Biological markers in amyotrophic lateral sclerosis: help or hindrance?
Walter G. Bradley
Biological markers play an important role in the development of the understanding of a disease, its diagnosis and treatment. This is particularly true of amyotrophic lateral sclerosis (ALS) at this time. We need better biological markers for the diagnosis, for improved understanding of the underlying pathogenetic mechanisms, and for assistance in new drug development. This review of currently available biological and surrogate markers in ALS discusses novel approaches to the use of such markers, and new drugs for the treatment of ALS.
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This review will consider the role of biological and
surrogate markers in the diagnosis of amyotrophic lateral
sclerosis (ALS), in measuring disease progression during
therapeutic trials in ALS, and in developing potential new Use of biological markers in the diagnosis
therapies for the disease. A biological marker is an indi- of patients with symptoms suggestive of ALS
cator of a change associated with the disease, and can be
either a marker of the direct cause of the disease or a sec- If there is a known family history of similar disease in a
ondary effect. Currently the primary underlying cause or patient presenting with signs and symptoms suggestive of
causes of ALS are unknown, although many biological ALS, genetic techniques may be able to establish the
dichanges resulting from the disease process have been rec- agnosis. These can screen for mutations of known genes
ognized. The cascade of biochemical changes occurring such as the SOD-1 gene in familial ALS. If the
chromowithin the motor system in ALS leads eventually to de- somal localization but not the actual gene is known,
linkgeneration of the lower and upper motor neurons (LMNs age to other genes and haplotype analysis can be used.
and UMNs), and it is this degeneration which is responsi- The diagnosis of ALS in the early stages can be
diffible for the clinical symptoms and signs of the disease. cult because there may not be clear evidence of both
Ideally, we should use direct evidence of motor neuronal UMN and LMN involvement and of multi-level damage.
degeneration as the primary biological marker in studies Biological markers can be used to clarify the diagnosis.
of ALS, but since brain or spinal cord biopsies cannot be Evidence of LMN denervation on electromyography can
obtained we are forced to use secondary or surrogate assist in confirming the diagnosis of ALS in a patient with
markers. clinical signs that are purely restricted to the UMN.
Simi
The term surrogate marker is frequently used in dis- larly, magnetic resonance imaging (MRI) evidence of
corcussions about biological markers. A surrogate marker is ticospinal tract degeneration or evidence of UMN
dysa substitute for another marker, with the implication that function as indicated by 1H-magnetic resonance
spectroscopy (1H-MRS) can be used to demonstrate UMN in- cons. Unfortunately, such tests cannot separate
dysfuncvolvement in a patient with signs restricted to the LMN tion due to UMN impairment from that due to LMN; this
[2]. Unfortunately, neither technique for the detection of increases the variability and complexity of interpretation.
UMN involvement is sensitive since clinical signs usually The final gold standard of disease progression in ALS
antedate the appearance of MR abnormalities. is respiratory vital capacity, which also has generated an
Theories of the etiology of ALS abound, based upon extensive literature. It is subject to significant variation
biochemical abnormalities noted in patients or the biolog- over time, and like all motor measurements, is affected by
ical products derived from those patients. Biological mark- both LMN and UMN impairment.
ers which have been advanced as potential surrogate 1H-MRS quantification of motor cortex and brainstem
markers for the diagnosis of ALS include increased levels NAA has been shown to decrease with time and
progresof glutamate in the cerebrospinal fluid (CSF) and blood, sion of ALS. The ability to demonstrate a significant
benoxidative products in the blood, abnormal splicing variants eficial effect of 3 weeks treatment with riluzole on NAA/
of mRNA from EAAT2 (GLT1) in the CSF, DNA repair Cr ratios in the motor cortex of ALS patients has been
reenzyme defects in cells, and changes of 1H-MRS in levels ported [5, 1, 3]. Statistically significant results were
obof N-acetyl aspartate (NAA) and glutamate [5]. tained in a study involving 11 riluzole-treated patients and
12 untreated patients [3]. However, we have been unable
to substantiate this finding [2].
Use of biological markers The major problem for clinical trials in ALS is the
biin measuring disease progression ological variability of the disease. Some patients die
within therapeutic trials of ALS in a month of onset if the respiratory muscles are the
initial sites of affliction, while others may live for decades.
One of my patients has had the disease for 37 years, and
A positive therapeutic trial of an agent ef (...truncated)