Cognitive assessment in Alzheimer’s disease

Vol.2, No.4, 123-125 (2013) Advances in Alzheimer’s Disease

http://dx.doi.org/10.4236/aad.2013.24016

Cognitive assessment in Alzheimer’s disease*

Mario A. Parra

Human Cognitive Neuroscience and Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh,

Alzheimer Scotland Dementia Research Centre and Scottish Dementia Clinical Research Network, Edinburgh, UK;

mprodri1@staffmail.ed.ac.uk

Received 31 May 2013; revised 12 July 2013; accepted 20 July 2013

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

No effective treatments are currently available to tackle

Alzheimer’s disease (AD), yet there seems to be a grow-

ing consensus in support to prevention initiatives [1-4].

This poses important challenges to the scientific com-

munity as prevention entails at least two targets, early

detection and effective treatments neither of which meets

current needs. Regarding the latter target, recent failures

in clinical trials have led to question whether the under-

taken treatments have been too little or too late [2,4].

This question seems to emerge from current under-

standing of the neuropathological changes underlying

AD, which suggests that anti-amyloid treatments might

need to be administered earlier than we thought [1].

However, to achieve this we first need to identify who

could be suitable for such prevention trials and this re-

quires early detection. Significant progress has been

made in the area of biomarkers for AD, yet available

tests still face important challenges [5-8]. Less has been

done in the area of cognitiv e markers for AD, albeit cog-

nition plays a fundamental role in the disease diagnosis,

prognosis and follow up. The present short communica-

tion aims to reflect on current approaches to cognitive

assessment in AD and the extent to which the conundrum

“too little, too late” also applies to the early detection of

cognitive impairments in this form of dementia.

Traditional assessment of cognitive functions in AD

has largely focused on episodic memory. This tendency

has been driven by neuropathological evidence which

suggests that regions within the medial temporal lobe

known to be crucial from long-term memory formation

are affected by AD since very early. However, episodic

memory, as assessed by available tests, reveals impair-

ments which characterize the rather advanced stages of

the disease. It might be that for AD-related episodic me-

mory changes to reach the pathological threshold of

these tests, substantial damage to th e hippocampus needs

to accumulate because this structure and associated func-

tions also decline as part of the normal aging process.

Distilling age-related and AD-related decline of hippo-

campal functions is a subject which requires further re-

search. Moreover, the negative results currently reported

by clinical trials might also rest, at least in part, on the

outcome measures used to assess memory functions. The

disease mechanisms tackled by available drugs (e.g.,

anti-amyloid compounds) might impact on brain regions

and functions different from those taxed by available

episodic memory tests [9-11]. Episodic memory tests

might be unveiling the impact of advanced pathological

changes (e.g., Tauopathy and tangle formation; [12]).

Memory tests capable of detecting the impact of earlier

mechanism s woul d be desi red (see Sperling et al. [13]).

In a recent hypothesis paper, Didic et al. [14] proposed

a novel approach which calls for a new conception of

memory assessment in AD. In their paper, the authors

addressed the question of which memory system is im-

paired first in AD. They suggest a model which sees the

hippocampal damage as a rather late consequence of AD.

In the model, a subhippocampal phase precedes the hip-

pocampal damage in the neurodegenerative course of AD.

Interestingly, the hippocampal phase seems to corre-

spond to the Braak’s stages III-IV while the subhippo-

campal phase reflects earlier pathological stages (I-III),

thus suggesting that memory tests capable of detecting

this phase would be more promising in the early detec-

tion of AD. They suggest that tests measuring con-

text-free memory (e.g., item memory, familiarity based

recognition) as opposed to tests measuring context-rich

memory (e.g., inter-item association, freed and cued re-

call), appear to be promising candidates (see Wolk et al.

[15] for recent evidence). This proposal is appealing as

regions supporting item memory and familiarity based

recognition fall outside the hippocampus and map well

onto areas known to be affected by amyloid-induced

changes early in the course of AD (e.g., entorhinal cortex,

perirhinal cortex, parahippocampus, and regions within

the visual ventral stream; [9,12,14]). There is now ac-

crued evidence suggesting that the neuropathological

changes accompanying AD spread through these extra-

*Mario A Parra’s work is currently supported by Alzheimer’s Society,

UK.

M. A. Parra / Advances in Alzheimer’s Disease 2 (2013) 123-125

124

hippocampal regions in the very early stages of the dis-

ease [16-22]. Of note, whereas healthy aging impacts on

the hippocampus, it seems to spare these extra hippo-

campal regions which are affected by AD [23-25]. Hence,

memory tests assessing the functions supported by these

regions would help detect early AD-related changes not

accounted for by age.

A recent methodology, namely short-term memory

binding (STMB), adheres to this new conception of

memory assessment in AD. STMB refers to the cognitive

function responsible for retaining, on a temporary basis,

intra-item features thus contributing to the formation of

objects’ identity. This function has been investigated

using a change d etection task during which the examinee

judges whether arrays of shapes, colors or shape-color

combinations presented in two sequential screens are the

same or different. STMB has proved insensitive to

healthy aging [26,27] but very sensitive to AD [28,29].

AD seems to impact on STMB much earlier than on

other memory functions [28,30]. Relative to other de-

mentias and depression, STMB declines only in AD

[31,32]. A recent fMRI study confirmed that STMB does

not rely on the hippocampus but it does recruit regions

within the visual ventral stream [33]. Interestingly, recent

studies carried out in the asymptomatic population of

carriers of the mutation E280A of the PSEN1 gene [34]

who will go on to develop familial AD with 100 % prob-

ability and who had previously shown STMB deficits at

a mean age of 35 [28,30], suggest that amyloid changes

are the most prominent pathological feature of this pre-

clinical stage [35,36]. Based on the evidence reviewed

above, the STMB task appears to be taxing the subhip-

pocampal phase of AD [4].

A shift in the concep tion of early cognitiv e assessment

of AD and of the tools necessary to undertake this task is

already due. Current revised guidelines continue to em-

phasize on tests that assess the hippocampal phase of AD

(e.g., associative learning, cued recall, etc.) despite they

detect changes late in the course of the disease and are

sensitive to a number of unwanted factors (e.g., age,

cognitive reserve, and other individual differences). Fu-

ture assessment of AD should focus on theory-driven

tests which tap into specific cognitive domains and are

insensitive to confounding factors. More effort will be

required in the forthcoming years to further investigate

the usefulness of tests of subhippocampal memory func-

tions in the prediction of AD among the elderly popula-

tion. Such tests would become screening tools to detect

individuals at risk who could then be referred to preven-

tion programs.

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