Journal of Alzheimer’s Disease 44 (2015) 635–647 DOI 10.3233/JAD-141230 IOS Press
635
More Atrophy of Deep Gray Matter Structures in Frontotemporal Dementia Compared to Alzheimer’s Disease Christiane M¨ollera,∗ , Nikki Dielemane , Wiesje M. van der Fliera,b , Adriaan Versteegc , Yolande Pijnenburga , Philip Scheltensa , Frederik Barkhofc and Hugo Vrenkenc,d a Alzheimer
center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands b Department of Epidemiology & Biostatistics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands c Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands d Department of Physics & Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands e Department of Radiology, University Medical Center Utrecht, GA Utrecht, The Netherlands Handling Associate Editor: Josephine Barnes Accepted 15 September 2014
Abstract. Background: The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. Objective: We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer’s disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. Methods: For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of hippocampus, amygdala, thalamus, caudate nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. Results: Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. Conclusion: Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD. Keywords: Alzheimer’s disease, atrophy, basal ganglia, frontotemporal dementia
∗ Correspondence to: Christiane M¨ oller, Department of Neurology, Alzheimer Center, VU University Medical center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 4440823; Fax: +31 20 4440715; E-mail: [email protected].
ISSN 1387-2877/15/$27.50 © 2015 – IOS Press and the authors. All rights reserved
636
C. M¨oller et al. / Deep Gray Matter Atrophy in Dementia
INTRODUCTION Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the leading causes of early-onset dementia [1, 2]. Cortical atrophy of the two forms of dementia has been extensively studied. Typically, atrophy of the medial temporal lobe (MTL) is seen in AD patients and associated with episodic memory problems [3, 4]. However, MTL atrophy is also common in behavioral variant FTD (bvFTD) [5, 6]. Conversely, FTD is typically characterized by atrophy of frontal and anterior temporal lobes, which is associated with changes in behavior and executive functioning [7–9], but atrophy in these regions does not exclude a diagnosis of AD [10, 11]. In the discrimination of AD and FTD, deep gray matter (DGM) structures have received less attention. So far, magnetic resonance imaging (MRI)-based studies have demonstrated that AD is associated with atrophy of thalamus, putamen, and caudate nucleus [12–16]. However, results from published studies are difficult to compare as they used different image analysis techniques or focused on different DGM structures [13, 15, 17, 18]. In the context of FTD, DGM structures may be even more important, as they are part of the frontostriatal circuits, known to be affected in FTD [19, 20]. Thalamus, neostriatum, nucleus accumbens, and globus pallidus connect motor- and cognitive-loops with the prefrontal cortex. Degeneration of these DGM structures may lead to circuit failure and eventually alterations of cognition and behavior [17, 19, 21]. MRI-based measures of DGM structures could provide important information on the differential distribution of pathology between AD and FTD and may explain some of the clinical characteristics typical of the diseases. Therefore, the aim of this study was to investigate atrophy of hippocampus, amygdala, and the DGM structures in AD, FTD, and control subjects and to explore the effect of DGM atrophy on cognitive and neuropsychiatric functioning. MATERIALS AND METHODS Patients All patients visited the Alzheimer Center of the VU University Medical center between 2008 and 2011 where they underwent a standardized one-day assessment for clinical evaluation including medical history, informant-based history, physical and neurological examination, blood tests, neuropsychological assessment, electroencephalography, and MRI of the
brain. Patients are asked informed consent for the use of their clinical data for research purposes and are as such included in the Amsterdam Dementia Cohort [22]. For the current study, we retrospectively selected 24 FTD patients who met the inclusion criteria as described below. One of the authors matched these patients through visual inspection on a 1:3 basis by age, gender, and educational level to 72 AD patients and 72 patients with subjective complaints (SC) who were used as controls. All diagnoses were made in a multidisciplinary consensus meeting according to the core clinical criteria of the National Institute on Aging and the Alzheimer’s Association workgroup for probable AD and according to the clinical diagnostic criteria of FTD based on the results of the one-day assessment as described above [23–25]. Among the AD patients, one patient met the criteria for posterior cortical atrophy (PCA). Six AD patients susceptible for genetic mutations underwent a genetic screening. None of them were positive for genetic mutations. Among the FTD patients, there were four patients with amyotrophic lateral sclerosis (ALS) and one patient with motor neuron disease. Eight FTD patients susceptible for genetic mutations underwent a genetic screening. None of them were positive for known genetic mutations. On visual inspection of the MRI scans, frontal atrophy was worse than temporal atrophy in all FTD patients. No progressive nonfluent aphasia or semantic dementia cases were identified. As controls, we used patients who presented at our memory clinic with subjective complaints. They were labeled as having subjective complaints when they presented with memory complaints, but cognitive functioning was normal and criteria for MCI, dementia, or any other neurological or psychiatric disorder known to cause cognitive decline were not met. The diagnosis was also made in a multidisciplinary consensus meeting taking into account results of all examinations as described above. For inclusion in the present study, all patients had to fulfill the following criteria: (1) meet the criteria for AD, FTD, or subjective complaints based on the core clinical criteria, (2) diagnosis stayed unchanged after 12 months clinical follow-up, (3) availability of a T1weighted 3-dimensional MRI scan (3DT1) at 3 tesla MRI (details see section below), and (4) availability of neuropsychological examination. Exclusion criteria were: (1) age younger than 40 years; (2) failure of segmentation software to analyze DGM volumes due to abnormal tracing of structures (details see section below); and (3) lacunar infarction in the DGM structures. Disease duration was calculated based on the time difference between date of diagnosis and the year
30 (41.7%) 63 ± 8.1 5.4 ± 1.5 40.4 ± 35.9
30 (41.7%) 63 ± 8.2 5.5 ± 1.1 40.0 ± 24.8
70 67 48 48 48 48 48 48 48 48 48 48 48 48 48
0.0 ± 0.8 0.0 ± 0.8 7.2 ± 7.8 0.0 ± 0.2 0.0 ± 0.0 0.4 ± 1.5 0.7 ± 1.9 0.9 ± 2.5 0.1 ± 0.7 1.3 ± 1.8 0.5 ± 1.4 1.8 ± 2.3 0.3 ± 1.1 0.8 ± 1.6 0.5 ± 1.2
31
31
0.9 ± 2.3
0.7 ± 1.8
−1.8 ± 1.7a −2.1 ± 1.7a 13.0 ± 12.1a 0.1 ± 0.6 0.2 ± 0.7 0.9 ± 2.5 0.6 ± 1.7 0.9 ± 2.1 0.6 ± 1.6 4.4 ± 3.9a 1.1 ± 2.9 2.2 ± 3.4 0.4 ± 1.0
72 1.29 ± 0.1 72 1387 ± 72.9a 62 444.5 (268–1365)a 62 567.5 (148–1779)a 62 82.5 (33–262)a 72 21 ± 4.9a 71 −3.4 ± 2.4a 65 −1.3 ± 1.6a 65 −2.3 ± 3.2a
72 72 71 69
70 69 31 31 31 31 31 31 31 31 31 31 31
72 1.31 ± 0.1 72 1459 ± 81.3 59 825 (293–1343) 59 274 (69–2088) 59 50 (18–190) 72 28 ± 2.2 70 0.0 ± 0.8 63 0.0 ± 0.8 68 0.0 ± 0.7
72 72 70 66
AD n
14
14
23 22 14 14 14 14 14 14 14 14 14 14 14
24 24 19 19 19 24 23 19 20
24 24 24 23
FTD n
2.1 ± 2.4a,b
0.5 ± 1.0
−1.3 ± 1.9a −1.3 ± 1.3a,b 21.6 ± 14.6a,b 0.3 ± 1.1 0.0 ± 0.0 1.4 ± 3.4 0.4 ± 1.6 1.7 ± 3.7 1.1 ± 2.6 6.6 ± 4.2a 1.8 ± 2.7 3.7 ± 3.9 1.9 ± 3.3a,b
1.28 ± 0.2 1369 ± 83.2a 876 (611–1264)b 335 (106–680)b 42 (19–112)b 24 ± 4.5a,b −1.7 ± 2.2a,b −1 ± 0.8a −0.9 ± 2.2a,b
10 (41.7%) 63 ± 8.0 5.4 ± 1.3 48.5 ± 40.7
K = 8450
K = 0.444
K = 53.389 K = 72.193 K = 16.036 K = 0.899 K = 3.874 K = 2.256 K = 0.909 K = 0.198 K = 4.467 K = 24.238 K = 4.169 K = 2.169 K = 9.982
0.015
0.801
635
More Atrophy of Deep Gray Matter Structures in Frontotemporal Dementia Compared to Alzheimer’s Disease Christiane M¨ollera,∗ , Nikki Dielemane , Wiesje M. van der Fliera,b , Adriaan Versteegc , Yolande Pijnenburga , Philip Scheltensa , Frederik Barkhofc and Hugo Vrenkenc,d a Alzheimer
center & Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands b Department of Epidemiology & Biostatistics, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands c Department of Radiology & Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands d Department of Physics & Medical Technology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands e Department of Radiology, University Medical Center Utrecht, GA Utrecht, The Netherlands Handling Associate Editor: Josephine Barnes Accepted 15 September 2014
Abstract. Background: The involvement of frontostriatal circuits in frontotemporal dementia (FTD) suggests that deep gray matter structures (DGM) may be affected in this disease. Objective: We investigated whether volumes of DGM structures differed between patients with behavioral variant FTD (bvFTD), Alzheimer’s disease (AD), and subjective complaints (SC) and explored relationships between DGM structures, cognition, and neuropsychiatric functioning. Methods: For this cross-sectional study, we included 24 patients with FTD and matched them based on age, gender, and education at a ratio of 1:3 to 72 AD patients and 72 patients with SC who served as controls. Volumes of hippocampus, amygdala, thalamus, caudate nucleus, putamen, globus pallidus, and nucleus accumbens were estimated by automated segmentation of 3D T1weighted MRI. MANOVA with Bonferroni adjusted post-hoc tests was used to compare volumes between groups. Relationships between volumes, cognition, and neuropsychiatric functioning were examined using multivariate linear regression and Spearman correlations. Results: Nucleus accumbens and caudate nucleus discriminated all groups, with most severe atrophy in FTD. Globus pallidus volumes were smallest in FTD and discriminated FTD from AD and SC. Hippocampus, amygdala, thalamus, and putamen were smaller in both dementia groups compared to SC. Associations between amygdala and memory were found to be different in AD and FTD. Globus pallidus and nucleus accumbens were related to attention and executive functioning in FTD. Conclusion: Nucleus accumbens, caudate nucleus, and globus pallidus were more severely affected in FTD than in AD and SC. The associations between cognition and DGM structures varied between the diagnostic groups. The observed difference in volume of these DGM structures supports the idea that next to frontal cortical atrophy, DGM structures, as parts of the frontal circuits, are damaged in FTD rather than in AD. Keywords: Alzheimer’s disease, atrophy, basal ganglia, frontotemporal dementia
∗ Correspondence to: Christiane M¨ oller, Department of Neurology, Alzheimer Center, VU University Medical center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. Tel.: +31 20 4440823; Fax: +31 20 4440715; E-mail: [email protected].
ISSN 1387-2877/15/$27.50 © 2015 – IOS Press and the authors. All rights reserved
636
C. M¨oller et al. / Deep Gray Matter Atrophy in Dementia
INTRODUCTION Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are the leading causes of early-onset dementia [1, 2]. Cortical atrophy of the two forms of dementia has been extensively studied. Typically, atrophy of the medial temporal lobe (MTL) is seen in AD patients and associated with episodic memory problems [3, 4]. However, MTL atrophy is also common in behavioral variant FTD (bvFTD) [5, 6]. Conversely, FTD is typically characterized by atrophy of frontal and anterior temporal lobes, which is associated with changes in behavior and executive functioning [7–9], but atrophy in these regions does not exclude a diagnosis of AD [10, 11]. In the discrimination of AD and FTD, deep gray matter (DGM) structures have received less attention. So far, magnetic resonance imaging (MRI)-based studies have demonstrated that AD is associated with atrophy of thalamus, putamen, and caudate nucleus [12–16]. However, results from published studies are difficult to compare as they used different image analysis techniques or focused on different DGM structures [13, 15, 17, 18]. In the context of FTD, DGM structures may be even more important, as they are part of the frontostriatal circuits, known to be affected in FTD [19, 20]. Thalamus, neostriatum, nucleus accumbens, and globus pallidus connect motor- and cognitive-loops with the prefrontal cortex. Degeneration of these DGM structures may lead to circuit failure and eventually alterations of cognition and behavior [17, 19, 21]. MRI-based measures of DGM structures could provide important information on the differential distribution of pathology between AD and FTD and may explain some of the clinical characteristics typical of the diseases. Therefore, the aim of this study was to investigate atrophy of hippocampus, amygdala, and the DGM structures in AD, FTD, and control subjects and to explore the effect of DGM atrophy on cognitive and neuropsychiatric functioning. MATERIALS AND METHODS Patients All patients visited the Alzheimer Center of the VU University Medical center between 2008 and 2011 where they underwent a standardized one-day assessment for clinical evaluation including medical history, informant-based history, physical and neurological examination, blood tests, neuropsychological assessment, electroencephalography, and MRI of the
brain. Patients are asked informed consent for the use of their clinical data for research purposes and are as such included in the Amsterdam Dementia Cohort [22]. For the current study, we retrospectively selected 24 FTD patients who met the inclusion criteria as described below. One of the authors matched these patients through visual inspection on a 1:3 basis by age, gender, and educational level to 72 AD patients and 72 patients with subjective complaints (SC) who were used as controls. All diagnoses were made in a multidisciplinary consensus meeting according to the core clinical criteria of the National Institute on Aging and the Alzheimer’s Association workgroup for probable AD and according to the clinical diagnostic criteria of FTD based on the results of the one-day assessment as described above [23–25]. Among the AD patients, one patient met the criteria for posterior cortical atrophy (PCA). Six AD patients susceptible for genetic mutations underwent a genetic screening. None of them were positive for genetic mutations. Among the FTD patients, there were four patients with amyotrophic lateral sclerosis (ALS) and one patient with motor neuron disease. Eight FTD patients susceptible for genetic mutations underwent a genetic screening. None of them were positive for known genetic mutations. On visual inspection of the MRI scans, frontal atrophy was worse than temporal atrophy in all FTD patients. No progressive nonfluent aphasia or semantic dementia cases were identified. As controls, we used patients who presented at our memory clinic with subjective complaints. They were labeled as having subjective complaints when they presented with memory complaints, but cognitive functioning was normal and criteria for MCI, dementia, or any other neurological or psychiatric disorder known to cause cognitive decline were not met. The diagnosis was also made in a multidisciplinary consensus meeting taking into account results of all examinations as described above. For inclusion in the present study, all patients had to fulfill the following criteria: (1) meet the criteria for AD, FTD, or subjective complaints based on the core clinical criteria, (2) diagnosis stayed unchanged after 12 months clinical follow-up, (3) availability of a T1weighted 3-dimensional MRI scan (3DT1) at 3 tesla MRI (details see section below), and (4) availability of neuropsychological examination. Exclusion criteria were: (1) age younger than 40 years; (2) failure of segmentation software to analyze DGM volumes due to abnormal tracing of structures (details see section below); and (3) lacunar infarction in the DGM structures. Disease duration was calculated based on the time difference between date of diagnosis and the year
30 (41.7%) 63 ± 8.1 5.4 ± 1.5 40.4 ± 35.9
30 (41.7%) 63 ± 8.2 5.5 ± 1.1 40.0 ± 24.8
70 67 48 48 48 48 48 48 48 48 48 48 48 48 48
0.0 ± 0.8 0.0 ± 0.8 7.2 ± 7.8 0.0 ± 0.2 0.0 ± 0.0 0.4 ± 1.5 0.7 ± 1.9 0.9 ± 2.5 0.1 ± 0.7 1.3 ± 1.8 0.5 ± 1.4 1.8 ± 2.3 0.3 ± 1.1 0.8 ± 1.6 0.5 ± 1.2
31
31
0.9 ± 2.3
0.7 ± 1.8
−1.8 ± 1.7a −2.1 ± 1.7a 13.0 ± 12.1a 0.1 ± 0.6 0.2 ± 0.7 0.9 ± 2.5 0.6 ± 1.7 0.9 ± 2.1 0.6 ± 1.6 4.4 ± 3.9a 1.1 ± 2.9 2.2 ± 3.4 0.4 ± 1.0
72 1.29 ± 0.1 72 1387 ± 72.9a 62 444.5 (268–1365)a 62 567.5 (148–1779)a 62 82.5 (33–262)a 72 21 ± 4.9a 71 −3.4 ± 2.4a 65 −1.3 ± 1.6a 65 −2.3 ± 3.2a
72 72 71 69
70 69 31 31 31 31 31 31 31 31 31 31 31
72 1.31 ± 0.1 72 1459 ± 81.3 59 825 (293–1343) 59 274 (69–2088) 59 50 (18–190) 72 28 ± 2.2 70 0.0 ± 0.8 63 0.0 ± 0.8 68 0.0 ± 0.7
72 72 70 66
AD n
14
14
23 22 14 14 14 14 14 14 14 14 14 14 14
24 24 19 19 19 24 23 19 20
24 24 24 23
FTD n
2.1 ± 2.4a,b
0.5 ± 1.0
−1.3 ± 1.9a −1.3 ± 1.3a,b 21.6 ± 14.6a,b 0.3 ± 1.1 0.0 ± 0.0 1.4 ± 3.4 0.4 ± 1.6 1.7 ± 3.7 1.1 ± 2.6 6.6 ± 4.2a 1.8 ± 2.7 3.7 ± 3.9 1.9 ± 3.3a,b
1.28 ± 0.2 1369 ± 83.2a 876 (611–1264)b 335 (106–680)b 42 (19–112)b 24 ± 4.5a,b −1.7 ± 2.2a,b −1 ± 0.8a −0.9 ± 2.2a,b
10 (41.7%) 63 ± 8.0 5.4 ± 1.3 48.5 ± 40.7
K = 8450
K = 0.444
K = 53.389 K = 72.193 K = 16.036 K = 0.899 K = 3.874 K = 2.256 K = 0.909 K = 0.198 K = 4.467 K = 24.238 K = 4.169 K = 2.169 K = 9.982
0.015
0.801
