Dementia

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Dementia is "progressive decline in two or more cognitive domains that is severe enough to interfere with the performance of everyday activities."[1]

Deficits in cognitive function contribute to impaired functional status.[2] The deficits in the domains of cognitive function are[3]:

  • Agnosia - "Failure to recognize or identify objects despite intact sensory function"[3]
  • Aphasia - "Deterioration of language function"[3]
  • Apraxia - "Impaired ability to execute motor activities despite intact motor abilities, sensory function, and comprehension of the required task"[3]
  • Disturbance in executive functioning - "The ability to think abstractly and to plan, initiate, sequence, monitor, and stop complex behavior"[3]

Classification

Vascular dementia can affect both cortical and subcortial locations.

Cortical dementias

Among the many causes of cortical dementia, common causes are:

Subcortical dementias

Among the many causes of subcortical dementia, common causes are:

Epidemiology

22.2% of individuals in the United States age 71 years or older have cognitive impairment without dementia (Dementia Severity Rating Scale score of 6 to 11). 12% of these patients progress to dementia annually. Progression is more common among patients with subtypes of prodromal Alzheimer disease and cerebrovascular disease.[5]

Risk factors

Repeated episodes of hypoglycemia are associated with dementia.[6]

Diagnosis

Studies on diagnosing dementia are compromised by the lack of a true reference standard for comparison.[7][8]

A number of systematic reviews, including ones by the U.S. Preventive Services Task Force (USPSTF)[9], Rational Clinical Examination[3], and others[10], have summarized the diagnostic accuracy of screening tests.

Consequences of labeling

In one study, learning of having mild cognitive impairment reduced stress.[11]

Neuropsychiatric testing

Mini-mental state examination

The Mini-mental state examination (MMSE) is the most studied test.[3] A systematic review concluded that the accuracy of the MMSE is:[9]:

A copy of the Mini-mental state examination can be found in the appendix of the original publication.[12]

Modified Mini-Mental State examination (3MS)

A meta-analysis concluded that the Modified Mini-Mental State (3MS) examination has:[10]

A copy of the 3MS is online.[13]

Abbreviated mental test score

A meta-analysis concluded:[10]

sensitivity 73% to 100%
specificity 71% to 100%

Clinical Dementia Rating

The Clinical Dementia Rating scale can quantify severity of functional impairment.[14]

Clock drawing task

Dementia type CLOX1
(Executive control) 		CLOX2
(Posterior cortical) 		Pentagons copying
on MMSE 		Total MMSE score
Posterior cortical and
diffuse cortical
dementias 		Abnormal Abnormal Abnormal Abnormal
Subcortical and
frontal cortical
dementias 		Abnormal Normal Normal Normal

The Clock drawing task (CLOX) consists of two tests and is available online at PubMed Central.[15] The CLOX1 task has the subject draw a clock face without any prompting other than the instructions "Draw me a clock that says 1:45. Set the hands and numbers on the face so that a child could read them". The CLOX1 is tests executive function and correlates with the EXIT25 test of executive function. The CLOX2 task has the subject copy a clock face from an example, does not test executive function and correlates with the MMSE.

The CLOX may avoid the bias of the MMSE toward cortical dementias.[15] In addition, "as Alzheimer’s disease affects posterior cortical regions before invading the frontal cortex, isolated ECF impairment (CLOX1) is not likely to represent early Alzheimer’s disease."[15] Thus, isolated abnormalities of the CLOX1 may be able to detect reversible dementias such as subcortical stroke, depression, vitamin B12 deficiency, polypharmacy, and hypothyroidism.[15]

Other examinations

Many other tests have been studied [16][17][1] including the Executive Interview (EXIT)[18].

Laboratory tests

Apolipoprotein E4

Although apolipoprotein E4 is an important susceptibility gene for Alzheimer's disease[19], its sensitivity and specificity are insufficient (65 and 68 percent, respectively) to be used as a diagnostic test.[20]

Apolipoprotein E4 does not added to other tests in predicting who will develop Alzheimer's.[21]

Treatment

Approaches to treatment

"Actively involving caregivers in making choices about treatments" my be the most important way to delay institutionalization of patients with dementia.[22]

The use of care managers may help.[23][24]

Non drug treatments

Behavior management techniques (BMT)

Behavior management techniques (BMT) might help.[25] More specifically, " interventions that address behavioral issues and unmet needs" may help.[23]

Exercise

Home-based program of physical activity might benefit according to a randomized controlled trial.[26]

Bright lights

Any initial randomized controlled trial suggests that bright light helps.[27]

Medications

According to the clinical practice guideline by the American College of Physicians, "the evidence is insufficient to compare the effectiveness of different pharmacologic agents for the treatment of dementia."[28]

"Treatment of dementia with cholinesterase inhibitors and memantine can result in statistically significant but clinically marginal improvement in measures of cognition and global assessment of dementia" according to a systematic review for the clinical practice guideline.[29]

Cholinesterase inhibitors

Available cholinesterase inhibitors drugs are donepezil, galantamine, rivastigmine, and tacrine.

Neuropeptide-modifier

Memantine is a neuropeptide-modifier that acts on the N-Methyl-D-Aspartate (NMDA) cell surface receptors for the neurotransmitter glutamate.

Anti-psychotics

The newer, atypical antipsychotic agents (olanzapine, quetiapine, risperidone), were found to have "adverse effects offset advantages in the efficacy of atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in patients with Alzheimer's disease."[30] A more recent randomized controlled trial that compared the second generation anti-psychotic agents found that none improved functioning, care needs, or quality of life with statistical significance[30]; however, olanzapine and risperidone may reduce anger.[31] Regardless, antipsychotic agents may increase mortality.[32]

Withdrawing psychotropics agents may prevent accidental falls.[33]

Melatonin

Melatonin may[34]or may not[35][36][37][38] help with associated sleep and behavior disturbance.

Dietary supplements

Ginkgo biloba has conflicting evidence regarding its efficacy.[39][40][41]

Prevention

Physical activity

Most[42][43][44][45], but not all[46] studies find that physical activity is associated with reduced risk of dementia. These observational studies cannot prove cause and effect.

Mental activity

Maintaining activities such as cognitive games and reading, playing musical instruments, and physical activities are associated with reduced the risk of dementia in an observational study.[46]

Medications

Various medications have been associated with progression or prevention (cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonists, renin-angiotensin system blockers, and hydroxymethylglutaryl-coenzyme A reductase inhibitors) of dementia.[47]

Observational, non-ramdomized cohort studies suggest that hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) may[48][49] or may not[50][51] prevent dementia.

Supplements

Ginkgo biloba does not prevent dementia according to a large randomized controlled trial[52] and systematic review[41] by the Cochrane Collaboration in spite of earlier studies that were positive[53].

Screening

Practice guidelines

In 2003, a clinical practice guideline by the U.S. Preventive Services Task Force (USPSTF) gave a grade I recommendation, indicating "the evidence is insufficient to recommend for or against routine screening for dementia in older adults".[54]

Evidence

The late-life dementia risk index:[55]

late-life dementia risk index
Risk Score Incidence of dementia
within 6 years
High ≥8 56%
Intermediate 4-7 23%
Low 0-3 4%
Based on Table 3 from Barnes et al.[55]
  • older age (1–2 points)
  • poor cognitive test performance (2–4 points)
  • body mass index <18.5 (2 points)
  • ≥1 apolipoprotein E 4 alleles (1 point)
  • cerebral MRI findings of white matter disease (1 point)
  • cerebral ventricular enlargement (1 point)
  • internal carotid artery thickening on ultrasonography (1 point)
  • history of coronary artery bypass surgery (1 point)
  • slow physical performance (1 point)
  • lack of alcohol consumption (1 point)

Prognosis

A systematic review of cohort studies concluded that the rate conversion of mild cognitive impairment to dementia is about 4% per year."[56]

Once a patient has advanced dementia, defined as a score of 5 or 6 on the Cognitive Performance Scale from the most recent Minimum Data Set assessment (a score of 5 corresponds to a score of 5.1 (95% CI: ±10) on the Folstein Mini–Mental State Examination, the median survival is about 18 months.[57]

References

  1. ↑ 1.0 1.1 Karlawish, J. & Clark, C. (2003). "Diagnostic evaluation of elderly patients with mild memory problems". Ann Intern Med 138 (5): 411-9. PMID 12614094.
  2. ↑ Royall DR, Lauterbach EC, Kaufer D, Malloy P, Coburn KL, Black KJ (2007). "The cognitive correlates of functional status: a review from the Committee on Research of the American Neuropsychiatric Association". The Journal of neuropsychiatry and clinical neurosciences 19 (3): 249–65. DOI:10.1176/appi.neuropsych.19.3.249. PMID 17827410. Research Blogging.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 Holsinger T, Deveau J, Boustani M, Williams JW (2007). "Does this patient have dementia?". JAMA 297 (21): 2391–404. DOI:10.1001/jama.297.21.2391. PMID 17551132. Research Blogging.
  4. ↑ McKeith IG, Fairbairn AF, Perry RH, Thompson P (September 1994). "The clinical diagnosis and misdiagnosis of senile dementia of Lewy body type (SDLT)". Br J Psychiatry 165 (3): 324–32. PMID 7994501. [e]
  5. ↑ Plassman BL, Langa KM, Fisher GG, et al (March 2008). "Prevalence of cognitive impairment without dementia in the United States". Ann. Intern. Med. 148 (6): 427–34. PMID 18347351. [e]
  6. ↑ Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV (April 2009). "Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus". JAMA 301 (15): 1565–72. DOI:10.1001/jama.2009.460. PMID 19366776. Research Blogging.
  7. ↑ Erkinjuntti T, Ostbye T, Steenhuis R, Hachinski V (December 1997). "The effect of different diagnostic criteria on the prevalence of dementia". N. Engl. J. Med. 337 (23): 1667–74. PMID 9385127. [e]
  8. ↑ Rockwood K et al. Toward a revision of criteria for the dementias. Alzheimer's and Dementia 3 (4), 428 (2007) DOI:10.1016/j.jalz.2007.07.014
  9. ↑ 9.0 9.1 Boustani, M.; Peterson, B.; Hanson, L.; Harris, R.; & Lohr, K. (2003). "Screening for dementia in primary care: a summary of the evidence for the U.S. Preventive Services Task Force". Ann Intern Med 138 (11): 927-37. PMID 12779304.
  10. ↑ 10.0 10.1 10.2 Cullen B, O'Neill B, Evans JJ, Coen RF, Lawlor BA (2007). "A review of screening tests for cognitive impairment". J. Neurol. Neurosurg. Psychiatr. 78 (8): 790–9. DOI:10.1136/jnnp.2006.095414. PMID 17178826. Research Blogging.
  11. ↑ Carpenter, B. D., Xiong, C., Porensky, E. K., Lee, M. M., Brown, P. J., Coats, M., et al. (2008). Reaction to a dementia diagnosis in individuals with alzheimer's disease and mild cognitive impairment, Journal of the American Geriatrics Society, 56(3), 405-412. DOI:doi:10.1111/j.1532-5415.2007.01600.x. doi:10.1111/j.1532-5415.2007.01600.x.
  12. ↑ Folstein MF, Folstein SE, McHugh PR (1975). ""Mini-mental state". A practical method for grading the cognitive state of patients for the clinician". Journal of psychiatric research 12 (3): 189-98. DOI:10.1016/0022-3956(75)90026-6. PMID 1202204. Research Blogging.
  13. ↑ Hogan DB, Ebly EM (2000). "Predicting who will develop dementia in a cohort of Canadian seniors". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 27 (1): 18–24. PMID 10676583. [e] [Appendix: The Modified Mini-Mental State (3MS)]
  14. ↑ Morris JC (1993). "The Clinical Dementia Rating (CDR): current version and scoring rules.". Neurology 43 (11): 2412-4. PMID 8232972.
  15. ↑ 15.0 15.1 15.2 15.3 Royall, D.; Cordes J.; & Polk M. (1998). "CLOX: an executive clock drawing task". J Neurol Neurosurg Psychiatry 64 (5): 588-94. PMID 9598672. Full text at PubMed Central Example form
  16. ↑ Sager, M.; Hermann, B.; La Rue, A.; & Woodard, J. (2006). "Screening for dementia in community-based memory clinics". WMJ 105 (7): 25-9. PMID 17163083.
  17. ↑ Fleisher, A.; Sowell B.; Taylor C.; Gamst A.; Petersen R.; & Thal L. (2007). "Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment". Neurology 68 (19): 1588-95. PMID 17287448.
  18. ↑ Royall DR, Mahurin RK, Gray KF. Bedside assessment of executive cognitive impairment: the executive interview. J Am Geriatr Soc. 1992;40:1221-6. PMID 1447438
  19. ↑ Skoog I (August 2000). "Detection of preclinical Alzheimer's disease". N. Engl. J. Med. 343 (7): 502–3. PMID 10944568. “The APOE 4 allele is a susceptibility gene for Alzheimer's disease and seems to affect the age of onset of the disease. However, the presence of this allele alone is not sufficient to predict which asymptomatic subjects will ultimately have Alzheimer's disease, and the disease never develops in many subjects with this genotype” [e]
  20. ↑ Kivipelto M, Helkala EL, Laakso MP, et al (August 2002). "Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease". Ann. Intern. Med. 137 (3): 149–55. PMID 12160362. [e]
  21. ↑ Devanand DP, Liu X, Tabert MH, et al (November 2008). "Combining early markers strongly predicts conversion from mild cognitive impairment to Alzheimer's disease". Biol. Psychiatry 64 (10): 871–9. DOI:10.1016/j.biopsych.2008.06.020. PMID 18723162. Research Blogging.
  22. ↑ Spijker A et al. Effectiveness of Nonpharmacological Interventions in Delaying the Institutionalization of Patients with Dementia: A Meta-Analysis.J Am Geriatr Soc. 2008 Apr 11. PMID 18410323
  23. ↑ 23.0 23.1 Ayalon L, Gum AM, Feliciano L, Areán PA (2006). "Effectiveness of nonpharmacological interventions for the management of neuropsychiatric symptoms in patients with dementia: a systematic review". Arch. Intern. Med. 166 (20): 2182–8. DOI:10.1001/archinte.166.20.2182. PMID 17101935. Research Blogging.
  24. ↑ Vickrey BG, Mittman BS, Connor KI, et al (2006). "The effect of a disease management intervention on quality and outcomes of dementia care: a randomized, controlled trial". Ann. Intern. Med. 145 (10): 713–26. PMID 17116916. [e]
  25. ↑ Teri L, Gibbons LE, McCurry SM, et al (2003). "Exercise plus behavioral management in patients with Alzheimer disease: a randomized controlled trial". JAMA 290 (15): 2015–22. DOI:10.1001/jama.290.15.2015. PMID 14559955. Research Blogging.
  26. ↑ Lautenschlager NT, Cox KL, Flicker L, Foster JK, van Bockxmeer FM, Xiao J, et al. Effect of Physical Activity on Cognitive Function in Older Adults at Risk for Alzheimer Disease: A Randomized Trial. JAMA. 2008 Sep 3;300(9):1027-1037.
  27. ↑ Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ (June 2008). "Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial". JAMA 299 (22): 2642–55. DOI:10.1001/jama.299.22.2642. PMID 18544724. Research Blogging.
  28. ↑ Qaseem A, Snow V, Cross JT, et al (March 2008). "Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians". Ann. Intern. Med. 148 (5): 370–8. PMID 18316755. [e]
  29. ↑ Raina P, Santaguida P, Ismaila A, et al (March 2008). "Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline". Ann. Intern. Med. 148 (5): 379–97. PMID 18316756. [e]
  30. ↑ 30.0 30.1 Schneider LS, Tariot PN, Dagerman KS, et al (2006). "Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease". N. Engl. J. Med. 355 (15): 1525–38. DOI:10.1056/NEJMoa061240. PMID 17035647. Research Blogging. Cite error: Invalid <ref> tag; name "pmid17035647" defined multiple times with different content
  31. ↑ Sultzer DL, Davis SM, Tariot PN, Dagerman KS, Lebowitz BD, Lyketsos CG et al. (2008). "Clinical symptom responses to atypical antipsychotic medications in Alzheimer's disease: phase 1 outcomes from the CATIE-AD effectiveness trial.". Am J Psychiatry 165 (7): 844-54. DOI:10.1176/appi.ajp.2008.07111779. PMID 18519523. PMC PMC2714365. Research Blogging. Review in: Evid Based Ment Health. 2009 Feb;12(1):20
  32. ↑ Ballard C, Hanney ML, Theodoulou M, Douglas S, McShane R, Kossakowski K et al. (2009). "The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial.". Lancet Neurol 8 (2): 151-7. DOI:10.1016/S1474-4422(08)70295-3. PMID 19138567. Research Blogging. Review in: Ann Intern Med. 2009 Jun 16;150(12):JC6-8 Review in: Evid Based Med. 2009 Aug;14(4):115
  33. ↑ Campbell AJ, Robertson MC, Gardner MM, Norton RN, Buchner DM (1999). "Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial". J Am Geriatr Soc 47 (7): 850–3. PMID 10404930. [e]
  34. ↑ Dowling GA, Burr RL, Van Someren EJ, Hubbard EM, Luxenberg JS, Mastick J et al. (2008). "Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer's disease.". J Am Geriatr Soc 56 (2): 239-46. DOI:10.1111/j.1532-5415.2007.01543.x. PMID 18070004. PMC PMC2642966. Research Blogging.
  35. ↑ Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S (2009). "Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease.". Am J Geriatr Psychiatry 17 (2): 166-9. DOI:10.1097/JGP.0b013e318187de18. PMID 19155748. PMC PMC2630117. Research Blogging.
  36. ↑ Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M et al. (2003). "A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease.". Sleep 26 (7): 893-901. PMID 14655926.
  37. ↑ Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P (2002). "Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia.". Int J Geriatr Psychiatry 17 (12): 1120-7. DOI:10.1002/gps.760. PMID 12461760. Research Blogging.
  38. ↑ Haffmans PM, Sival RC, Lucius SA, Cats Q, van Gelder L (2001). "Bright light therapy and melatonin in motor restless behaviour in dementia: a placebo-controlled study.". Int J Geriatr Psychiatry 16 (1): 106-10. PMID 11180494.
  39. ↑ Solomon PR, Adams F, Silver A, Zimmer J, DeVeaux R (2002). "Ginkgo for memory enhancement: a randomized controlled trial". JAMA 288 (7): 835–40. PMID 12186600. [e]
  40. ↑ Le Bars PL, Katz MM, Berman N, Itil TM, Freedman AM, Schatzberg AF (1997). "A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group". JAMA 278 (16): 1327–32. PMID 9343463. [e]
  41. ↑ 41.0 41.1 Birks J, Grimley Evans J (2009). "Ginkgo biloba for cognitive impairment and dementia". Cochrane Database Syst Rev (1): CD003120. DOI:10.1002/14651858.CD003120.pub3. PMID 19160216. Research Blogging.
  42. ↑ Byles JE, Sanson-Fisher RW (June 1996). "Mass mailing campaigns to promote screening for cervical cancer: do they work, and do they continue to work?". Aust N Z J Public Health 20 (3): 254–60. PMID 8768414. [e]
  43. ↑ Ravaglia G, Forti P, Lucicesare A, et al (2007). "Physical activity and dementia risk in the elderly. Findings from a prospective Italian study". Neurology. DOI:10.1212/01.wnl.0000296276.50595.86. PMID 18094335. Research Blogging.
  44. ↑ Larson EB, Wang L, Bowen JD, et al (2006). "Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older". Ann. Intern. Med. 144 (2): 73–81. PMID 16418406. [e]
  45. ↑ Abbott RD, White LR, Ross GW, Masaki KH, Curb JD, Petrovitch H (2004). "Walking and dementia in physically capable elderly men". JAMA 292 (12): 1447–53. DOI:10.1001/jama.292.12.1447. PMID 15383515. Research Blogging.
  46. ↑ 46.0 46.1 Verghese J, Lipton RB, Katz MJ, et al (2003). "Leisure activities and the risk of dementia in the elderly". N. Engl. J. Med. 348 (25): 2508–16. DOI:10.1056/NEJMoa022252. PMID 12815136. Research Blogging.
  47. ↑ Ellul J, Archer N, Foy CM, et al (March 2007). "The effects of commonly prescribed drugs in patients with Alzheimer's disease on the rate of deterioration". J. Neurol. Neurosurg. Psychiatr. 78 (3): 233–9. DOI:10.1136/jnnp.2006.104034. PMID 17012333. Research Blogging.
  48. ↑ Cramer C, Haan MN, Galea S, Langa KM, Kalbfleisch JD (July 2008). "Use of statins and incidence of dementia and cognitive impairment without dementia in a cohort study". Neurology 71 (5): 344–50. DOI:10.1212/01.wnl.0000319647.15752.7b. PMID 18663180. Research Blogging.
  49. ↑ Haag MD, Hofman A, Koudstaal PJ, Stricker BH, Breteler MM (January 2009). "Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study". J. Neurol. Neurosurg. Psychiatr. 80 (1): 13–7. DOI:10.1136/jnnp.2008.150433. PMID 18931004. Research Blogging.
  50. ↑ Zandi PP, Sparks DL, Khachaturian AS, et al (February 2005). "Do statins reduce risk of incident dementia and Alzheimer disease? The Cache County Study". Arch. Gen. Psychiatry 62 (2): 217–24. DOI:10.1001/archpsyc.62.2.217. PMID 15699299. Research Blogging.
  51. ↑ Li G, Higdon R, Kukull WA, et al (November 2004). "Statin therapy and risk of dementia in the elderly: a community-based prospective cohort study". Neurology 63 (9): 1624–8. PMID 15534246. [e]
  52. ↑ DeKosky ST, Williamson JD, Fitzpatrick AL, et al (November 2008). "Ginkgo biloba for prevention of dementia: a randomized controlled trial". JAMA 300 (19): 2253–62. DOI:10.1001/jama.2008.683. PMID 19017911. Research Blogging.
  53. ↑ Mix JA, Crews WD (August 2002). "A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings". Hum Psychopharmacol 17 (6): 267–77. DOI:10.1002/hup.412. PMID 12404671. Research Blogging.
  54. ↑ U.S. Preventive Services Task Force (2003). "Screening for dementia: recommendation and rationale". Ann. Intern. Med. 138 (11): 925–6. PMID 12779303. [e]
  55. ↑ 55.0 55.1 Barnes DE et al (2009). "Predicting risk of dementia in older adults. The late-life dementia risk index". Neurology. DOI:10.1212/WNL.0b013e3181a8163. PMID 19439724. Research Blogging.
  56. ↑ Mitchell AJ, Shiri-Feshki M (December 2008). "Temporal trends in the long term risk of progression of mild cognitive impairment: a pooled analysis". J. Neurol. Neurosurg. Psychiatr. 79 (12): 1386–91. DOI:10.1136/jnnp.2007.142679. PMID 19010949. Research Blogging.
  57. ↑ Mitchell SL, Teno JM, Kiely DK, Shaffer ML, Jones RN, Prigerson HG et al. (2009). "The Clinical Course of Advanced Dementia.". N Engl J Med 361 (16): 1529-1538. DOI:10.1056/NEJMoa0902234. PMID 19828530. Research Blogging.
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