2007 overview: Developments in dementia diagnosis and treatment

Introduction

2007 has been a year without new drugs approved for Alzheimer's disease (AD), but consolidation on the use of the current ones in AD and related dementias, including mixed AD/vascular disease, Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB).

Sadly Leon J. Thal died on February 3rd 2007, the leader of North-American efforts to improve clinical trial designs in AD (one of his obituaries has been written by Zaven Khachaturian in Neurobiology of Aging, (ref. 1). One of Leon's dreams was primary prevention trials in populations at risk of dementia and much of the clinical research in 2008 will be geared towards this goal.

Can we improve tolerability and safety of cholinesterase inhibitors?

Cholinesterase inhibitors (CI) as a class have parasympatic actions leading to nausea, vomiting and diarrhea, which can be dose limiting in low body weight persons. A trans-dermal formulation of rivastigmine has been studied by Winblad et al. (ref. 2) and will lead to higher tolerability of this drug, allowing more patients to reach the full therapeutic dose of 12mg/day.

Cardio-vascular effects of CI include brady-arrhythmia and syncope, which in a critical review of the literature by Ferreri et al. (ref. 3) have been found to be relatively rare but requiring vigilance in patients with risk factors such as prior history of unexplained syncope.

Where do we stand on Mild Cognitive Impairment?

After the massive investment of time, efforts and money on drugs for Mild Cognitive Impairment (MCI), the latest publication being that of the rivastigmine InDDEx study (ref. 4), there is now an interest in finding within the MCI population those with clinical and laboratory features of "pre-dementia AD" (ref. 5).

These "modified NINCDS-ADRDA criteria" are a combination of impaired episodic memory impairment and abnormal MRI, PET, SPECT or CSF that would lead an earlier diagnosis of AD, where CI have not proven effective, thus allowing for testing of potential disease-modifying drugs vs placebo without background symptomatic therapy.

The outcomes may be cognitive decline (which will require new cognitive tests such as the CANTAB) and loss of instrumental activities of daily living (using for instance the Disability Assessment in Dementia scale). A detailed review of candidate drugs for disease-modification in presymptomatic populations and persons with minimal symptoms (MCI or "predementia AD") has been published by Cummings et al. (ref. 6), and the European perspective on disease-modification trials in AD has been published (ref. 7).

Does diet and exercise matter in the prevention of Alzheimer's disease?

There is increasing interest in dietary constituents that may help prevent or delay Alzheimer's disease (AD). For instance Luchsinger et al. (ref. 8) found in a cohort of subjects over age 65, a 50% lower risk of AD in persons who had the highest ingestion of folate intake in their diet.

These findings were supported by a prospective 3-year study with folate supplementation vs placebo demonstrating a significant difference in cognitive tests (ref. 9). Physical exercises have been found in epidemiologic studies to reduce the risk of dementia (ref. 10). An exercise program in nursing home residents with AD was found to slow the functional decline (ref. 11). The evidence of benefit from diet enrichment, physical exercise and cognitive training (the best evidence for the latter is from Willis et al., (ref. 12)) is such that multi-intervention trials are being planned in Canada, France and the USA in order to reduce the rate of age-associated cognitive decline.

Can we treat behavioral and psychological symptoms of dementia (BPSD) without neuroleptics?

Atypical neuroleptics have not been found to be very effective in the treatment of BPSD in the CATIE-AD Study (ref. 13) and no new evidence came out in 2007 to improve their efficacy/safety ratio (ref. 14). Alternatives include non-pharmacological approaches, CI and memantine (ref. 15). The methodology of measuring BPSD is also evolving from total scores on the NeuroPsychiatric Inventory (NPI) to factor analysis (ref. 16), longitudinal follow-up to detect disruptive behaviors (ref. 17) and emerging vs improving symptoms in clinical trials (ref. 18).

Can we diagnose PDD and treat it?

There has been significant progress in the field of cognitive decline associated with Parkinson's disease: the natural history of cognitive dysfunction in an incident Parkinson's cohort (ref. 19), REM sleep behavior disorder as predictor of cognitive impairment in PD (ref. 20), clinical diagnostic criteria for PDD (ref. 21), a critical review of the use of CI in Dementia in Parkinsonian Syndromes (ref. 22).

The Parkinson Study Group has an active task force working on cognitive aspects of PD. The very successful AD/PD Congress that took place in Salzburg this year was a testimony to the high interest of behavioral neurologists and movement disorders specialists in PDD and DLB.

What about vascular dementia?

It has been difficult to demonstrate improvement of cognition, function and behavior in vascular dementia using CI and memantine: the results are encouraging but not conclusive (ref. 23). What is perhaps more significant is the recognition that mixed brain pathologies (AD, vascular, Lewy Bodies) account for most cases in community-dwelling older persons (ref. 24) and that hypertension increases the risk of MCI (ref. 25), leading to recommendations that dementia and cerebrovascular pathology be treated concurrently (ref. 26).

This means that all clinicians treating persons at risk of dementia, with minimal symptoms or with dementia must be aware of changing guidelines in the management of diabetes, hypertension and hypercholesterolemia: joint Continuous Medical Education programs between internal medicine, geriatric medicine neurology and psychiatry are strongly recommended.

Best wishes for the New Year 2008!

References

1. Khachaturian ZS. Leon J. Thal, MD (17 June 1944–3 February 2007). Neurobiology of Aging 2007; 28 (6); 809-812

2. Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer's disease - rivastigmine patch versus capsule. International Journal of Geriatric Psychiatry 2007, 22 (5); 456-467

3. FERRERI F, AGBOKOU C, GAUTHIER S. Effets cardio-vasculaires des inhibiteurs de la cholinesterase dans la maladie d'Alzheimer. Revue Neurologique 2007; 163 (10); 968-974

4. Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, et al. Effect of rivastigmine on delay to diagnosis of Alzheimer's disease from mild cognitive impairment: the InDDEx study.. Lancet Neurology 2007; 6 (6); 501-512

5. 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

6. Cummings JL, Doody R, Clark C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 2007; 69 (16); 1622-1634

7. Vellas B, Andrieu S, Sampaio C, Wilcock G. Disease-modifying trials in Alzheimer's disease: a European task force consensus. Lancet Neurology 2007; 6; 56-62

8. Luchsinger JA, Tang MX, Miller J, Green R, Mayeux R. Relation of higher folate intake to lower risk of Alzheimer disease in the elderly. Archives of Neurology 2007; 64 (1); 86-92

9. Durga J, van Boxtel MP, Schouten EG, Kok FJ, Jolles J, Katan MB, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 2007; 369 (9557); 208-216

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12. Willis SL, Tennstedt SL, Marsiske M, Ball K, Elias J, Koepke KM, et al. Long-term effects of cognitive training on everyday functional outcomes in older adults. JAMA 2006; 296 (23): 2805-2814

13. Schneider LS, Tariot PN, Dagerman KS, Davis SM, Hsiao JK, Ismail MS, et al. Effectiveness of atypical antipsychotic drugs in patients with Alzheimer's disease. New England Journal of Medicine 2006; 355 (15); 1525-1538

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17. Scarmeas N, Brandt J, Blacker D, Albert M, Hadjigeorgiou G, Dubois B, et al. Disruptive Behavior as a Predictor in Alzheimer Disease. Archives of Neurology 2007; 64(12); 1755-1761

18. 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; (DOI: 10.102/gps1949)

19. Williams-Gray CH, Foltynie T, Brayne CE, Robbins TW, Barker RA. Evolution of cognitive dysfunction in an incident Parkinson's disease cohort.. Brain 2007; 130 (7); 1787-1798. [Epub 2007 May 29]

20. Vendette M, Gagnon JF, Décary A, Massicotte-Marquez J, Postuma RB, Doyon J, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007; 69 (19); 1843-1849

21. Ehrt U, Brønnick K, De Deyn PP, Emre M, Tekin S, Lane R, et al. Subthreshold depression in patients with Parkinson's disease and dementia--clinical and demographic correlates. International Journal of Geriatric Psychiatry 2007; 22 (10); 980-985

22. Liepelt I, Maetzler W, Blaicher HP, Gasser T, Berg D. Treatment of dementia in parkinsonian syndromes with cholinesterase inhibitors. Dementia and Geriatric Cognitive Disorders 2007 ; 23 (6); 351-367. [Epub 2007 Mar 26]

23. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurology 2007; 6 (9); 782-792

24. Schneider JA, Arvanitakis Z, Bang W, Bennett DA. Mixed brain pathologies account for most dementia cases in community-dwelling older persons. Neurology 2007; 69 (24); 2197-2204. [Epub 2007 Jun 13]

25. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Archives of Neurology 2007; 64 (12); 1734-1740

26. Bocti C, Black S, Frank C. Management of dementia with a cerebrovascular component. Alzheimer's and Dementia 2007; 3 (4); 398-403