2008 overview: Developments in dementia diagnosis and treatment

Introduction

2008 has been a year with no new drug approved for Alzheimer's disease (AD) and related disorders, but much work is under way for earlier diagnosis of AD, better use of cholinesterase inhibitors, prove the efficacy and safety of anti-amyloid agents, explore the potential benefit of nutraceuticals and vitamins, improve the treatment of neuro-psychiatric symptoms associated with dementia. This overview will highlight the articles published in 2008 most relevant to these topics, with a glimpse at 2009.

Can the diagnosis of Alzheimer's disease be made before the dementia?

Not quite yet but very soon. The revised NINCDS-ADRDA diagnostic criteria proposed by Dubois et al. (ref. 1) with an update this year (ref. 2) are being validated in multiple locations. Recent findings include the fact that amyloid deposition measured by PIB-PET scans is very common in cognitively heathly subjects (ref. 3), and that a patient with a brain biopsy showing significant amyloid deposition had a negative PIB scan (ref. 4).

Not surprisingly cerebral hypometabolism using FDG-PET scans in the cingulate, parietal and prefrontal regions correlated with cognitive decline in healthy elderly subjects (ref. 5). The sensitivity of positive PIB-PET scans appears to be better than abnormal (lower) Aß42 CSF levels  in predicting progression from amnestic MCI to AD (ref. 6).

There is thus an international effort to collect data on the neuropsychological, brain imaging and CSF profiles in subjects with mild cognitive complaints in order to make a very early diagnosis of AD and test potential disease-modifying therapies.

What is new on cholinesterase inhibitors?

This class of drugs (donepezil, rivastigmine, galantamine) has matured well over the past decade and will soon be available at lower costs because of the end of the patent protection. Donepezil has confirmed its safety and efficacy in severe stages of Alzheimer's disease (AD) over 24 weeks in Japan (ref. 7), and a responder analysis on the original Swedish severe AD study confirmed benefit over placebo on cognitive, functional and behavioral symptoms (ref. 8).

Rivastigmine's transdermal formulation which had been demonstrated to be of equal efficacy to the oral formulation but much better tolerated (ref. 9) has been made available in multiple countries; rivastigmine has now been clearly established as first line treatment in Parkinson Disease Dementia (ref. 10).

The galantamine study in Mild Cognitive Impairment was published and concerns about safety were alleviated by a retrieved drop out analysis (ref. 11); a combined analysis of four studies comparing galantamine to placebo in mild to moderate AD or AD with cerebro-vascular features suggest a delay in time to nursing home placement (ref. 12); the SERAD study in a nursing home setting showed an improvement on galantamine vs placebo, but no difference in activities of daily living (ref. 13).

Are we under dosing some patients, e.g. not achieving optimal cholinesterase inhibition? This is quite possible, and a randomized study is under way to compare standard size rivastigmine patch #10 to a new #15 dose for patients who lose the initial therapeutic benefit after six to twelve months of use.

Are anti-amyloid therapies effective in Alzheimer's disease?

The short answer is that we do not know yet. Despite encouraging results from Phase II studies with tramiprosate which acts on amyloid aggregation (ref. 14) and tarenflurbil which modulates γ-secretase activity (ref. 15), large scales and lengthy Phase III studies were negative for the primary clinical outcomes (reports made at ICAD 2008).

A pathological study of patients who were immunized with AN1792 in 2000 and later died of their condition confirmed amyloid plaque removal, but no evidence of improved survival and more importantly no evidence of a delay of progression to severe dementia (ref. 16). On the positive side a Phase II study with the γ-secretase inhibitor LY450139 gave encouraging results for plasma Aß40 lowering effects (64.6% at the highest dose) and large scales Phase III studies are under way.

A number of studies utilizing active and passive immunotherapy and studies using ß and other γ secretase inhibitors are also under way in early to moderate stages of AD. Whether these treatments will work better in the pre-dementia stages of AD, or in very early familial AD remains open questions, hopefully to be explored in 2009.

Are nutraceuticals and vitamins useful?

Ginkgo Biloba (GB) has been extensively studied as an antioxidant. The large scale (N=522 over 6+ years) placebo-controlled Gingko Evaluation of Memory (GEM) study, was negative as a mean of prevention of AD (ref. 17). The accompanying editorial highlights that the study design itself was successful in terms of enrollment, retention and efficacy outcomes, and will serve as a model for future studies aiming at delaying incident dementia in populations at risk (ref. 18).

Tramiprosate which was not found effective in mild to moderate stages of AD has been made available as a nutraceutical since it is made of homotaurine which was originally extracted from algae. Evidence was published that low normal levels of Vitamin B12 in blood were correlated with rate of brain volume loss in community-dwelling elderly without cognitive impairment, suggesting that B12 supplementation should be used more often (ref. 19).

Ideally tramiprosate, B12 and diet supplements such as omega-3 should be tested in prospective studies such as GEM, but funding and completion of such large scale studies are a major challenge. Fortunately an international working group to facilitate preventive studies is meeting yearly in Las Vegas' new Lou Ruvo Brain Institute (ref. 20).

Can we help neuropsychiatric symptoms associated with dementia?

Clearly yes but we must do better. Measurement tools are being refined, such as the NeuroPsychiatric Inventory with Clinicians' input (NPI-C) currently undergoing validation, trans-national comparisons are being made for the consistency of neuropsychiatric syndromes across dementias (ref. 21), pooled analysis of memantine studies have been published (ref. 22), as well as results of psychosocial interventions for caregivers (ref. 23).

Non-pharmacologic and pharmacologic managements of neuropsychological symptoms associated with severe AD have been reviewed by Herrmann & Gauthier (ref. 24), based on discussions that took place during the 3rd Canadian Consensus Conference on the Diagnosis and treatment of Dementia (CCCDTD). Guidelines from the CCCDTD for management of AD (from "at risk" to severe stage) can be found in the CMAJ web-page (ref. 25, ref. 26, ref. 27, ref. 28, ref. 29, ref. 30) and a case-study approach facilitates translation from guidelines to clinical practice.

What is on the horizon for 2009 and beyond?

Dimebon, acting as cholinesterase inhibitor, NMDA receptor antagonist, and inhibitor of mitochondrial permeability transition pore opening, showed remarkable clinical benefit in mild to moderate AD when tested in Russia over 12 months (ref. 31). It is currently being tested in many countries as monotherapy and soon in combination with cholinesterase inhibitors.

Positive results in Phase III would greatly modify current symptomatic treatment strategies, since the improvement "above baseline" would be more evident than with current drugs.

Similarly positive findings in a study aiming at disease-modification would change approaches to treatment since benefit in the dementia stage of AD would justify treatment in the pre-dementia stage and potentially in high risk asymptomatic persons. "High risk" may be defined using a risk score such as the one proposed by Kivipelto et al. (ref. 32). Whichever group is treated, clear guidelines about "when to start" and "when to stop" will need to be agreed upon, potentially needing a pharmaco-genomic approach (ref. 33).

Best wishes for the New Year 2009!

References

1. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurology 2007; 6 (8); 734-746

2. Gauthier S, Dubois B, Feldman H, Scheltens P. Revised research diagnostic criteria for Alzheimer's disease. Lancet Neurology 2008; 7; 668-670

3. Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, et al. Frequent amyloid deposition without significant cognitive impairment among the elderly. Archives of Neurology 2008; 65 (11); 1509-1517

4. Leinonen V, Alafuzoff I, Aalto S, Suotunen T, Savolainen S, Någren K, et al. Assessment of beta-amyloid in a frontal cortical brain biopsy specimen and by positron emission tomography with carbon 11-labeled Pittsburgh Compound B. Archives of Neurology 2008; 65 (10); 1304-1309. [Epub 2008 Aug 11]

5. Caselli RJ, Chen K, Lee W, Alexander GE, Reiman EM. Correlating cerebral hypometabolism with future memory decline in subsequent converters to amnestic pre-mild cognitive impairment. Archives of Neurology 2008; 65 (9); 1231-1236

6. Koivunen J, Pirttilä T, Kemppainen N, Aalto S, Herukka SK, Jauhianen AM, et al. PET amyloid ligand [11C]PIB uptake and cerebrospinal fluid beta-amyloid in mild cognitive impairment. Dementia and Geriatric Cognitive Disorders 2008; 26 (4); 378-383. [Epub 2008 Oct 16]

7. Homma A, Imai Y, Tago H, Asada T, Shigeta M, Iwamoto T, et al. Donepezil treatment of patients with severe Alzheimer's disease in a Japanese population: results from a 24-week, double-blind, placebo-controlled, randomized trial. Dementia and Geriatric Cognitive Disorders 2008; 25 (5); 399-407. [Epub 2008 Apr 3]

8. Jelic V, Haglund A, Kowalski J, Langworth S, Winblad B. Donepezil treatment of severe Alzheimer's disease in nursing home settings. A responder analysis. Dementia and Geriatric Cognitive Disorders 2008; 26 (5); 458-466. [Epub 2008 Nov 4]

9. Winblad B, Grossberg G, Frölich L, Farlow M, Zechner S, Nagel J, et al. IDEAL: a 6-month, double-blind, placebo-controlled study of the first skin patch for Alzheimer disease. Neurology 2007; 69 (4 Suppl 1); 14-22

10. Poewe W, Gauthier S, Aarsland D, Leverenz JB, Barone P, Weintraub D, et al. Diagnosis and management of Parkinson's disease dementia. International Journal of Clinical Practice 2008; 62 (10); 1581-1587

11. Winblad B, Gauthier S, Scinto L, Feldman H, Wilcock GK, Truyen L, et al. Safety and efficacy of galantamine in subjects with mild cognitive impairment. Neurology 2008; 70 (22); 2024-2035. [Epub 2008 Mar 5]

12. Feldman HH, Pirttila T, Dartigues JF, Everitt B, Van Baelen B, Schwalen S, et al. Treatment with galantamine and time to nursing home placement in Alzheimer's disease patients with and without cerebrovascular disease. International Journal of Geriatric Psychiatry 2008. [Epub ahead of print/DOI: 10.1002/gps.2141]

13. Burns A, Bernabei R, Bullock R, Jentoft AJ, Frölich L, Hock C, et al. Safety and efficacy of galantamine (Reminyl) in severe Alzheimer's disease (the SERAD study): a randomised, placebo-controlled, double-blind trial. Lancet Neurology 2009; 8 (1); 39-47. [Epub 2008 Nov 29]

14. Aisen PS, Gauthier S, Vellas B, Briand R, Saumier D, Laurin J, et al. Alzhemed: a potential treatment for Alzheimer's disease. Current Alzheimer Research 2007; 4 (4); 473-478

15. Wilcock GK, Black SE, Hendrix SB, Zavitz KH, Swabb EA, Laughlin MA, et al. Efficacy and safety of tarenflurbil in mild to moderate Alzheimer's disease: a randomised phase II trial. Lancet Neurology 2008; 7 (6); 483-493. [Epub 2008 Apr 29]

16. Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, et al. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet 2008; 372 (9634); 216-223

17. DeKosky ST, Williamson JD, Fitzpatrick AL, Kronmal RA, Ives DG, Saxton JA, et al. Ginkgo biloba for prevention of dementia: a randomized controlled trial. JAMA 2008; 300 (19); 2253-2262

18. Schneider LS. Ginkgo biloba extract and preventing Alzheimer disease. JAMA 2008; 300 (19); 2306-2308

19. Vogiatzoglou A, Refsum H, Johnston C, Smith SM, Bradley KM, de Jager C, et al. Vitamin B12 status and rate of brain volume loss in community-dwelling elderly. Neurology 2008; 71 (11); 826-832

20. Khachaturian ZS, Petersen RC, Gauthier S, Buckholtz N, Corey-Bloom JP, Evans B, et al. A roadmap for the prevention of dementia: the inaugural Leon Thal Symposium. Alzheimer's and Dementia 2008; 4 (3); 156-163. (Free author manuscript)

21. Aalten P, Verhey FR, Boziki M, Brugnolo A, Bullock R, Byrne EJ, et al. Consistency of neuropsychiatric syndromes across dementias: results from the European Alzheimer Disease Consortium. Part II. Dementia and Geriatric Cognitive Disorders 2008; 25 (1); 1-8. [Epub 2007 Nov 15]

22. Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer's disease by memantine: a pooled data analysis. International Journal of Geriatric Psychiatry 2008; 23 (5); 537-545

23. Mittelman MS, Brodaty H, Wallen AS, Burns A. A three-country randomized controlled trial of a psychosocial intervention for caregivers combined with pharmacological treatment for patients with Alzheimer disease: effects on caregiver depression. American Journal of Geriatric Psychiatry 2008; 16 (11); 893-904

24. Herrmann N Md, Gauthier S Md. Diagnosis and treatment of dementia: 6. Management of severe Alzheimer disease. CMAJ 2008; 179 (12); 1279-1287. (Free full text article)

25. Chertkow H. Diagnosis and treatment of dementia: introduction. Introducing a series based on the Third Canadian Consensus Conference on the Diagnosis and Treatment of Dementia. CMAJ 2008; 178 (3); 316-21. (Free full text article)

26. Patterson C, Feightner JW, Garcia A, Hsiung GY, MacKnight C, Sadovnick AD. Diagnosis and treatment of dementia: 1. Risk assessment and primary prevention of Alzheimer disease. CMAJ 2008; 178 (5); 548-556. (Free full text article)

27. Feldman HH, Jacova C, Robillard A, Garcia A, Chow T, Borrie M, et al. Diagnosis and treatment of dementia: 2. Diagnosis. CMAJ 2008; 178 (7); 825-836. (Free full text article)

28. Chertkow H, Massoud F, Nasreddine Z, Belleville S, Joanette Y, Bocti C, et al. Diagnosis and treatment of dementia: 3. Mild cognitive impairment and cognitive impairment without dementia. CMAJ 2008; 178 (10); 1273-1285. (Free full text article)

29. Hogan DB, Bailey P, Black S, Carswell A, Chertkow H, Clarke B, et al. Diagnosis and treatment of dementia: 4. Approach to management of mild to moderate dementia. CMAJ 2008; 179 (8); 787-793. (Free full text article)

30. Hogan DB, Bailey P, Black S, Carswell A, Chertkow H, Clarke B, et al. Diagnosis and treatment of dementia: 5. Nonpharmacologic and pharmacologic therapy for mild to moderate dementia. CMAJ 2008; 179 (10); 1019-1026. (Free full text article)

31. Doody RS, Gavrilova SI, Sano M, Thomas RG, Aisen PS, Bachurin SO, et al. Effect of dimebon on cognition, activities of daily living, behaviour, and global function in patients with mild-to-moderate Alzheimer's disease: a randomised, double-blind, placebo-controlled study. Lancet 2008; 372 (9634); 207-215

32. Kivipelto M, Ngandu T, Laatikainen T, Winblad B, Soininen H, Tuomilehto J. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurology 2006; 5 (9):735-741

33. Poirier J, Gauthier S. Pharmacogenomics and the treatment of sporadic Alzheimer’s disease: a decade of progress. Current Pharmacogenomics 2008; 6; in press