Left Anterior Temporal Lobe Sustains Naming in Alzheimer's Dementia and Amnestic Mild Cognitive Impairment

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1 Left Anterior Temporal Lobe Sustains Naming in Alzheimer's Dementia and Amnestic Mild Cognitive Impairment L. Frings, S. Klöppel,..., M. Hüll Department of Psychiatry and Psychotherapy, Section of Gerontopsychiatry and Neuropsychology Freiburg Brain Imaging, University Hospital Freiburg, Freiburg, Germany ABSTRACT Cognitive decline in degenerative dementia is paralleled by progressive atrophy, with the localization of atrophy reflecting specific cognitive impairment. Confrontation naming deficits are frequently observed in dementia across etiologies. In this study we aimed to identify the brain regions underlying this deficit. In patients with clinically diagnosed dementia or mild cognitive impairment (MCI) we investigated the relationship between gray matter volume (GMV) and performance on a standardized confrontation naming test. 268 patients with one of three probable etiologies were included: Alzheimer's Dementia (AD), AD with signs of cerebrovascular pathology (AD+vasc), and Frontotemporal Dementia (FTD). We contrasted voxel-wise GMV of patients performing within the normal range with those of patients with pathological performance. In a second analysis, we investigated differential effects of gray matter atrophy on impaired performance in subsamples of amnestic MCI (amci) vs. AD patients. Results revealed significantly reduced GMV in the left anterior temporal lobe (ATL) in pathological performers compared to normal performers. The subgroup analysis confined to amci and AD patients replicated this relationship. While left ATL atrophy is well known to be implicated in naming deficits in semantic dementia, our data confirm the same in AD and already in amci.

2 1. Introduction The predominant cognitive symptom of dementia is failure of the episodic memory system [1]. However, language disturbances, especially word finding difficulties, are frequently reported by patients with neurodegenerative diseases and their relatives, even in early states of the disease [2], especially in primary progressive aphasias [3]. Confrontation naming is typically used to assess word finding capabilities. It becomes impaired in all types of dementia, very early in semantic dementia (SD) and more variably and later in the course of AD [4]. Failure to name a depicted object or animal can be due to errors in different processing modules, whose correct functioning is required to produce the output. Whereas in SD the deficit typically lies in the verbal storage, in progressive nonfluent aphasia (PNFA) rather the phonological encoding of the verbal concept into speech sounds is disturbed [5, 6]. In AD in contrast, dysfunction already at the visual perception stage might hinder correct naming [7]. Different types of dementia are associated with different patterns of cortical and subcortical atrophy. Nevertheless, it has been demonstrated that despite differential atrophy patterns, subforms of dementia with naming impairment might share a common affection of a defined brain region in the left lateral temporal lobe [2]. We aimed to test the relationship between regional GMV throughout the brain and naming performance across different types of clinically diagnosed dementia and MCI in a large number of patients from a multi-center study. Irrespective of clinical diagnosis and etiology, patients were categorized based on the absence or presence of naming deficits with respect to published normative data [8]. They were subjected to either the normally performing group, or the group of pathologically performing patients. We considered the normally performing patient group as the ideal control group which as closely as possible matches the group with naming deficits. The rare, previous studies investigating gray matter (GM) atrophy and naming performance in dementia and MCI yielded inconsistent results. Worse naming correlated with less GM density in widespread cortical areas, among them temporal, occipital, and sensorimotor cortex in one study [9]. Another study by Grossman and

3 colleagues [2] identified atrophy in the left temporal lobe which was associated with impaired naming. As the numbers of participating patients were not sufficiently high (<20 AD patients in each study) to draw conclusions on the population level, we approached this topic with a larger multicenter data set. Following previous publications [10-13], it was hypothesized that less GMV in the temporal cortex would be associated with worse naming performance.

4 2. Methods 2.1. Subjects We analyzed data sets from 268 patients recruited from nine participating centers in Germany. Data acquisition was approved by the Ethics Committees at each individual center, and was conducted in accordance with the Declaration of Helsinki. The full description of the demographic data and data acquisition from the multicenter trial is published [14]. Diagnostic Groups Inclusion criteria were fulfillment of clinical, diagnostic criteria for dementia or MCI. Patients with other severe pathology of the central nervous system were excluded from the analyses. Analyses started with a larger data set of 348 patients. Six patients were discarded from the analysis due to incomplete data sets (missing BNT, MMSE, or years of education values). We only included dementia patients with clinically diagnosed dementia subtypes (1) Alzheimer dementia (AD [1]), (2) frontotemporal dementia (FTD [15]), or (3) dementia of Alzheimer's type with signs of vascular dementia (AD+vasc [1]). The group of MCI patients was subdivided accordingly into MCI probably converting into (1) AD, (2) FTD, or (3) AD+vasc. Patients with probable other etiologies were discarded (N=74), leaving a corpus of 268 data sets for the analyses described below. Participating Centers The data we present were acquired by German specialist memory clinics of university hospitals from May 2003 until November 2007, co-ordinated by the German Dementia Competence Network (DCN), which was funded by the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01GI0420). Further details are available in [14] and from the DCN website ( Centers from which data were included in the following analyses were:

5 Charite, Berlin, Campus Benjamin Franklin, Berlin; University of Bonn; Department of Psychiatry and Psychotherapy, University of Erlangen; University of Frankfurt; Center for Geriatric Medicine and Gerontology, University Hospital Freiburg; University of Hamburg; University of Heidelberg; University of Leipzig; Ludwig Maximilian University Munich Neuropsychological Assessment All patients were clinically tested as part of standard clinical diagnostics. All received the German version [8] of the CERAD NP test battery [16]. As our focus was an naming capabilities, we here report scores from the modified, 15-item Boston Naming Test (BNT; Table 1), which is a short version of the 60-item BNT [17] MR Imaging MR images were obtained on 1.5-Tesla scanners. Siemens scanners (Siemens Sonata or Siemens Magnetom Vision; sagittal magnetization-prepared rapid gradient echo sequence) or Philips scanners (Philips Gyroscan and Philips Intera; 3D fast T1- weighted gradient echo sequence) were used. For standardization of MRI acquisition across centers, acquisition parameters were provided to all centers as a guideline. The phantom test of the American College of Radiology MRI Accreditation Program was conducted repeatedly at sites of the DCN [18] and a healthy volunteer was examined at centers to ensure comparable data quality. The repetition time varied from 9.3 to 20 ms and echo time from 3.93 to 4.38 ms between centers MR Image Preprocessing Images were visually inspected for artifacts or structural abnormalities unrelated to dementia and segmented into GM, white matter (WM) and cerebro-spinal fluid (CSF) using SPM8 (Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London, UK Then, GM segments were further normalized to the population templates generated from all subjects using a diffeomorphic registration algorithm [19]. This non-linear warping technique minimizes structural variation between subjects. A separate modulation step [20] was used to ensure that the overall amount of each tissue class remained constant

6 after normalization. Normalized images were spatially smoothed using an 8 mm Gaussian kernel Analyis 1: NORMAL vs. PATHOLOGICAL PERFORMERS In order to investigate the effects of naming impairment, we analyzed data from patients who performed within the normal range (NORMAL PERFORMERS; N = 172), and from patients with more than 2 standard deviations below mean, (PATHOLOGICAL PERFORMERS; N = 62) according to normative data, which take sex, age, and education into account [8]. Patients with intermediate performance in the naming test (between 1 and 2 standard deviations below respective mean; N = 34) were excluded, leaving 234 data sets for this analysis. ANALYSIS 1 NORMAL PERFORMERS PATHOLOGICAL PERFORMERS SEVERITY DEMENTIA MCI DEMENTIA MCI Number of Subjects CLINICAL DIAGNOSIS 52; 7; 5 93; 10; 5 25; 3; 8 22; 1; 3 (AD; AD+vasc; FTD) SEX 79 male, 93 female 31 male, 31 female AGE [yrs; mean (SD)] 70.2 (8.9) 70.4 (6.6) EDU [yrs; mean (SD)] 11.7 (3.0) 11.5 (3.0) MMSE [Mean (SD)] * 25.7 (2.8) 23.8 (3.7) BNT [Mean (SD)] * 14.1 (0.9) 9.5 (2.3) Table 1: Demographics and test performance data of NORMAL & PATHOLOGICAL PERFORMERS. Asterisk indicates significant group difference (p<0.05; Two-sample T-Test). Circle represents significantly different distribution between groups (Chi-square Test, p<0.05). In order to test for a group difference in GMV between normal and pathological naming test performers, an ANCOVA was carried out with factor GROUP, including SEX, AGE, and education (EDU) as well as total intracranial volume (TIV; GM + WM

7 + CSF) as co-variates of no interest. We aimed to look for brain voxels that exhibited more GMV in NORMAL compared to PATHOLOGICAL PERFORMERS, as well as the opposite contrast. Results were regarded as significant when surviving a statistical threshold of p<0.05, FWE-corrected for multiple comparisons at the voxellevel Analysis 2: Relation between BNT & GMV in amci vs. AD Patients Aiming at the further investigation of the differential relation between naming performance and GMV in amci (MCI patients who were expected to convert to AD) and AD patients, we performed a 2 2 factorial ANCOVA with factors PERFORMANCE (NORMAL vs. PATHOLOGICAL) and DIAGNOSIS (amci vs. AD), including SEX, AGE, EDUCATION, and TIV as co-variates of no interest. The number of data sets in this analysis was reduced compared to Analysis 1 by patients not belonging to the AD or amci groups, leaving 192 data sets (see Table 2). We were interested in the main effect of factor PERFORMANCE irrespective of the diagnosis. This contrast was built to test if the result from Analysis 1 could be replicated in amci and AD patients. We further looked at patterns of reduced GMV associated with pathological performance in each of the diagnostic subgroups (amci and AD, respectively). Finally, the interaction between factors PERFORMANCE and DIAGNOSIS was tested for significance, looking for differential patterns of reduced GMV associated with impaired naming in amci vs. AD. Results were regarded as significant when surviving a statistical threshold of p<0.05, FWE-corrected for multiple comparisons at the voxel-level. Additionally, a lower threshold was applied (combined uncorrected threshold of p<0.005 at the voxel-level and p<0.05 at the cluster-level), in order not to overlook effects due to the smaller sample size in this analysis. ANALYSIS 2 NORMAL PERFORMERS PATHOLOGICAL PERFORMERS DIAGNOSIS amci AD amci AD SEX 42 m, 51 f 22 m, 30 f 12 m, 10 f 10 m, 15 f

8 AGE [yrs; mean (SD)] 69.3 (8.5) 72.6 (9.3) 69.1 (5.2) 72.8 (6.3) EDU [yrs; mean (SD)] 11.6 (2.8) 12.1 (3.6) 11 (2.9) 11.6 (3.1) MMSE [mean (SD)] 1, (2) 23.6 (3.2) 25.9 (2.4) 21.8 (4.1) BNT [mean (SD)] (0.9) 14.1 (0.8) 10.5 (1.3) 9.4 (2.2) Table 2: Demographics and test performance data of normally and pathologically performing amci and AD patients. Superscript numbers indicate significant group differences (T-test; p<0.05) between 1, normally performing amci & normally performing AD; 2, pathologically performing amci & pathologically performing AD. M, male; f, female.

9 3. Results 3.1. Analysis NORMAL > PATHOLOGICAL PERFORMERS We observed highly significantly more GMV in NORMAL compared to PATHOLOGICAL PERFORMERS in the left ATL. This cluster covered portions of the medial temporal pole, the anterior fusiform gyrus, and the anterior inferior temporal gyrus (ITG; Fig. 1). Smaller clusters in the left superior temporal sulcus (STS), left middle temporal gyrus (MTG), and collateral sulcus as well displayed a significant difference between the groups (Table 3). An additional, confirmatory posthoc analysis revealed a highly significant, positive correlation of GMV in the left ATL peak voxel and the naming test score (Spearman correlational analysis, p<0.01) across groups of NORMAL and PATHOLOGICAL PERFORMERS. Figure 1: Statistical parametric map displaying voxels with greater GMV in NORMAL than PATHOLOGICAL PERFORMERS (N=234; voxel-level threshold p<0.05, FWE-corrected for multiple comparisons), overlaid on a sample-specific GM template, bottom view. Anatomical Region Cluster Size (Voxels) Coordinates Z-Score Left Anterior Temporal Lobe Left Superior Temporal Sulcus Left Middle Temporal Gyrus Left Collateral Sulcus Table 3: Clusters of voxels displaying significantly reduced GMV in PATHOLOGICAL compared to NORMAL PERFORMERS (p<0.05, FWE-corrected; cf. Figure 1), with cluster size in voxels of 1.5mm

10 width in each direction, anatomical label, Talairach-coordinates, and z-score of the peak voxel PATHOLOGICAL > NORMAL PERFORMERS The opposite contrast did not reveal more GMV in PATHOLOGICAL vs. NORMAL PERFORMERS in any brain voxel at either threshold Analysis 2: Association between Naming Performance and GMV in amci and AD 1. Main Effect NORMAL > PATHOLOGICAL PERFORMERS The contrast NORMAL > PATHOLOGICAL PERFORMERS across the entire group of amci and AD patients revealed significantly greater GMV in NORMAL PERFORMERS in a large cluster with its peak in the left collateral sulcus, which further comprised portions of the neighboring fusiform and parahippocampal gyri, the left temporal pole, and the left hippocampus. Further regions of significantly different GMV were in the bilateral cerebellum and right posterior collateral sulcus (combined uncorrected threshold of p<0.005 (voxel-level) and p<0.05 (cluster-level); Figure 2, left; Table 4). Voxels in the left posterior collateral sulcus also survived the more conservative FWE-corrected thresholding at p<0.05. Figure 2: Regions of reduced GMV associated with impaired naming in the entire group of amci + AD patients (left), in amci (middle), and in AD patients (right). Combined threshold of p<0.005 at the voxel- and p<0.05 at the cluster-level. 2. Main Effect NORMAL > PATHOLOGICAL PERFORMERS in amci The contrast NORMAL > PATHOLOGICAL PERFORMERS in amci revealed an association between less GMV and worse naming in the left ATL (anterior ITG) and in the left cerebellum (Figure 2, middle; Table 4; combined uncorrected voxel-level

11 threshold p<0.005 and cluster-level threshold p<0.05). No voxels survived FWEcorrection (p<0.05). 3. Main Effect NORMAL > PATHOLOGICAL PERFORMERS in AD Regarding AD patients only, NORMAL PERFORMERS had greater GMV than PATHOLOGICAL PERFORMERS in a larger cluster with a peak in the left ATL, which also included parts of the left posterior collateral sulcus, anterior hippocampus, and amygdala. Further, worse naming was associated with less GMV in the right posterior collateral sulcus, bilateral cerebellum, and the left premotor cortex/inferior frontal gyrus (IFG), presumably corresponding to Brodmann Area 44 (Figure 2, right; combined uncorrected voxel-level threshold p<0.005 and cluster-level threshold p<0.05). No voxels survived FWE-correction (p<0.05). 4. Interaction between Factors PERFORMANCE and DIAGNOSIS This contrast did not reveal any voxels exhibiting a significant interaction regarding GMV between factors PERFORMANCE and DIAGNOSIS at FWE-corrected (p<0.05) or uncorrected thresholding (combined voxel-level threshold p<0.005 and cluster-level threshold p<0.05). Anatomical Region Cluster Size (Voxels) Coordinates Z-Score NORMAL > PATHOLOGICAL PERFORMERS amci + AD Left Collateral Sulcus Right Collateral Sulcus Right Cerebellum Left Cerebellum Right Cerebellum NORMAL > PATHOLOGICAL PERFORMERS amci Left Anterior Inferior Temporal Gyrus Left Cerebellum

12 NORMAL > PATHOLOGICAL PERFORMERS AD Left Anterior Temporal Lobe Right Collateral Sulcus Right Cerebellum Left Precentral Gyrus/ Inferior Frontal Gyrus Left Cerebellum Table 4: Clusters of voxels displaying significantly reduced GMV in PATHOLOGICAL compared to NORMAL PERFORMERS (combined uncorrected threshold of p<0.005 at the voxel-, p<0.05 at the cluster-level; cf. Figure 2), with cluster size in voxels of 1.5mm width in each direction, anatomical label, Talairach-coordinates, and z-score of the peak voxel.

13 4. Discussion In this study we identified significant naming impairment (<2SD below mean according to normative data) in one third of the AD patients and one fifth of the MCI patients. As all patient subgroups were rather mildly affected, with group mean MMSE scores well above 20, we conclude that naming impairment as a symptom of MCI and dementia is a rather early, relevant cognitive deficit. In this study we identified the brain regions whose atrophy underlies such naming deficits. By showing reduced GMV in a very circumscribed region in persons with naming deficits irrespective of the clinical diagnosis, we were able to demonstrate that the left ATL is crucial for successful confrontation naming. This is in line with current knowledge about the role the left ATL plays in semantic processing. The same relationship between naming capabilities and left ATL atrophy was detected in subgroups of amci and AD patients. Further regions which were associated with naming performance were bilateral medial/inferior temporal cortex, left frontal lobe, and the cerebellum. The pattern of naming-relevant regions was not significantly different between amci and AD patients Relationship between Left ATL and Confrontation Naming The predominant site that we found associated with impaired naming the left ATL has been evidenced to be affected by different types of dementias previously. Anterior TL atrophy is a characteristical sign of SD [11, 21-23]. It is often left-lateralized [24], or at least initially greater in the left hemisphere [25]. Schroeter et al. [26] recently presented a meta-analysis which yielded left ATL atrophy in AD and amci. A crucial step among the cognitive processes that are required for successful confrontation naming is the retrieval of semantic knowledge [27, 28]. Impaired retrieval of semantic, conceptual knowledge is the core deficit in SD [29, 30]. The left ATL has been termed the 'semantic hub', which is involved in storage and

14 retrieval of conceptual knowledge [10], and might therefore play a crucial role in confrontation naming. Evidence from SD that implicated the temporal pole in semantic memory showed an FDG-PET hypometabolism in left and, to a lesser extent, right ATL [31, 32]. Greater atrophy of left than right TL has been linked to anomia in SD [33]. In AD reduced metabolism of the left TL (including the ATL) was related to verbal and nonverbal semantic impairment [34]. Brain areas where less GMV was related to worse naming performance in our study largely overlapped with those that exhibited naming impairment associated with reduced metabolism in AD patients in a previous FDG-PET study [35]. Functional imaging studies assessing semantic processing-related activation frequently failed to show involvement of the ATL [36], which has been considered as evidence for methodological problems (e.g., susceptibility artifacts in fmri), rather than evidence for the ATL to be not implicated [37]. It has recently been noted that it is not clear whether impairment of AD patients in semantic tasks indicates dysfunction in the semantic system, or whether deficits in other cognitive domains produce the impairments [4], e.g. visual perception [7]. Our observation of reduced GMV in the left ATL associated with impaired naming largely replicates the pattern of atrophy/cortical thinning in semantic dementia [38, 39], the type of dementia which is most closely related to naming impairment. Interestingly, we found this pattern of reduced GMV to be involved in naming deficits in subgroups of AD and amci. Our data thus provide evidence that in AD and amci the impaired processing stage that explains the most variability in naming abilities lies at the semantic level, which has been linked to the ATL. This might indicate that semantic deficits are present in some, but not all amci and AD patients. The weaker association in bilateral medial/inferior temporal cortex might reflect additional dysfunction already at the visual perception level.

15 4.2. Medial/inferior Temporal Cortex and Confrontation Naming Our results furthermore implicated bilateral regions in the collateral sulcus, covering also portions of the neighboring parahippocampal and fusiform gyri, in naming. Located within the collateral sulcus is the transentorhinal cortex, which is presumably the earliest region affected by neurofibrillary tangles in AD [40]. The term transentorhinal cortex refers to the transition zone between perirhinal cortex (PRC) and entorhinal cortex (ERC) and lies at the medial bank of the collateral sulcus [41]. The PRC forms a strongly, functionally interconnected system together with ERC, anterior hippocampus, and lateral and polar temporal cortex, as has recently been demonstarted with resting state connectivity analysis of fmri data [42]. Rhinal cortices PRC and ERC play an important role in declarative memory, which comprises episodic and semantic memory [43, 44]. Bilateral perirhinal and parahippocampal GM atrophy has recently been linked to impaired semantic retrieval in a study investigating semantic fluency in AD [45]. Medial temporal lobe and inferior temporal cortex have as well been demonstrated to be involved as part of the ventral visual system (VVS) in visual object recognition [46], with increasing object feature complexity being processed along the posterior-anterior axis. In the same vein, Tyler and co-workers [47] proposed a hierarchical organization of visual representations in the TL. While posterior TL is assumed to process on a coarse entry level (e.g., 'living' or 'manmade'), the anterior TL processes complex feature configurations, allowing for fine-grained distinctions between members of one category. The regions in bilateral perirhinal/ parahippocampal/fusiform cortex that we found associated with confrontation naming might thus reflect processing at the interface between visual object perception and semantic retrieval Frontal and Cerebellar Involvement In AD patients, we detected a frontal region (most likely BA 44) whose GMV

16 reduction was related to impaired naming. This might indicate that in AD, in addition to a temporally-based semantic knowledge based system, a rather frontally-based system involved in retrieval might be disturbed, as has been hypothesized previously [35]. We observed a relation between GMV and naming performance in the bilateral cerebellum in amci and AD patients when a less stringent, uncorrected threshold was used. The cerebellum has previously been implicated in language performance. Patients with cerebellar degeneration have been shown to be impaired in language tasks like semantic fluency, even when correcting for reduced language output speed [48]. Activation studies have as well implicated the cerebellum in confrontation naming (for a review, see Indefrey & Levelt [28]). In AD patients, confrontation naming performance has recently been shown to be correlated with GM density in the cerebellum [45]. However, in our analyses the relation between cerebellar local GMV and BNT performance did not exceed Z-scores of 4 and thus was considerably weaker compared to temporal regions. Consequently, we do not suspect cerebellar degeneration in our patient sample to be the driving force behind naming impairment. Compared to previous reports on the association between GMV and performance on the BNT in AD [2, 9, 45] and amci [9], our results were based on greater numbers of participants, which increased statistical power. This larger number of participants further allowed for a split into groups of normal and poor performers (>SD below mean, according to normative data). We avoided to use regression statistics on the test variable 'BNT score', which is usually not normally distributed and thus would violate regression analysis prerequisites. However, a considerable overlap can be detected between results of the study by [2] and our own results. The authors similarly found a correlation between BNT

17 score and GM atrophy in AD patients of comparable age and severity in the left anterior part of the left TL, which in turn largely overlapped with the pattern they found in SD patients. Furthermore, smaller bilateral inferior temporal regions were detected (in AD as well as FTD patients) which exhibited the same correlation. These spots might correspond to the bilateral areas centered in the collateral sulci that exhibited a relationship between GMV and BNT score in our study. Grossman and colleagues [2] concluded, based on correlation with other neuropsychological tests, that the cognitive process underlying confrontation naming deficits across groups of dementia patients was lexical retrieval. The rather posterior, left MTG region that showed common atrophy across patient groups has been linked to lexical representations in other studies (for a review, see Lau [49]). In contrast, the strong association that we observed between left ATL and naming leaves the question undecided, whether naming deficits in dementia and MCI are due to disruption of either amodal semantic information [10], or, alternatively, word-level access (c.f. [13]). However, this issue needs to be addressed in further studies using cognitive test instruments which are able to disentangle the sub-processes engaged with confrontation naming.

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