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Valor de la cuantificación plasmática de neurosina en el diagnóstico diferencial de las demencias

by Menendez, Manuel, MD


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Utilidad de la cuantificación plasmática de neurosina en el diagnóstico diferencial de las demencias

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VIII. ENGLISH SUMMARY
Dementia is one of the most common causes of institutionalization,
morbidity, and mortality among the elderly. As life expectancy increases, the
number of people affected by dementia also increases. The diagnosis of the
different causes of dementia remains based on clinical criteria which allow a
“probabilistic” diagnosis once other causes of cognitive impairment have been
discarded. Furthermore, symptoms of different dementias overlap with each other
and even with some psychiatric disorders with cognitive symptoms thus
complicating differential diagnosis. It is estimated that by the time a patient is
diagnosed with any neurodegenerative dementia, the disease has been progressing
for many years. Mild Cognitive Impairment (MCI) is a disorder considered to be a
transitional stage from health to dementia. Diagnosis of dementias at these early
stages is always troublesome because the pathophysiologic events leading to
dementia precede clinical symptoms. For these reasons the search for molecular
biomarkers that allow classifying different types of dementias is of high importance.
During recent years the number of studies that describe the potential value
of several proteins to diagnose or predict outcome of different types of dementias
have increased exponentially. One of such markers is neurosin (Kallikrein 6).
Neurosin is a “trypsin like” serine-protease expressed mainly in the brain. Previous
studies suggested that neurosin is a potential biomarker for Alzheimer’s disease
(AD) since its levels in brain tissue, CSF, and blood appear to be altered in AD.
However, the sensitivity and specificity of plasmatic neurosin in AD and other
dementias remain to be determined.
To address this gap in knowledge and test the value of measuring the levels
of neurosin as a diagnosis tool for MCI, AD and other dementias, we investigated
the correlation between plasmatic levels of neurosin and the final diagnosis of
patients with cognitive symptoms. Thus we measured plasmatic levels of neurosin
in healthy individuals and patients with cognitive symptoms independently of what
the final diagnosis was.
We collected plasma samples from 228 controls and 447 patients diagnosed
with either AD, Mild Cognitive Impairment MCI), Dementia with Lewy Bodies or
Parkinson-Dementia, Frontotemporal Dementia, Huntington’s disease, Primary
Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakob’s disease and
Pseudodementia. Sixty six MCI patients were observed for 18 months and then
plasmatic neurosin was measured again in 36.
Plasmatic levels of neurosin increase with age in healthy individuals and
decrease in patients with AD. Plasmatic levels of neurosin differ significantly
between AD and Dementia with Vascular Component, Pseudodementia and the

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control group. Analyses comparing any other form of neurodegenerative dementia
to the AD group did not show significant differences. The mean value of plasmatic
neurosin concentration differs significantly between MCI patients who converted to
Dementia with Vascular Component, those who converted to AD, and those who
remained at MCI stage. The risk of developing Dementia with Vascular Component
when neurosin levels are higher than 5.25 ng/ml is very high (Odds ratio 13) while
the risk of developing mild AD when neurosin levels are lower than 5.25 ng/ml is 2.
Increases in the levels of neurosin suggest progression to Dementia with Vascular
Component.
In conclusion, the measurement of plasmatic levels of neurosin is a useful
diagnostic tool to assist in distinguishing AD patients from subjects without
neurodegenerative dementia (either Pseudodementia, Vascular Dementia or
controls) although it is not useful to distinguish different types of
neurodegenerative dementias. The measurement of plasmatic neurosin
concentration in patients diagnosed with MCI may predict conversion from MCI to
Dementia with Vascular Component. A single measurement may be useful to
estimate the risk of developing AD and Dementia with vascular component. Finally,
repeated measurement of plasmatic neurosin might be a useful test to predict
outcome in patients with MCI.

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IX. ANEXO

Los estudios de esta tesis doctoral han dado lugar a la publicación de dos
artículos científicos en revistas internacionales, centrados en las entidades donde
los resultados han mostrado mayor utilidad: la Enfermedad de Alzheimer y el
Deterioro Cognitivo Leve. Las referencias se citan a continuación:

Menendez-Gonzalez M, Castro P, Suarez A, Calatayud MT, Perez-Pinera P,
Martinez M, Ribacoba R, Gutierrez C. Value of measuring plasmatic levels of
neurosin in the diagnosis of Alzheimer’s disease. Journal of Alzheimer’s
disease. 2008;14(1):59-67.

Menendez-Gonzalez M, Castro-Santos P, Calatayud MT, Perez-Pinera P,
Ribacoba R, Martinez-Rivera R, Gutierrez C, Lopez-Muñiz A, Suarez A.
Plasmatic level of neurosin predicts outcome of Mild Cognitive Impairment.
Int Arch Med. 2008;1:11.

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