Panel Calls for Biomarkers in Routine Clinical AD Diagnosis
Published: October 10, 2010
Aging Wrkshp: Older Age, HIV, and Antiretrovirals Linked to Neurodegenerative Marker - (10/06/10)
"Older age, HIV infection, antiretroviral therapy, and greater CD4 recovery were all associated with higher levels of phosphorylated Tau (pTau), a marker of neurodegenerative disease, in a small study of people with and without HIV....Older age was associated with higher pTau levels in the entire study group (r = 0.25, P = 0.03), and the correlation was strongest in the antiretroviral-treated group. For every year of life, pTau rose 0.5 pg/mL in people without HIV and 0.8 in people with HIV.....Higher pTau levels correlated with worse prospective memory as measured by the Memory for Intentions Test (MIST) summary score"
* Explain to interested patients that clinicians should try to incorporate biomarker data in their diagnosis of patients with Alzheimer's disease or conditions potentially leading to it, according to an expert panel.
* Note that the group also put forth what it called a "lexicon" to standardize the taxonomy of Alzheimer-related conditions.
Clinicians should try to incorporate biomarker data in their diagnosis of patients with Alzheimer's disease or conditions potentially leading to it, an ad hoc expert panel recommended.
Levels of beta-amyloid or tau proteins in cerebrospinal fluid (CSF), or data from MRI or PET scans using amyloid-specific tracers, should be part of the differential diagnosis of Alzheimer-related disorders, according to two dozen members of the International Working Group for New Research Criteria for the Diagnosis of Alzheimer's Disease.
Led by Bruno Dubois, MD, of Salpetriere Hospital in Paris, the group also put forth what it called a "lexicon" to standardize the taxonomy of Alzheimer-related conditions.
Their recommendations, which would give biomarkers a more prominent role in clinical practice than suggested this summer by a U.S.-based working group, appeared online in Lancet Neurology.
The lexicon's proposed classification scheme included six diagnostic categories: typical, atypical, mixed, prodromal, and preclinical Alzheimer's disease (AD), and mild cognitive impairment. It also proposed criteria for Alzheimer dementia, not as a separate diagnostic category but rather as a critical milestone in disease progression that distinguishes some of their categories from others.
Dubois and colleagues contended that biomarker data was good enough for clinicians to use in diagnosing most of these conditions, mainly excepting mild cognitive impairment.
"This reliable identification of AD biomarkers supports a major change in the conceptualization and diagnosis of AD, because both clinical and in-vivo biological manifestations of the disease can now be integrated into the diagnosis," they wrote. "Laboratory and neuroimaging biomarkers are very highly correlated with the neuropathological lesions of AD."
In an accompanying editorial, Lon S. Schneider, MD, of the University of Southern California in Los Angeles, disagreed that biomarkers were ready for routine clinical use.
"Given the importance of biomarkers in this lexicon, it should be remembered that, although several biomarkers have been correlated with neuropathological changes of Alzheimer's disease, clinical symptoms, and disease stage, none has yet been shown to have clear criterion validity," he wrote.
He said the data on biomarkers do support their use in at least some clinical trials. But, even apart from the currently known biomarkers' diagnostic accuracy, Schneider questioned their clinical utility on practical grounds.
"Clinicians will assess cognitive function before considering lumbar punctures or brain imaging, and will be unlikely to undertake lumbar punctures when patients are asymptomatic or have no clear clinical findings," he observed.
"Although this lexicon is well integrated and conceptually attractive, field trials are needed to establish whether the diagnostic criteria will work effectively in clinical or research situations," Schneider concluded.
The International Working Group's lexicon goes beyond the guidelines proposed in July by another working group assembled by the National Institute on Aging (NIA) and the U.S. Alzheimer's Association (USAA). Those guidelines suggested three broad categories of disease: full-blown Alzheimer's disease, mild cognitive impairment, and a preclinical Alzheimer state.
The NIA/USAA guidelines stated that brain imaging results and CSF biomarkers can be used clinically to diagnose these conditions -- to "improve the certainty" of clinical evaluations -- but stopped short of suggesting they should be required, as the proposal from Dubois and colleagues would do.
The international group's lexicon described the clinical presentations that would go along with biomarker findings for each of the six diagnostic categories.
* Typical Alzheimer's disease: progressive worsening of episodic memory along with less specific abnormalities in executive function, attention, and word-finding.
* Atypical disease: other well-recognized presentations associated with autopsy-confirmed disease that differ from the typical pattern. "These include non-amnestic focal cortical syndromes, such as primary progressive nonfluent aphasia, logopenic aphasia, posterior cortical atrophy, and frontal variant [disease]," Dubois and colleagues wrote.
* Mixed disease: features of typical or atypical Alzheimer's disease occurring alongside other sources of dementia such as cerebrovascular disease or Lewy body infestations.
* Alzheimer dementia: not intended to be separate from the above types of Alzheimer's disease, but included as an entity in the lexicon "to identify the dementia threshold as a severity milestone in the source of the disease," Dubois and colleagues indicated. The onset of frank dementia "adds a set of management issues for clinicians to address," and hence deserves its own diagnostic focus, they argued.
* Prodromal disease: early episodic memory loss of the hippocampal type, absent a dementia diagnosis but accompanied by Alzheimer-associated biomarkers.
* Preclinical-asymptomatic disease: clinically normal, but Alzheimer-related CSF or imaging markers are present.
* Mild cognitive impairment: any clinical presentation involving cognitive changes that may or not resemble prodromal Alzheimer's disease and can be diagnosed if biomarkers are negative. It is also the category for patients with positive biomarker findings and mild cognitive symptoms that do not fit the Alzheimer prodrome.
Dubois and colleagues acknowledged that the association with biomarkers in some of these categories -- such as atypical disease -- has not been confirmed to the same degree as for classic Alzheimer's disease.
They also recognized that lumbar punctures and expensive high-tech imaging may not be feasible to use on all patients with cognitive deficits, particularly in the absence of regulatory approvals and the insurance reimbursements that depend on them.
In general, they said, the recommendations should be more immediately applied in clinical research.
Still, Dubois and colleagues also indicated that clinicians should follow suit as soon as practical.
One aim of publishing the lexicon now "is to provide clinicians with a clear view of this evolving field in which use of biomarkers is advancing and might reach regulatory qualification and approval in the foreseeable future."
It's important, Dubois and colleagues wrote, "to keep the research and clinical view of the disease from becoming too widely separated."
But Schneider questions how much clinical utility the CSF markers and brain imaging data would actually provide in routine practice, issues of cost and patient acceptance notwithstanding.
"Data from several cohort studies suggest that more than 70% of patients diagnosed with mild cognitive impairment due to Alzheimer's disease and 90% of patients with Alzheimer's disease dementia had positive amyloid biomarkers, including 90%Ð100% of the apolipoprotein E epsilon-4 carriers," he pointed out.
Dubois and colleagues noted that their work was necessarily provisional.
"This lexicon is a proposal that will require revisions and updating by the scientific community," the researchers stressed.
One apparent oddity in their scheme was a subgroup they offered within the preclinical category, dubbed "presymptomatic." These are healthy individuals without CSF markers or brain imaging abnormalities but who possess a genetic mutation that inevitably leads to Alzheimer's disease.
This is currently a hypothetical group, because such a mutation, if one exists, has not yet been discovered in several genome-wide scans of large numbers of individuals. The APOE epsilon-4 variant is strongly predictive of Alzheimer risk but not "fully penetrant" -- a significant minority of homozygous carriers do not develop Alzheimer's disease, indicating that the genotype, by itself, is insufficient to cause the disease.
In fact, Dubois and colleagues did not include a role for apolipoprotein E genotype status in their diagnostic criteria.
Some researchers have suggested that additional searches for fully penetrant mutations would likely be fruitless and that any success would apply only to the few individuals who possess such rare mutations.
Eisai provided meeting space during development of the recommendations.
Dubois reported consulting or advisory relationships with Bristol-Myers Squibb, Novartis, Roche, Elan, Eli Lilly, Eisai, GE Healthcare, Janssen, and sanofi-aventis. His employer has received grants from several of these firms. Other co-authors reported relationships with these and other firms including Merck, AstraZeneca, Lundbeck, Neuropharma, Pfizer, Servier, Abbott, Forest, GlaxoSmithKline, Myriad, Schering-Plough, UCB, and others.
Schneider reported consulting relationships with Abbott Laboratories, AC Immune, Allergan, Allon, AstraZeneca, Bristol-Myers Squibb, Elan, Eli Lilly, Exonhit, Forest, GlaxoSmithKline, Ipsen, Johnson & Johnson, Lundbeck, Myriad, Medavante, Medivation, Merck, Merz, Novartis, Pfizer, Roche, sanofi-aventis, Servier, Toyama, and Transition Therapeutics, and research funding from Baxter, Ban, Johnson & Johnson, Lilly, Myriad, Novartis, and Pfizer. He has also received grants from the Alzheimer's Association and discussed the lexicon manuscript with Dubois and colleagues before its publication.
Primary source: Lancet Neurology
Dubois B, et al "Revising the definition of Alzheimer's disease: a new lexicon,"
Lancet Neurology 2010; DOI:10.1016/S1474-4422(10)70223-4.
Additional source: Lancet Neurology
Schneider L, "Organising the language of Alzheimer's disease in light of biomarkers," Lancet Neurology 2010; DOI:10.1016/S1474-4422(10)70246-5.