2005 overview: Developments in dementia treatment

There have been many studies in the diagnosis and management of Alzheimer’s disease and related disorders in 2005, including randomized clinical trials (RCT) using symptomatic drugs as well as disease-modifying treatments. Furthermore the concept of "pure AD" is evolving towards mixed dementias with multiple risk factors and pathological processes.

Mild cognitive impairment: earlier diagnosis of Alzheimer’s disease or a syndrome?

There is ongoing controversy as to whether mild cognitive complaints and measurable decline without functional changes are a prodromal stage of AD, or a heterogeneous syndrome of mild depression, small strokes, upper airway obstruction and a host of other causes.

A new instrument has been published in order to better capture subtle cognitive impairment at the physician’s office, the Montreal Cognitive Assessment (MoCA; ref. 1). RCT have shown a predictable rate of conversion to AD in the amnestic subtype of AD, particularly in carriers of the apoE4 genotype (ref. 2). Attempts at symptomatic treatments reveal that patient’s input is quite important in this population (ref. 3), and response to cognitive training has been very encouraging (ref. 4).  

Are mixed dementias more common than Alzheimer’s disease?

There has been a broadening of the concept of "mixed dementias", with the obvious overlap in the neuropathology of Alzheimer’s disease (AD), vascular dementia (VaD), Dementia with Lewy Bodies (DLB) and Parkinson Disease associated-Dementia (PDD). There is also an overlap of vascular risk factors between AD and VaD, and in the response to cholinesterase inhibitors (CI) between DLB, PDD, AD and VaD, in this order of magnitude, as demonstrated by RCT (although only AD has been accepted by regulatory bodies as an indication for CI so far).

Drug treatments of Alzheimer’s disease: are they effective?

Despite the large amount of level I evidence in favor of a small but clinically meaningful effect of CI in mild to moderately severe AD, newcomers to the field challenged the outcome measures used in RCT (ref. 5). This is surprising, in the light of favorable Numbers Needed to Treat of CI relative to other drug treatments in different neurological conditions (ref. 6).

Furthermore there is evidence for benefit in more severe AD using donepezil (ref. 7). Memantine has been shown to exert an anti-agitation effect that many reduce the need for neuroleptics (ref. 7), the neuroleptics being under scrutiny for possible risks of stroke and death (ref. 8).

How can we prove the efficacy of a disease modifying treatment?

Numerous hypothesis on the pathophysiology of AD are being tested simultaneously, including statins, amyloid modification through immunotherapy or a gag-mimetic, or nerve growth factor enhancement. These RCT use parallel groups add-on to CI over 12 to 18 months in mild to moderate AD, looking for divergence of declining curves of cognition, global measures, activities of daily living, and brain volume.

The next "Springfield/Geneva" meeting in April 2006 and ICAD in Madrid mid-July 2006 will hopefully bring positive results on some of these studies, possibly leading the way to secondary prevention in amnestic MCI or pre-dementia stages of AD, where pathological changes may be more responsive to disease-modifying treatment.

Long term primary prevention studies may also become more common, possibly bridging resources between the US, European, Canadian, Australian and the newly constituted Asian Consortia for treatment of AD and related disorders. Studies under way using Gingko Biloba in the US and Europe with incident dementia as primary outcome may become the model to follow.

Translation of knowledge from research to treatment

One of the challenges of evidence-based medicine has been the transfer of knowledge from basic and clinical research to clinical practice. The Canadian Guidelines for the Diagnosis and Management of Dementia will be updated in March 2006, and no doubt other countries will be doing the same exercise, considering the wealth of new information on diagnosis using biological markers and brain imaging, as well as response to treatment from amnestic MCI to severe dementia.

Noteworthy in 2005 was the publication by the Société Française de Gériatrie et Gérontologie of a Consensus Statement on the severe stage of AD (ref. 9).

Conclusions

The year 2005 has been busy with consolidation of knowledge on symptomatic drugs in mild to severe stages of AD. Guidelines for use in primary care are now needed, including clear stopping rules when they are not effective.

References

1. Nasreddine et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. Journal of the American Geriatrics Society 2005; 53 (4); 695-699

2. Petersen et al.  New England Journal of Medicine 2005; 352; 1-10

3. Salloway et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo-controlled trial. Neurology 2004; 63 (4): 651-657

4. Gilbert et al. International Psychogeriatrics 2005; 17 (S2); 241

5. Kaduszkiewicz et al. Cholinesterase inhibitors for patients with Alzheimer's disease: systematic review of randomised clinical trials. BMJ 2005; 331 (7512); 321-327 (Free full text article)

6. Bussière M and Wiebe S. PROGRESS IN CLINICAL NEUROSCIENCES: Measuring the Benefit of Therapies for Neurological Disorders. Canadian Journal of Neurological Sciences 2005; 32 (4): 419-424

7. Feldman H, Gauthier S, et al. Efficacy and safety of donepezil in patients with more severe Alzheimer's disease: a subgroup analysis from a randomized, placebo-controlled trial. International Journal of Geriatric Psychiatry 2005; 20 (6); 559-569

8. Wang et al. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. New England Journal of Medicine 2005; 353 (22); 2335-2341

9. Vellas et al. Consensus statement on dementia of Alzheimer type in the severe stage. Journal of Nutrition, Health and Aging 2005; 9 (5); 330-338