Research reportBrain networks in posterior cortical atrophy: A single case tractography study and literature review
Introduction
PCA is a rare, early-onset (usually before 65 years) neurodegenerative dementia, characterized by initially isolated, progressive impairment of higher order visual and visuo-spatial skills, which usually manifest as visual agnosia, prosopagnosia, environmental disorientation, elements of Balint’s syndrome and visual neglect (Andrade et al., 2010). While these deficits are hallmark features of the clinical syndrome, at presentation to specialized clinics, they can often be accompanied by deficits in praxis and language (e.g., dressing apraxia, transcortical sensory aphasia, and alexia) (Benson et al., 1988, Freedman et al., 1991, Mendez et al., 2002, Tang-Wai et al., 2004, McMonagle et al., 2006). Consistent with their clinical presentation, patients with PCA show gray matter (GM) loss in parieto-occipital and posterior temporal cortices, which is often more prominent in the right hemisphere (Galton et al., 2000, Whitwell et al., 2007). Positron emission topography (PET) studies have reported a prominent hypometabolism in the same posterior brain areas (Nestor et al., 2003, Schmidtke et al., 2005, Bokde et al., 2005). Although PCA patients do not meet clinical criteria for Alzheimer’s disease (AD), because of the lack of memory impairment as core of the syndrome, pathological series have found that the majority of PCA patients have senile plaques and neurofibrillary tangles, both hallmarks of AD, at autopsy (von Gunten et al., 2006, Renner et al., 2004, Tang-Wai et al., 2004, Alladi et al., 2007). In a recent study comparing clinical, biological and anatomical evidence between PCA and early-onset AD (age < 65) was directly performed (Migliaccio et al., 2009), voxel-based morphometry (VBM) results demonstrated a large region of overlapping atrophy between PCA and early-onset AD in the temporo-parietal regions. These regions are known to be preferentially affected in AD pathologically, structurally, and functionally, especially in younger patients (Yasuno et al., 1998, Frisoni et al., 2007, Rabinovici et al., 2010). Migliaccio et al. proposed that although location of atrophy is not an absolute marker of pathology, it does increase the probability of specific underlying pathologic processes, because different brain regions seem to be more vulnerable to specific diseases (Seeley et al., 2009). For these reasons and because of the early age at presentation (<65 years), the definition of “nontypical form of AD with an early age of onset” has been proposed for PCA (Migliaccio et al., 2009).
In PCA, the distribution of AD pathological changes is preponderant in occipital, parietal, and middle/inferior temporal cortices at the autopsy [see (von Gunten et al., 2006) for review]. However, recent studies conducted in vivo, using PET with [11C]-labeled Pittsburgh compound-B (Rosenbloom et al., 2011, de Souza et al., 2011), found no difference in the topography of fibrillar amyloid-β deposition between typical AD and PCA, and concluded that brain damage in PCA was not explained by the distribution of amyloid; if so, amyloid would not be the critical pathological change driving neurodegeneration in PCA.
White matter (WM) damage has attracted less interest. To date, only two single case studies (Yoshida et al., 2004, Duning et al., 2009) have assessed WM integrity in PCA by using diffusion tensor (DT) Magnetic Resonance Imaging (MRI) and a region of interest (ROI)-based approach. In one study (Duning et al., 2009), cognitive deterioration (over a period of 15 months) was associated with diffusivity changes of the occipito-parietal WM, rather than with overall GM and WM atrophy progression. In the other study (Yoshida et al., 2004), decreased fractional anisotropy (FA) was detected in the splenium of the corpus callosum (CC), possibly reflecting neuronal loss in caudal brain regions.
The lesional basis of PCA is not fully defined yet. Recent Single-photon emission computed tomography (SPECT) studies indicate a direct correlation between left inferior parietal hypoperfusion and acalculia, elements of Gerstmann’s syndrome, left–right disorientation and limb apraxia scores, whereas damage to the bilateral dorsal occipito-parietal regions appeared to be involved in Balint’s syndrome (Kas et al., 2011). In another study, structural MRI demonstrated a tendency toward a decreased cortical thickness in occipito-temporal and occipito-parietal cortices in PCA patients with predominant visuo-perceptual and visuo-spatial deficits, respectively (Lehmann et al., 2011). These results are consistent with the classical dichotomy between ventral (occipito-temporal) and dorsal (occipito-parietal) cortical visual streams (see Ungerleider and Mishkin, 1982).
It is to be noted, however, that the ventral–dorsal dichotomy may represent an oversimplification. Both the ventral and the dorsal streams are composed of several distinct pathways, which are starting to be defined both anatomically and functionally (Rizzolatti and Matelli, 2003, Schmahmann and Pandya, 2006, Kravitz et al., 2011, Thiebaut de Schotten et al., 2011). It is conceivable that different combinations of damage to these pathways give rise to distinct patterns of visual or visuo-motor impairment (Bartolomeo et al., 2007).
In neurodegenerative conditions, the prevalently cortical pathology usually inspires accounts of structure-function correlations based on strict cortical localization. Thus, neuropsychological deficits are conceived as resulting from cortical degeneration. However, in recent years a strict cortical localization approach for cognitive functions is changing toward more network-based hypotheses, according to which cognitive functions emerge from the interruption of the flow of information across large-scale networks linking different cortical regions (Catani and ffytche, 2005, Bartolomeo, 2011). The network-based approach contends that not only cortical lesions, but also damage to the WM connections between cortical areas can induce network dysfunction and, hence, cognitive disorders (Mesulam, 2009). On the other hand, WM abnormalities such as rarefaction, loss of axons, oligodendrocytes and reactive astrocytosis have also been reported in neurodegenerative conditions. However, it remains to be seen whether and to what extent damage to WM pathways can correlate with neuropsychological deficits.
A network approach to clinico-anatomical correlations seems particularly appropriate to degenerative disorders, in which neural damage does not distribute along vascular territories such as in stroke, but seem to follow neurofunctional systems implemented in large-scale brain networks. According to the network vulnerability target hypothesis, different networks show peculiar patterns of vulnerability in different neurodegenerative conditions (Seeley et al., 2009).
Section snippets
Case report
The present case report aims at exploring these open issues by taking advantage of detailed neuropsychological and neuroimaging studies, including DT MRI-based tractography of long-range WM tracts, which permits to explore microscopic changes undetected when using conventional MRI. Once specific tracts were identified, values of fiber integrity were obtained, such as mean diffusivity (MD), FA, parallel (λ//) and transverse (λ⊥) diffusivities. These metrics have the potential to elucidate the
Neuropsychological study
The patient had moderate rightward deviation on both visual (19%) and tactile (25%) line bisection (Table 1), and pathological scores on landscape drawing copy (.5/4) and clock drawing test (0/4) (Fig. 2). Patient showed no auditory extinction (9/9), although she had some difficulty to identify auditory stimuli presented on the left side. There were rare left tactile extinctions on double stimulation (10/12).
Fig. 3 shows the setting of computerized assessment of optic ataxia (panel A) and the
Discussion
Neurodegenerative diseases are likely to progress along functionally and anatomically defined large-scale brain networks. These circuits may become the targets of specific neurodegenerative disorders (Seeley et al., 2009), consistent with the notion of selective vulnerability of anatomo-functional networks in neurodegenerative conditions (Mesulam, 2009). Long-range projections within functional neural circuits may thus play a critical role in brain–behavior relationships.
We studied a
Acknowledgments
We thank our patient Dr. B.N. for her willingness, will-power, and interest in our research. We also thank Bastien Oliveiro, Sophie Ferrieux and Elisabetta Pagani for their useful support. The authors acknowledge the support of the French Agence Nationale de la Recherche (ANR-07-LVIE-002-01 – Biomage study). Dr. Migliaccio was funded by the Neuropole de Recherche Francilien (NeRF) and the European Neurological Society (ENS).
References (79)
A fast diffeomorphic image registration algorithm
NeuroImage
(2007)The quest for the ‘critical lesion site’ in cognitive deficits: Problems and perspectives
Cortex
(2011)- et al.
Parietal modules for reaching
Neuropsychologia
(2009) - et al.
A diffusion tensor imaging tractography atlas for virtual in vivo dissections
Cortex
(2008) - et al.
Action control in visual neglect
Neuropsychologia
(2006) - et al.
Investigation of the single case in neuropsychology: Confidence limits on the abnormality of test scores and test score differences
Neuropsychologia
(2002) - et al.
A modified damped Richardson–Lucy algorithm to reduce isotropic background effects in spherical deconvolution
NeuroImage
(2010) - et al.
White matter (dis)connections and gray matter (dys)functions in visual neglect: Gaining insights into the brain networks of spatial awareness
Cortex
(2008) Apraxia and beyond: Life and work of Hugo Liepmann
Cortex
(2003)- et al.
Breakdown of functional connectivity in frontoparietal networks underlies behavioral deficits in spatial neglect
Neuron
(2007)
The disconnection apraxias
Cortex
Where the eye looks, the hand follows; limb-dependent magnetic misreaching in optic ataxia
Current Biology
High resolution diffusion-weighted imaging in fixed human brain using diffusion-weighted steady state free precession
NeuroImage
Defining neurocognitive networks in the BOLD new world of computed connectivity
Neuron
Water diffusion changes in Wallerian degeneration and their dependence on white matter architecture
NeuroImage
Optic ataxia and Balint’s syndrome: Neuropsychological and neurophysiological prospects
Handbook of Clinical Neurology
Optic ataxia and the function of the dorsal stream: Contributions to perception and action
Neuropsychologia
Neurodegenerative diseases target large-scale human brain networks
Neuron
Right posterior cortical functions in a tumour patient series
Cortex
Decreased white matter integrity in late-myelinating fiber pathways in Alzheimer’s disease supports retrogenesis
NeuroImage
Neural substrates of cognitive and behavioral deficits in atypical Alzheimer’s disease
Brain Research Reviews
Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers
NeuroImage
Imaging correlates of posterior cortical atrophy
Neurobiology of Aging
Language networks in semantic dementia
Brain
Focal cortical presentations of Alzheimer’s disease
Brain
Visual neglect in posterior cortical atrophy
BMC Neurology
A battery of tests for the quantitative assessment of unilateral neglect
Restorative Neurology and Neuroscience
Visual neglect
Current Opinion in Neurology
Left unilateral neglect as a disconnection syndrome
Cerebral Cortex
The basis of anisotropic water diffusion in the nervous system – a technical review
NMR in Biomedicine
Posterior cortical atrophy
Archives of Neurology
Association between cognitive performance and cortical glucose metabolism in patients with mild Alzheimer’s disease
Dementia and Geriatric Cognitive Disorders
Postmortem MRI and histopathology of white matter changes in Alzheimer brains. A quantitative, comparative study
Dementia and Geriatric Cognitive Disorders
A white matter disorder in dementia of the Alzheimer type: A pathoanatomical study
Annals of Neurology
Symmetries in human brain language pathways correlate with verbal recall
Proceedings of the National Academy of Sciences USA
The rises and falls of disconnection syndromes
Brain
Fully automatic hippocampus segmentation and classification in Alzheimer’s disease and mild cognitive impairment applied on data from ADNI
Hippocampus
White matter tract integrity in aging and Alzheimer’s disease
Human Brain Mapping
Similar amyloid-beta burden in posterior cortical atrophy and Alzheimer’s disease
Brain
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