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Page 320 Kapaki et al. Neuroimmunol Neuroinflammation 2020;7:319-29 I http://dx.doi.org/10.20517/2347-8659.2019.26
[2]
[3]
AD patients may present with mild cognitive impairment , or may even be asymptomatic . When
[4,5]
symptomatic, amnestic dementia of the hippocampal type is the typical presentation . However, atypical
presentations are not infrequent, especially in presenile patients, including frontal-predominant, language-
[4,5]
predominant, “posterior” or mixed presentations . Such presentations may lead to diagnostic confusion,
[6]
whilst even the typical hippocampal amnestic presentation may occur in non-AD disorders . Thus, clinical
presentations or phenotypes are rather viewed as syndromes, and they are by no means synonymous with
a specific disease. Various types of biomarkers may be helpful in the diagnostic approach of such typical or
atypical presentations, and they have been incorporated in various diagnostic criteria for AD [2,4,5] .

Recently, the National Institute of Ageing and Alzheimer Association (NIA-AA) Research Framework
group recommended a system for classifying subjects/patients on the basis of their biomarker profile, since
[7]
it may result from different biomarker categories, especially neurochemical and imaging . The objective
was to update a scheme for defining and staging AD mainly across its entire spectrum, to be used for
research purposes, either observational or interventional. A further shift in thinking is the separation of
the syndrome from the disease, as symptoms are considered part of the disease continuum and not its
definition. Looking towards a biological definition of AD, as it is identified post mortem by accumulation
of amyloid-β and tau and reflected in vivo by biomarkers, the group discriminates them according to
their molecular specificity [i.e., amyloid-β (Aβ) and pathological tau (phospho-tau)]. For this scope, they
[7]
propose the AT(N) system , where A stands for amyloid-β plaques or associated pathological state, T for
aggregated hyperphoshorylated tau or associated pathological state and (N) for neurodegeneration. The
parentheses are to indicate that it represents cumulative brain injury/neurodegeneration from all etiologies
and is not specific for any certain etiology. A (C) component is used to define mental decline and staging,
from cognitively unimpaired to mild cognitive impairment and finally dementia, according to cognitive
symptoms and neuropsychological testing. Thus, each biomarker category can be dichotomized as positive
(+) or negative (-), resulting in eight different biomarker profiles and 3 “biomarker categories”: normal
[A-T-(N)-], Alzheimer’s continuum [A+T-(N)-, A+T+(N)-, A+T+(N)+, A+T-(N)+] and suspected non-AD
[7]
pathological change [A-T+(N)-, A-T-(N)+, A-T+(N)+] .

Here, we present a case series of six patients with different types of cognitive disorders using this system.
Cases were selected with the only criterion being that they were educationally useful and interesting
for clinicians and medical students, and all co-authors helped in the selection of cases, in an unblinded
manner. We describe their clinical, imaging and cerebrospinal fluid (CSF) biomarker data and how these
could be suggestive of diagnosis, according to the AT(N) system. All patients were analyzed routinely in
our department as part of the everyday diagnostic approach and they were not included in any particular
study.

Lumbar puncture was performed at 10-11 am, after overnight fasting, at the L4-L5 interspace, according to
[8]
recently proposed recommendations on standardized operating procedures (SOPs) for CSF biomarkers ,
[9]
as described elsewhere . In brief, 4 polypropylene tubes were used for CSF collection. The initial tube
(2 mL) was used for routine cytology and biochemistry and the 2nd tube (2 mL) was used for
determination of IgG index, oligoclonal bands and for syphilis serology. The last 2 tubes (5 mL each) were
immediately centrifuged, aliquoted in polypropylene tubes (750 μL each) and, finally, stored at -80 °C until
analysis. Aliquots were thawed only once, just before analysis, which was performed within 6 months of
storage.

CSF levels of total tau protein (τ ), amyloid-β peptide and tau phosphorylated at threonine-181 (τ P-181 ) were
T
measured blindly, in duplicate by double-sandwich, enzyme-linked immunosorbent assay (ELISA) using
commercially available kits (Fujirebio, Gent, Belgium) according to the manufacturer’s instructions, as
[9]
previously described . In-house standards were used during every to ensure minimal measurement error