The utility of cerebrospinal fluid biomarkers of Alzheimerâ€™s disease
The clinical-investigative approach to patients with cognitive impairment differs substantially between specialized dementia consultations and general neurology clinics where the clinical approach and the practical application of recommendations from neurologist specializing in dementia prevail. One example in this context is the use of both MRI and CSF biomarkers for the characterization of amnestic MCI as prodromal AD. This approach is likely to provide added value to the quality of care of patients with cognitive impairment.
Although MCI is an entity with multiple aetiologies and an annual rate of progression to clinical dementia of 7-10%, there are currently no approved pharmacological treatments for this progressive phase of dementia. The clinical and therapeutic benefit of using biomarkers in MCI to determine whether it is due to AD is tremendous, as it allows identifying AD in its prodromal phase and justifies the initiation of treatment with acetylcholinesterase inhibitors (ACEI) in these patients in order to try to slow down disease progression.
Cognitive tests commonly used to assess episodic memory in patients with cognitive impairment were of no use for identifying amnestic MCI when the physiopathogenesis was due to AD. Our study focused on the application of MAT, and we found no differences between groups and no associations with CSF biomarkers or medial temporal atrophy on MRI.
MRI functions as a biomarker of MCI-AD, allowing identifying neuronal damage, atrophy of the cerebral cortex and parenchyma, and the presence of ischemic lesions that may contribute to the progression of cognitive impairment. In general neurology clinics, there is limited access to neuroimaging studies that use three-dimensional software to assess hippocampal volume, which is decreased in amnestic MCI and AD, but not in multi-domain MCI . However, the detection of medial temporal lobe atrophy using the easy-to-apply Scheltens visual rating scale has proved useful for the diagnosis of AD , and MTA has been correlated with progression to dementia in MCI . In our daily clinical practice, we use the Scheltens scale to assess the degree of hippocampal and medial temporal lobe atrophy. However, in our series, it proved of little use to identify patients with MCIAD, in that more severe atrophy was not associated with a decreased MAT score or Hulstaert index. Another approach to assessing neuronal damage which we used in our study relies on CSF biomarkers, specifically elevated levels of total and phosphorylated Tau protein, the latter adding specificity to the diagnosis of AD.
We use imaging techniques such as PiB-PET, which is currently restricted to a few tertiary care/research centres to assess the physiopathological process of cerebral amyloid deposition. Though more accessible, the determination of CSF levels of β-amyloid 1-42 also involves more invasive methods. This biomarker is decreased in patients with AD, which is attributed to its deposition in cerebral amyloid plaques. It is well known that CSF biomarkers are also altered in patients with MCI who progress to dementia during follow-up . In our series, although the behaviour of biomarkers showed the involvement of the two pathogenic pathways involved in AD (amyloid and Tau protein), what was most interesting from a clinical viewpoint was the index that correlates β-amyloid peptide with total Tau protein, known as the Hulstaert index, and p-Tau levels, since both allow to classify amnestic MCI as prodromal AD. In this regard, previous international  and national  publications have shown that the combination of biomarkers is a highly accurate and specific predictor of progression from MCI to dementia.
Patients with MCI-AD tended to have a more extensive family history of dementia, but the difference was not statistically significant. However, the ApoE genotype was discriminative, in that the ε4 allele was more prevalent in the MCI-AD group. This supports the diagnostic probability of presenting with AD based on the increased relative risk conferred by the presence of this allele in the context of dementia  and highlights the predictive value of MCI progression to AD .
The diagnostic procedure allowed starting ACEI treatment (which is not approved in MCI) early in about 90% of the patients, in combination with cognitive stimulation therapy. However, current evidence does not support treatment with donepezil, rivastigmine or galantamine to prevent the progression of MCI to clinical dementia , although it should be noted that patients in these studies were selected solely on the basis of clinical criteria and not based on biomarkers. Part of the current therapeutic approach focuses on treating aggravating factors of cognitive decline such as depression and cardiovascular risk factors, especially hypertension, which requires more focus and emphasis in patients with MCI-AD. In addition, while donepezil could be effective in the cohort of patients with MCI associated with depression , this aspect was not adequately assessed in our study, since we did not make strict enough use of scales validated for the diagnosis of depression to allow conclusions to be drawn in this regard.
Our study, which was conducted under conditions of daily clinical practice, allows concluding the following: 1) amnestic MCI can be classified as prodromal AD based on the use of AD biomarkers in the CSF and the presence of at least one ApoE ε4 allele. 2) the assessment of medial temporal atrophy with a visual rating scale does not allow to differentiate patients with MCI-AD from those who do not have a pathogenesis characteristic of AD, and 3) the identification of prodromal AD allows early initiation of specific ACEI treatment.
Journal of Neurology and Clinical Neuroscience