611
Journal of Alzheimer’s Disease 39 (2014) 611–616 DOI 10.3233/JAD-131382 IOS Press
Increased Cerebrospinal Fluid Tau Levels in Logopenic Variant of Alzheimer’s Disease Eloi Magnina,∗ , Claire Paquetb , Mait´e Formaglioc , Bernard Croisilec , Ludivine Chamarda , Carole Miguet-Alfonsid , Gregory Tioa , Julien Dumurgierb , Isabelle Roullet-Solignacc , Mathilde Sauv´eee , Catherine Thomas-Ant´erionf , Alain Vighettoc , Jacques Hugonb and Pierre Vandela a Research
Memory Center (CMRR), CHU Besan¸con, Besan¸con, France Memory Center (CMRR) Paris-Nord-Ile-de France, AP-HP, Universit´e Paris Diderot, Paris, France c Research Memory Center (CMRR), CHU Lyon, Lyon, France d Department of Biology, CHU Besan¸ con, Besan¸con, France e Department of Neurology, CHU Nancy, Nancy, France f Regional Memory Center (CMRR), CHU Saint-Etienne, Saint Priest en Jarez, France b Research
Handling Associate Editor: Audrey Gabelle
Accepted 29 September 2013
Abstract. Background: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer’s disease (AD). Objective: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). Methods: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). Results: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. Conclusions: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD. Keywords: Alzheimer’s disease, cerebrospinal fluid markers, logopenic, mild cognitive impairment, primary progressive aphasia
INTRODUCTION The logopenic variant of primary progressive aphasia (lvPPA) described by Gorno-Tempini et al. [1] is characterized by anomia, with more frequent difficulties for word retrieval in spontaneous speech than in ∗ Correspondence
to: Eloi Magnin, Department of Neurology, University Hospital, 25000 Besancon, France. Tel.: +33 381668098; Fax: +33 381668470; E-mail: [email protected].
naming tests and a length-dependent repetition deficit. A postmortem study showed that neuropathological lesions of Alzheimer’s disease (AD) type are the most frequent underlying process in patients with lvPPA [2]. However, other neuropathological lesions can also be linked to lvPPA such as frontotemporal dementia with tauopathy or dementia associated with progranulin mutation [2–4]. Cerebrospinal fluid (CSF) biomarkers of AD (amyloid-, total tau, and phosphorylated tau
ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
612
E. Magnin et al. / Increased Tau in Logopenic Variant of AD
protein) are now used and reflect the underlying AD pathology in vivo in patients with AD, amnestic mild cognitive impairment (aMCI), and lvPPA [5, 6]. The lvPPA associated with underlying AD pathology is sometimes considered as a left form of typical AD [6], but similar patterns of molecular imaging of amyloid deposits as in typical AD are detected [7, 8]. However, despite histological limitations in postmortem analysis that are often observed at the terminal stage of the disease, a study has revealed that the density of neurofibrillary tangles in lvPPA due to AD is more marked in the left temporo-parietal junction than in typical AD [9]. CSF AD biomarkers are performed very often at the time of diagnosis. We hypothesize that CSF AD biomarkers in lvPPA due to AD might also reflect this neuropathological difference concerning tau at an earlier stage of the disease. The objective of this study was to compare the levels CSF AD biomarkers in three groups: patients with lvPPA with biological CSF AD profile (lvPPA-AD), patients with aMCI with biological CSF AD profile (aMCI-AD), and mild typical and non-logopenic AD with CSF AD profile (nlAD).
MATERIAL AND METHODS Subject selection Between January 2008 and December 2012, all included patients were referred to the French regional memory centers (Besanc¸on, Lyon, Nancy, Paris, SaintEtienne) and were diagnosed in each center by a multidisciplinary team of neurologists and neuropsychologists, specializing in cognitive disorders, who were blind to the CSF results. A retrospective multicentric study was conducted in all patients diagnosed with lvPPA-AD and matched with nlAD and aMCIAD patients. To be included, patients with lvPPA-AD, nlAD, or aMCI had to display CSF biomarker results favoring an AD biological profile with abnormal values for at least two biomarkers and an Innogenetics Amyloid/Tau Index (IATI) below 0.8 or an A1-42 /pTau181 ratio below 9. In all involved laboratories, the following cut offs were used: A1-42 350 pg/mL, and p-Tau181 >50 pg/mL [10]. Because the manufacturer does not supply controls, the performance of the assays was controlled with internal surplus CSF samples. lvPPA-AD cases had to fulfill Mesulam’s criteria for the diagnosis of primary progressive aphasia [11] and
then display specific logopenic variant criteria according to the latest classification [12]: anomia, impaired sentence repetition, imaging-supported criteria defined as a left posterior perisylvian or parietal atrophy and/or left posterior perisylvian or parietal hypoperfusion, and at least three of the following linguistic features: phonologic paraphasia; spared single word comprehenstion and object knowledge; speared motor speech, or absence of agrammatism. aMCI was diagnosed according to Petersen criteria [13] and typical nlAD were selected according to NINCDS-ADRDA criteria [14]. CSF biomarkers levels were compared between the three groups and were adjusted for age, level of education, disease duration, and centers. Each regional ethics committee approved the use of human subjects for this study. Consent forms were signed by all patients. CSF analysis Lumbar punctures were performed in each center during the month following the clinical diagnosis. CSF was collected directly in polypropylene tubes, under standardized conditions. Each CSF sample was transferred to each local laboratory less than 4 hours after collection and was centrifuged at 1,000 g for 10 minutes at 4◦ C. CSF was aliquoted in polypropylene tubes of 0.5 mL and stored at −80◦ C until further analysis. CSF peptide A1–42 , protein total tau (tTau), and phosphorylated on threonine 181 Tau (p-Tau181) biomarker tests were performed for all subjects in local laboratories. Since the establishment of two national cohorts [15, 16] and a national network [17], all laboratories work together using the same procedures of INNOTEST® sandwich ELISA (Innogenetics, Ghent, Belgium). Biological teams involved in the CSF analysis were unaware of the clinical diagnosis. Statistical analysis The Gaussian distribution assumption was tested using the Shapiro-Wilk test. The results for the groups were compared using the Student’s t-test or the MannWhitney-Wilcoxon test for continuous variables and the chi-squared (χ2 ) test for categorical variables. Correlations between CSF biomarkers and Mini-Mental State Examination (MMSE), age, and disease duration were tested using Spearman’s rank correlation. ANOVA was used to compare biomarkers value between the three levels of education groups. All statistical analyses were performed with strata software (release 8.0, Statacorp, College Station, TX).
E. Magnin et al. / Increased Tau in Logopenic Variant of AD
613
Table 1 Characteristics of the study sample lvPPA-AD (n = 30)
nlAD (n = 67)
aMCI-AD (n = 27)
p
68.63 [52–86] (SD 7.79) 60% / 40% 2.96 [1–8] (SD 1.6) 41% / 22% / 37% 20.06* [9–30] (SD 5.72)
72.14 [53–88] (SD 8.49) 63% / 37% 2.47 [0.5–10] (SD 1.85) 45% / 20% / 35% 18.87◦ [11–26] (SD 5.02)
72.88 [50–86] (SD 8.31) 59% / 41% 2.67 [0.5–8] (SD 1.66) 33% / 11% / 56% 25.59 [18–29] (sSD 2.79)
0.0973
Age (years) Gender (Female/Male) Disease duration (years) Level of education (low/average/high) MMSE (/30)
0.45 0.1567 0.4510 0.0001
lvPPA-AD, logopenic variant of primary progressive aphasia due to Alzheimer’s disease; nlAD, non-logopenic Alzheimer’s disease; aMCI-AD, amnesic mild cognitive impairment due to Alzheimer’s disease; MMSE, Mini-Mental State Examination; SD, standard deviation; *significant difference between lvPPA-AD (p < 0.001) and aMCI-AD; ◦ significant difference between nlAD and aMCI–AD (p < 0.001). pTau181 (pg/mL)
Aβ1-42 (pg/mL) 1400
Total Tau (pg/mL) 3000
300
A
B
1200
C
250
2500
200
2000
150
1500
100
1000
50
500
1000
800
600
400
200
0
0
0 IvPPA-AD
nI-AD
aMCI-AD
IvPPA-AD
nI-AD
aMCI-AD
IvPPA-AD
nI-AD
aMCI-AD
Fig. 1. Vertical scatter plot showing the distribution of CSF AD biomarker values in the three groups. A) A1-42 ; B) p-Tau181; C) total tau. lvPPA-AD, logopenic variant of primary progressive aphasia due to Alzheimer’s disease; nlAD, non-logopenic Alzheimer’s disease; aMCI-AD, amnesic mild cognitive impairment due to Alzheimer’s disease; *p < 0.05, ***p < 0.001.
RESULTS Demographic data of the three groups are included in Table 1. No significant difference was observed between lvPPA-AD and the other groups for age, gender, level of education, or disease duration from onset of symptoms. Mean MMSE was lower in lvPPAAD and nlAD groups compared to aMCI-AD group (p < 0.05). No significant difference was observed between lvPPA-AD and nlAD for MMSE. The mean A1-42 value was 459.87 pg/mL (164−1,162, SD 202.18) in the lvPPA-AD group, 439.32 pg/mL (125−1,089, SD 175.15) in the nl-AD group, and 444.11 pg/mL (125–1176, SD 193.12) in the aMCIAD group. The mean total tau value was 883.44 pg/mL (376.1−2,452, SD 434.21) in the lvPPA-AD group,
690.96 pg/mL (191−1,899, SD 343.81) in the nl-AD group, and 592.05 pg/mL (188−1,200, SD 272.55) in the aMCI-AD group. The mean p-Tau181 value was 110.06 pg/mL (67–246, SD 36.69) in the lvPPA-AD group, 101.25 pg/mL (45.7–229, SD 36.55) in the nlAD group, and 93.35 pg/mL (35–206, SD 43.66) in the aMCI-AD group. The mean p-Tau181 value was higher in the lvPPA-AD group compared to the aMCIAD group (p < 0.05), while the mean total tau value was higher in the lvPPA-AD group compared to the nlAD (p < 0.05) and aMCI-AD groups (p < 0.001) (Fig. 1). There was a significant negative correlation between pTau181 and age of the patients (p < 0.05; r = −0.38) in the lvPPA-AD group. No significant difference was observed for CSF A1-42 levels between the three groups. No correlation was observed between CSF
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biomarkers, MMSE, or disease duration in lvPPA-AD group. No difference in biomarker value was observed between the three levels of education in lvPPA-AD group.
DISCUSSION In a multi-centric study of lvPPA-AD patients, we report higher mean CSF levels of tau or p181tau in lvPPA-AD patients compared to matched nlAD or aMCI-AD subjects. Neuropathologic findings confirm different patterns of the distribution of AD neuropathologic lesions between lvPPA due to AD and typical AD. lvPPA-AD is associated with enhanced temporoparietal neurodegeneration compared to typical AD [9]. In our study, according to biomarker results, lvPPAAD appears more severe compared to nlAD; total tau levels are increased reflecting a more pronounced neuronal loss that probably results from a larger volume of damage, especially in the parieto-temporal junction [9]. The higher p-Tau181 levels in the lvPPA-AD group compared to the aMCI-AD group suggest that tauopathy lesions are enhanced in lvPPA in accordance with the higher neurofibrillary tangle density shown by Joseph et al. [9]. The magnitude of tauopathy (as reflected by p181 levels and neuronal death reflected by tau levels in these forms of AD) are enhanced in lvPPAAD, which could be considered as a more aggressive form of AD with regards to neurodegeneration. The negative correlation between age and p-Tau181 in the CSF suggest that in living lvPPA-AD patients, tauopathy is more severe in younger patients. This finding is concordant with the faster cognitive decline detected particularly in nonverbal domains in lvPPA compared to the APP semantic variant in the majority of cases meeting criteria for dementia within 12 months [18]. However, the decline of activities of daily living is similar between lvPPA and nlAD [19]. The differences between CSF biomarker levels are not explained by age, disease duration, level of education, or the center. This is the first work that demonstrates a difference in CSF AD biomarker results between lvPPA-AD and different stages of typical AD (MCI and dementia). Others papers have reported very high total tau and p-Tau181 levels in 5 and 7 patients [6–20], respectively, without direct comparison of CSF AD biomarkers between lvPPA-AD and typical AD or MCI. Furthermore, Koric et al. studied an heterogeneous group of atypical AD patients (language and visuospatial disorders) and reported high tTau level [21].
Neuropsychological studies showed that different profiles, especially on verbal memory and linguistic tests, were observed between lvPPA, typical AD, and MCI patients [22, 23]. A neuroimaging study demonstrated that patterns of atrophy and hypometabolism differ between lvPPA and AD [24]. Therefore, lvPPA appears to be different from typical AD and other atypical AD. Seguin and colleagues found comparable CSF AD biomarker results in AD CSF between typical AD and posterior cortical atrophy (PCA), while 10% of PCA patients did not have CSF profiles consistent with AD [25]. The absence of a difference between A1-42 in the three groups is not in agreement with a molecular imaging study that has shown that total amyloid load was lower in lvPPA patients compared to typical AD patients [26]. However, methodologies and groups of patients were different and further studies in larger cohorts are needed to explore these different results. Some limitations have to be considered. The retrospective method can lead to bias, patients did not undergo the same clinical follow up, and we have no neuropathological confirmation. Thus histological and longitudinal clinical studies that could confirm our biological conclusions were not possible. As we have previously reported, inter-center and intra-center variability of CSF [27], harmonization of procedures have been performed in France to optimize the accuracy of CSF biomarkers in AD and minimize inter-center variability [15–17, 28]. Common international Innogennetics cut-offs were used to interpret CSF biomarkers in the three centers [10]. To explore A formation and release, it would be better in the future to also determine A1-40 levels and compare A1-42/A1-40 ratio in each group in order to overcome the bias introduced by inter-individual variability of amyloid production [29]. Therefore, lvPPA-AD could be considered as a specific form of AD with peculiar localization of lesions and a more extensive cellular tau pathology and neurodegeneration as compared to nlAD. Future prospective and longitudinal studies including biomarkers would be useful to investigate correlations between cognitive performances, cognitive decline, atrophy rate on MRI, biological profile, cortical metabolisms, or uptake of amyloid and/or tau radiotracers. Improvement of clinical, biologica,l and neuroimaging classifications and stratifications of atypical AD are needed to better understand the mechanisms underlying these clinical syndromes in order to predict their evolution and to offer adapted clinical trials focused either on amyloidopathy or tauopathy [30].
E. Magnin et al. / Increased Tau in Logopenic Variant of AD
DISCLOSURE STATEMENT Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1972).
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Journal of Alzheimer’s Disease 39 (2014) 611–616 DOI 10.3233/JAD-131382 IOS Press
Increased Cerebrospinal Fluid Tau Levels in Logopenic Variant of Alzheimer’s Disease Eloi Magnina,∗ , Claire Paquetb , Mait´e Formaglioc , Bernard Croisilec , Ludivine Chamarda , Carole Miguet-Alfonsid , Gregory Tioa , Julien Dumurgierb , Isabelle Roullet-Solignacc , Mathilde Sauv´eee , Catherine Thomas-Ant´erionf , Alain Vighettoc , Jacques Hugonb and Pierre Vandela a Research
Memory Center (CMRR), CHU Besan¸con, Besan¸con, France Memory Center (CMRR) Paris-Nord-Ile-de France, AP-HP, Universit´e Paris Diderot, Paris, France c Research Memory Center (CMRR), CHU Lyon, Lyon, France d Department of Biology, CHU Besan¸ con, Besan¸con, France e Department of Neurology, CHU Nancy, Nancy, France f Regional Memory Center (CMRR), CHU Saint-Etienne, Saint Priest en Jarez, France b Research
Handling Associate Editor: Audrey Gabelle
Accepted 29 September 2013
Abstract. Background: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer’s disease (AD). Objective: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). Methods: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). Results: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. Conclusions: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD. Keywords: Alzheimer’s disease, cerebrospinal fluid markers, logopenic, mild cognitive impairment, primary progressive aphasia
INTRODUCTION The logopenic variant of primary progressive aphasia (lvPPA) described by Gorno-Tempini et al. [1] is characterized by anomia, with more frequent difficulties for word retrieval in spontaneous speech than in ∗ Correspondence
to: Eloi Magnin, Department of Neurology, University Hospital, 25000 Besancon, France. Tel.: +33 381668098; Fax: +33 381668470; E-mail: [email protected].
naming tests and a length-dependent repetition deficit. A postmortem study showed that neuropathological lesions of Alzheimer’s disease (AD) type are the most frequent underlying process in patients with lvPPA [2]. However, other neuropathological lesions can also be linked to lvPPA such as frontotemporal dementia with tauopathy or dementia associated with progranulin mutation [2–4]. Cerebrospinal fluid (CSF) biomarkers of AD (amyloid-, total tau, and phosphorylated tau
ISSN 1387-2877/14/$27.50 © 2014 – IOS Press and the authors. All rights reserved
612
E. Magnin et al. / Increased Tau in Logopenic Variant of AD
protein) are now used and reflect the underlying AD pathology in vivo in patients with AD, amnestic mild cognitive impairment (aMCI), and lvPPA [5, 6]. The lvPPA associated with underlying AD pathology is sometimes considered as a left form of typical AD [6], but similar patterns of molecular imaging of amyloid deposits as in typical AD are detected [7, 8]. However, despite histological limitations in postmortem analysis that are often observed at the terminal stage of the disease, a study has revealed that the density of neurofibrillary tangles in lvPPA due to AD is more marked in the left temporo-parietal junction than in typical AD [9]. CSF AD biomarkers are performed very often at the time of diagnosis. We hypothesize that CSF AD biomarkers in lvPPA due to AD might also reflect this neuropathological difference concerning tau at an earlier stage of the disease. The objective of this study was to compare the levels CSF AD biomarkers in three groups: patients with lvPPA with biological CSF AD profile (lvPPA-AD), patients with aMCI with biological CSF AD profile (aMCI-AD), and mild typical and non-logopenic AD with CSF AD profile (nlAD).
MATERIAL AND METHODS Subject selection Between January 2008 and December 2012, all included patients were referred to the French regional memory centers (Besanc¸on, Lyon, Nancy, Paris, SaintEtienne) and were diagnosed in each center by a multidisciplinary team of neurologists and neuropsychologists, specializing in cognitive disorders, who were blind to the CSF results. A retrospective multicentric study was conducted in all patients diagnosed with lvPPA-AD and matched with nlAD and aMCIAD patients. To be included, patients with lvPPA-AD, nlAD, or aMCI had to display CSF biomarker results favoring an AD biological profile with abnormal values for at least two biomarkers and an Innogenetics Amyloid/Tau Index (IATI) below 0.8 or an A1-42 /pTau181 ratio below 9. In all involved laboratories, the following cut offs were used: A1-42 350 pg/mL, and p-Tau181 >50 pg/mL [10]. Because the manufacturer does not supply controls, the performance of the assays was controlled with internal surplus CSF samples. lvPPA-AD cases had to fulfill Mesulam’s criteria for the diagnosis of primary progressive aphasia [11] and
then display specific logopenic variant criteria according to the latest classification [12]: anomia, impaired sentence repetition, imaging-supported criteria defined as a left posterior perisylvian or parietal atrophy and/or left posterior perisylvian or parietal hypoperfusion, and at least three of the following linguistic features: phonologic paraphasia; spared single word comprehenstion and object knowledge; speared motor speech, or absence of agrammatism. aMCI was diagnosed according to Petersen criteria [13] and typical nlAD were selected according to NINCDS-ADRDA criteria [14]. CSF biomarkers levels were compared between the three groups and were adjusted for age, level of education, disease duration, and centers. Each regional ethics committee approved the use of human subjects for this study. Consent forms were signed by all patients. CSF analysis Lumbar punctures were performed in each center during the month following the clinical diagnosis. CSF was collected directly in polypropylene tubes, under standardized conditions. Each CSF sample was transferred to each local laboratory less than 4 hours after collection and was centrifuged at 1,000 g for 10 minutes at 4◦ C. CSF was aliquoted in polypropylene tubes of 0.5 mL and stored at −80◦ C until further analysis. CSF peptide A1–42 , protein total tau (tTau), and phosphorylated on threonine 181 Tau (p-Tau181) biomarker tests were performed for all subjects in local laboratories. Since the establishment of two national cohorts [15, 16] and a national network [17], all laboratories work together using the same procedures of INNOTEST® sandwich ELISA (Innogenetics, Ghent, Belgium). Biological teams involved in the CSF analysis were unaware of the clinical diagnosis. Statistical analysis The Gaussian distribution assumption was tested using the Shapiro-Wilk test. The results for the groups were compared using the Student’s t-test or the MannWhitney-Wilcoxon test for continuous variables and the chi-squared (χ2 ) test for categorical variables. Correlations between CSF biomarkers and Mini-Mental State Examination (MMSE), age, and disease duration were tested using Spearman’s rank correlation. ANOVA was used to compare biomarkers value between the three levels of education groups. All statistical analyses were performed with strata software (release 8.0, Statacorp, College Station, TX).
E. Magnin et al. / Increased Tau in Logopenic Variant of AD
613
Table 1 Characteristics of the study sample lvPPA-AD (n = 30)
nlAD (n = 67)
aMCI-AD (n = 27)
p
68.63 [52–86] (SD 7.79) 60% / 40% 2.96 [1–8] (SD 1.6) 41% / 22% / 37% 20.06* [9–30] (SD 5.72)
72.14 [53–88] (SD 8.49) 63% / 37% 2.47 [0.5–10] (SD 1.85) 45% / 20% / 35% 18.87◦ [11–26] (SD 5.02)
72.88 [50–86] (SD 8.31) 59% / 41% 2.67 [0.5–8] (SD 1.66) 33% / 11% / 56% 25.59 [18–29] (sSD 2.79)
0.0973
Age (years) Gender (Female/Male) Disease duration (years) Level of education (low/average/high) MMSE (/30)
0.45 0.1567 0.4510 0.0001
lvPPA-AD, logopenic variant of primary progressive aphasia due to Alzheimer’s disease; nlAD, non-logopenic Alzheimer’s disease; aMCI-AD, amnesic mild cognitive impairment due to Alzheimer’s disease; MMSE, Mini-Mental State Examination; SD, standard deviation; *significant difference between lvPPA-AD (p < 0.001) and aMCI-AD; ◦ significant difference between nlAD and aMCI–AD (p < 0.001). pTau181 (pg/mL)
Aβ1-42 (pg/mL) 1400
Total Tau (pg/mL) 3000
300
A
B
1200
C
250
2500
200
2000
150
1500
100
1000
50
500
1000
800
600
400
200
0
0
0 IvPPA-AD
nI-AD
aMCI-AD
IvPPA-AD
nI-AD
aMCI-AD
IvPPA-AD
nI-AD
aMCI-AD
Fig. 1. Vertical scatter plot showing the distribution of CSF AD biomarker values in the three groups. A) A1-42 ; B) p-Tau181; C) total tau. lvPPA-AD, logopenic variant of primary progressive aphasia due to Alzheimer’s disease; nlAD, non-logopenic Alzheimer’s disease; aMCI-AD, amnesic mild cognitive impairment due to Alzheimer’s disease; *p < 0.05, ***p < 0.001.
RESULTS Demographic data of the three groups are included in Table 1. No significant difference was observed between lvPPA-AD and the other groups for age, gender, level of education, or disease duration from onset of symptoms. Mean MMSE was lower in lvPPAAD and nlAD groups compared to aMCI-AD group (p < 0.05). No significant difference was observed between lvPPA-AD and nlAD for MMSE. The mean A1-42 value was 459.87 pg/mL (164−1,162, SD 202.18) in the lvPPA-AD group, 439.32 pg/mL (125−1,089, SD 175.15) in the nl-AD group, and 444.11 pg/mL (125–1176, SD 193.12) in the aMCIAD group. The mean total tau value was 883.44 pg/mL (376.1−2,452, SD 434.21) in the lvPPA-AD group,
690.96 pg/mL (191−1,899, SD 343.81) in the nl-AD group, and 592.05 pg/mL (188−1,200, SD 272.55) in the aMCI-AD group. The mean p-Tau181 value was 110.06 pg/mL (67–246, SD 36.69) in the lvPPA-AD group, 101.25 pg/mL (45.7–229, SD 36.55) in the nlAD group, and 93.35 pg/mL (35–206, SD 43.66) in the aMCI-AD group. The mean p-Tau181 value was higher in the lvPPA-AD group compared to the aMCIAD group (p < 0.05), while the mean total tau value was higher in the lvPPA-AD group compared to the nlAD (p < 0.05) and aMCI-AD groups (p < 0.001) (Fig. 1). There was a significant negative correlation between pTau181 and age of the patients (p < 0.05; r = −0.38) in the lvPPA-AD group. No significant difference was observed for CSF A1-42 levels between the three groups. No correlation was observed between CSF
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biomarkers, MMSE, or disease duration in lvPPA-AD group. No difference in biomarker value was observed between the three levels of education in lvPPA-AD group.
DISCUSSION In a multi-centric study of lvPPA-AD patients, we report higher mean CSF levels of tau or p181tau in lvPPA-AD patients compared to matched nlAD or aMCI-AD subjects. Neuropathologic findings confirm different patterns of the distribution of AD neuropathologic lesions between lvPPA due to AD and typical AD. lvPPA-AD is associated with enhanced temporoparietal neurodegeneration compared to typical AD [9]. In our study, according to biomarker results, lvPPAAD appears more severe compared to nlAD; total tau levels are increased reflecting a more pronounced neuronal loss that probably results from a larger volume of damage, especially in the parieto-temporal junction [9]. The higher p-Tau181 levels in the lvPPA-AD group compared to the aMCI-AD group suggest that tauopathy lesions are enhanced in lvPPA in accordance with the higher neurofibrillary tangle density shown by Joseph et al. [9]. The magnitude of tauopathy (as reflected by p181 levels and neuronal death reflected by tau levels in these forms of AD) are enhanced in lvPPAAD, which could be considered as a more aggressive form of AD with regards to neurodegeneration. The negative correlation between age and p-Tau181 in the CSF suggest that in living lvPPA-AD patients, tauopathy is more severe in younger patients. This finding is concordant with the faster cognitive decline detected particularly in nonverbal domains in lvPPA compared to the APP semantic variant in the majority of cases meeting criteria for dementia within 12 months [18]. However, the decline of activities of daily living is similar between lvPPA and nlAD [19]. The differences between CSF biomarker levels are not explained by age, disease duration, level of education, or the center. This is the first work that demonstrates a difference in CSF AD biomarker results between lvPPA-AD and different stages of typical AD (MCI and dementia). Others papers have reported very high total tau and p-Tau181 levels in 5 and 7 patients [6–20], respectively, without direct comparison of CSF AD biomarkers between lvPPA-AD and typical AD or MCI. Furthermore, Koric et al. studied an heterogeneous group of atypical AD patients (language and visuospatial disorders) and reported high tTau level [21].
Neuropsychological studies showed that different profiles, especially on verbal memory and linguistic tests, were observed between lvPPA, typical AD, and MCI patients [22, 23]. A neuroimaging study demonstrated that patterns of atrophy and hypometabolism differ between lvPPA and AD [24]. Therefore, lvPPA appears to be different from typical AD and other atypical AD. Seguin and colleagues found comparable CSF AD biomarker results in AD CSF between typical AD and posterior cortical atrophy (PCA), while 10% of PCA patients did not have CSF profiles consistent with AD [25]. The absence of a difference between A1-42 in the three groups is not in agreement with a molecular imaging study that has shown that total amyloid load was lower in lvPPA patients compared to typical AD patients [26]. However, methodologies and groups of patients were different and further studies in larger cohorts are needed to explore these different results. Some limitations have to be considered. The retrospective method can lead to bias, patients did not undergo the same clinical follow up, and we have no neuropathological confirmation. Thus histological and longitudinal clinical studies that could confirm our biological conclusions were not possible. As we have previously reported, inter-center and intra-center variability of CSF [27], harmonization of procedures have been performed in France to optimize the accuracy of CSF biomarkers in AD and minimize inter-center variability [15–17, 28]. Common international Innogennetics cut-offs were used to interpret CSF biomarkers in the three centers [10]. To explore A formation and release, it would be better in the future to also determine A1-40 levels and compare A1-42/A1-40 ratio in each group in order to overcome the bias introduced by inter-individual variability of amyloid production [29]. Therefore, lvPPA-AD could be considered as a specific form of AD with peculiar localization of lesions and a more extensive cellular tau pathology and neurodegeneration as compared to nlAD. Future prospective and longitudinal studies including biomarkers would be useful to investigate correlations between cognitive performances, cognitive decline, atrophy rate on MRI, biological profile, cortical metabolisms, or uptake of amyloid and/or tau radiotracers. Improvement of clinical, biologica,l and neuroimaging classifications and stratifications of atypical AD are needed to better understand the mechanisms underlying these clinical syndromes in order to predict their evolution and to offer adapted clinical trials focused either on amyloidopathy or tauopathy [30].
E. Magnin et al. / Increased Tau in Logopenic Variant of AD
DISCLOSURE STATEMENT Authors’ disclosures available online (http://www.jalz.com/disclosures/view.php?id=1972).
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