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Mild Cognitive Decline, Alzheimer Disease and other common dementias Torna agli editoriali

Anna Giulia Cattaneo
DBSM, University of Insubria, Varese.

This Editorial is intended to compare and update modern trends for early recognition of Alzheimer disease (AD) and differentiation of it from other dementias, in they're early and sub clinical phase, mild cognitive impairment (MCI).

Alzheimer Disease (AD) develops in humans in two forms, different for their early or late onset in individual life. Regional, and namely parieto-temporal and posterior cingulate gray matter loss are nearly exclusive of the early-onset form (EOAD). Metabolic impairment localized to the temporal gyrus is heavier in EOAD than in dementias, namely those due to frontotemporal lobar degeneration. Also seizures are more frequent and more severe in subjects suffering from EOAD.

In general, and independently from the age of onset, AD in its clinical form is a complex cognitive impairment involving visual and spatial memory, as well as episodic memory. Speech presents similarities with fluent aphasia, however lexical encoding seems to be poorer in AD, up to the highest degree of disturbance, known as "empty speech". The defects start in the hippocampal region: volumetric decrement in the CA1 hippocampal area have been found accompanied by an altered feedback of the hypothalamic-hypophysis-adrenal axis, and both defects are linked to specific mental impairment present in AD.

However, the most invalidating symptoms are preceded by a sub clinical period of MCI. MCI seems to be a critical period to prevent or reduce progression of cognitive decline, however adoption of efficacious preventive measures is counteracted by the lack of sensitive and specific tests for early differential diagnosis between true AD and other type of dementias sharing a prodromal MCI period. In other words, we are today in search of a "gold standard" for diagnosis of AD in its earlier stage, MCI.

New and interesting perspectives have been opened by recently introduced biomarkers, and by bio imaging: unfortunately studies in these sectors are ongoing and incomplete.

The state of art of clinical and psychiatric testing for mental impairment seems to be controversial under this point of view. To be predictive, diagnostic tests need very high specificity and sensitivity for the disease to be investigated. At the present geriatrics specialists can use of a variety of well-standardized test batteries, useful in diagnostic assessment of the AD in its symptomatic stage, or in the prodromal stage. However the cognitive tests specific for symptomatic AD, like the AD Assessment Scale (ADAS), lack sensitivity when applied in the MCI phase. In the preclinical stage of dementias, the MCI, the test most widely used is the Mini Mental State Examination (MMSE) and its modifications. The MMSE score derives from a combination of tasks measuring comprehension, reading, writing and drawing abilities. Its major advantage is the high degree of standardization and possibility to computerize data for large-scale analysis. However, the MMSE lacks specificity and predictive power concerning the risk of subsequent development of AD.

Recently the efforts to ameliorate the performance of predictive procedures have been focused on test able to recognize cognitive failures that are specifically present in different types of dementias. In this regard, in early recognition of AD the more general MMSE scores much lower than the Travelling Salesman Problem, a computerized item specifically intended to test spatial memory by scoring the ability to join separated points on a map. Interestingly, a similar test performed in a real space (a round chamber in which the patient's motions can be registered and analysed) gave similar results.

Authors generally agree that combination of more items, and even multidisciplinary investigations, seems to represent the most valuable mean to reach the focused aim.

Between test batteries for psychological and cognitive assessment, a very promising one is that of the CERAD NAB, the Consortium to Establish a Registry for Alzheimer's Disease - Neuropsychological Assessment Battery. The complete item associates the MMSE with subset of language testing and results in a sensitive means to differentiate frontotemporal dementia from semantic dementia and from AD at their onset.

A short neuropsychological screening for dementia (DemTect, Dement Geriatr Cogn Disord (2005), 20: 271-7) have been recently proposed and its validation reported in comparison with (18)FDG PET, but the lack of specificity suggests that this test could be interesting for rapid and wide screening as needed in population studies, more than for clinical early diagnosis.

Between multidisciplinary testing, advanced imaging techniques and selective genetic biomarkers associated to psychological selective tests are the preferred choices.

Standardized neuropsychological testing added to MRI of the medial temporal lobe show highly specificity and sensitivity: both the two diagnostic procedures used separately score significantly lower. This association has proved useful in differentiating early AD from vascular dementia and normal aging

Between genetic biomarkers, the apolipoprotein E epsilon 4 allele seems to be a promising one, scoring very highly in association with the sophisticated and costly technique of imaging, (18)F-fluorodeoxyglucose Positron Emission Tomography (FDG PET), but even with the most affordable multicentric electroencephalography.

In summary, the way to an early diagnosis of AD is open, and the search for tests specific and sensitive for the disease when it does not differentiate from other forms of mild cognitive impairment moves its first successful steps.The "gold standard" for diagnosis and prediction of evolution is far from acquired. A careful combination of accurate and focused neuropsychological assessment with other functional tests, like imaging or electroencephalographic fingerprinting, seems to be the most promising procedure in a near future.

However the development of studies on predictability of biomarkers should be taken into account. Genetic and phenotypic assessment should open new perspectives in recognizing individuals or groups at risk of developing AD in a very early and symptom-free phase, when sensitivity to treatment could be high. A radical change in considering and treating this frequent and burden disease could follow to a better understanding of its basic defect, undetectable at the present time/

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