comparison between clinical diagnosis and csf biomarkers of alzheimer disease in elderly patients...

Comparison Between Clinical Diagnosisand CSF Biomarkers of Alzheimer Disease

in Elderly Patients with Late OnsetPsychosis: Helsinki Old Age Psychosis

Study (HOPS)

Toni T. Seppälä, M.D., Ph.D., Ulla-Marja Louhija, M.D., Björn Appelberg, M.D., Ph.D.,Sanna-Kaisa Herukka, M.Sc., M.D., Ph.D., Kati Juva, M.D., Ph.D.

Received Marchof Eastern FinlaHelsinki, Finlandspondence andMedicine e Neu

� 2013 Amehttp://dx.d

Am J Geriatr Ps

Objectives: To determine the proportion of elderly people with a first psychotic

episode actually suffering from dementia, especially Alzheimer disease (AD), by using

cerebrospinal fluid (CSF) biomarkers. Design: Prospective case-control study. Settingand participants: Sixty-six patients age 65 years and older with recent psychotic

symptoms and 12 comparison subjects with chronic schizophrenia over 10 years that

were referred to acute old age psychiatry, in-ward treatment. Measurements:Concentration levels of CSF Ab42, tau and p-tau-181 measured by ELISA compared to

clinical diagnosis made by a multiprofessional team of one neurologist and several

psychiatrists. Results: The CSF specimen was obtained from 51 (65.4%) of the

patients. In five subjects out of 13 with a clinical diagnosis of AD, all the CSF

biomarkers (Ab42, tau and p-tau) were normal. Only one patient out of 25 with

a psychiatric diagnosis and none out of the comparison group with schizophrenia

showed a CSF profile typical of AD. Three patients with an AD diagnosis, four patients

with a psychiatric diagnosis and one patient with schizophrenia had a low Ab42concentration with normal levels of tau or p-tau. The patients with AD had lower CSF

Ab42 levels than other patients. Conclusions: The CSF biomarkers are important and

useful as part of the diagnostic procedure for detecting AD and other dementia in

elderly patients displaying psychotic symptoms. The accuracy of AD diagnosis

encounters problems due to atypical behavioural symptoms in psychiatric settings

and thus the differential diagnostics can be improved by using CSF biomarkers of AD

more frequently. (Am J Geriatr Psychiatry 2013; -:-e-)

Key Words: Late-onset psychosis, Alzheimer disease, biomarker, cerebrospinal fluid,amyloid, tau, dementia

5, 2012; revised July 2, 2012; accepted August 1, 2012. From the Unit of Neurology, Institute of Clinical Medicine, Universitynd, Kuopio, Finland (TTS, S-KH); Unit of Psychogeriatrics, Division of Psychiatry, Helsinki University Central Hospital,(U-ML, BA, KJ); and the Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland (S-KH). Send corre-

reprint requests to Toni T. Seppälä, M.D., Ph.D., University of Eastern Finland, School of Medicine, Institute of Clinicalrology, P.O. Box 1627 (Yliopistonranta 1 C), FI-70211 Kuopio, Finland. e-mail: [email protected] Association for Geriatric Psychiatryoi.org/10.1016/j.jagp.2012.08.020

ychiatry -:-, - 2013 1

mailto:[email protected]

http://dx.doi.org/10.1016/j.jagp.2012.08.020

Clinical Diagnosis and CSF Markers in Psychosis

lzheimer disease (AD) is the most common cause
Aof dementia. It is estimated that 5.4% of peopleover 65 years old have AD,1 with the prevalencedoubling every 5 years after the age of 65 years2 (e.g.,the prevalence of AD after the age of 85 years is 43% inthe United States3). The typical early symptoms of ADare problems in short-term memory and difficulties inlearning new tasks. These symptoms can be assessedby cognitive screening tests and by neuropsychologicalexaminations,4 but definitive biomarkers have notbeen introduced. The new research criteria for ADdiagnosis include several possible biomarkers as sup-porting features but are specifically designed to iden-tify a typical amnestic form of preclinical or prodromalAD that includes approximately 85% of all AD.5 Insome cases, however, AD can begin with neuropsy-chiatric symptoms, which can be prominent longbefore there are any clear cognitive symptoms—alternatively, the cognitive symptoms may be inter-preted as being secondary to mental illness. Therecently proposed clinical criteria for AD incorporatebiomarkers in the diagnostic algorithms also in thecase of possible AD (i.e., when there is a clinicalpresentation that is atypical to AD6).
In a study of 100 neuropathologically verified ADpatients, a large proportion of patients had paranoidideation before the diagnosis of AD and at the time ofthe diagnosis, 45% had displayed some kind ofpsychotic symptom (hallucinations, paranoia, otherdelusions). The average time from first paranoidideations to AD diagnosis was 18 months.7 Psychosisis also significantly associated with impairedworking memory in AD.8 In addition, diffuse Lewybody disease (DLB) tends to begin with symptomsoften interpreted as functional. Two of the three corefeatures are recurrent visual hallucinations and fluc-tuating cognition,9 which can be a reason why thepatient is admitted into a psychiatric hospital.Fortunately, DLB can be quite reliably diagnosedwith single photon emission computed tomography(123I-FP-SPECT). Although frontotemporal degener-ations are quite rare in the population aged 65 andover, they may present with psychotic symptoms(e.g., mania10). Neuropsychiatric symptoms may beamong the earliest symptoms of AD because in mildcognitive impairment they are associated with anincreased risk of dementia and therefore representa valuable target to therapeutic interventions.11 There

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are very few studies of the prevalence of neurode-generative diseases in the elderly with recentpsychotic symptoms. In Post’s study,12 15% of para-noid patients in a psychogeriatric hospital developeddementia, and in Holden’s study,13 35% of patientswith paraphrenia had become demented after 3 years.

Protein changes in cerebrospinal fluid (CSF) can beidentified in AD. The concentration of 42 amino acidlength amyloid-b (Ab42) diminishes whereas those ofprotein tau and its hyperphosphorylated form p-tauincrease in AD many years before the appearance ofclinical dementia. The pooled 86% sensitivity and90% specificity for CSF Ab42 have been reported todiscriminate AD patients from controls.14 The corre-sponding figures for total tau were 81% and 90%, andfor p-tau 80% and 92%, respectively.14 By combiningthe abnormal CSF biomarkers, a sensitivity of greaterthan 90% and a specificity of greater than 85% havebeen achieved.15 The biomarker profile of elderlyschizophrenia patients is reported to show a normalCSF tau level and a slightly decreased Ab42concentration.16

Cholinergic medication has changed the treatmentof AD and several other neurodegenerative illnesses,and because it seems that early intervention is thebest way to support the independent daily living anddelay hospitalization, it has become extremelyimportant to diagnose these diseases at an earlystage, preferably before the onset of dementia.

An important aimof theHelsinki OldAge PsychosisStudy is to identify, what proportion of elderly peoplewith a first psychotic episode are actually sufferingfrom a dementing illness, especially AD.

METHODS

Participants

The unit of geriatric psychiatry department ofHelsinki University Central Hospital serves a pop-ulation of 1,116,000 inhabitants in the capital area ofFinland. The population aged 65 and over in the areais 151,000. The department consists of four wards witha total of 68 beds, and is the only hospital offeringacute psychogeriatric in-ward treatment in the area.

Ninety-three patients aged 65 years and over wereincluded in the study after ten patients refused to

Am J Geriatr Psychiatry -:-, - 2013

Seppälä et al.

participate. All but one of the refused were women(90%), they did not differ by age (mean: 79.2 years)but AD (40%) was more frequent than in the studygroup. The recruitment began on January 12, 2009,and ended on March 10, 2011, but during the studythere were some pauses (from 1e3 months) becauseof other commitments of the main researcher.

All study patients were psychotic at the time ofadmission to the hospital, but their psychotic symp-toms had not lasted more than 2 years before theiradmission. The comparison group consisted ofpatients with chronic schizophrenia (disease historyover 10 years) experiencing acute psychotic symp-toms. No patients with a known diagnosis ofa dementia (AD, DLB, etc.) at admission wereincluded. Patients with other diseases of centralnervous system (e.g., Parkinson disease [PD] or majorstroke) were also excluded.

Clinical Diagnosis

All patients were evaluated clinically by a psychia-trist. A magnetic resonance imaging (MRI) examina-tion of the brain was taken when possible, and if not(e.g., presence of a pacemaker), then a computedtomography scan was carried out. In the MRI exami-nations, the hippocampus was assessed by the Schel-tens grade17 and vascular lesions by Fazekas grade.18

All patients were neuropsychologically examined.The CERAD battery4,19 was performed by nurseswith a wider testing conducted by a trained neuro-psychologist. Routine blood tests were carried out.

All patients with a suspicion of a memory disease(according to clinical signs, neuropsychological tests,or imaging) were examined and evaluated also bya neurologist. The diagnosis of AD was madeaccording to the guidelines of the new EFNS researchcriteria20 excluding the use of CSF biomarkers. Anexception was made to the criteria, which normallydemand a dementia-stage cognitive decline, becausehere we wanted to diagnose AD as early aspossible—that is, before signs of severe cognitiveproblems reaching dementia level. AD begins witha mild cognitive impairment, and when neuropsy-chiatric symptoms, especially delusions, precede themore disruptive cognitive symptoms, these psychi-atric symptoms often significantly interfere withusual social activities and relationships with otherpeople evenwithout the presence of a severe cognitive


decline. So when the neuropsychological tests showedan amnestic memory disorder and imaging supportedthe diagnosis, and there was no other explanation forthe state, we diagnosed the patient as having AD evenwhen the cognitive decline did not fulfil the criteria ofdementia. All subjects with the clinical diagnosis ofAD had clear deficits in delayed episodic memory.

DLB was diagnosed according to the McKeithcriteria,9 and the 123I-FP-SPECT was conducted toverify the diagnosis.21 The diagnoses of vasculardementia (VaD) and psychiatric disorders were madeaccording to the DSM-IV-TR criteria. Very-late-onsetschizophrenia-like psychosis was defined as schizo-phrenia where symptoms initially present at the ageof 60 years or later.22 When the patients fulfilled boththe diagnoses of degenerative or vascular memoryillness and that of a psychiatric illness, the diagnosisof memory illness was used.

The final clinical diagnosis was made according toall clinical (psychiatric and neurological), neuro-psychological, and imaging data. The diagnosis wasbased on the information from the first ward periodand was made as a consensus in the research team oftwo psychiatrists and one neurologist. All subjectswith the diagnosis of an organic brain disorder hadclear cognitive deficits in neuropsychological tests.Regarding the concept of dementia, they all hadsymptoms that caused disturbance that significantlyinterfered with usual social activities and relationshipwith others, but it was sometimes difficult to deter-mine whether this was due to this cognitive declineor the psychiatric symptoms. This kind of distur-bance was present also with many of the psychiatricsubjects. The results of the CSF analysis or follow-updid not influence the diagnosis.

After the analysis and comparison of the clinicaldiagnoses and the CSF findings, we re-examined thedata of those patients in whom there was a discrep-ancy between diagnosis and the biomarkers in anattempt to discern the reasons for this paradox.

CSF Analysis

A CSF sample was obtained from 51 patients.Some patients refused to participate in this part ofthe study, some had contraindications (warfarintreatment) and in some the lumbar puncture failed.Lumbar puncture was performed in L3/L4 or L4/L5vertebrae interspace with a 0.7-mm needle and CSF

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TABLE 1. Demographic Information and the Diagnoses in the Samples

N

Study Sample CSF Sample No CSF

p78 51 27

Age, years; mean (SD) 76.7 (63.5e91.7) 77.3 (63.5e91.7) 75.4 (65.5e89.0) 0.244Female 63 (81) 40 (78) 23 (85) 0.345Psychiatric diagnosis, N (%) 41 (53) 25 (49) 16 (59) 0.342

Delusion disorder 16 10 6VLOSLP 17 10 7Psychotic depression 8 5 3

Organic diagnosis total, N (%) 25 (32) 19 (37) 6 (22) 0.306AD 14 10 4AD with CVD 3 3VaD 2 1 1DLB 1 1FTD 3 3Alcohol dementia 1 1Delirium 1 1

Schizophrenia > 10 years, N (%) 12 (15) 7 (14) 5 (19) 0.743

Notes: t test (age, t ¼ 1.175, df ¼ 76) and c2-test were used (No CSF vs. CSF sample, df ¼ 1). CSF: cerebrospinal fluid; VLOSLP: very late-onset schizophrenia-like psychosis; AD: Alzheimer disease dementia; CVD: cerebrovascular disease; VaD: vascular dementia; DLB: Lewybody dementia; FTD: frontotemporal degeneration (includes one patient with primary progressive aphasia [PPA]). Schizophrenia over10 years ¼ comparison group.


was collected into a polypropylene tube. The sampleswere stored at �80�C or lower until analysis.

The common biomarkers for AD (Ab42, tau,p-tau-181) were analyzed using commercial ELISAs(Innotest beta-amyloid 1-42, Innotest hTau-Ag,Innotest Phospho-tau (181 P), Innogenetics, Ghent,Belgium) according to the manufacturer’s protocol.The CSF analyses were made after the ward periodand the results did not influence the clinical diag-nosis. The analyses were conducted in clinical labroutine in our biomarker laboratory in the Universityof Eastern Finland. The laboratory has a stringentquality control program, which includes internallongitudinal controls to ensure the validity offormerly determined cutoff levels in the current use.The laboratory also participates in the ongoinginternational quality control program.

Reference standards from pooled CSF sampleswere used in order to examine the intra-assay varia-tion. The inter-assay coefficient of variation (CV%)for control samples with their concentration near thecut-off limit were 4.5% for Ab42, 6.7% for tau, and2.5% for p-tau-181. The intra-assay CV% for sampleswere 7.0% for Ab42, 4.6% for tau, and 2.4% for p-tau-181 near the cut-off limit. The regular cut-off limits inour laboratory were used.23 These cutoffs referring toAD were Ab42 less than 450 pg/mL, tau greater than400 pg/mL, and p-tau greater than 70 pg/mL.

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Statistics

The statistical analyses were conducted with SPSS19.0.0 (IBM, Armonk, NY). The Kolmogorov-Smirnov test was used to test the normality of thedata. The student t test was used for normallydistributed continuous data and c2-test for ordinaland nominal data. ANOVA with Bonferroni post hoccorrection was used for group comparisons of nor-mally distributed continuous data.

Ethical Aspects

All subjects and in most cases also a relative signedan informed consent form. The study was approvedby the ethics committee of the Helsinki and Uusimaahospital district.

RESULTS

Demographic data and the diagnosis of the entirestudy sample and those with CSF sample obtainedare presented in Table 1.

Of the 93 subjects in the study, 15 were excludedbecause in the final analysis they did not fulfil theinclusion criteria: Three were not clearly psychotic,seven were found to have had psychotic symptomsfor more than 2 years (e.g., episodes of psychotic


TABLE 2. The Reasons for Missing CSF Sample and the Comparison Between Those With and Those Without a CSF Samplefor Analysis

Age, years Mean (SD) Female, N (%)

Clinical Diagnosis, N (%)

Psychiatric Organic Schizophrenia over 10 years

CSF obtained (N ¼ 51) 77.3 (7.0) 40 (78.4) 25 (49.0) 19 (37.3) 7 (13.7)CSF not obtained (N ¼ 27)

Patient refused (N¼ 17) 73.5 (5.3) 14 (82.4) 13 (76.5) 2 (11.8) 2 (11.8)LP failure (N ¼ 7) 77.8 (6.9) 7 (100) 3 (42.9) 2 (28.6) 2 (28.6)Warfarin treatment (N ¼ 3) 80.7 (8.2) 2 (66.6) 1 (33.3) 1 (33.3) 1 (33.3)

Notes: LP: lumbar puncture; CSF: cerebrospinal fluid.

TABLE 3. Normal and Abnormal CSF Biomarker Levels Subdivided According to Diagnoses

Clinical Diagnosis

Delusiondisorder VLOSLP Depression AD ADDCVD VaD

FTD(PPA*)

Other organicdiagnosis

Schizophrenia>10 years

Normal CSF biomarker levels 6 5 4 3 2 1 1 3CSF Ab42 level decreased, but normal

tau and p-tau concentrations1 2 1 2 1 2 1

CSF tau or p-tau (or both) levelsincreased, but normal Ab42 level

1 (2) 2 (1) 1* 1 3

CSF Ab42 level decreased and tauor p-tau (or both) level increased

(1) 3 (1)

Notes: CSF: cerebrospinal fluid; Ab42: amyloid beta 42; P-tau: hyperphosphorylated tau; VLOSLP: very late-onset schizophrenia-likepsychosis; AD: Alzheimer disease dementia; CVD: cerebrovascular disease; VaD: vascular dementia; FTD: frontotemporal degeneration(includes one patient* with primary progressive aphasia [PPA]). Schizophrenia over 10 years ¼ comparison group. The cutoffs were set to:Ab42 < 450 pg/mL, tau > 400 pg/mL, and p-tau > 70 pg/mL (indicative to AD).

Seppälä et al.

depression, bipolardisease, or late-onset schizophrenia),one had PD, two had previously diagnosed AD, andtwo had suffered amajor stroke. Thus, the study sampleconsisted of 78 subjects. Twelve were comparisonpatients who had suffered from schizophrenia for over10 years and 66 had recent psychotic symptoms.

A CSF specimen was obtained from 51 (65.4%) ofthe patients. Table 2 compares the sample fromwhom a CSF sample was obtained with those fromwhom CSF was not available (N ¼ 27).

The regular cutoff values of our validated labora-tory were used. Twenty-five (49.0%) patients hadcompletely normal CSF biomarkers of AD. Elevenpatients (21.6%) had elevated tau or p-tau or both,and 16 patients (31.4%) had only diminished CSFAb42 concentrations. Six patients (11.8%) had bothelevated p-tau levels and decreased Ab42 concen-trations. In two patients, all three biomarker levelswere abnormal. Table 3 shows the distribution of thebiomarkers with respect to diagnoses.

The clinically diagnosed AD dementia patients(without cerebrovascular disease [CVD]) had a


higher CSF p-tau concentration (66.7 � 19.6 pg/mL)compared with all other subjects (47.4 � 22.4 pg/mL;t ¼ �2.49, df ¼ 49, p ¼ 0.016). The patients withdiagnoses of AD or ADþCVD had lower Ab42 levelsthan patients with psychiatric diagnoses or schizo-phrenia (Figure 1). Otherwise, the mean biomarkerlevels did not differ statistically between diagnosticgroups. Table 4 presents the biomarker concentra-tions by all diagnostic groups. Figure 1 presents theCSF biomarker concentrations by dot plots presentedby simplified diagnostic groups.

Figure 2 presents the individual Ab42/p-tau ratiosby all diagnostic groups. The mean CSF Ab42/p-tauratio of those with AD or ADþCVD was 11.3 � 9.1,whereas the mean ratio of those with other diagnoseswas 18.7 � 15.6 (t ¼ 1.611, df ¼ 49, p ¼ 0.114).

Analysis of Those with a Discrepancy BetweenClinical Diagnosis and AD Biomarker Findings

Therewere a total of five patientswith a diagnosis ofAD dementia having all three CSF biomarkers (Ab42,

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FIGURE 1. CSF biomarker concentrations in thediagnostic groups of AD, psychiatric diagnoses, and com-parison group (schizophrenia).

Notes: CSF ¼ cerebrospinal fluid. Psychiatric diagnoses include: very late-onset schizophrenia-like psychosis (10), delusion disorder (10), andpsychoticdepression (5).AD¼Alzheimer’sdiseasedementia (10patientswithADand3patientswithADþCVD).CVD¼ cerebrovasculardisease.A patient suffering pure vascular dementia, two patients with frontotem-poral degeneration, one patient with primary progressive aphasia, andtwopatientswith other organic diagnoseswere left out of the analysis. Schizophrenia over 10 years¼ comparison group. Thedata are presented aspg/mL. The horizontal line presents the mean level within group. The group difference for statistical significance is testedwith ANOVA (df¼ 2).

6 Am J Geriatr Psychiatry -:-, - 2013


TABLE 4. The Biomarker Concentrations in the Different Diagnostic Groups

The CSFSample

Clinical Diagnosis

DelusionDisorder VLOSLP Depression AD ADDCVD VaD

FTD(PPA*)

Other OrganicDiagnosis

Schizophrenia> 10 years

n 51 10 10 5 10 3 1 3 2 7CSF Ab42 636 � 283 603 � 195 704 � 268 631 � 163 567 � 367 397 � 133 642 549 � 427 491 � 23 865 � 323CSF tau 276 � 199 266 � 160 274 � 199 158 � 39 284 � 162 160 � 125 336 265 � 112 180 � 46 322 � 146CSF p-tau 55 � 37 52 � 25 48 � 27 30 � 7.1 67 � 20 18 � 14 62 50 � 17 56 � 47 56 � 17CSF Ab42/p-tau 16.7 � 14.6 21.1 � 26.5 18.8 � 10.3 21.9 � 7.8 9.1 � 6.6 18.5 � 14.2 10.4 10.1 � 4.7 13.2 � 10.6 16.6 � 7.6

Notes: CSF: cerebrospinal fluid; VLOSLP: very late-onset schizophrenia-like psychosis; AD: Alzheimer disease dementia; CVD: cerebro-vascular disease; VaD: vascular dementia; FTD: frontotemporal degeneration (includes one patient* with primary progressive aphasia [PPA]).Schizophrenia over 10 years ¼ comparison group. Other organic diagnosis includes two subjects with alcohol dementia and one withdelirium.

The data are presented as mean � SD, unit pg/mL.The group differences do not reach statistical significance by ANOVA after post hoc correction.

FIGURE 2. CSF Ab42/p-tau ratio of individual patients displayed by different diagnostic groups.

Notes: CSF ¼ cerebrospinal fluid; VLSOP ¼ very late-onset schizophrenia-like psychosis; AD ¼ Alzheimer’s disease dementia; CVD ¼cerebrovascular disease; VaD ¼ vascular dementia; FTD ¼ frontotemporal degeneration (includes one patient with primary progressiveaphasia [PPA]). Other organic diagnosis includes two subjects with alcohol dementia and one with delirium. Schizophrenia over 10 years ¼comparison group. The data are presented as pg/mL.

Seppälä et al.

tau, and p-tau) at the normal level. Two of those witha combined diagnosis of ADþCVD displayed a clearcognitive decline, in both the hippocampus was smallin MRI (Scheltens 2) and severe vascular degenerationwas observed (Fazekas 3).Accordingly, they seemed tohave had pure vascular dementia and not AD accord-ing to the CSF biomarkers. One of those patients witha pure AD dementia diagnosis had a small hippo-campus (Scheltens 2e3) and also vascular degenera-tion (Fazekas 2), so she probably also had vasculardementia based on the normal CSF biomarkers.


The other two with a clinical diagnosis of AD andnormal CSF biomarkers did not seem to have had anorganic brain disease at all. One had previously sufferedfrom several major depressions (no psychotic episodesbefore), had clear amnestic memory problems in neuro-psychological testing, and hippocampal atrophy (Schel-tens 2e3) inMRI but no vascular changes. The other hadan amnestic cognitive decline but a normal MRI. Thesetwo patients seem to have been clearly misdiagnosed.

The two individuals with an AD diagnosis anda low Ab42 level but normal tau and p-tau

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concentrations may well have had very early stage ofAD. Both displayed evidence of hippocampalatrophy (Scheltens 2), and in the follow-up of 1.5years, the cognitive decline had a typical Alzheimer-like progression.

The one patient with the diagnosis of ADþCVDshowing low Ab42 level but normal tau and p-tauconcentrations did exhibit hippocampal atrophy(Scheltens 3) and severe vascular degeneration(Fazekas 3), so she may well have had both disorders.

The subject with a diagnosis of very-late-onsetschizophrenia-like psychosis with both a low levelof Ab42 and elevated tau and p-tau concentrationsdid not have major memory problems. Her MMSEwas 28/30 and in CERAD only in the recognition ofthe wordlist was she slightly below normal and herscore in the clock-drawing test was 4/6. Her MRI didnot show any signs of hippocampal atrophy orvascular degeneration. Therefore, it would have beenvery difficult to assess her as having AD without theCSF biomarkers.

DISCUSSION

As expected, the psychotic patients who hadsuffered schizophrenia for decades did not displaya profile of CSF biomarkers typical for Alzheimerdisease. In one earlier study examining elderly early-onset schizophrenia patients, several had normal CSFtau or p-tau levels, but Ab42 concentration was lowerthan that found in healthy controls.16 In our study,three out of seven patients with early onset schizo-phrenia had normal AD biomarkers, one had a lowAb42 level but normal tau and p-tau levels, and threehad a normal Ab42 concentration but elevated tau orp-tau levels, so the results are rather inconclusive.

Five out of 13 clinically diagnosed AD patients hadcompletely normal concentrations of AD biomarkersin CSF. Three of these seemed to have had purevascular dementia and two were clear misdiagnoses(no organic brain disease at all). Three patients hada low Ab42 level with normal tau or p-tau values.

Two patients with a low Ab42 level but a normaltau or p-tau concentrations were probably at a veryearly stage of AD. Ab42 decreases before one sees anyelevations in tau or p-tau concentrations, so thisprofile can well be indicative of early AD pathology.24

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One reason for the tendency for overdiagnosingAD in memory patients may be that in Finland thepatient only receives reimbursement for medication(acetylcholinesterase inhibitors or memantine) byhaving a verified diagnosis of AD or PD dementia, sowhen there is a doubt of the cause, the clinicians tendto ensure the availability of subsidized medication.

Among the subjects with psychiatric diagnosesthere was only one subject with a clear Alzheimer-like biomarker profile. She was not demented,however, and had a normal MRI. One reason for thisfinding may be that the biomarkers may becomeabnormal before there are any prominent clinicalsymptoms of AD as described earlier in theliterature.25

The mean biomarker concentrations in the differentdiagnostic groups did not show the statistical differ-ences as clear as would be expected in these types ofstudies. For example, the group of ten AD patientshad a relatively high mean concentration of CSFAb42 and both AD and ADþCVD groups showeda low mean CSF tau level. When combined, patientswith AD and ADþCVD displayed a lower mean CSFAb42 level than those in other groups, but the meanconcentration was still rather high. This probablyresults from the proportion of VaD and psychiatricdisorders being misdiagnosed as AD and thus pre-senting more normal concentrations. Certainly, thediagnostic subgroups were too small for singlebiomarkers to achieve statistical significance afterpost hoc corrections. The AD group did exhibit withthe highest p-tau levels leading to lowest CSF Ab42/p-tau ratio, however, which is a common finding inAD subgroups in cross-sectional measurements.

It is interesting that in this sample of psychoticelderly people, 4 out of the 17 subjects (23.6%) witha diagnosis of an organic brain disease (in the finalanalysis, after the CSF biomarker analysis) seemed tohave had vascular dementia. In population-basedstudies the proportion of vascular dementia has beensignificantly lower (e.g., 15.8% in the study by Loboet al.26). One explanation can be that vasculardementia tends to cause psychotic symptoms moreoften in the early stages and the patients are thus morelikely to be referred to psychiatry, or that classical ADis more easily diagnosed in primary care or in geriatricsettings, and the patients are not referred to psychiatryeven when psychotic symptoms are present. What-ever the reason, it is very important to bear in mind


Seppälä et al.

the possibility of vascular small vessel disease asa reason for psychiatric symptoms in the elderly.

Two of the frontotemporal dementia (FTD)patients had low CSF Ab42 levels, as has been re-ported previously.27 Usually the most effective wayto distinguish FTD from AD is the lower CSF Ab42/p-tau ratio in AD,27 but it did not reveal a significantdifference to FTD in the present study, possibly dueto potentially misdiagnosed patients in the AD groupor the small number of FTDs.

The limitation of this study was the relatively smallsample size resulting from the high number ofpatients refusing or otherwise being excluded andthus not providing a CSF sample. The majority ofnonparticipating patients were those with a psychi-atric diagnosis, which may have been due to theirsymptoms (i.e., suspiciousness about the lumbarpuncture and paranoid behavior towards the figuresof authority). The women were more likely to refuseto undergo the lumbar puncture and all whoselumbar puncture failed were women. The reasons forfailure of the lumbar puncture were usually related toobesity and some of the women were also verysensitive to puncture. In addition, we did not havethe benefit of providing an autopsy confirmation forthe AD diagnosis, which is also a limitation.


This study shows the importance and the useful-ness of the CSF biomarkers as part of the diagnosticprocedure for detecting AD and other dementingillnesses. Especially in a psychiatric setting, it seems tobe very difficult even with good availability of MRI,neuropsychological examinations, and a multiprofes-sional team, to make an exact diagnosis of memorydisorders without access to the CSF biomarkers ofAD. The study strongly recommends that the patientswith AD diagnosis with atypical or psychotic symp-toms should not be included in AD groups of clinicaltrials unless this is confirmed by CSF biomarkers ofAD or some other additional biomarker.

We thankMs. Päivi Räsänen andMs. Tarja Kauppinenfor technical assistance in the project.

This study has been supported by Health ResearchCouncil of the Academy of Finland, The Finnish MedicalFoundation, The Foundation of Maire Taponen, EVOgrants no. 5883, 5772708, 5772720, 5772722, and5772725 from the Kuopio University Hospital, an EVOgrant from the Helsinki University Central Hospital, thestrategic funding for UEFBRAIN from the University ofEastern Finland, and the Nordic Center of Excellence inNeurodegeneration.

The authors have no disclosures to report.

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comparison between clinical diagnosis and csf biomarkers of alzheimer disease in elderly patients...

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