J Neurol DOI 10.1007/s00415-014-7439-z
ORIGINAL COMMUNICATION
Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia Michel J. Grothe • Christina Schuster • Florian Bauer • Helmut Heinsen • Johannes Prudlo Stefan J. Teipel
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Received: 16 April 2014 / Revised: 10 July 2014 / Accepted: 11 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Similar to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer’s disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was
comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20–25 %, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions. Keywords Dementia with Lewy bodies Alzheimer’s disease Cholinergic basal forebrain Nucleus basalis Meynert Harmonized hippocampus protocol MRI
Introduction C. Schuster and M. J. Grothe contributed equally to the manuscript M. J. Grothe (&) C. Schuster F. Bauer J. Prudlo S. J. Teipel German Center for Neurodegenerative Diseases (DZNE), Gehlsheimer Str. 20, 18147 Rostock, Germany e-mail: [email protected] H. Heinsen Department of Psychiatry, Laboratory of Morphological Brain Research, University of Wu¨rzburg, Josef-Schneider-Str. 2, 97080 Wu¨rzburg, Germany J. Prudlo Department of Neurology, University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany S. J. Teipel Department of Psychosomatic Medicine, University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia disorder after Alzheimer’s disease (AD) [45]. Its core clinical features consist of fluctuating cognitive impairment, recurrent visual hallucinations and parkinsonism. Patients with DLB typically present with impaired attention, executive functions and visuospatial skills, whereas impairments in learning and memory typically appear later during the disease [11, 17, 44, 45]. While neuropathological examinations point to largely distinct pathologic substrates underlying DLB and AD dementia [43], both dementing disorders are associated with severe degeneration of the cortically-projecting cholinergic neurons of the basal forebrain (BF) [9, 20, 41, 71–73]. Furthermore, in both disorders the cholinergic degeneration
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and associated depletion of cortical cholinergic activity were found to correlate with the degree of dementia severity ante mortem [33, 54, 69], thus motivating the use of cholinomimetics for antidementive treatment in these conditions [4, 50, 56]. Although acetylcholinesterase inhibitors (AChE-I) were originally developed, and first approved, for medical treatment of AD dementia [16], DLB patients may even be more responsive to this type of treatment [39, 40], which has been attributed to a stronger cholinergic deficit in this disease [19, 55, 69]. This assumed strong cholinergic deficit in DLB corresponds to the clinical characteristics of the disease, i.e. fluctuating cognition and prominent impairment in visuospatial attention. In recent years, neuroimaging markers for in vivo measurements of the cholinergic deficit have emerged, which could partly replicate and extend the early neuropathological findings. Molecular imaging studies based on positron emission tomography (PET)-suitable radiotracers for AChE could demonstrate widespread reductions in cortical cholinergic activity in DLB patients in vivo [38, 60]. Measurement of the thickness of the substantia innominata (SI) on structural magnetic resonance imaging (MRI) scans has been used as in vivo marker of cholinergic BF degeneration, revealing strong atrophy of this region in both DLB and AD dementia patients [30, 74]. Interestingly, the degree of SI atrophy was also found to be predictive of the response to AChE-I treatment in these conditions [29, 64]. However, the manual measurement protocol of SI atrophy employed in these studies was limited in that it focused on a small region of the BF at the level of the crossing of the anterior commissure. The BF cholinergic system contains several groups of cholinergic cell clusters that extend approximately 20 mm in anterior-posterior direction from the medial septum up to the level of the centromedian nucleus of the amygdala [27, 66, 67, 77]. These cholinergic subdivisions of the BF are characterized by a differential innervation preference for distinct functional cortical networks [48, 76], show differential associations with specific cognitive and behavioral functions [52, 54], and vary in their vulnerability to AD-related neurodegeneration [71]. Recently, automated image processing techniques have been developed that allow a more comprehensive analysis of in vivo BF atrophy, based on cytoarchitectonic mappings of the cholinergic BF nuclei combined with deformation-based morphometry of high-resolution MRI scans [23–26, 37, 65, 68]. Reproducing previous neuropathological findings, these methods revealed a subregion-specific degeneration of the cholinergic BF in AD which was also associated with impairments in global cognitive function and specific memory tests.
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In the present study we used these morphometry techniques to explore subregional atrophy pattern of the BF in a sample of DLB patients and compare it with the pattern of BF atrophy found in AD patients. For comparison we also assessed hippocampal volume within the same computational morphometry approach, given that several previous in vivo imaging studies have consistently reported more severe hippocampal atrophy in AD compared to DLB [2, 7, 10, 36, 62, 63, 74].
Methods Subjects A sample of 11 patients who fulfilled criteria for clinically probable DLB [44] and had high-resolution structural MRI scans available were identified from our memory clinicbased patient cohort. Eleven patients with clinically probable AD [47] and 22 healthy controls (HC) were selected randomly from the larger study cohort with the constraint of matching DLB patients in terms of age, sex and education; AD patients were further matched to the DLB patients with regard to dementia severity as reflected by Mini-Mental State Examination (MMSE) scores. Demographics and global cognitive profile of the study groups are summarized in Table 1. The HC group consists of spouses of patients, or community dwelling elderly who were recruited through public advertisement. All participants underwent standard clinical assessment including complete medical history, clinical, psychiatric and neurological examinations. Furthermore, all subjects underwent detailed neuropsychological examination including the MMSE [18], the CERADPlus cognitive battery [3, 51], and the clock drawing test [61]. HC reported no subjective memory complaints and scored all tests within the normal range. Blood tests consisted of complete blood count, electrolytes, glucose, liverassociated enzymes, cholesterol, HDL, triglycerides, and Apo-E4 genotyping. All MRI scans were visually inspected by a radiologist to rule out major neuropathology not directly related to AD or DLB pathology, such as tumor, stroke or advanced white matter disease. Visual Table 1 Demographic characteristics DLB patients
AD patients
Healthy controls
Gender (M/F)
7/4
7/4
14/8
Age, years (SD)
73.9 (4.5)
73.6 (4.3)
73.0 (3.9)
Education, years (SD)
12.7 (2.6)
12.5 (2.5)
13.3 (2.8)
MMSE score, mean (SD)
24.4 (2.6)
23.7 (3.1)
28.5 (0.9)
DLB dementia with Lewy bodies, AD Alzheimer’s disease dementia, M male, F female, MMSE Mini Mental State Examination
J Neurol
hallucinations were present in five DLB patients, but also in one AD patient. SPECT-based dopamine transporter imaging was available for nine of the DLB patients and a marked presynaptic dopaminergic deficit of the nigrostriatal pathway was detected in eight of these patients. Five of the DLB patients and two of the AD patients were taking cholinergic drugs (AChE-I) as antidementive treatment. All participants gave written informed consent in agreement with the local ethics committee; the study was conducted according to the 1964 Declaration of Helsinki and its later amendments. MRI acquisition All data were acquired in Rostock with a 3T Siemens MAGNETOM Verio Scanner (Siemens, Erlangen, Germany, software syngo MR B17) using 32 channel head coils. T1-weighted, high-resolution structural MRI volumes of the brain were obtained using a 3D-MPRAGE sequence (TE = 2.52 ms, TR = 1,900 ms, TI = 900 ms, flip angle = 9°, bandwidth = 170 Hz/pixel, matrix = 256 9 256 9 176, isometric voxel size = 1.0 mm3). MRI preprocessing MRI data were processed using statistical parametric mapping (SPM8, Wellcome Trust Center for Neuroimaging) and the VBM8 toolbox (http://dbm.neuro.uni-jena.de/ vbm/) implemented in Matlab R2013a (MathWorks, Natick, MA, USA). The main processing steps and computational analyses have been described previously [24, 37]. Briefly, MRI scans were segmented into gray matter (GM), white matter, and cerebrospinal fluid partitions and high-dimensionally registered to Montreal Neurological Institute (MNI) standard space using the VBM8 toolbox. Warping parameters were applied to individual GM maps and GM-voxel values were modulated to account for the volumetric differences introduced by the high-dimensional warps. GM volumes of the BF cholinergic nuclei and hippocampus were automatically extracted by summing up the modulated GM voxel values within the respective regions of interest (ROIs) (see ‘‘Definition of the basal forebrain and hippocampus regions of interest’’). The total intracranial volume (TIV) was calculated as the sum of the total segmented gray matter, white matter and cerebrospinal fluid volumes. Definition of the basal forebrain and hippocampus regions of interest According to Mesulam’s nomenclature [49], the cholinergic BF is composed of four groups of cholinergic cells
which correspond to the medial septum (Ch1), the vertical and horizontal limb of the diagonal band of Broca (Ch2 and Ch3), and the nucleus basalis Meynert (NBM, Ch4). The NBM is the largest cholinergic nucleus of the BF and can be further subdivided into anterior medial and lateral (Ch4am and Ch4al), intermediate (Ch4i) and posterior regions (Ch4p). A further part of the cholinergic BF is the nucleus subputaminalis, which has only been described in the human and anthropoid monkey brain, and can be regarded as a lateral extension of rostral and antero intermediate parts of the NBM [5]. The cholinergic nuclei are not directly visible on current structural MRI contrasts and no comprehensive set of external landmarks has been identified that could be used for indirect manual delineation of the cholinergic BF on MRI scans. In the current study, we localized the cholinergic BF based on a cytoarchitectonic map of BF cholinergic nuclei in MNI space, derived from combined histology and in cranio MRI of a postmortem brain [37, 66]. This map is similar in general outline to a previously defined BF map based on a different postmortem MRI scan [67], but in contrast to this previous mask, it comprises outlines of the Ch1/2, Ch3, Ch4a–i, Ch4p and nucleus subputaminalis subregions of the BF. In the present study we analysed group differences in total BF volume (all cholinergic nuclei combined, BFtot), and separately for the subregions belonging to the NBM proper (Ch4a–i and Ch4p) and those belonging to the most rostral nuclei (Ch1/2), as these regions have been found to be differentially affected in AD in previous studies using independent cohorts [23, 37, 65]. The ROI mask for the hippocampus was obtained by manual delineation of the hippocampus in the standard space template used for high-dimensional image normalization in the VBM8 toolbox. Tracing of the hippocampus outlines followed recently developed international consensus criteria for manual hippocampus segmentation on MRI [6] and was performed by a certified tracer (MJG) using MultiTracer 1.0 software (http://www.loni.usc.edu/ Software/MultiTracer). Statistical analysis The effect of diagnosis on regional volumes was investigated using analysis of covariance (ANCOVA), controlling for TIV. The significance level was set to p \ 0.05. Post hoc comparisons of the estimated marginal means were corrected for multiple testing using Bonferroni–Holm correction. In addition to the group-wise volumetric comparisons, correlations between TIV-adjusted NBM volume (Ch4a– i ? Ch4p; TIV-related variance removed using linear regression) and global cognitive deterioration, as reflected by MMSE scores, were calculated for each of the dementia
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groups separately. While the MMSE has been designed to capture the memory-predominant cognitive impairments typical for AD, cognitive dysfunction in DLB is mainly characterized by visuoperceptual and attentional-executive function deficits [11]. Thus, we also assessed associations between BF volume and the Trail Making Test A (TMT-A), a widely used test of visuoperceptual abilities included in the CERAD-plus cognitive battery that has been shown to be specifically impaired in DLB relative to AD [8, 17, 57]. Two DLB patients were not capable of performing the test and had to be excluded from this analysis. Part B of the TMT, which is a more specific measure of executive function deficits and similarly useful in distinguishing DLB from AD [17], could not be analysed due to the low number of DLB patients (N = 4) who successfully completed the test within the allowed time interval (300 s). Based on previous evidence implicating the cholinergic system in the pathophysiology of visual hallucinations [1, 12, 42], a distinct clinical feature with high specificity for Lewy body pathology [70], NBM volumes were also compared between dementia patients with and without visual hallucinations.
Results Table 2 shows the mean volumes for each diagnostic group. Figure 1 illustrates the percent volume reductions of the TIV-adjusted ROI volumes in the dementia groups relative to the reference values of the healthy control group. Both dementia groups showed a similar degree of total BF volume reduction, exceeding 20 % compared to the control values. Atrophy in both dementia groups was differentially expressed among BF subregions: volume reductions were most pronounced in the NBM (Ch4p in AD: -23.3 %, and Ch4a-i in DLB: -25.1 %), whereas the rostral Ch1/2 nuclei were less affected in both dementia groups (-17.4 and -17.5 % in AD and DLB, respectively). In contrast to BF volume, hippocampus volume
was markedly more reduced in AD patients (-23.2 %) compared to DLB patients (-12.4 %). ANCOVAs estimating the effect of diagnosis on ROI volumes, while controlling for TIV, revealed significant effects for all ROIs [Ch1/2: F(2, 40) = 5.3, p = 0.009 Ch4a–i: F(2,40) = 14.7, p \ 0.001; Ch4p: F(2, 40) = 17.6, p \ 0.001; BFtot: F(2,40) = 17.6, p \ 0.001; Hippocampus: F(2, 40) = 22, p \ 0.001]. Post hoc group comparisons using Bonferroni–Holm correction for multiple comparisons demonstrated volume reductions in both dementia groups to be statistically significant for all ROIs when compared to the healthy control group, with the exception of Ch1/2 volume reduction, reaching only trend level significance in both patient groups (AD: pBonferroniHolm = 0.07; DLB: pBonferroni-Holm = 0.08). None of the BF volumes differed significantly between DLB and AD groups, but the difference in hippocampus volume between AD and DLB patients reached trend level statistical significance (pBonferroni-Holm = 0.06). TIV-adjusted volumes of the NBM correlated significantly with MMSE scores within the AD group (r = 0.79, p = 0.004), but not within the DLB group (r = 0.17, p = 0.62). By contrast, lower NBM volumes showed a trend-level association with worse performance on the TMT-A test in the DLB group (r = -0.62, p = 0.08), but not in the AD group (r = 0.19, p = 0.59). Figure 2 plots the respective relationships. NBM volumes were slightly smaller in dementia patients with visual hallucinations compared to patients that did not present this clinical feature, but this difference did not reach statistical significance (-10.3 %, p = 0.11).
Discussion This study investigated volumetric changes of the BF in DLB in vivo and compared it to the pattern of BF atrophy found in AD dementia. Both dementia groups demonstrated a pronounced atrophy of the BF, which was similar
Table 2 Mean basal forebrain and hippocampus volumes of dementia and healthy control groups DLB patients
AD patients
Healthy controls
Ch1/2
66.9 (58.3–75.6)9
67.0 (58.3–75.6)9
81.1 (74.9–87.3)
Ch4a–i
71.5 (63.3–79.7)*
75.3 (67.2–83.5)*
95.5 (89.7–101.4)
Ch4p
58.6 (53.4–63.8)*
55.3 (50.1–60.4)*
72.1 (68.4–75.8)
BFtot
355.5 (322.6–388.3)*
354.4 (321.7–387.1)*
452.3 (429.0–475.5)
Hippocampus
6,245.5 (5,826.4–6,664.7)*,
#
5,477.9 (5,060.9–5,894.8)*
7,131.2 (6,834.4–7,427.9)
Volumes (in mm3; confidence interval in brackets) are adjusted for total intracranial volume (estimated marginal means) * 9 #
Significantly different compared to healthy controls at pBonferroni-Holm \ 0.01 Trend level significance for difference compared to healthy controls, pBonferroni-Holm \ 0.1 Trend level significance for difference compared to AD group, pBonferroni-Holm \ 0.1
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Fig. 1 Regional volume reductions in DLB and AD. TIV-adjusted volumes (estimated marginal means) of the total basal forebrain (BFtot), Ch1/2, Ch4a–i, Ch4p and hippocampus are plotted as percent volume reductions relative to the reference values of the healthy control group. DLB patients with Lewy body dementia, AD patients with Alzheimer’s disease dementia, TIV total intracranial volume. **p \ 0.01; 9p \ 0.1; all p values Bonferroni-Holm corrected
in terms of severity and regional pattern: volume of the NBM (Ch4a–i, Ch4p) was significantly reduced by 20–25 % in both dementia groups compared with the healthy control group, whereas volume of the rostral BF nuclei (Ch1/2) was only marginally affected. Interestingly, NBM volume was highly correlated with global cognitive functioning in terms of MMSE scores within the AD patient sample, but not within the DLB patient sample. In contrast to BF volume, hippocampus volume was differentially affected in the two dementia syndromes, with severe atrophy in the AD group and relative sparing in the DLB group. Degeneration of the NBM and associated depletion of cortical cholinergic activity are well described characteristics of both AD dementia and DLB [9, 20, 33, 41, 54, 69, 71–73]. However, less neuropathological data are available on the subregional specificity of cholinergic BF atrophy in these conditions. In AD, a subregion-specific pattern of cholinergic BF atrophy has been described, where loss of cholinergic cells is most pronounced in the posterior subdivision of the NBM (Ch4p) and relatively spared in the most rostral BF nuclei (Ch1/2) [71]. This pattern matches well to the in vivo BF atrophy pattern observed in AD patients in this and previous studies using independent cohorts [23, 24, 37, 65]. One neuropathological study found cholinergic cell numbers of the Ch1/2 complex to be significantly reduced in a group of DLB patients, but not in AD patients, when compared to normal controls [20]. However, AD patients also showed significant
neurofibrillary tangle pathology in the Ch1/2 complex and mean surface area of the cholinergic neurons was similarly reduced in AD and DLB patients. The MRI-based in vivo measurement of BF integrity employed in the present study cannot distinguish whether the volumetric changes in our AD and DLB samples reflect neurodegenerative cell shrinkage, definite cell loss, or a mixture of both. Previous imaging studies assessed the thickness of the SI at the level of the crossing of the anterior commissure as in vivo marker of NBM atrophy in DLB and AD. Similar to our present results, strong atrophy of this region was found in both DLB and AD groups compared to healthy control groups [28–30, 74]. In a study by Hanyu and colleagues [30], atrophy of the SI was even more pronounced in the DLB group (-34.0 %) compared to the AD group (-28.2 %), which was interpreted by the authors to be reflective of neuropathological evidence of a stronger cholinergic deficit in DLB compared to AD [19, 55, 69]. The anatomic delineation of the SI measurement overlaps with the Ch4a–i subdivision of the cytoarchitectonic map of cholinergic BF nuclei employed in the present study. Interestingly, this BF region was also slightly more atrophic in the DLB (-25.1 %) compared to the AD group (-21.1 %), although this difference was not statistically significant in our small study sample. The generally higher degree of SI atrophy in both dementia groups observed by Hanyu et al. [30] may partly be due to differences in the employed methods, but also due to the significantly more advanced disease stage (lower MMSE scores) of the examined dementia groups compared to our sample. Given the comparable degree of BF atrophy in both dementia groups in the present study, it is interesting that only the AD group showed a strong association between NBM atrophy and cognitive decline in terms of MMSE scores. Similar findings were reported in previous studies using thickness of the SI as an in vivo marker of NBM atrophy [28, 74], where significant associations between SI atrophy and MMSE scores were found in AD, but not in DLB [74] or Parkinson-associated dementia [28]. A possible explanation for this differential association could be that the MMSE mainly captures memory-predominant cognitive impairments typical for AD and may not be equally sensitive to the specific cognitive symptoms that determine dementia severity in DLB, most notably visualperceptual and attentional-executive dysfunction [8, 11, 17]. In line with this notion we found evidence for an association between lower NBM volume and visuoperceptual deficits, as assessed with the TMT-A, in the DLB group, but not in the AD group. Besides the supposed role of cholinergic BF atrophy for cognitive deficits, previous pharmacologic and neurophysiologic studies have also implicated the cholinergic system in the pathophysiology of behavioral disturbances in dementia, most notably visual
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Fig. 2 Relationship between NBM volume and cognitive deterioration in DLB and AD. TIV-related variance was removed from the NBM volumes using linear regression and the residuals are plotted against MMSE and TMT-A scores of the patients. Triangles refer to
patients with Lewy body dementia (DLB); rhombi refer to patients with Alzheimer’s disease dementia (AD); TIV total intracranial volume; NBM nucleus basalis Meynert; MMSE Mini Mental State Examination
hallucinations [1, 12, 42]. The lack of a significant association between NBM volume and the occurrence of visual hallucinations among dementia patients in the present study may in part be related to methodical issues, such as the small sample size and the dichotomous parameterization of visual hallucinations instead of more detailed metrics [13]. However, visual hallucinations in Parkinson’s disease and DLB have recently been found to be closely linked to direct atrophic changes of visuoperceptive areas in the occipital and parietal lobes [15, 21]. Interestingly, visual hallucinations in Parkinson’s disease, but not in DLB, have also been linked to atrophic changes in cholinergic brainstem nuclei with primary projections to the thalamus, rather than to changes in the cortically-projecting cholinergic BF [31, 34]. Future studies should assess the cognitive and behavioral correlates of BF atrophy in DLB in more detail using larger sample sizes and comprehensive psychometric evaluations specifically designed to capture the complex symptomatology of DLB. In contrast to the similar degree of BF atrophy across AD and DLB groups, hippocampus volume was markedly
more reduced in AD patients than in DLB patients. This difference in hippocampus atrophy between the two dementia syndromes has also been found in several previous imaging studies [2, 7, 10, 36, 62, 63, 74] and is likely to reflect the relatively spared memory function in DLB compared with AD [11, 17]. In the present study, simultaneous assessment of BF and hippocampus volumes in the same patient population allowed evaluating the relative degrees of BF and hippocampus atrophy in DLB and AD dementia. While atrophy of the BF was markedly more pronounced than hippocampus atrophy in the DLB group, both regions were similarly affected in the AD group. This finding may partially explain differences in the responsiveness to AChE-I treatment between the two dementia forms [40, 50]. Thus, the generally good responsiveness to AChE-I treatment in DLB may in part be due to a relatively selective degeneration of the cholinergic system in the absence of severe hippocampus atrophy. In general, the presence of any additional pathological mechanisms unrelated to the cholinergic deficit is likely to limit the beneficial effects of AChE-I treatment on dementia symptoms
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[22]. Detailed longitudinal studies on the potential of in vivo BF volumetry for the prediction of AChE-I treatment outcome in large patient cohorts are warranted. A limitation of our study is that the structural in vivo marker of BF volume loss that we utilized is only an indirect marker of cholinergic degeneration. The correspondence of the analysed brain region with the cholinergic space of the BF was determined based on cytoarchitectonic maps derived from combined histology and post-mortem MRI [37, 66], but one cannot exclude that the volumetric differences might also reflect change in other neuronal or glial components of the BF. Furthermore, our patient categorisation is based on clinical diagnoses, and thus one cannot exclude overlapping pathologies of both disorders. However, SPECTbased dopamine transporter imaging was available for nine of the DLB patients, demonstrating marked nigrostriatal dopaminergic degeneration characteristic of Lewy body pathology [46] in all but one of these subjects. When excluding the three DLB subjects without imaging evidence of dopaminergic degeneration from analysis, volumetric group differences and neuropsychological correlations remained virtually unchanged albeit at lower statistical significance (data not shown). It is also noteworthy that the difference in hippocampus atrophy between the DLB and AD groups in our study closely reflects previous imaging findings of DLB and AD cohorts with pathologically confirmed diagnoses [7]. An interesting research question that could not be adequately addressed in the current study is the potential interplay between neurodegenerative changes across dopaminergic and cholinergic systems in DLB. While we used standard clinical evaluations of SPECT-based dopamine transporter imaging scans within diagnostic workup, these images were not suitable for a detailed quantitative analysis of regional dopaminergic deficits. While some of the cognitive and behavioral deficits in Lewy body diseases are believed to be primarily attributable to degeneration of the cholinergic or dopaminergic systems, respectively, exacerbation of symptoms has also been linked to a converging impact of both pathologic processes [53, 58]. Recent multimodal imaging studies have started to unravel the interactions between pathologic changes across several neuronal systems, as well as their separate and combined contributions to disease symptoms [32, 38, 59]. In future multimodal imaging studies, MRI-based in vivo volumetry of the cholinergic BF may become a useful tool to investigate interactions between structural and functional changes across cholinergic and dopaminergic systems in Lewy body diseases, including Parkinson’s disease and DLB. The relatively small sample size limits the statistical power of the study and precluded us from a more exhaustive statistical testing of the significance of the
differential atrophy pattern among BF subregions within diagnostic groups [37, 65]. Yet, the marked reduction in BF volume in DLB and AD compared to healthy controls appears to be a very robust measure as it reaches statistical significance even in a small sample and after rigorous control for multiple pair-wise testing. Future studies including larger sample sizes will allow for more explorative analyses of the clinical correlates of BF atrophy in DLB and AD, as well as of the genetic and molecular modulators of BF volume in these conditions [14, 26, 75]. In summary, we were able to identify a specific pattern of in vivo BF atrophy in DLB which was similar to the one found in AD. A severely atrophied NBM in the posterior part of the BF in addition to a less severely atrophied anterior part could be observed in both dementia groups. By contrast, atrophy of the hippocampus was less pronounced in DLB than in AD patients. NBM atrophy was correlated with global cognitive decline in the AD group and with more specific measures of visuoperceptual deficits in the DLB group. Future studies should explore in vivo patterns of BF atrophy and their possible associations with cognitive and behavioral deficits in predementia stages of DLB [35]. Acknowledgments The study was supported by the Department ‘Aging of the individual and the Society’ of the University of Rostock. Conflicts of interest of interest.
The authors declare that they have no conflict
Ethical standards All participants gave written informed consent in agreement with the local ethics committee; the study was conducted according to the 1964 Declaration of Helsinki and its later amendments.
References 1. Ballard C, Aarsland D, Francis P, Corbett A (2013) Neuropsychiatric symptoms in patients with dementias associated with cortical Lewy bodies: pathophysiology, clinical features, and pharmacological management. Drugs Aging 30:603–611 2. Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, O’Brien JT (1999) Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology 52:1153–1158 3. Basel MC (2005) CERAD-Plus: the consortium to establish a registry for Alzheimer’s disease. Univerista¨tsspital, Basel 4. Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 1:CD005593 5. Boban M, Kostovic I, Simic G (2006) Nucleus subputaminalis: neglected part of the basal nucleus of Meynert. Brain 129:E42 (author reply E43) 6. Boccardi M, Bocchetta M, Ganzola R, Robitaille N, Redolfi A, Duchesne S, Jack CR Jr, Frisoni GB (2013) Operationalizing protocol differences for EADC-ADNI manual hippocampal segmentation. Alzheimers Dement. doi:10.1016/j.jalz.2013.03.001 7. Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E, Kalaria RN, O’Brien JT (2009) Medial temporal lobe atrophy on MRI differentiates Alzheimer’s disease from
123
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8.
9.
10.
11.
12.
13.
14.
15.
16. 17.
18.
19.
20.
21.
22.
dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain 132:195–203 Cagnin A, Gnoato F, Jelcic N, Favaretto S, Zarantonello G, Ermani M, Dam M (2013) Clinical and cognitive correlates of visual hallucinations in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 84:505–510 Candy J, Perry R, Perry E, Irving D, Blessed G, Fairbairn A, Tomlinson B (1983) Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases. J Neurol Sci 59:277–289 Chow N, Aarsland D, Honarpisheh H, Beyer MK, Somme JH, Elashoff D, Rongve A, Tysnes OB, Thompson PM, Apostolova LG (2012) Comparing hippocampal atrophy in Alzheimer’s dementia and dementia with Lewy bodies. Dement Geriatr Cogn Disord 34:44–50 Collerton D, Burn D, McKeith I, O’Brien J (2003) Systematic review and meta-analysis show that dementia with Lewy bodies is a visual-perceptual and attentional-executive dementia. Dement Geriatr Cogn Disord 16:229–237 Cummings J, Emre M, Aarsland D, Tekin S, Dronamraju N, Lane R (2010) Effects of rivastigmine in Alzheimer’s disease patients with and without hallucinations. J Alzheimers Dis 20:301–311 de Medeiros K, Robert P, Gauthier S, Stella F, Politis A, Leoutsakos J, Taragano F, Kremer J, Brugnolo A, Porsteinsson AP, Geda YE, Brodaty H, Gazdag G, Cummings J, Lyketsos C (2010) The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr 22:984–994 de Souza Silva MA, Lenz B, Rotter A, Biermann T, Peters O, Ramirez A, Jessen F, Maier W, Hull M, Schroder J, Frolich L, Teipel S, Gruber O, Kornhuber J, Huston JP, Muller CP, Schable S (2013) Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism. Proc Natl Acad Sci USA 110:15097–15102 Delli Pizzi S, Franciotti R, Tartaro A, Caulo M, Thomas A, Onofrj M, Bonanni L (2014) Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: a cortical thickness MRI study. PLoS One 9:e86624 Eagger SA, Levy R, Sahakian BJ (1991) Tacrine in Alzheimer’s disease. Lancet 337:989–992 Ferman TJ, Smith GE, Boeve BF, Graff-Radford NR, Lucas JA, Knopman DS, Petersen RC, Ivnik RJ, Wszolek Z, Uitti R, Dickson DW (2006) Neuropsychological differentiation of dementia with Lewy bodies from normal aging and Alzheimer’s disease. Clin Neuropsychol 20:623–636 Folstein MF, Folstein SE, McHugh PR (1975) ‘‘Mini-mental state’’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198 Fo¨rstl H, Burns A, Luthert P, Cairns N, Levy R (1993) The Lewybody variant of Alzheimer’s disease. Clinical and pathological findings. Br J Psychiatry 162:385–392 Fujishiro H, Umegaki H, Isojima D, Akatsu H, Iguchi A, Kosaka K (2006) Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies. Acta Neuropathol 111:109–114 Goldman JG, Stebbins GT, Dinh V, Bernard B, Merkitch D, deToledo-Morrell L, Goetz CG (2014) Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson’s disease with hallucinations. Brain 137:849–859 Graff-Radford J, Boeve BF, Pedraza O, Ferman TJ, Przybelski S, Lesnick TG, Vemuri P, Senjem ML, Smith GE, Knopman DS, Lowe V, Jack CR Jr, Petersen RC, Kantarci K (2012) Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies. Brain 135:2470–2477
123
23. Grothe M, Heinsen H, Teipel S (2013) Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer’s disease. Neurobiol Aging 34:1210–1220 24. Grothe M, Heinsen H, Teipel SJ (2012) Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry 71:805–813 25. Grothe M, Zaborszky L, Atienza M, Gil-Neciga E, RodriguezRomero R, Teipel SJ, Amunts K, Suarez-Gonzalez A, Cantero JL (2010) Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer’s disease. Cereb Cortex 20:1685–1695 26. Grothe MJ, Ewers M, Krause B, Heinsen H, Teipel SJ (2014) Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement 27. Halliday GM, Cullen K, Cairns MJ (1993) Quantitation and three-dimensional reconstruction of Ch4 nucleus in the human basal forebrain. Synapse 15:1–16 28. Hanyu H, Asano T, Sakurai H, Tanaka Y, Takasaki M, Abe K (2002) MR analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia. AJNR Am J Neuroradiol 23:27–32 29. Hanyu H, Shimizu S, Tanaka Y, Hirao K, Iwamoto T, Abe K (2007) MR features of the substantia innominata and therapeutic implications in dementias. Neurobiol Aging 28:548–554 30. Hanyu H, Tanaka Y, Shimizu S, Sakurai H, Iwamoto T, Abe K (2005) Differences in MR features of the substantia innominata between dementia with Lewy bodies and Alzheimer’s disease. J Neurol 252:482–484 31. Hepp DH, Ruiter AM, Galis Y, Voorn P, Rozemuller AJ, Berendse HW, Foncke EM, van de Berg WD (2013) Pedunculopontine cholinergic cell loss in hallucinating Parkinson disease patients but not in dementia with Lewy bodies patients. J Neuropathol Exp Neurol 72:1162–1170 32. Hirano S, Shinotoh H, Eidelberg D (2012) Functional brain imaging of cognitive dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry 83:963–969 33. Iraizoz I, Guijarro JL, Gonzalo LM, de Lacalle S (1999) Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia. Acta Neuropathol 98:186–196 34. Janzen J, van‘t Ent D, Lemstra AW, Berendse HW, Barkhof F, Foncke EM (2012) The pedunculopontine nucleus is related to visual hallucinations in Parkinson’s disease: preliminary results of a voxel-based morphometry study. J Neurol 259:147–154 35. Jicha GA, Schmitt FA, Abner E, Nelson PT, Cooper GE, Smith CD, Markesbery WR (2010) Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiol Aging 31:1805–1813 36. Kantarci K, Ferman TJ, Boeve BF, Weigand SD, Przybelski S, Vemuri P, Murray MM, Senjem ML, Smith GE, Knopman DS (2012) Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies. Neurology 79:553–560 37. Kilimann I, Grothe M, Heinsen H, Alho EJ, Grinberg L, Amaro E Jr, Dos Santos GA, da Silva RE, Mitchell AJ, Frisoni GB, Bokde AL, Fellgiebel A, Filippi M, Hampel H, Kloppel S, Teipel SJ (2014) Subregional basal forebrain atrophy in Alzheimer’s disease: a multicenter study. J Alzheimers Dis 40:687–700 38. Klein JC, Eggers C, Kalbe E, Weisenbach S, Hohmann C, Vollmar S, Baudrexel S, Diederich NJ, Heiss WD, Hilker R (2010) Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology 74:885–892 39. Levy R, Eagger S, Griffiths M, Perry E, Honavar M, Dean A, Lantos P (1994) Lewy bodies and response to tacrine in Alzheimer’s disease. Lancet 343:176 40. Liberini P, Valerio A, Memo M, Spano PF (1996) Lewy-body dementia and responsiveness to cholinesterase inhibitors: a
J Neurol
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. 53.
54.
55.
56.
paradigm for heterogeneity of Alzheimer’s disease? Trends Pharmacol Sci 17:155–160 Lippa CF, Smith TW, Perry E (1999) Dementia with Lewy bodies: choline acetyltransferase parallels nucleus basalis pathology. J Neural Transm 106:525–535 Marra C, Quaranta D, Profice P, Pilato F, Capone F, Iodice F, Di Lazzaro V, Gainotti G (2012) Central cholinergic dysfunction measured ‘‘in vivo’’ correlates with different behavioral disorders in Alzheimer’s disease and dementia with Lewy body. Brain Stimul 5:533–538 Marui W, Iseki E, Kato M, Akatsu H, Kosaka K (2004) Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease. Acta Neuropathol 108:121–128 McKeith I, Dickson D, Lowe J, Emre M, O’brien J, Feldman H, Cummings J, Duda J, Lippa C, Perry E (2005) Diagnosis and management of dementia with Lewy bodies third report of the DLB consortium. Neurology 65:1863–1872 McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, CohenMansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Machado JC, O’Brien J, Playfer J (2004) Dementia with Lewy bodies. Lancet Neurol 3:19–28 McKeith I, O’Brien J, Walker Z, Tatsch K, Booij J, Darcourt J, Padovani A, Giubbini R, Bonuccelli U, Volterrani D, Holmes C, Kemp P, Tabet N, Meyer I, Reininger C (2007) Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol 6:305–313 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939 Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 214:170–197 Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201 Mori E, Ikeda M, Kosaka K (2012) Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol 72:41–52 Morris J, Heyman A, Mohs R, Hughes J, Van Belle G, Fillenbaum G, Mellits E, Clark C, the CERAD investigators (1989) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39:1159–1165 Muir JL (1997) Acetylcholine, aging, and Alzheimer’s disease. Pharmacol Biochem Behav 56:687–696 Narayanan NS, Rodnitzky RL, Uc EY (2013) Prefrontal dopamine signaling and cognitive symptoms of Parkinson’s disease. Rev Neurosci 24:267–278 Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ (2000) Choline acetyltransferase activity and cognitive domain scores of Alzheimer’s patients. Neurobiol Aging 21:11–17 Perry EK, Haroutunian V, Davis KL, Levy R, Lantos P, Eagger S, Honavar M, Dean A, Griffiths M, McKeith IG et al (1994) Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer’s disease. NeuroReport 5:747–749 Rolinski M, Fox C, Maidment I, McShane R (2012) Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease. Cochrane Database Syst Rev 3:CD006504
57. Sanchez-Cubillo I, Perianez JA, Adrover-Roig D, RodriguezSanchez JM, Rios-Lago M, Tirapu J, Barcelo F (2009) Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc 15:438–450 58. Sarter M, Albin RL, Kucinski A, Lustig C (2014) Where attention falls: increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function. Exp Neurol 257C:120–129 59. Scherfler C, Esterhammer R, Nocker M, Mahlknecht P, Stockner H, Warwitz B, Spielberger S, Pinter B, Donnemiller E, Decristoforo C, Virgolini I, Schocke M, Poewe W, Seppi K (2013) Correlation of dopaminergic terminal dysfunction and microstructural abnormalities of the basal ganglia and the olfactory tract in Parkinson’s disease. Brain 136:3028–3037 60. Shimada H, Hirano S, Shinotoh H, Aotsuka A, Sato K, Tanaka N, Ota T, Asahina M, Fukushi K, Kuwabara S (2009) Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 73:273–278 61. Shulman KI (2000) Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 15:548–561 62. Takahashi R, Ishii K, Miyamoto N, Yoshikawa T, Shimada K, Ohkawa S, Kakigi T, Yokoyama K (2010) Measurement of gray and white matter atrophy in dementia with Lewy bodies using diffeomorphic anatomic registration through exponentiated lie algebra: a comparison with conventional voxel-based morphometry. AJNR Am J Neuroradiol 31:1873–1878 63. Tam CW, Burton EJ, McKeith IG, Burn DJ, O’Brien JT (2005) Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies. Neurology 64:861–865 64. Tanaka Y, Hanyu H, Sakurai H, Takasaki M, Abe K (2003) Atrophy of the substantia innominata on magnetic resonance imaging predicts response to donepezil treatment in Alzheimer’s disease patients. Dement Geriatr Cogn Disord 16:119–125 65. Teipel S, Heinsen H, Amaro E Jr, Grinberg LT, Krause B, Grothe M (2014) Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer’s disease. Neurobiol Aging 35:482–491 66. Teipel SJ, Flatz W, Ackl N, Grothe M, Kilimann I, Bokde AL, Grinberg L, Amaro E Jr, Kljajevic V, Alho E, Knels C, Ebert A, Heinsen H, Danek A (2014) Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala’s nucleus. Psychiatry Res 221:187–194 67. Teipel SJ, Flatz WH, Heinsen H, Bokde AL, Schoenberg SO, Sto¨ckel S, Dietrich O, Reiser MF, Mo¨ller H-J, Hampel H (2005) Measurement of basal forebrain atrophy in Alzheimer’s disease using MRI. Brain 128:2626–2644 68. Teipel SJ, Meindl T, Grinberg L, Grothe M, Cantero JL, Reiser MF, Moller HJ, Heinsen H, Hampel H (2011) The cholinergic system in mild cognitive impairment and Alzheimer’s disease: an in vivo MRI and DTI study. Hum Brain Mapp 32: 1349–1362 69. Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E, Thal LJ, Corey-Bloom J (2002) Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 59:946–951 70. Tiraboschi P, Salmon DP, Hansen LA, Hofstetter RC, Thal LJ, Corey-Bloom J (2006) What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain 129:729–735 71. Vogels OJ, Broere CA, ter Laak HJ, ten Donkelaar HJ, Nieuwenhuys R, Schulte BP (1990) Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer’s disease. Neurobiol Aging 11:3–13 72. Whitehouse PJ, Hedreen JC, White CL, Price DL (1983) Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol 13:243–248
123
J Neurol 73. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126 74. Whitwell JL, Weigand SD, Shiung MM, Boeve BF, Ferman TJ, Smith GE, Knopman DS, Petersen RC, Benarroch EE, Josephs KA, Jack CR Jr (2007) Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain 130:708–719 75. Wider C, Ross OA, Nishioka K, Heckman MG, Vilarino-Guell C, Jasinska-Myga B, Erketin-Taner N, Rademakers R, Graff-Radford NR, Mash DC, Papapetropoulos S, Duara R, Uchikado H, Wszolek ZK, Farrer MJ, Dickson DW (2012) An evaluation of the impact of MAPT, SNCA and APOE on the burden of
123
Alzheimer’s and Lewy body pathology. J Neurol Neurosurg Psychiatry 83:424–429 76. Zaborszky L, Csordas A, Mosca K, Kim J, Gielow MR, Vadasz C, Nadasdy Z (2013) Neurons in the basal forebrain project to the cortex in a complex topographic organization that reflects corticocortical connectivity patterns: an experimental study based on retrograde tracing and 3D reconstruction. Cereb Cortex 77. Zaborszky L, Hoemke L, Mohlberg H, Schleicher A, Amunts K, Zilles K (2008) Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. Neuroimage 42:1127–1141
ORIGINAL COMMUNICATION
Atrophy of the cholinergic basal forebrain in dementia with Lewy bodies and Alzheimer’s disease dementia Michel J. Grothe • Christina Schuster • Florian Bauer • Helmut Heinsen • Johannes Prudlo Stefan J. Teipel
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Received: 16 April 2014 / Revised: 10 July 2014 / Accepted: 11 July 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Similar to Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) is characterized by a profound degeneration of cortically-projecting cholinergic neurons of the basal forebrain (BF) and associated depletion of cortical cholinergic activity. We aimed to investigate subregional atrophy of the BF in DLB in vivo and compare it to the pattern of BF atrophy in AD. Structural MRI scans of 11 patients with DLB, 11 patients with Alzheimer’s disease, and 22 healthy controls were analysed using a recently developed technique for automated BF morphometry based on high-dimensional image warping and cytoarchitectonic maps of BF cholinergic nuclei. For comparison, hippocampus volume was assessed within the same morphometric framework using recently published consensus criteria for the definition of hippocampus outlines on MRI. The DLB group demonstrated pronounced and subregion-specific atrophy of the BF which was
comparable to BF atrophy in AD: volume of the nucleus basalis Meynert was significantly reduced by 20–25 %, whereas rostral BF nuclei were only marginally affected. By contrast, hippocampus volume was markedly less affected in DLB compared to AD. Global cognition as determined by MMSE score was associated with BF volume in AD, but not in DLB, whereas visuoperceptual function as determined by the trail making test was associated with BF volume in DLB, but not in AD. DLB may be characterized by a more selective degeneration of the cholinergic BF compared to AD, which may be related to the differential cognitive profiles in both conditions. Keywords Dementia with Lewy bodies Alzheimer’s disease Cholinergic basal forebrain Nucleus basalis Meynert Harmonized hippocampus protocol MRI
Introduction C. Schuster and M. J. Grothe contributed equally to the manuscript M. J. Grothe (&) C. Schuster F. Bauer J. Prudlo S. J. Teipel German Center for Neurodegenerative Diseases (DZNE), Gehlsheimer Str. 20, 18147 Rostock, Germany e-mail: [email protected] H. Heinsen Department of Psychiatry, Laboratory of Morphological Brain Research, University of Wu¨rzburg, Josef-Schneider-Str. 2, 97080 Wu¨rzburg, Germany J. Prudlo Department of Neurology, University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany S. J. Teipel Department of Psychosomatic Medicine, University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia disorder after Alzheimer’s disease (AD) [45]. Its core clinical features consist of fluctuating cognitive impairment, recurrent visual hallucinations and parkinsonism. Patients with DLB typically present with impaired attention, executive functions and visuospatial skills, whereas impairments in learning and memory typically appear later during the disease [11, 17, 44, 45]. While neuropathological examinations point to largely distinct pathologic substrates underlying DLB and AD dementia [43], both dementing disorders are associated with severe degeneration of the cortically-projecting cholinergic neurons of the basal forebrain (BF) [9, 20, 41, 71–73]. Furthermore, in both disorders the cholinergic degeneration
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and associated depletion of cortical cholinergic activity were found to correlate with the degree of dementia severity ante mortem [33, 54, 69], thus motivating the use of cholinomimetics for antidementive treatment in these conditions [4, 50, 56]. Although acetylcholinesterase inhibitors (AChE-I) were originally developed, and first approved, for medical treatment of AD dementia [16], DLB patients may even be more responsive to this type of treatment [39, 40], which has been attributed to a stronger cholinergic deficit in this disease [19, 55, 69]. This assumed strong cholinergic deficit in DLB corresponds to the clinical characteristics of the disease, i.e. fluctuating cognition and prominent impairment in visuospatial attention. In recent years, neuroimaging markers for in vivo measurements of the cholinergic deficit have emerged, which could partly replicate and extend the early neuropathological findings. Molecular imaging studies based on positron emission tomography (PET)-suitable radiotracers for AChE could demonstrate widespread reductions in cortical cholinergic activity in DLB patients in vivo [38, 60]. Measurement of the thickness of the substantia innominata (SI) on structural magnetic resonance imaging (MRI) scans has been used as in vivo marker of cholinergic BF degeneration, revealing strong atrophy of this region in both DLB and AD dementia patients [30, 74]. Interestingly, the degree of SI atrophy was also found to be predictive of the response to AChE-I treatment in these conditions [29, 64]. However, the manual measurement protocol of SI atrophy employed in these studies was limited in that it focused on a small region of the BF at the level of the crossing of the anterior commissure. The BF cholinergic system contains several groups of cholinergic cell clusters that extend approximately 20 mm in anterior-posterior direction from the medial septum up to the level of the centromedian nucleus of the amygdala [27, 66, 67, 77]. These cholinergic subdivisions of the BF are characterized by a differential innervation preference for distinct functional cortical networks [48, 76], show differential associations with specific cognitive and behavioral functions [52, 54], and vary in their vulnerability to AD-related neurodegeneration [71]. Recently, automated image processing techniques have been developed that allow a more comprehensive analysis of in vivo BF atrophy, based on cytoarchitectonic mappings of the cholinergic BF nuclei combined with deformation-based morphometry of high-resolution MRI scans [23–26, 37, 65, 68]. Reproducing previous neuropathological findings, these methods revealed a subregion-specific degeneration of the cholinergic BF in AD which was also associated with impairments in global cognitive function and specific memory tests.
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In the present study we used these morphometry techniques to explore subregional atrophy pattern of the BF in a sample of DLB patients and compare it with the pattern of BF atrophy found in AD patients. For comparison we also assessed hippocampal volume within the same computational morphometry approach, given that several previous in vivo imaging studies have consistently reported more severe hippocampal atrophy in AD compared to DLB [2, 7, 10, 36, 62, 63, 74].
Methods Subjects A sample of 11 patients who fulfilled criteria for clinically probable DLB [44] and had high-resolution structural MRI scans available were identified from our memory clinicbased patient cohort. Eleven patients with clinically probable AD [47] and 22 healthy controls (HC) were selected randomly from the larger study cohort with the constraint of matching DLB patients in terms of age, sex and education; AD patients were further matched to the DLB patients with regard to dementia severity as reflected by Mini-Mental State Examination (MMSE) scores. Demographics and global cognitive profile of the study groups are summarized in Table 1. The HC group consists of spouses of patients, or community dwelling elderly who were recruited through public advertisement. All participants underwent standard clinical assessment including complete medical history, clinical, psychiatric and neurological examinations. Furthermore, all subjects underwent detailed neuropsychological examination including the MMSE [18], the CERADPlus cognitive battery [3, 51], and the clock drawing test [61]. HC reported no subjective memory complaints and scored all tests within the normal range. Blood tests consisted of complete blood count, electrolytes, glucose, liverassociated enzymes, cholesterol, HDL, triglycerides, and Apo-E4 genotyping. All MRI scans were visually inspected by a radiologist to rule out major neuropathology not directly related to AD or DLB pathology, such as tumor, stroke or advanced white matter disease. Visual Table 1 Demographic characteristics DLB patients
AD patients
Healthy controls
Gender (M/F)
7/4
7/4
14/8
Age, years (SD)
73.9 (4.5)
73.6 (4.3)
73.0 (3.9)
Education, years (SD)
12.7 (2.6)
12.5 (2.5)
13.3 (2.8)
MMSE score, mean (SD)
24.4 (2.6)
23.7 (3.1)
28.5 (0.9)
DLB dementia with Lewy bodies, AD Alzheimer’s disease dementia, M male, F female, MMSE Mini Mental State Examination
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hallucinations were present in five DLB patients, but also in one AD patient. SPECT-based dopamine transporter imaging was available for nine of the DLB patients and a marked presynaptic dopaminergic deficit of the nigrostriatal pathway was detected in eight of these patients. Five of the DLB patients and two of the AD patients were taking cholinergic drugs (AChE-I) as antidementive treatment. All participants gave written informed consent in agreement with the local ethics committee; the study was conducted according to the 1964 Declaration of Helsinki and its later amendments. MRI acquisition All data were acquired in Rostock with a 3T Siemens MAGNETOM Verio Scanner (Siemens, Erlangen, Germany, software syngo MR B17) using 32 channel head coils. T1-weighted, high-resolution structural MRI volumes of the brain were obtained using a 3D-MPRAGE sequence (TE = 2.52 ms, TR = 1,900 ms, TI = 900 ms, flip angle = 9°, bandwidth = 170 Hz/pixel, matrix = 256 9 256 9 176, isometric voxel size = 1.0 mm3). MRI preprocessing MRI data were processed using statistical parametric mapping (SPM8, Wellcome Trust Center for Neuroimaging) and the VBM8 toolbox (http://dbm.neuro.uni-jena.de/ vbm/) implemented in Matlab R2013a (MathWorks, Natick, MA, USA). The main processing steps and computational analyses have been described previously [24, 37]. Briefly, MRI scans were segmented into gray matter (GM), white matter, and cerebrospinal fluid partitions and high-dimensionally registered to Montreal Neurological Institute (MNI) standard space using the VBM8 toolbox. Warping parameters were applied to individual GM maps and GM-voxel values were modulated to account for the volumetric differences introduced by the high-dimensional warps. GM volumes of the BF cholinergic nuclei and hippocampus were automatically extracted by summing up the modulated GM voxel values within the respective regions of interest (ROIs) (see ‘‘Definition of the basal forebrain and hippocampus regions of interest’’). The total intracranial volume (TIV) was calculated as the sum of the total segmented gray matter, white matter and cerebrospinal fluid volumes. Definition of the basal forebrain and hippocampus regions of interest According to Mesulam’s nomenclature [49], the cholinergic BF is composed of four groups of cholinergic cells
which correspond to the medial septum (Ch1), the vertical and horizontal limb of the diagonal band of Broca (Ch2 and Ch3), and the nucleus basalis Meynert (NBM, Ch4). The NBM is the largest cholinergic nucleus of the BF and can be further subdivided into anterior medial and lateral (Ch4am and Ch4al), intermediate (Ch4i) and posterior regions (Ch4p). A further part of the cholinergic BF is the nucleus subputaminalis, which has only been described in the human and anthropoid monkey brain, and can be regarded as a lateral extension of rostral and antero intermediate parts of the NBM [5]. The cholinergic nuclei are not directly visible on current structural MRI contrasts and no comprehensive set of external landmarks has been identified that could be used for indirect manual delineation of the cholinergic BF on MRI scans. In the current study, we localized the cholinergic BF based on a cytoarchitectonic map of BF cholinergic nuclei in MNI space, derived from combined histology and in cranio MRI of a postmortem brain [37, 66]. This map is similar in general outline to a previously defined BF map based on a different postmortem MRI scan [67], but in contrast to this previous mask, it comprises outlines of the Ch1/2, Ch3, Ch4a–i, Ch4p and nucleus subputaminalis subregions of the BF. In the present study we analysed group differences in total BF volume (all cholinergic nuclei combined, BFtot), and separately for the subregions belonging to the NBM proper (Ch4a–i and Ch4p) and those belonging to the most rostral nuclei (Ch1/2), as these regions have been found to be differentially affected in AD in previous studies using independent cohorts [23, 37, 65]. The ROI mask for the hippocampus was obtained by manual delineation of the hippocampus in the standard space template used for high-dimensional image normalization in the VBM8 toolbox. Tracing of the hippocampus outlines followed recently developed international consensus criteria for manual hippocampus segmentation on MRI [6] and was performed by a certified tracer (MJG) using MultiTracer 1.0 software (http://www.loni.usc.edu/ Software/MultiTracer). Statistical analysis The effect of diagnosis on regional volumes was investigated using analysis of covariance (ANCOVA), controlling for TIV. The significance level was set to p \ 0.05. Post hoc comparisons of the estimated marginal means were corrected for multiple testing using Bonferroni–Holm correction. In addition to the group-wise volumetric comparisons, correlations between TIV-adjusted NBM volume (Ch4a– i ? Ch4p; TIV-related variance removed using linear regression) and global cognitive deterioration, as reflected by MMSE scores, were calculated for each of the dementia
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groups separately. While the MMSE has been designed to capture the memory-predominant cognitive impairments typical for AD, cognitive dysfunction in DLB is mainly characterized by visuoperceptual and attentional-executive function deficits [11]. Thus, we also assessed associations between BF volume and the Trail Making Test A (TMT-A), a widely used test of visuoperceptual abilities included in the CERAD-plus cognitive battery that has been shown to be specifically impaired in DLB relative to AD [8, 17, 57]. Two DLB patients were not capable of performing the test and had to be excluded from this analysis. Part B of the TMT, which is a more specific measure of executive function deficits and similarly useful in distinguishing DLB from AD [17], could not be analysed due to the low number of DLB patients (N = 4) who successfully completed the test within the allowed time interval (300 s). Based on previous evidence implicating the cholinergic system in the pathophysiology of visual hallucinations [1, 12, 42], a distinct clinical feature with high specificity for Lewy body pathology [70], NBM volumes were also compared between dementia patients with and without visual hallucinations.
Results Table 2 shows the mean volumes for each diagnostic group. Figure 1 illustrates the percent volume reductions of the TIV-adjusted ROI volumes in the dementia groups relative to the reference values of the healthy control group. Both dementia groups showed a similar degree of total BF volume reduction, exceeding 20 % compared to the control values. Atrophy in both dementia groups was differentially expressed among BF subregions: volume reductions were most pronounced in the NBM (Ch4p in AD: -23.3 %, and Ch4a-i in DLB: -25.1 %), whereas the rostral Ch1/2 nuclei were less affected in both dementia groups (-17.4 and -17.5 % in AD and DLB, respectively). In contrast to BF volume, hippocampus volume
was markedly more reduced in AD patients (-23.2 %) compared to DLB patients (-12.4 %). ANCOVAs estimating the effect of diagnosis on ROI volumes, while controlling for TIV, revealed significant effects for all ROIs [Ch1/2: F(2, 40) = 5.3, p = 0.009 Ch4a–i: F(2,40) = 14.7, p \ 0.001; Ch4p: F(2, 40) = 17.6, p \ 0.001; BFtot: F(2,40) = 17.6, p \ 0.001; Hippocampus: F(2, 40) = 22, p \ 0.001]. Post hoc group comparisons using Bonferroni–Holm correction for multiple comparisons demonstrated volume reductions in both dementia groups to be statistically significant for all ROIs when compared to the healthy control group, with the exception of Ch1/2 volume reduction, reaching only trend level significance in both patient groups (AD: pBonferroniHolm = 0.07; DLB: pBonferroni-Holm = 0.08). None of the BF volumes differed significantly between DLB and AD groups, but the difference in hippocampus volume between AD and DLB patients reached trend level statistical significance (pBonferroni-Holm = 0.06). TIV-adjusted volumes of the NBM correlated significantly with MMSE scores within the AD group (r = 0.79, p = 0.004), but not within the DLB group (r = 0.17, p = 0.62). By contrast, lower NBM volumes showed a trend-level association with worse performance on the TMT-A test in the DLB group (r = -0.62, p = 0.08), but not in the AD group (r = 0.19, p = 0.59). Figure 2 plots the respective relationships. NBM volumes were slightly smaller in dementia patients with visual hallucinations compared to patients that did not present this clinical feature, but this difference did not reach statistical significance (-10.3 %, p = 0.11).
Discussion This study investigated volumetric changes of the BF in DLB in vivo and compared it to the pattern of BF atrophy found in AD dementia. Both dementia groups demonstrated a pronounced atrophy of the BF, which was similar
Table 2 Mean basal forebrain and hippocampus volumes of dementia and healthy control groups DLB patients
AD patients
Healthy controls
Ch1/2
66.9 (58.3–75.6)9
67.0 (58.3–75.6)9
81.1 (74.9–87.3)
Ch4a–i
71.5 (63.3–79.7)*
75.3 (67.2–83.5)*
95.5 (89.7–101.4)
Ch4p
58.6 (53.4–63.8)*
55.3 (50.1–60.4)*
72.1 (68.4–75.8)
BFtot
355.5 (322.6–388.3)*
354.4 (321.7–387.1)*
452.3 (429.0–475.5)
Hippocampus
6,245.5 (5,826.4–6,664.7)*,
#
5,477.9 (5,060.9–5,894.8)*
7,131.2 (6,834.4–7,427.9)
Volumes (in mm3; confidence interval in brackets) are adjusted for total intracranial volume (estimated marginal means) * 9 #
Significantly different compared to healthy controls at pBonferroni-Holm \ 0.01 Trend level significance for difference compared to healthy controls, pBonferroni-Holm \ 0.1 Trend level significance for difference compared to AD group, pBonferroni-Holm \ 0.1
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Fig. 1 Regional volume reductions in DLB and AD. TIV-adjusted volumes (estimated marginal means) of the total basal forebrain (BFtot), Ch1/2, Ch4a–i, Ch4p and hippocampus are plotted as percent volume reductions relative to the reference values of the healthy control group. DLB patients with Lewy body dementia, AD patients with Alzheimer’s disease dementia, TIV total intracranial volume. **p \ 0.01; 9p \ 0.1; all p values Bonferroni-Holm corrected
in terms of severity and regional pattern: volume of the NBM (Ch4a–i, Ch4p) was significantly reduced by 20–25 % in both dementia groups compared with the healthy control group, whereas volume of the rostral BF nuclei (Ch1/2) was only marginally affected. Interestingly, NBM volume was highly correlated with global cognitive functioning in terms of MMSE scores within the AD patient sample, but not within the DLB patient sample. In contrast to BF volume, hippocampus volume was differentially affected in the two dementia syndromes, with severe atrophy in the AD group and relative sparing in the DLB group. Degeneration of the NBM and associated depletion of cortical cholinergic activity are well described characteristics of both AD dementia and DLB [9, 20, 33, 41, 54, 69, 71–73]. However, less neuropathological data are available on the subregional specificity of cholinergic BF atrophy in these conditions. In AD, a subregion-specific pattern of cholinergic BF atrophy has been described, where loss of cholinergic cells is most pronounced in the posterior subdivision of the NBM (Ch4p) and relatively spared in the most rostral BF nuclei (Ch1/2) [71]. This pattern matches well to the in vivo BF atrophy pattern observed in AD patients in this and previous studies using independent cohorts [23, 24, 37, 65]. One neuropathological study found cholinergic cell numbers of the Ch1/2 complex to be significantly reduced in a group of DLB patients, but not in AD patients, when compared to normal controls [20]. However, AD patients also showed significant
neurofibrillary tangle pathology in the Ch1/2 complex and mean surface area of the cholinergic neurons was similarly reduced in AD and DLB patients. The MRI-based in vivo measurement of BF integrity employed in the present study cannot distinguish whether the volumetric changes in our AD and DLB samples reflect neurodegenerative cell shrinkage, definite cell loss, or a mixture of both. Previous imaging studies assessed the thickness of the SI at the level of the crossing of the anterior commissure as in vivo marker of NBM atrophy in DLB and AD. Similar to our present results, strong atrophy of this region was found in both DLB and AD groups compared to healthy control groups [28–30, 74]. In a study by Hanyu and colleagues [30], atrophy of the SI was even more pronounced in the DLB group (-34.0 %) compared to the AD group (-28.2 %), which was interpreted by the authors to be reflective of neuropathological evidence of a stronger cholinergic deficit in DLB compared to AD [19, 55, 69]. The anatomic delineation of the SI measurement overlaps with the Ch4a–i subdivision of the cytoarchitectonic map of cholinergic BF nuclei employed in the present study. Interestingly, this BF region was also slightly more atrophic in the DLB (-25.1 %) compared to the AD group (-21.1 %), although this difference was not statistically significant in our small study sample. The generally higher degree of SI atrophy in both dementia groups observed by Hanyu et al. [30] may partly be due to differences in the employed methods, but also due to the significantly more advanced disease stage (lower MMSE scores) of the examined dementia groups compared to our sample. Given the comparable degree of BF atrophy in both dementia groups in the present study, it is interesting that only the AD group showed a strong association between NBM atrophy and cognitive decline in terms of MMSE scores. Similar findings were reported in previous studies using thickness of the SI as an in vivo marker of NBM atrophy [28, 74], where significant associations between SI atrophy and MMSE scores were found in AD, but not in DLB [74] or Parkinson-associated dementia [28]. A possible explanation for this differential association could be that the MMSE mainly captures memory-predominant cognitive impairments typical for AD and may not be equally sensitive to the specific cognitive symptoms that determine dementia severity in DLB, most notably visualperceptual and attentional-executive dysfunction [8, 11, 17]. In line with this notion we found evidence for an association between lower NBM volume and visuoperceptual deficits, as assessed with the TMT-A, in the DLB group, but not in the AD group. Besides the supposed role of cholinergic BF atrophy for cognitive deficits, previous pharmacologic and neurophysiologic studies have also implicated the cholinergic system in the pathophysiology of behavioral disturbances in dementia, most notably visual
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Fig. 2 Relationship between NBM volume and cognitive deterioration in DLB and AD. TIV-related variance was removed from the NBM volumes using linear regression and the residuals are plotted against MMSE and TMT-A scores of the patients. Triangles refer to
patients with Lewy body dementia (DLB); rhombi refer to patients with Alzheimer’s disease dementia (AD); TIV total intracranial volume; NBM nucleus basalis Meynert; MMSE Mini Mental State Examination
hallucinations [1, 12, 42]. The lack of a significant association between NBM volume and the occurrence of visual hallucinations among dementia patients in the present study may in part be related to methodical issues, such as the small sample size and the dichotomous parameterization of visual hallucinations instead of more detailed metrics [13]. However, visual hallucinations in Parkinson’s disease and DLB have recently been found to be closely linked to direct atrophic changes of visuoperceptive areas in the occipital and parietal lobes [15, 21]. Interestingly, visual hallucinations in Parkinson’s disease, but not in DLB, have also been linked to atrophic changes in cholinergic brainstem nuclei with primary projections to the thalamus, rather than to changes in the cortically-projecting cholinergic BF [31, 34]. Future studies should assess the cognitive and behavioral correlates of BF atrophy in DLB in more detail using larger sample sizes and comprehensive psychometric evaluations specifically designed to capture the complex symptomatology of DLB. In contrast to the similar degree of BF atrophy across AD and DLB groups, hippocampus volume was markedly
more reduced in AD patients than in DLB patients. This difference in hippocampus atrophy between the two dementia syndromes has also been found in several previous imaging studies [2, 7, 10, 36, 62, 63, 74] and is likely to reflect the relatively spared memory function in DLB compared with AD [11, 17]. In the present study, simultaneous assessment of BF and hippocampus volumes in the same patient population allowed evaluating the relative degrees of BF and hippocampus atrophy in DLB and AD dementia. While atrophy of the BF was markedly more pronounced than hippocampus atrophy in the DLB group, both regions were similarly affected in the AD group. This finding may partially explain differences in the responsiveness to AChE-I treatment between the two dementia forms [40, 50]. Thus, the generally good responsiveness to AChE-I treatment in DLB may in part be due to a relatively selective degeneration of the cholinergic system in the absence of severe hippocampus atrophy. In general, the presence of any additional pathological mechanisms unrelated to the cholinergic deficit is likely to limit the beneficial effects of AChE-I treatment on dementia symptoms
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[22]. Detailed longitudinal studies on the potential of in vivo BF volumetry for the prediction of AChE-I treatment outcome in large patient cohorts are warranted. A limitation of our study is that the structural in vivo marker of BF volume loss that we utilized is only an indirect marker of cholinergic degeneration. The correspondence of the analysed brain region with the cholinergic space of the BF was determined based on cytoarchitectonic maps derived from combined histology and post-mortem MRI [37, 66], but one cannot exclude that the volumetric differences might also reflect change in other neuronal or glial components of the BF. Furthermore, our patient categorisation is based on clinical diagnoses, and thus one cannot exclude overlapping pathologies of both disorders. However, SPECTbased dopamine transporter imaging was available for nine of the DLB patients, demonstrating marked nigrostriatal dopaminergic degeneration characteristic of Lewy body pathology [46] in all but one of these subjects. When excluding the three DLB subjects without imaging evidence of dopaminergic degeneration from analysis, volumetric group differences and neuropsychological correlations remained virtually unchanged albeit at lower statistical significance (data not shown). It is also noteworthy that the difference in hippocampus atrophy between the DLB and AD groups in our study closely reflects previous imaging findings of DLB and AD cohorts with pathologically confirmed diagnoses [7]. An interesting research question that could not be adequately addressed in the current study is the potential interplay between neurodegenerative changes across dopaminergic and cholinergic systems in DLB. While we used standard clinical evaluations of SPECT-based dopamine transporter imaging scans within diagnostic workup, these images were not suitable for a detailed quantitative analysis of regional dopaminergic deficits. While some of the cognitive and behavioral deficits in Lewy body diseases are believed to be primarily attributable to degeneration of the cholinergic or dopaminergic systems, respectively, exacerbation of symptoms has also been linked to a converging impact of both pathologic processes [53, 58]. Recent multimodal imaging studies have started to unravel the interactions between pathologic changes across several neuronal systems, as well as their separate and combined contributions to disease symptoms [32, 38, 59]. In future multimodal imaging studies, MRI-based in vivo volumetry of the cholinergic BF may become a useful tool to investigate interactions between structural and functional changes across cholinergic and dopaminergic systems in Lewy body diseases, including Parkinson’s disease and DLB. The relatively small sample size limits the statistical power of the study and precluded us from a more exhaustive statistical testing of the significance of the
differential atrophy pattern among BF subregions within diagnostic groups [37, 65]. Yet, the marked reduction in BF volume in DLB and AD compared to healthy controls appears to be a very robust measure as it reaches statistical significance even in a small sample and after rigorous control for multiple pair-wise testing. Future studies including larger sample sizes will allow for more explorative analyses of the clinical correlates of BF atrophy in DLB and AD, as well as of the genetic and molecular modulators of BF volume in these conditions [14, 26, 75]. In summary, we were able to identify a specific pattern of in vivo BF atrophy in DLB which was similar to the one found in AD. A severely atrophied NBM in the posterior part of the BF in addition to a less severely atrophied anterior part could be observed in both dementia groups. By contrast, atrophy of the hippocampus was less pronounced in DLB than in AD patients. NBM atrophy was correlated with global cognitive decline in the AD group and with more specific measures of visuoperceptual deficits in the DLB group. Future studies should explore in vivo patterns of BF atrophy and their possible associations with cognitive and behavioral deficits in predementia stages of DLB [35]. Acknowledgments The study was supported by the Department ‘Aging of the individual and the Society’ of the University of Rostock. Conflicts of interest of interest.
The authors declare that they have no conflict
Ethical standards All participants gave written informed consent in agreement with the local ethics committee; the study was conducted according to the 1964 Declaration of Helsinki and its later amendments.
References 1. Ballard C, Aarsland D, Francis P, Corbett A (2013) Neuropsychiatric symptoms in patients with dementias associated with cortical Lewy bodies: pathophysiology, clinical features, and pharmacological management. Drugs Aging 30:603–611 2. Barber R, Gholkar A, Scheltens P, Ballard C, McKeith IG, O’Brien JT (1999) Medial temporal lobe atrophy on MRI in dementia with Lewy bodies. Neurology 52:1153–1158 3. Basel MC (2005) CERAD-Plus: the consortium to establish a registry for Alzheimer’s disease. Univerista¨tsspital, Basel 4. Birks J (2006) Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev 1:CD005593 5. Boban M, Kostovic I, Simic G (2006) Nucleus subputaminalis: neglected part of the basal nucleus of Meynert. Brain 129:E42 (author reply E43) 6. Boccardi M, Bocchetta M, Ganzola R, Robitaille N, Redolfi A, Duchesne S, Jack CR Jr, Frisoni GB (2013) Operationalizing protocol differences for EADC-ADNI manual hippocampal segmentation. Alzheimers Dement. doi:10.1016/j.jalz.2013.03.001 7. Burton EJ, Barber R, Mukaetova-Ladinska EB, Robson J, Perry RH, Jaros E, Kalaria RN, O’Brien JT (2009) Medial temporal lobe atrophy on MRI differentiates Alzheimer’s disease from
123
J Neurol
8.
9.
10.
11.
12.
13.
14.
15.
16. 17.
18.
19.
20.
21.
22.
dementia with Lewy bodies and vascular cognitive impairment: a prospective study with pathological verification of diagnosis. Brain 132:195–203 Cagnin A, Gnoato F, Jelcic N, Favaretto S, Zarantonello G, Ermani M, Dam M (2013) Clinical and cognitive correlates of visual hallucinations in dementia with Lewy bodies. J Neurol Neurosurg Psychiatry 84:505–510 Candy J, Perry R, Perry E, Irving D, Blessed G, Fairbairn A, Tomlinson B (1983) Pathological changes in the nucleus of Meynert in Alzheimer’s and Parkinson’s diseases. J Neurol Sci 59:277–289 Chow N, Aarsland D, Honarpisheh H, Beyer MK, Somme JH, Elashoff D, Rongve A, Tysnes OB, Thompson PM, Apostolova LG (2012) Comparing hippocampal atrophy in Alzheimer’s dementia and dementia with Lewy bodies. Dement Geriatr Cogn Disord 34:44–50 Collerton D, Burn D, McKeith I, O’Brien J (2003) Systematic review and meta-analysis show that dementia with Lewy bodies is a visual-perceptual and attentional-executive dementia. Dement Geriatr Cogn Disord 16:229–237 Cummings J, Emre M, Aarsland D, Tekin S, Dronamraju N, Lane R (2010) Effects of rivastigmine in Alzheimer’s disease patients with and without hallucinations. J Alzheimers Dis 20:301–311 de Medeiros K, Robert P, Gauthier S, Stella F, Politis A, Leoutsakos J, Taragano F, Kremer J, Brugnolo A, Porsteinsson AP, Geda YE, Brodaty H, Gazdag G, Cummings J, Lyketsos C (2010) The Neuropsychiatric Inventory-Clinician rating scale (NPI-C): reliability and validity of a revised assessment of neuropsychiatric symptoms in dementia. Int Psychogeriatr 22:984–994 de Souza Silva MA, Lenz B, Rotter A, Biermann T, Peters O, Ramirez A, Jessen F, Maier W, Hull M, Schroder J, Frolich L, Teipel S, Gruber O, Kornhuber J, Huston JP, Muller CP, Schable S (2013) Neurokinin3 receptor as a target to predict and improve learning and memory in the aged organism. Proc Natl Acad Sci USA 110:15097–15102 Delli Pizzi S, Franciotti R, Tartaro A, Caulo M, Thomas A, Onofrj M, Bonanni L (2014) Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: a cortical thickness MRI study. PLoS One 9:e86624 Eagger SA, Levy R, Sahakian BJ (1991) Tacrine in Alzheimer’s disease. Lancet 337:989–992 Ferman TJ, Smith GE, Boeve BF, Graff-Radford NR, Lucas JA, Knopman DS, Petersen RC, Ivnik RJ, Wszolek Z, Uitti R, Dickson DW (2006) Neuropsychological differentiation of dementia with Lewy bodies from normal aging and Alzheimer’s disease. Clin Neuropsychol 20:623–636 Folstein MF, Folstein SE, McHugh PR (1975) ‘‘Mini-mental state’’: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198 Fo¨rstl H, Burns A, Luthert P, Cairns N, Levy R (1993) The Lewybody variant of Alzheimer’s disease. Clinical and pathological findings. Br J Psychiatry 162:385–392 Fujishiro H, Umegaki H, Isojima D, Akatsu H, Iguchi A, Kosaka K (2006) Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies. Acta Neuropathol 111:109–114 Goldman JG, Stebbins GT, Dinh V, Bernard B, Merkitch D, deToledo-Morrell L, Goetz CG (2014) Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson’s disease with hallucinations. Brain 137:849–859 Graff-Radford J, Boeve BF, Pedraza O, Ferman TJ, Przybelski S, Lesnick TG, Vemuri P, Senjem ML, Smith GE, Knopman DS, Lowe V, Jack CR Jr, Petersen RC, Kantarci K (2012) Imaging and acetylcholinesterase inhibitor response in dementia with Lewy bodies. Brain 135:2470–2477
123
23. Grothe M, Heinsen H, Teipel S (2013) Longitudinal measures of cholinergic forebrain atrophy in the transition from healthy aging to Alzheimer’s disease. Neurobiol Aging 34:1210–1220 24. Grothe M, Heinsen H, Teipel SJ (2012) Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry 71:805–813 25. Grothe M, Zaborszky L, Atienza M, Gil-Neciga E, RodriguezRomero R, Teipel SJ, Amunts K, Suarez-Gonzalez A, Cantero JL (2010) Reduction of basal forebrain cholinergic system parallels cognitive impairment in patients at high risk of developing Alzheimer’s disease. Cereb Cortex 20:1685–1695 26. Grothe MJ, Ewers M, Krause B, Heinsen H, Teipel SJ (2014) Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects. Alzheimers Dement 27. Halliday GM, Cullen K, Cairns MJ (1993) Quantitation and three-dimensional reconstruction of Ch4 nucleus in the human basal forebrain. Synapse 15:1–16 28. Hanyu H, Asano T, Sakurai H, Tanaka Y, Takasaki M, Abe K (2002) MR analysis of the substantia innominata in normal aging, Alzheimer disease, and other types of dementia. AJNR Am J Neuroradiol 23:27–32 29. Hanyu H, Shimizu S, Tanaka Y, Hirao K, Iwamoto T, Abe K (2007) MR features of the substantia innominata and therapeutic implications in dementias. Neurobiol Aging 28:548–554 30. Hanyu H, Tanaka Y, Shimizu S, Sakurai H, Iwamoto T, Abe K (2005) Differences in MR features of the substantia innominata between dementia with Lewy bodies and Alzheimer’s disease. J Neurol 252:482–484 31. Hepp DH, Ruiter AM, Galis Y, Voorn P, Rozemuller AJ, Berendse HW, Foncke EM, van de Berg WD (2013) Pedunculopontine cholinergic cell loss in hallucinating Parkinson disease patients but not in dementia with Lewy bodies patients. J Neuropathol Exp Neurol 72:1162–1170 32. Hirano S, Shinotoh H, Eidelberg D (2012) Functional brain imaging of cognitive dysfunction in Parkinson’s disease. J Neurol Neurosurg Psychiatry 83:963–969 33. Iraizoz I, Guijarro JL, Gonzalo LM, de Lacalle S (1999) Neuropathological changes in the nucleus basalis correlate with clinical measures of dementia. Acta Neuropathol 98:186–196 34. Janzen J, van‘t Ent D, Lemstra AW, Berendse HW, Barkhof F, Foncke EM (2012) The pedunculopontine nucleus is related to visual hallucinations in Parkinson’s disease: preliminary results of a voxel-based morphometry study. J Neurol 259:147–154 35. Jicha GA, Schmitt FA, Abner E, Nelson PT, Cooper GE, Smith CD, Markesbery WR (2010) Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease. Neurobiol Aging 31:1805–1813 36. Kantarci K, Ferman TJ, Boeve BF, Weigand SD, Przybelski S, Vemuri P, Murray MM, Senjem ML, Smith GE, Knopman DS (2012) Focal atrophy on MRI and neuropathologic classification of dementia with Lewy bodies. Neurology 79:553–560 37. Kilimann I, Grothe M, Heinsen H, Alho EJ, Grinberg L, Amaro E Jr, Dos Santos GA, da Silva RE, Mitchell AJ, Frisoni GB, Bokde AL, Fellgiebel A, Filippi M, Hampel H, Kloppel S, Teipel SJ (2014) Subregional basal forebrain atrophy in Alzheimer’s disease: a multicenter study. J Alzheimers Dis 40:687–700 38. Klein JC, Eggers C, Kalbe E, Weisenbach S, Hohmann C, Vollmar S, Baudrexel S, Diederich NJ, Heiss WD, Hilker R (2010) Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo. Neurology 74:885–892 39. Levy R, Eagger S, Griffiths M, Perry E, Honavar M, Dean A, Lantos P (1994) Lewy bodies and response to tacrine in Alzheimer’s disease. Lancet 343:176 40. Liberini P, Valerio A, Memo M, Spano PF (1996) Lewy-body dementia and responsiveness to cholinesterase inhibitors: a
J Neurol
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. 53.
54.
55.
56.
paradigm for heterogeneity of Alzheimer’s disease? Trends Pharmacol Sci 17:155–160 Lippa CF, Smith TW, Perry E (1999) Dementia with Lewy bodies: choline acetyltransferase parallels nucleus basalis pathology. J Neural Transm 106:525–535 Marra C, Quaranta D, Profice P, Pilato F, Capone F, Iodice F, Di Lazzaro V, Gainotti G (2012) Central cholinergic dysfunction measured ‘‘in vivo’’ correlates with different behavioral disorders in Alzheimer’s disease and dementia with Lewy body. Brain Stimul 5:533–538 Marui W, Iseki E, Kato M, Akatsu H, Kosaka K (2004) Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease. Acta Neuropathol 108:121–128 McKeith I, Dickson D, Lowe J, Emre M, O’brien J, Feldman H, Cummings J, Duda J, Lippa C, Perry E (2005) Diagnosis and management of dementia with Lewy bodies third report of the DLB consortium. Neurology 65:1863–1872 McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, CohenMansfield J, Dickson D, Dubois B, Duda JE, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez OL, Machado JC, O’Brien J, Playfer J (2004) Dementia with Lewy bodies. Lancet Neurol 3:19–28 McKeith I, O’Brien J, Walker Z, Tatsch K, Booij J, Darcourt J, Padovani A, Giubbini R, Bonuccelli U, Volterrani D, Holmes C, Kemp P, Tabet N, Meyer I, Reininger C (2007) Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT SPECT in dementia with Lewy bodies: a phase III, multicentre study. Lancet Neurol 6:305–313 McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease Report of the NINCDS-ADRDA Work Group* under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939 Mesulam MM, Mufson EJ, Levey AI, Wainer BH (1983) Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey. J Comp Neurol 214:170–197 Mesulam MM, Mufson EJ, Wainer BH, Levey AI (1983) Central cholinergic pathways in the rat: an overview based on an alternative nomenclature (Ch1-Ch6). Neuroscience 10:1185–1201 Mori E, Ikeda M, Kosaka K (2012) Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Ann Neurol 72:41–52 Morris J, Heyman A, Mohs R, Hughes J, Van Belle G, Fillenbaum G, Mellits E, Clark C, the CERAD investigators (1989) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer’s disease. Neurology 39:1159–1165 Muir JL (1997) Acetylcholine, aging, and Alzheimer’s disease. Pharmacol Biochem Behav 56:687–696 Narayanan NS, Rodnitzky RL, Uc EY (2013) Prefrontal dopamine signaling and cognitive symptoms of Parkinson’s disease. Rev Neurosci 24:267–278 Pappas BA, Bayley PJ, Bui BK, Hansen LA, Thal LJ (2000) Choline acetyltransferase activity and cognitive domain scores of Alzheimer’s patients. Neurobiol Aging 21:11–17 Perry EK, Haroutunian V, Davis KL, Levy R, Lantos P, Eagger S, Honavar M, Dean A, Griffiths M, McKeith IG et al (1994) Neocortical cholinergic activities differentiate Lewy body dementia from classical Alzheimer’s disease. NeuroReport 5:747–749 Rolinski M, Fox C, Maidment I, McShane R (2012) Cholinesterase inhibitors for dementia with Lewy bodies, Parkinson’s disease dementia and cognitive impairment in Parkinson’s disease. Cochrane Database Syst Rev 3:CD006504
57. Sanchez-Cubillo I, Perianez JA, Adrover-Roig D, RodriguezSanchez JM, Rios-Lago M, Tirapu J, Barcelo F (2009) Construct validity of the Trail Making Test: role of task-switching, working memory, inhibition/interference control, and visuomotor abilities. J Int Neuropsychol Soc 15:438–450 58. Sarter M, Albin RL, Kucinski A, Lustig C (2014) Where attention falls: increased risk of falls from the converging impact of cortical cholinergic and midbrain dopamine loss on striatal function. Exp Neurol 257C:120–129 59. Scherfler C, Esterhammer R, Nocker M, Mahlknecht P, Stockner H, Warwitz B, Spielberger S, Pinter B, Donnemiller E, Decristoforo C, Virgolini I, Schocke M, Poewe W, Seppi K (2013) Correlation of dopaminergic terminal dysfunction and microstructural abnormalities of the basal ganglia and the olfactory tract in Parkinson’s disease. Brain 136:3028–3037 60. Shimada H, Hirano S, Shinotoh H, Aotsuka A, Sato K, Tanaka N, Ota T, Asahina M, Fukushi K, Kuwabara S (2009) Mapping of brain acetylcholinesterase alterations in Lewy body disease by PET. Neurology 73:273–278 61. Shulman KI (2000) Clock-drawing: is it the ideal cognitive screening test? Int J Geriatr Psychiatry 15:548–561 62. Takahashi R, Ishii K, Miyamoto N, Yoshikawa T, Shimada K, Ohkawa S, Kakigi T, Yokoyama K (2010) Measurement of gray and white matter atrophy in dementia with Lewy bodies using diffeomorphic anatomic registration through exponentiated lie algebra: a comparison with conventional voxel-based morphometry. AJNR Am J Neuroradiol 31:1873–1878 63. Tam CW, Burton EJ, McKeith IG, Burn DJ, O’Brien JT (2005) Temporal lobe atrophy on MRI in Parkinson disease with dementia: a comparison with Alzheimer disease and dementia with Lewy bodies. Neurology 64:861–865 64. Tanaka Y, Hanyu H, Sakurai H, Takasaki M, Abe K (2003) Atrophy of the substantia innominata on magnetic resonance imaging predicts response to donepezil treatment in Alzheimer’s disease patients. Dement Geriatr Cogn Disord 16:119–125 65. Teipel S, Heinsen H, Amaro E Jr, Grinberg LT, Krause B, Grothe M (2014) Cholinergic basal forebrain atrophy predicts amyloid burden in Alzheimer’s disease. Neurobiol Aging 35:482–491 66. Teipel SJ, Flatz W, Ackl N, Grothe M, Kilimann I, Bokde AL, Grinberg L, Amaro E Jr, Kljajevic V, Alho E, Knels C, Ebert A, Heinsen H, Danek A (2014) Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala’s nucleus. Psychiatry Res 221:187–194 67. Teipel SJ, Flatz WH, Heinsen H, Bokde AL, Schoenberg SO, Sto¨ckel S, Dietrich O, Reiser MF, Mo¨ller H-J, Hampel H (2005) Measurement of basal forebrain atrophy in Alzheimer’s disease using MRI. Brain 128:2626–2644 68. Teipel SJ, Meindl T, Grinberg L, Grothe M, Cantero JL, Reiser MF, Moller HJ, Heinsen H, Hampel H (2011) The cholinergic system in mild cognitive impairment and Alzheimer’s disease: an in vivo MRI and DTI study. Hum Brain Mapp 32: 1349–1362 69. Tiraboschi P, Hansen LA, Alford M, Merdes A, Masliah E, Thal LJ, Corey-Bloom J (2002) Early and widespread cholinergic losses differentiate dementia with Lewy bodies from Alzheimer disease. Arch Gen Psychiatry 59:946–951 70. Tiraboschi P, Salmon DP, Hansen LA, Hofstetter RC, Thal LJ, Corey-Bloom J (2006) What best differentiates Lewy body from Alzheimer’s disease in early-stage dementia? Brain 129:729–735 71. Vogels OJ, Broere CA, ter Laak HJ, ten Donkelaar HJ, Nieuwenhuys R, Schulte BP (1990) Cell loss and shrinkage in the nucleus basalis Meynert complex in Alzheimer’s disease. Neurobiol Aging 11:3–13 72. Whitehouse PJ, Hedreen JC, White CL, Price DL (1983) Basal forebrain neurons in the dementia of Parkinson disease. Ann Neurol 13:243–248
123
J Neurol 73. Whitehouse PJ, Price DL, Clark AW, Coyle JT, DeLong MR (1981) Alzheimer disease: evidence for selective loss of cholinergic neurons in the nucleus basalis. Ann Neurol 10:122–126 74. Whitwell JL, Weigand SD, Shiung MM, Boeve BF, Ferman TJ, Smith GE, Knopman DS, Petersen RC, Benarroch EE, Josephs KA, Jack CR Jr (2007) Focal atrophy in dementia with Lewy bodies on MRI: a distinct pattern from Alzheimer’s disease. Brain 130:708–719 75. Wider C, Ross OA, Nishioka K, Heckman MG, Vilarino-Guell C, Jasinska-Myga B, Erketin-Taner N, Rademakers R, Graff-Radford NR, Mash DC, Papapetropoulos S, Duara R, Uchikado H, Wszolek ZK, Farrer MJ, Dickson DW (2012) An evaluation of the impact of MAPT, SNCA and APOE on the burden of
123
Alzheimer’s and Lewy body pathology. J Neurol Neurosurg Psychiatry 83:424–429 76. Zaborszky L, Csordas A, Mosca K, Kim J, Gielow MR, Vadasz C, Nadasdy Z (2013) Neurons in the basal forebrain project to the cortex in a complex topographic organization that reflects corticocortical connectivity patterns: an experimental study based on retrograde tracing and 3D reconstruction. Cereb Cortex 77. Zaborszky L, Hoemke L, Mohlberg H, Schleicher A, Amunts K, Zilles K (2008) Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. Neuroimage 42:1127–1141
