lzheimers disease (AD) is the main cause ofdementia and accounts for two thirds of dementia syn-dromes in people older than 65 years. Memory impair-ment, especially impairment of episodic memory, is oneof the first symptoms of AD. Due to public awareness ofAD, it is often suspected to be the underlying cause ofmemory problems in elderly patients. Since AD is a pro-gressive neurodegenerative disorder with an untreatablecause and limited therapeutic options, it is highly impor-tant to carefully establish the correct diagnosis and beaware of medical conditions that may mimic AD by pres-enting with memory impairment. In clinical research thecorrect classification of AD and non-AD is crucial tostudy disease mechanisms or new treatment possibilitiesin homogenous study populations. In this article, we aimto describe new aspects of the most common differentialdiagnoses that may clinically resemble AD, but whichhave different pathophysiological roots.
The term memory generally means the ability toreproduce or remember experienced or learned content.There are different types or constructs of memory, and
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Copyright 2013 AICH Servier Research Group. All rights reserved www.dialogues-cns.org
Non-Alzheimers diseaserelated memoryimpairment and dementiaSnke Arlt, PD, MD
Keywords: Alzheimers disease; Lewy body dementia; frontotemporal dementia;depression; differential diagnosis; biomarker
Author affiliations: Department of Psychiatry and Psychotherapy,University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Address for correspondence: Snke Arlt, MD, Department of Psychiatry andPsychotherapy, University Medical Center Hamburg-Eppendorf, Martinistrasse52, Building W 37, 20246 Hamburg, Germany (e-mail: firstname.lastname@example.org)
Although Alzheimers disease (AD) is a common cause ofmemory impairment and dementia in the elderly, dis-turbed memory function is a widespread subjective and/orobjective symptom in a variety of medical conditions. Theearly detection and correct distinction of AD from non-ADmemory impairment is critically important to detect pos-sibly treatable and reversible underlying causes. In thecontext of clinical research, it is crucial to correctly distin-guish between AD or non-AD memory impairment inorder to build homogenous study populations for theassessment of new therapeutic possibilities. The distinc-tion of AD from non-AD memory impairment may be dif-ficult, especially in mildly affected patients, due to anoverlap of clinical symptoms and biomarker alterationsbetween AD and certain non-AD conditions. This reviewaims to describe recent aspects of the differential diag-nosis of AD and non-AD related memory impairment, andhow these may be considered in the presence of memorydeficits. 2013, AICH Servier Research Group Dialogues Clin Neurosci. 2013;15:465-473.
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the classification of memory categories is still subject tochange and discussion.1 Memory may be classified asimplicit or explicit: implicit memory mainly stands fornonverbal habitual memory, such as motor learning (eg,playing a musical instrument or riding a bicycle); explicitmemory contains active or passive recall of facts orimpressions (biographical knowledge, chronologicalsequence of experienced events, speech, etc). Anothercommon distinction is between short-term and long-term memory: short-term memory describes a time spanof seconds or minutes (sometimes also referred to asworking memory), and long-term memory comprisesencoding, consolidation, and recall over or after a longperiod of time. Memory can also be classified withregard to content: episodic memory, verbal memory,visual memory, or olfactory memory.Although there are fewer common syndromic variantsof AD, one of its main and early features is an impair-ment of episodic memorythe capacity to rememberpast events together with details about the context inwhich they occurred.2 Episodic memory is an essentialcognitive function that supports our ability to form anautobiographical history and helps us to create a conceptof the past and the future.The hippocampal network, including the parahip-pocampal gyrus, hippocampus, and neocortical areas,play a major role in the process of memory consolida-tion and retrieval.3 Although its function has not yet fullybeen understood, the hippocampus seems to be involved
in binding features of an event into a mental represen-tation, which is important to form episodic memory. Virtually any neurological, neurodegenerative, toxic, ortraumatic damage to brain structures involved inepisodic memory generation, especially the hippocam-pus, may lead to deficits in episodic memory that mayresemble or precede AD,4 especially in the absence ofother neurological or neuropsychological symptoms orsigns indicative of an alternative cause.
Diagnostic approach and diagnostic criteria
The diagnostic procedure of memory impairment isfirstly based on a comprehensive clinical investigation.This should comprise a detailed medical history, med-ication history, proxy report of the perceived symptoms,neuropsychological memory testing, and a neurologicaland psychiatric examination. Additional investigations,such as a cranial magnetic resonance imaging (MRI)scan, 18fluorine-2-deoxy-D-glucose positron emissiontomography (18F-FDG-PET), cerebrospinal fluid (CSF)examination, and AD biomarkers (-amyloid42 [A42],total tau protein [t-tau], and tau phosphorylated at posi-tion threonine 181 [p-tau]), may further help to establishthe correct diagnosis. A typical clinical picture for AD consists of a slowly pro-gressive memory loss and loss of other neuropsychologi-cal functions (eg, praxis, speech), absence of medical, neu-rological, or psychiatric condition that may explain thememory loss, brain imaging that is in line with AD, andbiomarkers supporting the diagnosis of AD.5 Atypicalsymptoms such as early neurological symptoms, mood dis-order, visual hallucinations, or an atypical sudden onsetmay hint at a diagnosis other than AD. Comprehensiveinformation on the clinical diagnosis and management ofthe most important dementing diseases other than AD (eg,vascular cognitive impairment, frontotemporal dementia(FTD), Lewy body dementia (LBD), corticobasal syn-drome, progressive supranuclear palsy, Parkinsons dis-easerelated dementia, Huntingtons disease, prion dis-eases, normal-pressure hydrocephalus, limbic encephalitisand other toxic and metabolic disorders) is provided in therecent EFNS-ENS guidelines (European Federation ofNeurological societiesEuropean Neurological Society).6
For the first time, the recently released revised diagnos-tic criteria for AD involve biomarkers to support thediagnosis of AD: (i) reduced CSF A42; (ii) raised CSFtau (t-tau and p-tau); (iii) positive PET amyloid imaging;
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Selected abbreviations and acronymsA42 -amyloid42AD Alzheimers diseaseCSF cerebrospinal fluidbvFTD behavioral variant of frontotemporal
dementia18F-FDG-PET 18fluorine-2-deoxy-D-glucose positron emis-
sion tomographyFTD frontotemporal dementiaLBD Lewy body dementiaMCI mild cognitive impairmentMRI magnetic resonance imagingOSA obstructive sleep apneaPiB Pittsburgh compound Bp-tau tau phosphorylated at position threonine 181SMI subjective memory impairmentTBI traumatic brain injuryt-tau total tau protein
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Non-Alzheimers diseaserelated memory impairment and dementia - Arlt Dialogues in Clinical Neuroscience - Vol 15 . No. 4 . 2013
(iv) typical patterns in 18F-FDG-PET; and (v) dispro-portionate atrophy involving medial, basal, and lateraltemporal lobes and medial and lateral parietal cortices.5,7-9 If available, these biomarkers may be helpful in the dis-tinction between AD and non-AD memory impairment.However, some alterations and biomarker constellationsthought to be typical for AD may also be found in otherneurodegenerative disorders, possibly hampering thediscrimination between AD and non-AD etiology ofmemory impairment. For example, CSF A42 valueshave been found to be decreased in AD as well as inLBD patients,10 and CNS amyloid accumulation can beobserved in patients with AD and LBD using amyloidimaging.11 Hippocampal atrophy, as seen in many ADpatients, is also found in patients with frontotemporaldementia (FTD), possibly due to hippocampal sclerosisrelated to this disease.12
During the diagnostic process for memory complaints, itis essential to objectively assess memory impairment,and the impact on activities of daily living, in order todiscriminate between subjective memory impairment(SMI), mild cognitive impairment (MCI), and dementia(mild, moderate, or severe). Memory impairment mayobjectively be quantified on the basis of neuropsycho-logical tests using age-specific standard values.Neuropsychological testing allows the differentiation ofmemory impairment with regard to age and education-specific normal values, eg, using the Wechsler Memoryscale or the CERAD (Consortium to Establish aRegistry for Alzheimers Disease) test. However, a nor-mal score on such tests does not exclude memoryimpairment, since SMI has been revealed as a strongpredictor of dementia and brain atrophy associated withdementia.13-17 In cases with SMI, or doubtful cases,repeated longitudinal testing to assess the course of thememory impairment is recommended.
In 2004, a significant step towards an improvement ofthe ante-mortem diagnosis of AD and estimating thebrain amyloid burden was made through the develop-ment of cerebral amyloid imaging using Pittsburgh com-pound B (PiB).18 Cerebral amyloid was not onlydetected in AD patients, but also in patients