one pathophysiologic process, with shared characteristic of "Lewy bodies" in the cerebral cortex (round, eosinophilic, nuclear inclusions in neurons) and other neuropathologic changes
    2. Pathophysiology not well-understood as of 2010
  2. Diagnosis
    1. Definitive diagnosis requires pathologic examination
    2. Clinical diagnostic criteria have been proposed (McKeith, IG, Dickson, DW, Lowe, J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005; 65:1863.)
    3. The diagnosis cannot be made if dementia is not present
  3. Mean age at presentation is 75yo; accounts for 10-20% of dementia cases; male: female around 2:1
  4. Clinical Features
    1. Dementia
      1. Degree of cognitive impairment tends to fluctuate rather than straight decline (standardized measures of fluctuation are available; see Br J. Psychiat 177:252, 2000), though tends to progress more rapidly than Alzheimer's
      2. Earliest symptoms usually reduced attention and executive & visuo-spatial function (e.g. getting lost or running stop signs while driving); memory impairment is usually later
    2. Clinical features apart from dementia:
      1. Visual hallucinations (occur in about 2/3 of pts with lewy body disease; helps to distinguish from Alzheimer's; tend to appear early in the course of hte disease))
      2. Parkinsonism (occurs in 70-90% of pts though usually NOT including tremor)
      3. Dysautonomia/extrapyramidal signs
      4. Sleep disorders
      5. Delusions (may occur in 75% of cases)
  5. In a retrospective study of patients with dementia, the following significantly predicted autopsy diagnosis of Lewy Body Disease instead of Alzheimer's:
    1. Visual hallucinations (OR 25.8, though sensitivity was only 22%)
    2. Visuospatial deficits on neuropsychological testing (OR 3.5%, sensitivity 74%)
  6. Radiologic features-Supportive rather than diagnostic.  MRI may show regional atrophy in areas typical for the condition but this is both nonspecific and insensitive.  SPECTand PET may show decreased perfusion/metabolic activity worst in the occipital lobe.
  7. Many pts with Lewy Body Disease have sensitivity to neuroleptics (can cause severe parkinsonism, impaired consciousness, and neuroleptic malignant syndrome)
  8. Responds better than Alzheimer's pts to cholinesterase inhibitors, e.g. Rivastigmine (viz. Lancet 356:2031, 2000--AFP)

V. Vascular Dementia

  1. Thought to result from gradual cortical loss due to small infarcts from thromboses in small cerebal arteries; strongly ass'd with Hypertension
  2. Treatment:
  1. Galantamine, developed for tx of Alzheimer's disease, was ass'd with sig. more improvement in cognitive function, ADL's, and behavioral sx than placebo  in a 6mo randomized trial of 588 pts with dementia and evidence of cerebrovascular disease on CT or MRI (Lancet 359:1283, 2002--JW)
  2. Donepezil

    1. Donepezil 5mg PO QD or 10mg PO QD associated with sig. greater improvement on the "ADAS-cog" dementia score compared with placebo in a 24wk randomized trial of 616 patients with probable vascular dementia.  No sig. diff. between these two doses (Neurol. 61:479, 2003--JW)

    2. 603 pts with dementia suspected to be from vascular etiologies randomized to donepezil 5mg/d, 10mg/d, or placebo x 24wks.  At 24wks, both donepezil had sig. greater improvements in cognitive function and global function than placebo group (Stroke 34:2323, 2003--abst)

VI. Alzheimer's Disease

  1. Pathophysiology of Alzheimer's:
    1. Beta-amyloid peptide deposited extracellularly; seems to have a neurotoxic effect (particularly A-beta-42), particularly on glutaminergic transmission
      1. In mice, an Alzheimer's-like disease can be prevented with immunization with A-beta-42 (Nature 400:173, 1999--JW)
    2. Patients with the epsilon-4 type of apolipoprotein E are at particular risk, possibly due to an interaction w/this type of apE and beta-amyloid that increases the neurotoxicity of beta-amyloid
    3. Endoplasmic-reticulum-associated binding protein (ERAB) is present in high concentrations in brains of pts w/Alzheimer's; it forms a complex w/beta-amyloid in a way that may attract more beta-amyloid
    4. Hyperhomocysteinemia may be a risk factor (NEJM 346:476, 2002--JW)
    5. Hypotestosteronemia may also be--In a prospective cohort study of 574 men w/o dementia at baseline, over 19y f/u, low baseline serum levels of free testosterone (but not total testosterone) was independently ass'd with risk of Alzheimer's disease (Neurol. 62:188, 2004--JW)
  2. Diagnosis of Alzheimer's
    1. Microscopic examination of brain tissue is the gold standard
    2. Noninvasive methods of diagnosis--all still investigational as of 1999:
    3. PET imaging of brain--looking for decreased metabolism in inferior parietal cortex
      1. PET with measurement of temporal lobe clearance rate of injected FDDNP may help identify pts with Alzheimer's
    4. SCECT imaging of brain
    5. A set of 18 serum proteins were found to be 91% sensitive for identifying which patients with mild cognitive impairment would develop Alzheimer's in 2-5y and 100% sensitive for identifying which patients with mild cognitive impairment would develop non-Alzheimer's dementia (Nature Medicine 13:1359, 2007--JW)
  3. Medications which may worsen Alzheimer's--Pretty much anything anticholinergic
    1. Antihistamines
    2. Antispasmodics
    3. Tricyclic antidepressants
    4. Antipsychotics
  4. Prevention of Alzheimer's
    1. Potential protective effect of HMG-CoA Reductase Inhibitors ("Statins")
      1. In a case-control study of 284 pts with dementia and 1080 age- and sex-matched controls, statin-users in multivariate analysis had RR 0.29 for dementia; users of non-statin lipid-lowering drugs had RR 0.96 for dementia (Lancet 356:1627, 2000--JW)
      2. In a prospective study of 4,000 adults > 64yo followed for 1y, there was no sig. diff. in dementia incidence based on use or non-use of statins at baseline (Arch. Gen. Psychiat. 62:217, 2005--JW)
      3. In a prospective study of 2,000 adults > 64yo followed x 4y, there was no sig. diff. in dementia incidence based on use or non-use of statins at baseline (Neurol. 63:1624, 2004--JW)
      4. In a prospective, nonrandomized study in 6,992 nondemented pts > 55yo, after adjustment for potential confounders, statins (but not non-statin cholesterol-lowering drugs) was associated with a sig. reduced incidence of alzheimer's (HR 0.57) (J. Neuol. Neurosurg. Psychiat. 80:1, 2009-JW)
    2. Potential protective effect of NSAIDs and COX-2 inhibitors
      1. In in vitro studies, some NSAIDs (ibuprofen, indomethacin, sulindac) decrease A-beta-42 production; others do not (ASA, naproxen, celecoxib) (Nature 414:212, 2001--JW)
      2. Prospective cohort study of 6989 pts > 55yo w/o dementia at baseline.  During avg. f/u 7y, RR for development of Alzheimer's (compared with never-users) was 0.95 with NSAID exposure < 1mo, 0.83 with NSAID exposure 1-24mos, and 0.20 with NSAID exposure > 24mos (sig. for the latter group)--after adjustmenet for confounders (NEJM 345:1515, 2001--JW)
      3. Neither rofecoxib nor naproxen slowed progression of mild-moderate Alzheimer's Disease in a randomized placebocontrolled trial of 351 such patients (JAMA 289:2819, 2003--abst)
      4. In a meta-analysis of 9 non-randomized studies, any NSAID use was ass'd with RR 0.72 (sig.) of Alzheimer's disease; RR was 0.95 (nonsig.) with short-term use (< 1mo), 0.83 (nonsig.) with intermediate-term (1-24mos), and 0.27 (sig.) with long-term (> 24mos) of use.  RR among users of aspirin was 0.87 (nonsig.) (BMJ 327:128, 2003--abst)
      5. In a study in 2,528 pts > 70yo with no evidence of dementia but with one first-degree relative with Alzheimer's like dementia, randomized to celecoxib 200mg BID, naproxen 220mg QD, or placebo, over 2y median f/u, there was no sig. diff. in incidence of Alzheimer's disease or mild cognitive impairment ("ADAPT" trial; Neurol. 68:1800, 2007--JW)
    3. Potential protective effect of postmenopausal hormone replacement therapy in women--click on links for details
  5. Drugs for treament of Alzheimer's
    1. (Acetyl)cholinesterase inhibitors
      1. All can cause bradycardia
      2. Tacrine (Cognex) 10-40mg QID; can cause hepatotoxicity, largely replaced by Donepezil
      3. Donepezil (Aricept) 5-10mg QD
        1. Mainly urinary excretion; t-1/2 about 70h
        2. Several randomized trials (2 unpublished but summarized in the package insert) studied >500 pts using 5-10mg QHS; modest but stat. sig. improvement c/w placebo in scores on neuropsych testing, behavior and ADLs. At least one published trial showed a sustained benefit over 6mos in pts with mod-severe Alzheimer's (Mini-Mental Status Exam scores 5-17; Neurol. 57:613, 2001--JW; see also Lancet 363:2105, 2004--AFP)
        3. In a study in 248 nursing home residents with severe Alzheimer's (Mini-Mental State Examination scores 1-10) randomized to donepezil (5 or 10mg) vs. placebo x 6mos, the active-tx group had sig. higher scores for both primary outcomes (an ADL score and a cognitive-function score) (Lancet 367:1057, 2006--JW)
        4. No head-head trials with Tacrine as of 1997
        5. Can cause bradycardia, nausea, vomiting, diarrhea, insomnia, fatigue, and myalgia; these side f/x tend to be dose-related
        6. No reports of hepatotoxicity as w/Tacrine
      4. Metrifonate
        1. 480 pts with mild-moderate Alzheimer's randomized to metrifonate 30-60mg/d adjusted by weight vs. placebo x 12wks; sig. diff at 12 wks in mean scores for cognition and global functioning c/w placebo (Neurology 50:1214, 1998--JW)
        2. 408 pts with Alzheimer's randomized to 30-60mg metrifonate vs. placebo x 26wks; sig. improvement in cognition and global functioning c/w placebo (Neurology 50:1222, 1998--JW)
        3. Most common side f/x included diarrhea, leg cramps, and rhinitis
      5. Rivastigmine (Exelon) 1.5-6mg BID (increase dose @ 2wk intervals; take with food)
        1. Can cause nausea, vomiting, and tremor
        2. 725 pts 50-85yo with mild-mod Alzheimer's randomized to low-dose (1-4mg/d) or high-dose (6-12mg) rivastigmine vs. placebo. High-dose rivastigmine group had sig. improvement in cognitive function c/w placebo but not the low-dose group. Side f/x more common than w/placebo included n/v, diarrhea, abdominal pain, and anorexia (BMJ 318:633, 1999--JW)
      6. Galamantine (Reminyl; an acetylcholinesterase inhibitor) 4-12mg BID
        1. Galamantine 24-32mg/d ass'd with sig. better cognitive function c/w placebo in a 6mo randomized trial of 653 pts with mild-mod Alzheimer's (BMJ 321:1445, 2000--JW)
        2. Side f/x mostly GI (nausea, vomiting, anorexia, diarrhea)
        3. No reports of hepatotoxicity as of 2001
        4. Standard dosing: 4mg BID; increase at 4wk intervals to 8mg BID then 12mg BID
    2. Memantine 5mg QD-10mg BID
      1. An NMDA-receptor antagonist--Theoretically, prevents neurotoxicity from overstimulation of NMDA receptors in Alzheimer's
      2. Memantine 20mg/d vs. placebo was ass'd with sig. better outcomes as measured by the ADCS-ADLsev instrument in a 28-week randomized trial in 252 pts with moderate-to-severe Alzheimer's (NEJM 348:1333, 2003--Med. Lett.)
      3. Memantine 10mg BID vs. placebo was ass'd with sig. better cognition and function scores in a 24wk randomized trial of 403 pts with mod-to-severe Alzheimer's also on donepezil 5-10mg/d (Neurol. 60 supp. 1:A412, 2003--Med. Lett.)
      4. 404 pts with mod-severe Alzheimer's (Mini-Mental State exam scores 5-14) on donepezil 5-10mg/d x > 3mos randomized to addition of memantine (titrated from 5-20mg/d) vs. placebo x 24wks.  At 24wks, memantine recipients had significantly (but modestly) less decline than placebo recipients in cognitive function and ADLs.  (JAMA 291:317, 2004--JW)
      5. Adverse effects: Dizziness, HA, constipation, and confusion occur more frequently than w/placebo
    3. Selegiline + Vitamine E
      1. 341 pt w/mod. severe Alzheimer's randomized to selegiline 5mg BID, vit. E 1000 IU BID, both, or placebo. Time to primary outcome (death, institutionalization, inability to perform 2 or 3 basic ADL's, or progression to severe dementia) was 655d for selegiline, 670d for vit. E, 585d for combo therapy, and 440d for placebo. No improvement in cognition seen in any of the groups. Pts in tx groups, esp. combo group, had more falls & syncope than placebo group though us. mild. (NEJM 336:1216, 1997--AFP)
    4. NSAIDs
      1. 692 pts > 50yo with early Alzheimer's dementia randomized to rofecoxib 25mg PO QD vs. placebo; at 1y, no sig. diffs in degree of cognitive decline (Neurol. 62:66, 2004--JW)
    5. Antibiotics
      1. In a randomized trial in 101 pts with Alzheimers randomized to (doxycycline + rifampin) vs. placebo x 3mos (most also on cholinesterase inhibitors), decline in cognitive function at 6mos was sig. less in active-tx group (J. Am. Geriat. Soc. 52:381, 2004--AFP)
    6. Testosterone
      1. In a study in 15 men with Alzheimer's disease and 17 men with mild cognitive impairment, 63-85yo, randomized to testosterone enanthate 100mg IM Qwk vs. placebo x 6wks, after 6wks, the testosterone recipients had sig. improvements in certain measures of cognition (Neurol. 64:2063, 2005--JW)
VII. Treatment of behavioral disturbances in pts with dementia (e.g. aggressiveness, paranoid behavior, etc.)
  1. Typical antipyschotic drugs are traditionally used (e.g. haloperidol), but only mildly effective and prone to side effects
  2. Risperdone (starting at 0.25mg PO BID and titrated upward to avg. final dose of about 1mg BID) was better than Haloperidol at controlling such sx w/less extrapyramidal sx in a randomized trial of 344 pts with mean age 81y (Neurol. 53:946, 1999--JW)
  3. Use of "Atypical Antipsychotics" for treatment of behavioral manifestations of dementia
    1. Associated with sig. increased risk for death (RR 1.54) c/w placebo in a meta-analysis of randomized trials (JAMA 294:1934, 2005--abst)
    2. In a study in 93 pts w/dementia randomized to quetiapine vs. rivastigmine, or placebo x 26wks, neither drug had sig. diff. from placebo for agitation; cognitive function was no diff. with rivastigmine but sig. poorer with quetiapine (BMJ 330:874, 2005--JW)
    3. In a study in 421 pts with Alzheimer disease and psychosis, aggression, or agitation randomized to olanzapine, quetiapine, risperdone, or placebo x 36wks, incidence of drug discontinuation was not sig. diff. in the 4 groups though discontinuation due to lack of efficacy was sig. less frequent in the active-drug groups c/w placebo group (NEJM 355:1525, 2006--JW)