Neurobiology of Aging 32 (2011) 875–884
Subcortical and deep cortical atrophy in Frontotemporal Lobar Degeneration Valentina Garibotto a,d,1 , Barbara Borroni b,∗,1 , Chiara Agosti b , Enrico Premi b , Antonella Alberici b , Simon B. Eickhoff c,d , Simona M. Brambati e , Giuseppe Bellelli f , Roberto Gasparotti g , Daniela Perani a , Alessandro Padovani b a
Vita-Salute San Raffaele University, Division of Neuroscience-IRCCS San Raffaele, National Institute of Neuroscience (INN) and IBFM-CNR, Milan, Italy b Center for Brain Aging and Neurodegenerative Disorders, University of Brescia, Brescia, Italy c Jülich Forschungszentrum, Jülich, Germany d The Department of Psychiatry, University Hospital RWTH Aachen, Aachen, Germany e The Department of Medical Sciences, Université de Montreal, Montreal, Canada f The “Ancelle della Carità” Hospital, Cremona, Italy g The Neuroradiology Unit, University of Brescia, Brescia, Italy Received 11 November 2008; received in revised form 20 February 2009; accepted 4 May 2009 Available online 5 June 2009
Abstract Though neuroimaging, pathology and pathophysiology suggest a subcortical and deep cortical involvement in Frontotemporal Lobar Degeneration (FTLD), no studies have comprehensively assessed the associated gray matter (GM) volume changes. We measured caudate, putamen, thalamus, and amygdala GM volume using probabilistic a-priori regions of interest (ROIs) in 53 early FTLD patients (38 behavioral variant FTD [bvFTD], 9 Semantic Dementia [SD], 6 Progressive Non-Fluent Aphasia [PNFA]), and 25 age-matched healthy controls (HC). ANOVA showed significant (P < 0.001) main effect of diagnosis, and significant interactions for diagnosis and region, and diagnosis and hemisphere. Post-hoc comparisons with HC showed bilateral GM atrophy in the caudate, putamen and thalamus, in bvFTD; a left-confined GM reduction in the amygdala in SD; and bilateral GM atrophy in the caudate and thalamus, and left-sided GM reduction in the putamen and amygdala in PNFA. Correlation analyses suggested an association between GM volumes and language, psychomotor speed and behavioral disturbances. This study showed a widespread involvement of subcortical and deep cortical GM in early FTLD with patterns specific for clinical entity. © 2009 Elsevier Inc. All rights reserved. Keywords: Frontotemporal Lobar Degeneration; Basal ganglia; Probabilistic atlases; Behavioral variant Frontotemporal Dementia; Semantic Dementia; Progressive Non-Fluent Aphasia
1. Introduction Frontotemporal Lobar Degeneration (FTLD), the commonest cause for dementia after Alzheimer’s disease, refers to a complex neurodegenerative disorder primarily characterized by atrophy in the frontal lobes and the anterior portions ∗ Corresponding author. Clinica Neurologica, Università degli Studi di Brescia, Pza Spedali Civili, 1 - 25100 Brescia, Italy. Tel.: +39 0303995632; fax: +39 0303995632. E-mail address:
[email protected] (B. Borroni). 1 These authors equally contributed to this work.
0197-4580/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2009.05.004
of the temporal lobes. FTLD includes clinically, anatomically and genetically heterogeneous conditions, presenting mostly with personality changes and/or cognitive deficits, in particular language and executive functions. Three main clinical entities have been described, as the behavioral variant FTD (bvFTD), Semantic Dementia (SD), and Progressive NonFluent Aphasia (PNFA) (McKhann et al., 2001; Neary et al., 1998). Specifically, each entity is characterized by a separate and distinguishing pattern of cortical gray and white matter atrophy, as revealed by previous neuroimaging studies (Borroni et al., 2007; Gorno-Tempini et al., 2004).
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V. Garibotto et al. / Neurobiology of Aging 32 (2011) 875–884
Notwithstanding, neuropathologic investigations showed a subcortical involvement, with different degrees of atrophy and mild astrocytosis being present throughout caudate, putamen, pallidus, and amygdala (Hodges and Miller, 2001; Munoz et al., 2003; Yancopoulou et al., 2005). Furthermore, the frontal-subcortical circuitry has been well described: the orbitofrontal cortex (OFC) projects extensively to and forms feedback loops with subcortical structures such as the basal ganglia and limbic regions, particularly the amygdala (Kringelbach and Rolls, 2004). Thus, the subcortical and deep cortical structures may provide important clues on the clinical expression of this disorder, including also cognitive and behavioral abnormalities, given the growing consensus on the involvement of the basal ganglia in non-motor functions such as language, executive functions, memory, and learning (Graybiel, 2005). To date, no studies have comprehensively assessed the subcortical and deep cortical gray matter (GM) volume changes in FTLD, taking also the amygdala into account. To investigate it in an objective, quantitative way, and in a large subjects’ sample, we performed a fully-automated volumetric analysis using regions of interest (ROIs) based on recently developed probabilistic atlases (Eickhoff et al., 2005; Mazziotta et al., 2001). These atlases are based on the anatomical examination of large samples of healthy subjects and provide information about the voxel specific probability for observing a given structure in stereotactic space. Probabilistic maps are hence well suited not only as a reference for the allocation of functional imaging results but can also provide a-priori information about location and individual variability in volumetric investigations (Eickhoff et al., 2006; Hammers et al., 2003). We measured gray matter (GM) volumes of the caudate nucleus, putamen and thalamus, as well as the amygdala. We hypothesized that the clinical and behavioral differences among entities would be reflected by different patterns of subcortical changes, with selective involvement of anatomical structures, and with left-prevalent distribution in the language-variants (SD and PNFA).
2. Methods 2.1. Subjects Patients who met the Neary and McKhann criteria for FTLD were consecutively recruited from March 2002 through December 2007 at the “Center for Aging Brain and Neurodegenerative Diseases”, University of Brescia, Italy (McKhann et al., 2001; Neary et al., 1998). All patients underwent a general medical examination, a review of full medical history and routine laboratory screening before inclusion. The diagnostic assessment consisted of a full neurological examination, a semi-structured interview, and a complete mental status evaluation by two independent and experienced reviewers (B.B., C.A.), and brain MRI and
SPECT imaging. The investigators did not take imaging findings into account for the diagnosis at inclusion. Only patients with full consensus agreement on their diagnosis by the two reviewers, and in the early stage of illness (within three years from disease onset) were enrolled for the further investigation. All diagnoses were clinically confirmed at least at 2 years follow-up. Fifty-three patients were enrolled, including 38 bvFTD, 9 SD, and 6 PNFA. Demographic and further clinical characteristics are summarised in Table 1. Importantly, patients’ groups did not differ for age, age at onset and disease duration. Twenty five healthy subjects (10 males, 15 females, mean age ± SD = 65.4 ± 6.7) were recruited among patients’ spouses and relatives to serve as normal control subjects. Each subject underwent a formal standardized assessment, including Mini-Mental State Examination and Clinical Dementia Rating Scale, to exclude cognitive deficits; each subject had preserved instrumental and basic activities of daily living. All participants were made fully aware of the research goals, and informed consent was obtained from all patients and controls. This study was conducted in accordance with local clinical research regulations and conformed to Declaration of Helsinki. 2.2. Exclusion criteria In both patients and controls, the following exclusion criteria were applied: (a) cerebrovascular disorders, previous stroke, hydrocephalus, and intra-cranial mass as documented by MRI; (b) a history of traumatic brain injury or another neurological disease; (c) significant medical problems; (d) major depressive disorder, bipolar disorder, schizophrenia, substance abuse disorder, or mental retardation according to DSM-IV criteria. 2.3. Neuropsychological and behavioral assessment For each patient, cognitive function was evaluated according to a standardized battery, including the Mini-Mental State Examination (MMSE), Raven Colored Progressive Matrices, Controlled Oral Word Association Test and Category Fluency, Rey Complex Figure Copy and Recall, Story Recall Test, Digit Span, Trail Making Test A and B, Token Test (Lezak et al., 2004). Instrumental Activities of Daily Living (IADL) and Basic Activities of Daily Living (BADL) were also assessed. Behavioral and psychiatric disturbances were evaluated by means of the Neuropsychiatry Inventory (NPI), and the Frontal Behavioral Inventory (FBI, part A and B) (Kertesz et al., 1997). Neuropsychological and behavioral assessment is reported in Table 1. 2.4. MRI data acquisition and preprocessing MR imaging was performed on a 1.5 T system (Symphony, Siemens, Erlangen, Germany). 3D magnetization-prepared
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Table 1 Demographic and clinical characteristics of included FTLD patients. Diagnosis
FTLD overall
FTLD bvFTD
N Age, years Gender, F (%) (n) FH*, (%) (n) Education, years Age at onset, years Disease duration, years MMSE NPI FBI-AB BADL (lost) IADL (lost) Raven Colored Progressive Matrices Fluency, letter Fluency, category Rey complex figure, copy Rey complex figure, recall Story Recall Test Digit span Trail Making Test, A Trail Making Test, B Token Test
53 65.1 ± 7.1 62.3 (33) 41.2 (21) 7.2 ± 3.1 63.1 ± 8.7 2.1 ± 1.9 21.0 ± 6.0 14.0 ± 10.8 17.9 ± 13.3 0.3 ± 0.8 1.5 ± 2.2 21.7 ± 6.38 21.3 ± 11.9 26.3 ± 13.2 24.9 ± 10 10.7 ± 6.58 7.4 ± 5.4 5.13 ± 1.74 175 ± 183 303 ± 151 27.1 ± 6.79
SD
38 65.3 ± 6.6 50.0 (19) 43.2 (16) 6.8 ± 2.9 63.0 ± 6.4 2.5 ± 1.8 22.2 ± 4.9 15.7 ± 11.6 19.3 ± 13.3 0.37 ± 0.88 1.16 ± 1.96 22 ± 5.3 22.9 ± 11.3 29 ± 12.8 24.7 ± 9.71 11.4 ± 6.63 9.26 ± 5.04 5.47 ± 1.49 153 ± 172 290 ± 157 28.3 ± 5.81
9 67.8 ± 8.9 100 (9) 33.3 (3) 9.9 ± 3.6 65.6 ± 9.1 2.2 ± 2.3 20.8 ± 6.9 9.7 ± 8.5 16.7 ± 9.8 0.22 ± 0.66 2.42 ± 2.42 22.1 ± 7.47 22.3 ± 13.4 19.3 ± 9.85 26.3 ± 9.27 7.28 ± 5.31 3.31 ± 2.95 4.86 ± 1.44 197 ± 204 314 ± 156 25.8 ± 4.29
PNFA 6 60.1 ± 7.7 83.3 (5) 40.0 (2) 5.5 ± 1.2 57.7 ± 5.9 2.5 ± 2.0 14.3 ± 7.4 9.8 ± 6.9 11.1 ± 6.0 0.00 ± 0.00 2.83 ± 3.37 18.9 ± 11.6 8.2 ± 4.92 18.6 ± 15.9 24.7 ± 14.9 11.4 ± 7.57 1.58 ± 1.8 3.2 ± 2.65 280 ± 215 367 ± 113 20.2 ± 11.6
P 0.234 0.012 0.865 0.020 0.089 0.138 0.043 0.236 0.285 0.413 0.158 0.919 0.025 0.081 0.814 0.373
