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 di
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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