Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia

Alzheimer’s & Dementia 9 (2013) 269–275

Cognitive correlates of cerebrospinal fluid biomarkers in frontotemporal dementia Esther L. G. E. Koedama,*, Annelies E. van der Vliesa, Wiesje M. van der Fliera,b, Nicolaas A. Verweya,c, Ted Koenea, Philip Scheltensa, Marinus A. Blankensteinc, Yolande A. L. Pijnenburga a

Department of Neurology and Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands c Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands

b

Abstract

Objective: In this study we investigated the relationships between cerebrospinal fluid (CSF) biomarkers (tau and amyloid-b1-42 [Ab1-42]) and cognition or behavior in patients with frontotemporal dementia (the behavioral variant, bvFTD). Methods: We included 58 patients with bvFTD. All patients underwent a neuropsychological assessment and lumbar puncture. Relationships between CSF biomarkers and cognition or behavior were assessed with linear regression analysis. Results: After correction for age, sex, and education, CSF tau levels were found to be negatively related to the Visual Association Test (standardized b 5 20.3, P , .05), whereas CSF Ab1-42 levels were found to be positively related to the Mini-Mental State Examination (b 5 0.3, P ,.05), the frontal assessment battery (b 5 0.5, P ,.05), and digit span backwards test (b 5 0.3, P 5.01). We did not find relations between CSF biomarkers and behavior (measured by the neuropsychiatric inventory). After excluding all patients with a CSF biomarker profile often seen in Alzheimer’s disease (high levels of tau and low levels of Ab1-42), we still found relations between CSF Ab1-42 levels and Visual Association Test object naming (b 5 0.4, P ,.05), as well as between CSF Ab1-42 levels and the frontal assessment battery (b 5 0.5, P , .05, but there was no relation between CSF tau and cognition. Conclusion: Low CSF Ab1-42 levels are associated with worse general cognitive function and worse executive function in patients with bvFTD. Our results provide circumstantial evidence for a pathophysiological role of Ab1-42 in bvFTD. Ó 2013 The Alzheimer’s Association. All rights reserved.

Keywords:

Frontotemporal dementia; Neuropsychological assessment; Cerebrospinal fluid

1. Introduction Frontotemporal dementia (behavioral variant, bvFTD), the most common form of frontotemporal lobar degeneration (FTLD), is a heterogeneous disorder, both clinically and neuropathologically. Clinically, patients present with behavioral change often combined with executive dysfunction and language dysfunction [1]. Cognitive dysfunction, however, may vary between normal performance on neuropsychological *Corresponding author. Tel.: 131-20-444-0183; Fax: 131-20-4440715. E-mail address: [email protected]

assessment and the co-occurrence of episodic memory disturbances [2,3]. On a cellular pathological level, bvFTD is characterized by either tau-positive inclusions (tauopathies) or tau-negative ubiquitin-positive inclusions (FTLD-U), which are frequently related with pathology of the TAR DNA-binding protein Mr 43 kDa (TDP-43). A relatively smaller subgroup of bvFTD patients demonstrates TDP43-negative FTLD-U pathology, immunoreactive for the fused in sarcoma protein (FTLD-FUS) [4–6]. Alzheimer’s disease (AD) can be considered a tauopathy, as one of its pathological hallmarks is the presence of neurofibrillary tau-containing tangles. In AD, the concentration of total tau in cerebrospinal fluid (CSF) is increased, whereas

1552-5260/$ - see front matter Ó 2013 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2011.12.007

270

E.L.G.E. Koedam et al. / Alzheimer’s & Dementia 9 (2013) 269–275

that of amyloid-b1-42 (Ab1-42) is decreased. This combination has a high accuracy in discriminating AD patients from healthy elderly individuals, whereas these biomarkers should be used more cautiously in the differential diagnosis of dementia [7–9]. Several studies have investigated CSF biomarkers in either FTLD or the subgroup of bvFTD. In both groups, a wide range of CSF tau concentrations has been found, whereas the concentration of Ab1-42 varies between normal and low values [10–16]. This wide variability in levels of CSF biomarkers remains largely unexplained and might be related to the heterogeneity of underlying pathology or to varying neurodegenerative stages, particularly because it is known that disease duration in, for example, bvFTD varies from 2 to 20 years [17]. Progranulin (PGRN) mutations are a known cause of bvFTD, and PGRN and TDP-43 could be potential biological markers for FTLD. However, not much is known about plasma or CSF levels of PGRN or TDP-43 in FTLD patients. One study found a strongly reduced CSF progranulin level in PGRN mutation carriers [18]. Although the authors found that PGRN could be a useful marker for early identification of asymptomatic at-risk subjects, PGRN could not be considered as a marker for PGRN-negative FTLD subjects. In contrast to AD, a specific biomarker profile for FTLD or bvFTD has not yet been identified. However, low levels of CSF tau have been found in bvFTD and FTLD patients, but have never been reported in AD patients, and a low tau/Ab1-42 ratio seems to be able to discriminate FTLD from AD in patients with known pathology [11,15]. Assuming a relationship of cognitive decline to the degree of neurodegeneration and between CSF biomarkers and neurodegeneration, one would also expect a relationship between CSF biomarker levels and cognition. However, inconsistent results have been found in studies investigating relationships between CSF biomarkers and cognition in AD patients [10,12,14,19,20]. For FTLD, one study described relationships between CSF tau and cognition, whereas others reported no relationships between CSF biomarkers and either cognition or behavior [10,12,14,15]. The aim of our study was to investigate the relations between levels of the currently available CSF biomarkers (tau and Ab1-42) and cognition or behavioral symptoms in patients with bvFTD. We hypothesized that particularly CSF tau, either as a marker of the degree of intracerebral tau pathology or as a nonspecific marker of neurodegeneration, would be related to cognition or behavioral symptoms in bvFTD.

2. Methods

examination, including Mini-Mental State Examination (MMSE) [21], frontal assessment battery (FAB) [22], laboratory tests, neuropsychological assessment, behavioral assessment (neuropsychiatric inventory, NPI) [23], electroencephalography, and magnetic resonance imaging of the brain. We excluded eight patients because there was a period of more than a year between the neuropsychological assessment and lumbar puncture (LP), resulting in a sample size of 58 patients. In all patients, an LP was done within an average of 0.4 6 3 months from neuropsychological assessment. The diagnosis of bvFTD was made according to the International Consensus Diagnostic criteria by a multidisciplinary team including a neurologist, psychiatrist, neurophysiologist, radiologist, neuropsychologist, and specialist nurse [1]. Patients were followed up to confirm their diagnosis for at least 1 year. Postmortem confirmation of the diagnosis was available for five patients. CSF investigations are part of an ongoing study on CSF biomarkers in dementia, which has been approved by the ethical review board of the VU University Medical Center. All patients gave written informed consent. 2.2. CSF analysis CSF samples were obtained by LP between L3 and L4 or L4 and L5 intervertebral space; 12 mL was collected in polypropylene tubes and brought to the laboratory within 2 hours. Part of the CSF was used for routine analysis, including total cell count, as well as total protein determination. The remaining CSF was then centrifuged at 1800 g for 10 minutes at 4
C. The CSF samples were aliquoted into polypropylene tubes and stored at 280
C until further analysis. Ab1-42 and tau were measured in CSF with Innotest sandwich enzyme-linked immunosorbent assays, as described previously [19]. As the manufacturer does not supply controls, the performance of the assays was monitored with pools of surplus CSF specimens. In the study period, multiple specimens with various concentrations, which were included in 7 to 18 runs, have been used for this purpose. The interassay coefficient of variation (mean 6 SD) was 11.3% 6 4.9% for CSF Ab1-42 and 9.3% 6 1.5% for CSF tau. The team from the Department of Clinical Chemistry of the VU University Medical Center involved in the CSF analysis was not aware of the clinical diagnosis. Conversely, the results of CSF analysis were not known when the clinical diagnosis was made. The following cutoff values were used for this study: CSF Ab1-42 550 pg/mL and CSF tau 375 mg/mL [24].

2.1. Patients and clinical evaluation

2.3. Apolipoprotein E

We included 66 consecutive patients with a diagnosis of bvFTD, who presented at the Alzheimer Center of the VU University Medical Center in Amsterdam. All patients underwent a standard battery of investigations including a medical history, physical examination, and neurological

DNA was isolated from 10-mL blood samples in ethylenediaminetetraacetic acid. The apolipoprotein E (APOE) genotype was determined at the Department of Clinical Chemistry of the VU University Medical Center with the LightCycler APOE mutation detection method (Roche

E.L.G.E. Koedam et al. / Alzheimer’s & Dementia 9 (2013) 269–275

Diagnostics GmbH, Mannheim, Germany). APOE data were analyzed according to the presence or absence of an APOE 34 allele. APOE data were available for 51 patients. 2.4. Neuropsychological assessment Several neuropsychological tests were used to screen the major cognitive functions. Over time there was a variation in tests that were used, and therefore not all patients received the same test battery. This neuropsychological test battery included different tests. The forward condition of digit span was used for evaluating attention, whereas working memory was assessed with the backward condition [25]. In both cases, an extended version was used, with three trials per sequence length. In the forward condition, patients are asked to repeat a sequence of digits, starting from a twodigit sequence up to eight digits, if a patient answers correctly. In the backward condition, patients are asked to repeat the sequences in reverse order. Episodic memory was evaluated with the Visual Association Test (VAT) [26]. Patients are shown six cue cards with an object on it and associated cards with the earlier seen object plus an interacting object and are asked to name them. Subsequently, the cue cards are shown and the patients are asked to recall the missing interacting object. This is repeated in a second trial, and scores are summed to obtain a total score. Animal fluency, number of animals named in 1 minute, was used to assess semantic memory. For executive dysfunction, the Trail Making Test (TMT) part B and the Stroop color word test were used [27,28]. In the TMT-B, patients are asked to connect numbers and letters. In the Stroop test, a sheet is shown with words that are the names of colors, although the actual words are printed in a color of ink different from the color name they represent. The patients are asked to respond to the color they see (and disregard the word the read). VAT object naming was used for assessment of language [26]. Finally, the Rey–Osterrieth Complex Figure Copying test was used for evaluating visuospatial function [29]. 2.5. Statistical analysis For statistical analysis, SPSS version 15.0 (SPSS Inc., Chicago, IL) was used. Values of CSF tau and Ab1-42 from TMT and Stroop were log transformed before analysis, as they were not normally distributed. Basic demographic data were examined using c2 test for categorical data and t tests for continuous data. Linear regression analysis was used to analyse relations between CSF biomarkers and different neuropsychological tests and the NPI. In the first model, the relationship of each CSF biomarker (independent variable) with each cognitive test or NPI score (dependent variable) was assessed. In the second model, the same relationships were assessed after adjusting for age, sex, and education. In the third model, concentrations of both CSF biomarkers were entered simultaneously, together with age, sex, and education as covariates. In an additional

271

fourth model, we assessed the relationship of each CSF biomarker with each cognitive test or NPI additionally adjusted for APOE 34 status (presence or absence of an APOE 34 allele). Finally, we assessed the relationship between disease duration and each CSF biomarker. We repeated these analyses in a subgroup of patients, after excluding all patients with a CSF biomarker profile often seen in AD (high levels of tau and low levels of Ab1-42). Results are presented as standardized regression coefficients (bs) to allow comparison of effect sizes. Statistical significance was set at P , .05. 3. Results Table 1 shows the demographic characteristics of the patient group. The mean age was 63 6 8 years, and 33% were female. Mean CSF Ab1-42 was in the normal range according to the cutoff values used in the VU University Medical Center; mean levels of CSF tau, however, were above the cutoff value (CSF Ab1-42 550 pg/mL and CSF tau 375 mg/mL). Table 2 shows the linear regression coefficients between the two CSF biomarkers and the raw scores of the different neuropsychological tests. CSF tau was found to be negatively related with the VAT (b 5 20.3, P , .05), whereas CSF Ab1-42 was found to be positively related with the MMSE (b 5 0.3, P , .05) (Fig. 1A), FAB (b 5 0.6, P , .01) (Fig. 1B), VAT (b 5 0.3, P , .05), VAT object naming (b 5 0.4, P , .05), and digit span backwards test (b 5 0.3, P , .05). After correction for age, sex, and education, relationships remained largely unchanged, except for the relation between CSF Ab1-42 and the VAT and VAT object naming, which no longer reached statistical significance. Furthermore, we found that CSF Ab1-42 was related to digit span backwards test (b 5 0.4, P 5 .01) and to the MMSE (b 5 0.3, P , .05) independently of CSF tau, whereas CSF tau was related to the VAT (b 5 20.3, P , .05) independently of CSF Ab1-42 (data not shown). We did not find relations between CSF biomarkers and behavior abnormalities, measured using the NPI. Data on APOE were available for 51 patients, and 16 patients (31%) were APOE 34 carriers. When we additionally adjusted for APOE status, we still found relations between high levels of CSF Ab1-42 and lower scores on the digit Table 1 Demographic and clinical characteristics Age (at first symptoms) Females MMSE* Follow-up duration (years) Disease duration (years) NPI total scorey CSF tau, pg/mL CSF Ab1-42, pg/mL

63 (8) 19 (33%) 23 (7) 1.7 (1.6) 3.9 (3.8) 29 (16) 447 (337) 824 (278)

Abbreviations: CSF, cerebrospinal fluid; MMSE, Mini-Mental State Examination; NPI, neuropsychiatric inventory; Ab, amyloid b. NOTE. Data are presented as mean (SD) or N (%). *MMSE available for 53 patients. y NPI available for 20 patients.

272

E.L.G.E. Koedam et al. / Alzheimer’s & Dementia 9 (2013) 269–275

Table 2 Linear regression analysis between CSF biomarkers and neuropsychological tests N

Raw scores

MMSE

53

23 (7)

FAB

20

12 (5)

VAT

48

4 (2)

VAT object naming

38

11 (2)

Digit span forward

51

11 (3)

Digit span backward

49

6 (3)

Animal fluency

48

14 (6)

TMT-A{

45

72 (62)

TMT-B{

46

247 (184)

Stroop-1{

31

58 (16)

Stroop-2{

32

115 (165)

Stroop-3{

27

250 (277)

Rey–Osterrieth Figure

32

30 (7)

NPI

20

29 (16)

Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2 Model 1 Model 2

Ab1-42

Tau

0.3* 0.3y 0.6z 0.5* 0.3* 0.2 0.4* 0.3 0.2 0.2 0.3* 0.3x 0.02 0.02 20.3 20.2 20.3 20.2 0.1 0.2 0.2 0.2 20.005 0.08 20.1 20.1 0.2 0.2

20.2 20.1 20.02 0.2 20.3* 20.3* 20.07 0.02 20.04 20.02 20.06 20.05 20.1 20.1 20.04 20.1 20.1 20.1 0.2 0.2 0.1 0.04 0.3 0.2 0.1 0.04 0.2 0.2

Abbreviations: VAT, Visual Association Test; FAB, frontal assessment battery; TMT-A, Trail Making Test part A; TMT-B, Trail Making Test part B. NOTE. N represents the total number of patients for whom the different tests were available. Raw scores are presented as mean (SD). Results of the linear regression analysis are presented as standardized regression coefficients (bs) to allow comparison of effect sizes. Model 1 shows unadjusted associations, and in the second model, there was a correction for age, sex, and education. For statistical analysis, CSF biomarkers Ab1-42 and tau and neuropsychological tests TMT and Stroop were log transformed. *P , .05. y P 5 .05. z P , .01. x P 5 .01. { Results in seconds: lower scores signify better (i.e., faster) performance.

span backwards test (b 5 0.4, P , .05), the FAB (b 5 0.8, P , .05), and the MMSE (b 5 0.4, P , .05). Furthermore, high levels of CSF tau were associated with low scores on the VAT (b 5 20.3, P , .05). We did not find a correlation between values of CSFAb1-42 or CSF tau and disease duration (b 5 0.09, P 5 .5 and b 5 20.1, P 5 .5). We performed a second set of analyses in which we excluded patients (N 5 7, 12%) with a CSF profile often seen in AD patients (a combination of low CSF Ab1-42, 550 pg/mL and high CSF tau, 375 pg/mL; N 5 7, 12%). These patients performed worse on the MMSE (mean MMSE score 18 6 9); however, there were no differences in mean disease duration or follow-up duration

Fig. 1. (A) It shows a scatterplot of cerebrospinal fluid amyloid b1-42 (CSF Ab1-42) levels in relation to MMSE scores in behavioral variant of frontotemporal dementia. (B) It shows a scatterplot of CSF Ab1-42 levels in relation to frontal assessment battery scores in behavioral variant of frontotemporal dementia. Low CSF Ab1-42 levels were associated with lower scores on the MMSE and the frontal assessment battery. Please note the logarithmic scale on the y-axis.

between patients with and without this specific CSF profile. In the remaining sample (N 5 51), we found relations (corrected for age, sex, and education) between CSF Ab1-42 and VAT object naming (b 5 0.4, P , .05) and the FAB (b 5 0.5, P , .05), but there was no longer a relation with the MMSE, VAT, and digit span backwards test. In this sample of patients, there was no relation between CSF tau and cognition. 4. Discussion In this study, we studied relations between the currently available CSF biomarkers (tau and Ab1-42) and cognition or behavior in bvFTD. We found that low CSF Ab1-42 levels correlated with worse general cognitive performance,

E.L.G.E. Koedam et al. / Alzheimer’s & Dementia 9 (2013) 269–275

working memory performance, and executive function. We did not find relations between CSF biomarkers and severity of behavior symptoms. Not many studies have investigated the possible relationship between cognitive functioning or behavioral symptoms and CSF biomarkers in FTLD or bvFTD, and their results are inconsistent. One study reported negative relations between CSF tau and confrontation naming in FTLD patients, whereas others did not describe correlations between CSF tau and MMSE score or tests for executive function [10,12,14,15]. We found that high CSF tau levels were correlated with worse memory performance. However, caution must be taken into account with the interpretation of these results, as the correlations disappeared when patients with an AD-like CSF profile were excluded. No relations have been reported between CSF Ab1-42 and cognition in bvFTD, whereas in AD patients, low CSF Ab1-42 was associated with lower scores on the MMSE [10,14,19]. One study found a relation between CSF Ab1-42 and aggression in AD patients, but did not find such relations in patients with FTD [10]. We cannot fully compare our results with the previous studies, as we only looked at bvFTD patients, whereas in the literature, most studies focus on FTLD patients. We chose to include only patients with bvFTD to create a clinically homogeneous patient group. Furthermore, language impairment could very well influence results on cognitive examination, and therefore we excluded patients with the language variants of FTLD (semantic dementia and progressive nonfluent aphasia). We believe that our study gives a good representation of the relations between cognition and CSF biomarkers in bvFTD patients. It remains unclear whether in our sample low CSF Ab1-42 and high CSF tau reflect a more progressed disease stage or disease intensity or represent underlying pathology. Tau is believed to reflect the intensity of neurodegeneration in the brain and is known to be increased not only in AD patients but also after ischemic stroke or in patients with Creutzfeldt–Jakob disease [30,31]. High values of CSF tau in bvFTD could also be a reflection of possible tau pathology, like Pick’s disease or microtubule-associated protein tau gene mutations, although it has been found that patients with a known tau mutation did not have increased CSF tau levels [32,33]. In contrast, CSF Ab1-42 is suggested to reflect the disease stage with decreasing levels when the disease progresses in AD patients [7,34]. This seems to be supported by the finding that CSF Ab1-42 is correlated with lower MMSE scores in AD patients, which could indicate that a lower level of CSF Ab1-42 is associated with more severe cognitive impairment [10,19]. This hypothesis, however, is contradicted by longitudinal measurement of CSF Ab1-42 in AD, showing no decline over time [35]. We performed an additional analysis to investigate the relationship between CSF biomarkers and disease duration in our study group. We also did not find any correlations between CSF Ab1-42 or CSF tau values and disease duration (b 5 0.09, P 5 .5 and b 5 20.1, P 5 .5).

273

Surprisingly, the main finding of our study was the existence of robust relations between CSF Ab1-42 and cognition. Amyloid plaque deposition, however, is not a pathological hallmark of bvFTD, and it remains intriguing which role Ab1-42 plays in bvFTD pathology. Soluble Ab42 and Ab40 have been found to be increased in FTLD with tau mutations, suggesting Ab peptides are associated with tau pathology in this disorder [36]. It has been suggested that Ab and tau abnormalities are linked through common upstream drivers [37]. In this pathway, common upstream drivers (APOE 34 and glycogen synthase kinase 3) cause elevation in both Ab and tau hyperphosphorylation through independent, but parallel, mechanisms. Furthermore, one other study found that mutations in the glycogen synthase kinase 3 b gene are a potential genetic risk factor for AD and FTD [38]. Although the exact mechanism in which Ab relates to tau in bvFTD remains unclear, these studies suggest pathophysiological involvement of Ab in bvFTD. This suggestion is also strongly supported by our results, as even after entering both CSF biomarkers in the same model, we still found a relation between CSF Ab1-42 and the MMSE, FAB, and digit span backwards test independently of CSF tau, whereas CSF tau related with the VAT independently of CSF Ab1-42. It could be argued that the patients with a combination of low levels of CSF Ab1-42 and high levels of CSF tau, as well as lower MMSE scores, are less likely to have underlying FTLD pathology and more likely to have AD pathology. As none of these seven patients came to autopsy, this is only one possible hypothesis. On the other hand, these patients fulfilled clinical criteria for bvFTD and were followed for at least 1 year (mean follow-up: 1.7 6 1.6 years), in which time the clinical diagnosis remained stable. Combinations of high CSF tau and low CSF Ab1-42 have been described in other studies in bvFTD, which might as well represent a subgroup of bvFTD [12,14]. We, therefore, did not exclude these patients from our main analyses. Moreover, even after omitting cases with an AD-like CSF profile, associations between Ab1-42 and global cognition remained essentially the same. In the remaining sample, we found correlations between Ab1-42 and tests for language (VAT object naming) and executive function (FAB), two domains often impaired in bvFTD. These results suggest a possible role for Ab1-42 in bvFTD pathology. Although we cannot fully exclude other underlying pathology, we think it is highly unlikely that misdiagnosis would account for all our results. It has been found that cognition is more impaired in AD patients and patients with mild cognitive impairment when they possess one or more APOE 34 alleles [39,40]. It could, therefore, be argued that the presence of APOE 34 could be responsible for the relationships we found between CSF Ab142 and CSF tau and cognition. However, when we corrected for the presence of an APOE 34 allele, our results did not essentially change. We, therefore, do not believe that the presence of APOE 34 carriers is responsible for the

274

E.L.G.E. Koedam et al. / Alzheimer’s & Dementia 9 (2013) 269–275

relationships between CSF biomarkers and cognition in this study group. It might be hypothesized that more neurodegeneration in turn leads to more cognitive impairment. The most common manifestation of bvFTD is a profound change in behavior and personality, characterized by apathy and loss of initiative, or social disinhibition and distractibility. Cognitive deficits consist of impairment in abstraction, planning, and problem solving (dysexecutive syndrome), whereas memory, language, and spatial functions are relatively preserved [1]. However, a presentation with prominent memory impairment in patients with pathologically confirmed bvFTD has been reported by several studies and has been associated with the presence of hippocampal atrophy [2,41,42]. In addition, it has been found that patients with bvFTD perform more poorly than patients with AD on verbal ability and picture naming [43]. Finally, a small proportion of bvFTD patients do not have prominent behavioral abnormalities or cognitive impairment at presentation [3]. It has been found that less severe cognitive impairment typically occurs in bvFTD patients without atrophy on magnetic resonance imaging [44]. We extend these former findings by showing that a more abnormal CSF profile (low levels of Ab1-42 and high levels of tau) correlates with a relatively stronger impairment of cognition. Unfortunately, we did not find relations between CSF biomarkers and behavioral symptoms. However, further longitudinal research with standardized behavioral questionnaires and a larger, preferably pathologically confirmed, patient group is essential to determine exact relations between CSF biomarkers and behavioral deterioration or cognition in bvFTD. Acknowledgments The Alzheimer Center VUmc receives funding from Stichting VUmc Fonds, Stichting Alzheimer Nederland, and Stichting Dioraphte. The clinical database structure was developed with funding from Stichting Dioraphte. Statistical analyses were conducted by E.L.G.E.K. and W.M.V.F. P.S. serves as a book review editor of Alzheimer’s Disease and Associated Disorders, and works on the editorial board of Dementia and Geriatric Cognitive Disorders. References [1] Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 1998;51:1546–54. [2] Graham A, Davies R, Xuereb J, Halliday G, Kril J, Creasey H, et al. Pathologically proven frontotemporal dementia presenting with severe amnesia. Brain 2005;128(Pt 3):597–605. [3] Hornberger M, Piguet O, Kipps C, Hodges JR. Executive function in progressive and nonprogressive behavioral variant frontotemporal dementia. Neurology 2008;71:1481–8. [4] Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol 2007;171:227–40.

[5] Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 2007; 114:5–22. [6] Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010;119:1–4. [7] Blennow K, Vanmechelen E. CSF markers for pathogenic processes in Alzheimer’s disease: diagnostic implications and use in clinical neurochemistry. Brain Res Bull 2003;61:235–42. [8] Hampel H, Goernitz A, Buerger K. Advances in the development of biomarkers for Alzheimer’s disease: from CSF total tau and Abeta(1-42) proteins to phosphorylated tau protein. Brain Res Bull 2003;61:243–53. [9] Blennow K, Hampel H. CSF markers for incipient Alzheimer’s disease. Lancet Neurol 2003;2:605–13. [10] Engelborghs S, Maertens K, Vloeberghs E, Aerts T, Somers N, Marien P, et al. Neuropsychological and behavioural correlates of CSF biomarkers in dementia. Neurochem Int 2006;48:286–95. [11] Grossman M, Farmer J, Leight S, Work M, Moore P, Van DV, et al. Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer’s disease. Ann Neurol 2005;57:721–9. [12] Kapaki E, Paraskevas GP, Papageorgiou SG, Bonakis A, Kalfakis N, Zalonis I, et al. Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 2008; 22:47–53. [13] Pijnenburg YA, Schoonenboom NS, Scheltens P. Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2003;60:353–4. [14] Riemenschneider M, Wagenpfeil S, Diehl J, Lautenschlager N, Theml T, Heldmann B, et al. Tau and Abeta42 protein in CSF of patients with frontotemporal degeneration. Neurology 2002;58:1622–8. [15] Bian H, Van Swieten JC, Leight S, Massimo L, Wood E, Forman M, et al. CSF biomarkers in frontotemporal lobar degeneration with known pathology. Neurology 2008;70(19 Pt 2):1827–35. [16] de Souza LC, Lamari F, Belliard S, Jardel C, Houillier C, De PR, et al. Cerebrospinal fluid biomarkers in the differential diagnosis of Alzheimer’s disease from other cortical dementias. J Neurol Neurosurg Psychiatry 2011;82:240–6. [17] Neary D, Snowden J, Mann D. Frontotemporal dementia. Lancet Neurol 2005;4:771–80. [18] Ghidoni R, Benussi L, Glionna M, Franzoni M, Binetti G. Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 2008;71:1235–9. [19] Bouwman FH, Schoonenboom NS, Verwey NA, Van Elk EJ, Kok A, Blankenstein MA, et al. CSF biomarker levels in early and late onset Alzheimer’s disease. Neurobiol Aging 2009;30:1895–901. [20] van der Vlies AE, Verwey NA, Bouwman FH, Blankenstein MA, Klein M, Scheltens P, et al. CSF biomarkers in relationship to cognitive profiles in Alzheimer disease. Neurology 2009;72:1056–61. [21] Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189–98. [22] Dubois B, Slachevsky A, Litvan I, Pillon B, The FAB. a frontal assessment battery at bedside. Neurology 2000;55:1621–6. [23] Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44:2308–14. [24] Mulder C, Verwey NA, van der Flier WM, Bouwman FH, Kok A, Van Elk EJ, et al. Amyloid-beta(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem 2010;56:248–53. [25] Wechsler DA. Wechsler Adult Intelligence Scale: revised. New York, NY: The Psychological Corporation; 1981.

E.L.G.E. Koedam et al. / Alzheimer’s & Dementia 9 (2013) 269–275 [26] Lindeboom J, Schmand B, Tulner L, Walstra G, Jonker C. Visual association test to detect early dementia of the Alzheimer type. J Neurol Neurosurg Psychiatry 2002;73:126–33. [27] Reitan R. Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 1958;8:271–6. [28] Stroop J. Studies of interference in serial verbal reactions. J Exp Psychol 1935;18:643–62. [29] Osterrieth PA. Le test de copie dune figure complexe. Arch Psychol 1944;30:206–356. [30] Hesse C, Rosengren L, Vanmechelen E, Vanderstichele H, Jensen C, Davidsson P, et al. Cerebrospinal fluid markers for Alzheimer’s disease evaluated after acute ischemic stroke. JAlzheimers Dis 2000;2:199–206. [31] Van Everbroeck B, Green AJ, Pals P, Martin JJ, Cras P. Decreased levels of amyloid-beta 1-42 in cerebrospinal fluid of CreutzfeldtJakob disease patients. J Alzheimers Dis 1999;1:419–24. [32] Forman MS, Farmer J, Johnson JK, Clark CM, Arnold SE, Coslett HB, et al. Frontotemporal dementia: clinicopathological correlations. Ann Neurol 2006;59:952–62. [33] Rosso SM, van HE, Pijnenburg YA, Schoonenboom NS, Scheltens P, Heutink P, et al. Total tau and phosphorylated tau 181 levels in the cerebrospinal fluid of patients with frontotemporal dementia due to P301L and G272V tau mutations. Arch Neurol 2003;60:1209–13. [34] Wahlund LO, Blennow K. Cerebrospinal fluid biomarkers for disease stage and intensity in cognitively impaired patients. Neurosci Lett 2003;339:99–102. [35] Bouwman FH, van der Flier WM, Schoonenboom NS, Van Elk EJ, Kok A, Rijmen F, et al. Longitudinal changes of CSF biomarkers in memory clinic patients. Neurology 2007;69:1006–11.

275

[36] Vitali A, Piccini A, Borghi R, Fornaro P, Siedlak SL, Smith MA, et al. Soluble amyloid beta-protein is increased in frontotemporal dementia with tau gene mutations. J Alzheimers Dis 2004;6:45–51. [37] Small SA, Duff K. Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 2008;60:534–42. [38] Schaffer BA, Bertram L, Miller BL, Mullin K, Weintraub S, Johnson N, et al. Association of GSK3B with Alzheimer disease and frontotemporal dementia. Arch Neurol 2008;65:1368–74. [39] van der Vlies AE, Pijnenburg YA, Koene T, Klein M, Kok A, Scheltens P, et al. Cognitive impairment in Alzheimer’s disease is modified by APOE genotype. Dement Geriatr Cogn Disord 2007;24:98–103. [40] Smith GE, Bohac DL, Waring SC, Kokmen E, Tangalos EG, Ivnik RJ, et al. Apolipoprotein E genotype influences cognitive ’phenotype’ in patients with Alzheimer’s disease but not in healthy control subjects. Neurology 1998;50:355–62. [41] Hodges JR, Davies RR, Xuereb JH, Casey B, Broe M, Bak TH, et al. Clinicopathological correlates in frontotemporal dementia. Ann Neurol 2004;56:399–406. [42] Ostojic J, Elfgren C, Passant U, Nilsson K, Gustafson L, Lannfelt L, et al. The tau R406W mutation causes progressive presenile dementia with bitemporal atrophy. Dement Geriatr Cogn Disord 2004;17:298–301. [43] Hutchinson AD, Mathias JL. Neuropsychological deficits in frontotemporal dementia and Alzheimer’s disease: a meta-analytic review. J Neurol Neurosurg Psychiatry 2007;78:917–28. [44] Kipps CM, Davies RR, Mitchell J, Kril JJ, Halliday GM, Hodges JR. Clinical significance of lobar atrophy in frontotemporal dementia: application of an MRI visual rating scale. Dement Geriatr Cogn Disord 2007;23:334–42.