2006 overview: Developments in dementia diagnosis and treatment

There has been progress in the diagnosis and management of Alzheimer's disease (AD) and related disorders in 2006, based on evidence from randomized clinical trials (RCT) using symptomatic drugs as well as disease-modifying drugs (DMD). The 100th anniversary of the description of AD was emphasized in a number of journals e.g. Brain (ref. 1).

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

An overview of the field of MCI has been published by Gauthier et al. (ref. 2) after an expert conference of the International Psychogeriatric Association. Since there is agreement that MCI is not a distinct clinical entity but rather a risk state for progression towards dementia, there is an effort underway led by B. Dubois to update the classic diagnostic criteria for probable AD (ref. 3) to include a pre-dementia stage of AD, which would take into account amnestic MCI plus a surrogate marker to be agreed upon. This approach is supported by recent neuropathological evidence in MCI (ref. 4).

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

A placebo-controlled pivotal study of donepezil in a nursing home setting (ref. 5) has demonstrated benefit on cognitive and global outcomes (albeit not on behavior), a key consideration in the extension by the FDA of the regulatory label of donepezil in severe stages of AD.

How best to assess efficacy of symptomatic drugs in AD?

A novel approach to assessing treatment benefit using goal attainment scaling (GAS) has been used in a RCT comparing galantamine to placebo in mild to moderate AD (ref. 6). GAS can be used in RCT as well as in daily clinical practice. Non-cognitive benefits of cholinesterase inhibitors and memantine have also received emphasis this year (ref. 7), and their ability to reduce the need for treatment with psychotropic drugs such as neuroleptics is a component of new RCT in moderate to severe AD.

How can we prove the efficacy of a disease modifying treatments for Alzheimer’s disease?

There is an ongoing effort at establishing if certain treatments can truly modify disease progression in AD. Regulatory perspectives have been discussed by C. Sampaio (ref. 8), and academic perspectives by J. Cummings (ref. 9), S. Gauthier (ref. 10) and L. Thal (ref. 11). While there is relative consensus on the clinical outcomes in RCT, favoring measurement tools with a relatively linear decline over 18 months, there is uncertainty on the non-clinical outcomes to support disease modification such as delay in rate of atrophy of whole brain versus regions such as the hippocampal formation using MRI, or changes in biological markers in CSF (ref. 12). Early in 2007 results from the North-American study using 3APS (tramiprosate, Alzhemed) will be available, allowing a critical review of the clinical and non-clinical outcomes in RCT for DMD. Results from Phase II study of 3PS are now available (ref. 13).

How should we treat Parkinson Disease Dementia?

The pivotal study by Emre et al. (ref. 14) comparing rivastigmine to placebo has contributed greatly to the approval of rivastigmine for the symptomatic treatment of Parkinson Disease Dementia (PDD) by European and US regulatory authorities. Management guidelines for PDD have been published by members of the Dementia with Lewy Bodies (DLB) consortium, lead by I. McKeith (ref. 15) and are reaching family practitioners so that they may be aware of common neuropsychiatric complications of PD (ref. 16). The Movement Disorder Society is preparing positions papers on the diagnosis and management of PPD in clinical practice.

Is prevention of AD and vascular dementia possible?

There is an increasing interest in testing prospectively interventions in populations at risk of dementia (ref. 17). Options range from strict control of systolic hypertension (ref. 18) to the Mediterranean Diet (ref. 19), and exercices for the body and the mind. The ongoing RCT using Gingko Biloba  over 5 years (ref. 20) or 7 years (ref. 21) will likely be the model to follow in future RCT where the intervention will be tailored to the risk.

Conclusions

There is a realistic possibility that amyloid-controlling drugs such as tramiprosate and
R-flurbiprofen will act as DMD. It is also possible that such drugs will be effective in a distinct sub-group of persons with AD, based on phenotype (such as age of onset of symptoms, rapidity of progression, disease stage at onset of treatment) and genotype (apoE in particular).

The availability of evidence-based criteria for responders to DMD will hopefully obviate the need for arguments about cost-benefit which is delaying access of patients to currently available symptomatic drugs (ref. 22). It is also possible that combinations of cognitive training (ref. 23) and symptomatic drugs (ref. 24) will amplify the clinical benefit.

References

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