Neurobiology of Aging 26 (2005) 37–44
Frontotemporal dementia as a neural system disease Marina Boccardi a , Francesca Sabattoli a , Mikko P. Laakso a,b,c , Cristina Testa a , Roberta Rossi a , Alberto Beltramello d , Hilkka Soininen b , Giovanni B. Frisoni a,e,∗ a
Laboratory of Epidemiology and Neuroimaging, IRCCS San Giovanni di Dio-FBF, Brescia, Italy b Department of Neurology, Kuopio University Hospital, Kuopio, Finland c Department of Clinical Radiology, Kuopio University Hospital, Kuopio, Finland d Service of Neuroradiology, Ospedale Maggiore, Verona, Italy e AFaR Associazione Fatebenefratelli per la Ricerca, Rome, Italy Received 1 July 2003; received in revised form 14 January 2004; accepted 17 February 2004
Abstract Some brain structures atrophic in frontotemporal dementia (FTD) belong to the rostral limbic system (RLS), that regulates contextdependent behaviors after evaluation of the motivational content of stimuli. The clinical manifestations of FTD are consistent with its impairment. Aim of this study was to assess whole brain morphology in FTD using magnetic resonance imaging (MRI) and voxel-based morphometry with statistic parametric mapping (SPM99) to test the hypothesis that the RLS might be specifically targeted by FTD. Nine FTD patients and 26 healthy controls underwent high resolution 3D MRI. SPM99 performed (a) spatial normalization to a customized template, (b) segmentation, (c) smoothing, (d) voxel-by-voxel comparison of gray matter between cases and controls. P was set at 0.05 corrected for multiple comparisons. All but one regions of the RLS (the periaqueductal gray) were atrophic in FTD. At P < 0.001 uncorrected also the periaqueductal gray was atrophic. Atrophy outside the RLS was confined to a few voxels in the frontal and temporal gyri. FTD might be a neural-system disease where the RLS is predominantly damaged. © 2004 Elsevier Inc. All rights reserved. Keywords: Dementia; FTD; Frontotemporal dementia; Behavior; VBM; Morphometry; Limbic system
1. Introduction Brain imaging techniques have long been used to help the differential diagnosis between different dementias [16]. Nonetheless, consideration of single, although relevant, regions of interest is not always sufficient to clearly differentiate them, as exemplified by hippocampal atrophy [21,24]. Analogously, atrophy of a typical structure is not always necessary nor sufficient to explain the symptoms, as it happens for amygdaloid atrophy that, although relevant in AD, is not accompanied by its typical symptoms in this disease until its stage is rather severe [20]. Recent advances in image analysis techniques, such as voxel-based morphometry (VBM), allow to compare entire brains of groups of individuals, on voxel-by-voxel basis in a single experiment, rather than considering one or few regions at a time, and this allows to explore the possibility that entire ∗ Corresponding author. Tel.: +39-030-3501-361; fax: +39-027-004-35727. E-mail address:
[email protected] (G.B. Frisoni). URL: http://www.centroalzheimer.it.
0197-4580/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2004.02.019
and different neural systems might be involved in different dementias, helping both the differential diagnosis and the comprehension of the pathogenesis of these conditions. Frontotemporal dementia (FTD) is the most frequent clinical phenotype under the spectrum of frontotemporal lobar degenerative diseases (FTLD) [31]. FTLD is a rather heterogeneous group of diseases which also includes progressive aphasia (PA) and semantic dementia (SD). The diagnostic criteria for FTD list its core diagnostic features to consist of (A) insidious onset and gradual progression, (B) early decline in social interpersonal conduct, (C) early impairment in regulation of personal conduct, (D) early emotional blunting, and (E) early loss of insight [31]. These are in line with the earlier criteria, core diagnostic features of which, under the behavioral symptons subheading, consisted in addition of disinhibition, distractibility, impulsivity, and impersistence [29]. In short, it is a cocktail of behavioral symptoms that constitutes the core features of FTD. These symptoms of FTD point to the involvement of the rostral limbic system. This is a neural circuit consisting in the anterior portion of the limbic system, which interfaces limbic structures with the output-related (executive and behavioral)
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structures that need motivational evaluation of the stimuli to be processed. It consists of the anterior cingulate, anterior insular, and ventromedial prefrontal cortices, limbic ventral striatum, the amygdalae and the periaqueductal gray matter [17,42]. This system subserves a number of processes, such as the evaluation of the motivational or emotional content of internal and external stimuli, error detection, response selection and decision making, and subsequent regulation of context-dependent behaviors [17,35]. The complex output from this system is “appropriate” behavior. The ultimate aim of the system can be defined as the adaptive tuning of behavior for the benefit of one’s organism’s or species’ survival in general [15]. These very regions have recently been under a wide scrutiny in terms of neurology of behavior and social cognition, and under scrutiny perhaps even since 1848 when an iron rod pierced the skull of Phineas Gage, between the brain hemispheres, probably causing damage to the rostral limbic system, and leaving Gage alive but with altered, disturbed personality [13]. If the clinical manifestations of FTD are consistent with impairment of this circuit, can this be seen using brain imaging? The aim of this study was to test the hypothesis that the rostral limbic system is selectively affected in FTD. To this avail, we studied the pattern of atrophy in magnetic resonance imaging (MRI) scans of patients with FTD and healthy controls using VBM. The comparisons were carried out under the hypothesis that, if the rostral limbic system is involved, atrophy should be confirmed in the anterior cingulate, ventromedial prefrontal, anterior insular cortices [37] and amygdala [6], and found in the ventral striatum and periaqueductal gray, as components of the system suspected to be damaged [17].
2. Methods 2.1. Subjects and clinical assessment Patients and normal elders in this study have been previously described in reports on linear measures of atrophy in the degenerative dementias [21]. The demented were outpatients seen at the Alzheimer’s Unit, Brescia, Italy. Routine dementia assessment and work-up was carried out in all. History was taken from a knowledgeable informant (usually the patient’s spouse), and was particularly focused on those symptoms that might help in the diagnostic differentiation between different dementia forms (implicit and explicit memory, language and executive functions, behavioral disturbances, disability in daily activities, hallucinations and other psychiatric symptoms, and falls). Laboratory studies included complete blood count, chemistry profile, chest X-ray, thyroid function, B12 and folic acid, electrocardiography, electroencephalography, and computed tomography scan. Neurological examination (including elicitation of primitive reflexes such as grasping, sucking, palmomental, and snout) was performed by a neurologist, and physical
examination by a geriatrician. A comprehensive neuropsychological battery assessing visuospatial function, frontal functions, verbal and non-verbal memory, praxis, language and comprehension was part of the routine assessment [21]. Individual tests that could not be carried out in those patients with more severe cognitive or linguistic impairment were not administered. However, all patients were able to complete at least 50% of the tests of the battery. In the original series of 14 FTD patients [21], the diagnosis was made on clinical grounds following clinical descriptions [26] and guidelines [29] available at that time. Patients were diagnosed as FTD when they presented a pattern of symptoms characterized mainly by behavioral problems (lack of insight, dishinibition, emotional unconcern, impaired personal and social conduct) and by a “frontal” pattern of cognitive function (perseverative and utilization behaviors, lower performance on frontal function tests). Language impairment could be present, but patients with disproportionate language or comprehension impairment and minor behavioral deficits were excluded, as these should be diagnosed as PA or SD [31]. After clinical evaluation, patients underwent single photon emission tomography (SPET) with HM-PAO. It should be noted that all patients who satisfied criteria for FTD also showed anterior frontal or anterior temporal hypoperfusion at subsequent SPET imaging [22]. Thus, in the present study anterior hypoperfusion on SPET was confirmatory of a diagnosis made on clinical grounds. Moreover, the diagnosis of FTD was supported on follow-up evaluations, carried out from a minimum of 8 months to a maximum of 3 years. After excluding two patients with progressive aphasia in the absence of other cognitive and behavioral disturbances, one who displayed no deterioration in 3 years, one with very anomalous morphology characterized by ventricles smaller than controls’ and abnormal lobar proportions (a morphological outlier) and one subject whose complete digital data were not available for image processing, 9 FTD subjects remained. These were retrospectively assessed and judged to fulfill the criteria for the diagnosis of frontotemporal lobar degeneration [31] of FTD type representing a rather homogenous clinical phenotype. Disease duration was computed from the estimated onset to the date of MRI imaging. The estimated onset was assessed from informants and defined as the time of the first appearance of behavioral, language, or other symptoms that could be due to the degenerative brain disease. Overall dementia severity was assessed with the clinical dementia rating scale (CDR) [28]. Information on basic (bathing, dressing, grooming, walking, feeding, continence) and instrumental (using the telephone, shopping, cooking, doing housework, doing laundry, using public transportation, taking drugs, and handling finances) activities of daily living was taken from a proxy informant. Controls were patients’ relatives (mostly spouses) without detectable cognitive deficit. They had a negative history of neurological disease, though some reported mild subjective
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memory problems which did not result in impairment of daily activities. All had the Mini-Mental State Examination (MMSE) administered, and were judged not demented by a neurologist and a psychologist involved in the evaluation of the patients. Of the original 31 controls, 27 had MRI images suitable for the volumetric analyses of the present study. One of these was excluded for the development of multiple system atrophy a few years after scanning, and 26 control subjects remained. The study has been approved by the local ethics committee, and consent was obtained by both controls and cases or their primary caregivers. No compensation was provided. 2.2. MR acquisition For each subject, a high-resolution sagittal T1-weighted volumetric MRI scan was acquired at the Radiology Department, University of Verona, using a 1.5 T Magnetom scanner (Siemens, Erlangen, Germany), with a gradient echo 3D technique: TR = 10 ms, TE = 4 ms, TI = 300 ms, flip angle = 10◦ , field of view = 250 mm, acquisition matrix 160 × 256, and a slice thickness of 1.3 mm. 2.3. Image pre-processing After removing the voxels below the cerebellum with MRIcro (http://www.psychology.nottingham.ac.uk/staff/ cr1/mricro.html) [36], MRI scans were analyzed with SPM99 (http://www.fil.ion.ucl.ac.uk/spm) running under Matlab 6.0 (Mathworks, Sherborn, MA, USA) on a Sun Sparc Ultra 30 workstation (Sun Microsystem Inc., Mountain View, CA, USA). The following pre-processing was carried out: creation of a gray matter template, normalization of the gray matter to the template, and smoothing. A complete description of the pre-processing procedures can be found elsewhere [3]. 2.3.1. Gray matter template This is made through creation of a customized template of the whole brain, normalization of the original images to the template, extraction of the gray matter, and averaging. The customized template of the whole brain was obtained through normalization of the images of controls to the T1-stereotactic template of SPM99 [18] using a 12-parameter affine transformation followed by averaging of the normalized images. Then, the anterior commissure was identified and defined as the origin of the spatial coordinates [4]. The normalization of the original images to the template was obtained through a 12-parameter affine transformation. The gray matter of controls was then extracted through segmentation of images into gray matter, white matter, and CSF with a modified mixture model cluster algorithm and averaged thus obtaining a stereotactic customized gray matter template.
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2.3.2. Normalization The gray matter of cases was extracted with the same procedure as described above for controls and together with the gray matter of controls was normalized onto the gray matter template with affine and non-linear transformations, medium regularization, re-slicing 2 mm × 2 mm × 2 mm, and no masking [5]. The resulting images were visually inspected one by one in order to exclude gross segmentation errors. 2.3.3. Smoothing The normalized gray matter images were smoothed with an isotropic Gaussian filter of 8 mm. 2.4. Statistical analysis The “Compare populations—AnCova” procedure was used to compare the gray matter concentration between cases and controls, and statistical significance was set at P < 0.05 corrected for multiple comparisons. Age was used as a covariate. Total intracranial volume was not entered, as there was no significant difference between groups. Small volume correction was used in order to check whether the periaqueductal gray (significant at uncorrected P—see Section 3) was significant at corrected P. The origin of a sphere of 3 cm of diameter was located at the approximate center of the periaqueductal gray (voxel coordinates (0, −28, −10)), and the procedure “small volume correction” was carried out. This procedure compares only the voxels included in this sphere. 2.5. Definition of rostral limbic system structures The rostral limbic system consists of the ventromedial and anterior cingulate cortices, the anterior insula, the ventral striatum, the amygdala, and the periaqueductal gray. The ventromedial frontal cortex consists of the orbital cortex and of the medial portion of the frontal gyri (Brodman areas 11, 12 and medial 9 and 10). The anterior cingulate gyrus includes the part of the cingulate gyrus extending caudally from area 24, and continuing rostrally to include the subcallosal portion. The Brodmann designations for this structure are BA 24, 25, 32, 33. The anterior insula, which does not have Brodmann designation, is defined as the portion anterior to the central sulcus. The ventral striatum includes the ventral portion of the head of the caudate nucleus, the ventral part of the putamen and the entire nucleus accumbens.
3. Results FTD patients were younger and more often men than controls (Table 1), but had a similar level of education. The MMSE score was as expected for mild-moderate FTD, since the early involvement of language negatively affects performance on this test.
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Table 1 Clinical and demographic features of patients and controls
Age (years) Sex (male) Education (years) Disease duration (months) Mini-Mental State Examination Clinical dementia rating 0 0.5 1 2–3 Instrumental activities of daily living (n) of functions lost
Frontotemporal dementia (n = 9)
Controls (n = 26)
62 7 6 30 14
69 9 8 – 29
(5) (78%) (4) (15) (8)
0 4 (44.4%) 2 (22.2%) 3 (33.3%) 4.0 (2.4)
Values denote mean (S.D.) or number (%). P denotes significance on
χ2 -
Significance (P)
(8) (35%) (3)
0.01 0.01 NS –
