Superficial white matter damage in anti-NMDA receptor encephalitis.

BACKGROUND: Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter. METHODS: Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity. RESULTS: Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients. CONCLUSIONS: Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

The superficial white matter in Alzheimer's disease.

White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short-range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern-matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02 ± 5.84, 16M/28F) and 47 healthy controls (Age 69.23 ± 4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P < 0.001) with increases in diffusivity of more than 20% in the bilateral parahippocampal regions and the temporal and frontal lobes. Furthermore, diffusivity correlated with the cognitive deficits measured by the Mini-Mental State Examination scores (P < 0.001). The superficial white matter has a unique microstructure and is critical for the integration of multimodal information during brain maturation and aging. Here we show that there are major abnormalities in patients and the deterioration of these fibers relates to clinical symptoms in Alzheimer's disease.

Recollection and familiarity components of recognition: effect of side of mesio-temporal damage.

We investigated the memory performance of three patients with unilateral mesio-temporal lobe damage with the aim of evaluating the roles of the left and right hemispheres in recollection and familiarity. Consistent with the "Material Specificity Hypothesis", the right brain-damaged individual was selectively poor on recollection and familiarity tests for faces. Conversely, left-lesioned patients were severely deficient in recollection and familiarity of verbal material but mildly deficient on visual-spatial tests. This partially unexpected finding is interpreted in light of the ability of humans to verbally recode almost any material, thus giving rise to left-hemisphere effects for nominally nonverbal stimuli.

The role of iron in gray matter degeneration in Huntington's disease: a magnetic resonance imaging study.

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P = 0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P < 0.05). Volume instead decreases in basal ganglia, starting from the caudate (P < 0.0001) and extending to the putamen and globus pallidus (P ≤ 0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P < 0.027); extending to premotor and parieto-temporo-occipital areas in patients (P < 0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P < 0.023) and SS (P < 0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P < 0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex.

Selective Cognitive Dysfunction Is Related to a Specific Pattern of Cerebral Damage in Persons With Severe Traumatic Brain Injury.

OBJECTIVE: Cognitive dysfunction is a common sequela of traumatic brain injury (TBI); indeed, patients show a heterogeneous pattern of cognitive deficits. This study was aimed at investigating whether patients who show selective cognitive dysfunction after TBI present a selective pattern of cerebral damage. SETTING: Post-Coma Unit, IRCCS Santa Lucia Foundation, Rome, Italy. PARTICIPANTS: We collected data from 8 TBI patients with episodic memory disorder and without executive deficits, 7 patients with executive function impairment and preserved episodic memory capacities, and 16 healthy controls. DESIGN: We used 2 complementary analyses: (1) an exploratory and qualitative approach in which we investigated the distribution of lesions in the TBI groups, and (2) a hypothesis-driven and quantitative approach in which we calculated the volume of hippocampi of individuals in the TBI and control groups. MAIN MEASURES: Neuropsychological scores and hippocampal volumes. RESULTS: We found that patients with TBI and executive functions impairment presented focal lesions involving the frontal lobes, whereas patients with TBI and episodic memory disorders showed atrophic changes of the mesial temporal structure (hippocampus). CONCLUSION: The complexity of TBI is due to several heterogeneous factors. Indeed, studying patients with TBI and selective cognitive dysfunction should lead to a better understanding of correlations with specific brain impairment and damage, better follow-up of long-term outcome scenarios, and better planning of selective and focused rehabilitation programs.

Bihemispheric stimulation over left and right inferior frontal region enhances recovery from apraxia of speech in chronic aphasia.

Several studies have already shown that transcranial direct current stimulation (tDCS) is a useful tool for enhancing recovery in aphasia. However, all tDCS studies have previously investigated the effects using unihemisperic stimulation. No reports to date have examined the role of bihemispheric tDCS on aphasia recovery. Here, eight aphasic persons with apraxia of speech underwent intensive language therapy in two different conditions: real bihemispheric anodic ipsilesional stimulation over the left Broca's area and cathodic contralesional stimulation over the right homologue of Broca's area, and a sham condition. In both conditions, patients underwent concurrent language therapy for their apraxia of speech. The language treatment lasted 10 days (Monday to Friday, then weekend off, then Monday to Friday). There was a 14-day intersession interval between the real and the sham conditions. In all patients, language measures were collected before (T0), at the end of (T10) and 1 week after the end of (F/U) treatment. Results showed that after simultaneous excitatory stimulation to the left frontal hemisphere and inhibitory stimulation to the right frontal hemisphere regions, patients exhibited a significant recovery not only in terms of better accuracy and speed in articulating the treated stimuli but also in other language tasks (picture description, noun and verb naming, word repetition, word reading) which persisted in the follow-up session. Taken together, these data suggest that bihemispheric anodic ipsilesional and cathodic contralesional stimulation in chronic aphasia patients may affect the treated function, resulting in a positive influence on different language tasks.

Prolonged rock climbing activity induces structural changes in cerebellum and parietal lobe.

This article analyzes whether climbing, a motor activity featured by upward movements by using both feet and hands, generation of new strategies of motor control, maintenance of not stable equilibrium and adoption of long-lasting quadrupedal posture, is able to modify specific brain areas. MRI data of 10 word-class mountain climbers (MC) and 10 age-matched controls, with no climbing experience were acquired. Combining region-of-interest analyses and voxel-based morphometry we investigated cerebellar volumes and correlation between cerebellum and whole cerebral gray matter. In comparison to controls, world-class MC showed significantly larger vermian lobules I-V volumes, with no significant difference in other cerebellar vermian lobules or hemispheres. The cerebellar enlargement was associated with an enlargement of right medial posterior parietal area. The specific features of the motor climbing skills perfectly fit with the plastic anatomical changes we found. The enlargement of the vermian lobules I-V seems to be related to highly dexterous hand movements and to eye-hand coordination in the detection of and correction of visuomotor errors. The concomitant enlargement of the parietal area is related to parallel work in predicting sensory consequences of action to make movement corrections. Motor control and sensory-motor prediction of actions make the difference between survive or not at extreme altitude.

Cerebellar Agenesis and Bilateral Polimicrogyria Associated with Rare Variants of CUB and Sushi Multiple Domains 1 Gene (CSMD1): A Longitudinal Neuropsychological and Neuroradiological Case Study.

Cerebellar agenesis is an extremely rare condition characterized by a near complete absence of the cerebellum. The pathogenesis and molecular basis remain mostly unknown. We report the neuroradiological, molecular, neuropsychological and behavioral characterization of a 5-year-old girl, with cerebellar agenesis associated with parietal and peri-Sylvian polymicrogyria, followed-up for 10 years at four time points. Whole exome sequencing identified two rare variants in CSMD1, a gene associated with neurocognitive and psychiatric alterations. Mild intellectual impairment, cerebellar ataxia and deficits in language, memory and executive functions, with relatively preserved adaptive and psychopathological domains, were initially showed. Phonological awareness and verbal memory declined at 11 years of age, and social and anxiety problems emerged. Adaptive and psychopathological characteristics dramatically worsened at 15 years. In summary, the developmental clinical outcome showed impairment in multiple cognitive functions in childhood, with a progressive decline in cognitive and adaptive abilities and the emergence of psychopathological symptoms in adolescence. The observed phenotype could be the result of a complex interplay between cerebellar abnormality, brain malformation and the relations with CSMD1 variants. These findings may provide insights into the developmental clinical outcomes of a co-occurrence between rare brain malformation and rare genetic variants associated to neurodevelopmental disorders.

Relationship between brain abnormalities and cognitive profile in Williams syndrome.

Previous studies have shown inconsistent results when reporting brain abnormalities in Williams syndrome (WS). This makes an interpretation of clinical and behavioural data uncertain in terms of anatomical localization of brain tissue changes. In this study we employed voxel based morphometry to directly investigate the regional distribution of grey matter (GM) density as a function of individual neuropsychological profiles in individuals with WS. GM maps were regressed against the neuropsychological measures on which WS individuals performed worse than controls. Results showed an association between the regional GM density in the cerebellum, bilaterally, the right Supplementary Motor Area, the right fusiform gyrus, and measures of morpho-syntactic ability. An association was also found between measures of visuo-spatial and visuo-motor abilities and regional GM density in the left cerebellum, left parietal lobule, right superior and left orbital frontal gyri. The study shows the potential to clarify the anatomical substrate underlying specific cognitive deficits in WS.

Callosal atrophy in mild cognitive impairment and Alzheimer's disease: different effects in different stages.

Alzheimer's Disease (AD) is a neurodegenerative disorder that mainly affects grey matter (GM). Nevertheless, a number of investigations have documented white matter (WM) pathology associated with AD. The corpus callosum (CC) is the largest WM fiber bundle in the human brain. It has been shown to be susceptible to atrophy in AD mainly as a correlate of Wallerian degeneration of commissural nerve fibers of the neocortex. The aim of this study was to investigate which callosal regions are affected and whether callosal degeneration is associated with the stage of the disease. For this purpose, we analyzed high-resolution MRI data of patients with amnesic mild cognitive impairment (MCI) (n=20), mild AD (n=20), severe AD (n=10), and of healthy controls (n=20). Callosal morphology was investigated applying two different structural techniques: mesh-based geometrical modeling methods and whole-brain voxel-based analyses. Our findings indicate significant reductions in severe AD patients compared to healthy controls in anterior (genu and anterior body) and posterior (splenium) sections. In contrast, differences between healthy controls and mild AD patients or amnesic MCI patients were less pronounced and did not survive corrections for multiple comparisons. When correlating anterior and posterior WM density of the CC with GM density of the cortex in the severe AD group, we detected significant positive relationships between posterior sections of the CC and the cortex. We conclude that callosal atrophy is present predominantly in the latest stage of AD, where two mechanisms might contribute to WM alterations in severe AD: the Wallerian degeneration in posterior subregions and the myelin breakdown process in anterior subregions.

Smoothing that does not blur: effects of the anisotropic approach for evaluating diffusion tensor imaging data in the clinic.

PURPOSE: To compare the effects of anisotropic and Gaussian smoothing on the outcomes of diffusion tensor imaging (DTI) voxel-based (VB) analyses in the clinic, in terms of signal-to-noise ratio (SNR) enhancement and directional information and boundary structures preservation. MATERIALS AND METHODS: DTI data of 30 Alzheimer's disease (AD) patients and 30 matched control subjects were obtained at 3T. Fractional anisotropy (FA) maps with variable degrees and quality (Gaussian and anisotropic) of smoothing were created and compared with an unsmoothed dataset. The two smoothing approaches were evaluated in terms of SNR improvements, capability to separate differential effects between patients and controls by a standard VB analysis, and level of artifacts introduced by the preprocessing. RESULTS: Gaussian smoothing regionally biased the FA values and introduced a high variability of results in clinical analysis, greatly dependent on the kernel size. On the contrary, anisotropic smoothing proved itself capable of enhancing the SNR of images and maintaining boundary structures, with only moderate dependence of results on smoothing parameters. CONCLUSION: Our study suggests that anisotropic smoothing is more suitable in DTI studies; however, regardless of technique, a moderate level of smoothing seems to be preferable considering the artifacts introduced by this manipulation.

Reduced fronto-temporal connectivity is associated with frontal gray matter density reduction and neuropsychological deficit in schizophrenia.

OBJECTIVES: A "disconnectivity model" of schizophrenia has been proposed, but it is still unclear if white matter abnormalities are associated with gray matter changes and if they may be the anatomic substrate of cognitive impairment, which is a core symptom of the disorder. The first objective was to detect if white matter microstructure alterations in schizophrenia are associated with or independent of gray matter change, using an optimized method for white matter (Tract-Based Spatial Statistics) and gray matter analyses (whole-brain voxel-wise approach). The second objective was to identify the neuropsychological correlates of white matter abnormalities in the schizophrenic group, using a comprehensive neuropsychological battery. METHODS: In this case-control study 43 schizophrenic patients and 43 healthy volunteers were consecutively enrolled and matched for age and gender. RESULTS: Fractional anisotropy reduction was found in 6 fronto-temporal clusters (corrected p-values <0.05) in schizophrenic group in comparison with healthy volunteers, and 3 clusters showed fractional anisotropy increase (corrected p-values <0.05). Two of the clusters showing reduced fractional anisotropy were associated with reduced gray matter density in neuroanatomically-related regions in schizophrenic subjects (p-values ranging from 0.001 to 0.026). Executive, constructional-praxis, and working memory deficits were significant predictors of fractional anisotropy reduction in 4 clusters in the schizophrenic group (p-values ranging from <0.0001 to 0.0017). CONCLUSIONS: Our data support the disconnectivity hypothesis in schizophrenia, enlightening a link between reduced fronto-temporal connectivity and "frontal" cognitive deficits. Reduced gray matter density may be involved primarily in the pathogenesis of some of these disconnected areas.

Acquired amnesia in childhood: a single case study.

We report the case of C.L., an 8-year-old child who, following the surgical removal of an ependymoma from the left cerebral ventricle at the age of 4 years, developed significant difficulties in retaining day-to-day events and information. A thorough neuropsychological analysis documented in C.L. a severe anterograde amnesic syndrome, characterised by normal short-term memory, but poor performance on episodic long-term memory tests. In particular, C.L. demonstrated virtually no ability to recollect new verbal information several minutes after the presentation. As for semantic memory, C.L. demonstrated general semantic competencies, which, depending on the test, ranged from the level of a 6-year-old girl to a level corresponding to her actual chronological age. Finding a patient who, despite being severely impaired in the ability to recollect new episodic memories, still demonstrates at least partially preserved abilities to acquire new semantic knowledge suggests that neural circuits implicated in the memorisation of autobiographical events and factual information do not overlap completely. This case is examined in the light of growing literature concerned with the dissociation between episodic and semantic memory in childhood amnesia.

Prefrontal-thalamic-cerebellar gray matter networks and executive functioning in schizophrenia.

OBJECTIVE: Poor executive functioning is a core deficit in schizophrenia and has been linked to frontal lobe alterations. We aimed to identify (1) prefrontal cerebral areas in which decreased volume is linked to executive dysfunction in schizophrenia; and (2) areas throughout the brain that are volumetrically related to the prefrontal area identified in the first analysis, thus detecting more extended volumetric networks associated with executive functioning. METHOD: Fifty-three outpatients with schizophrenia and 62 healthy controls, matched for age, gender and handedness, were recruited. High-resolution images were acquired on a 1.5 tesla scanner and regional gray and white matter volumes were analyzed by voxel-based morphometry within SPM5 (statistical parametric mapping, University College London, UK). Executive functioning was assessed using the Wisconsin Card Sorting Test (WCST). RESULTS: Twenty-one patients with poor executive functioning showed reduced dorsolateral prefrontal and anterior cingulate gray matter volume as compared to 30 patients with high WCST performance, with a maximum effect in the left dorsolateral prefrontal cortex. Left dorsolateral prefrontal gray matter volume predicted WCST performance after controlling for possible confounding effects of global cognitive functioning, verbal attention span, negative symptoms, illness duration and education. In this area, both patient groups had less gray matter than healthy controls. Left dorsolateral prefrontal gray matter volume was positively related to dorsal prefrontal, anterior cingulate and parietal gray matter volume; and negatively related to thalamic, cerebellar, pontine and right parahippocampal gray matter volume. CONCLUSIONS: Volumetric alterations in prefrontal-thalamic-cerebellar gray matter networks may lead to executive dysfunction in schizophrenia.

Callosal morphology in Williams syndrome: a new evaluation of shape and thickness.

We applied novel mesh-based geometrical modeling methods to calculate and compare the thickness of the corpus callosum at high spatial resolution and to create profiles of average callosal shape in a well-matched sample (n=24) of individuals with Williams syndrome and controls. In close agreement with previous observations, superimposed surface maps indicate that the corpus callosum in Williams syndrome individuals is shorter and less curved. Moreover, we observed significantly thinner callosal regions in Williams syndrome individuals across the posterior surface, where group effects were less pronounced and spatially restricted in brain-size-adjusted data compared with native data. Circumscribed structural alterations in callosal morphology might be candidate anatomic substrates for the unique cognitive and behavioral profile associated with Williams syndrome.

White Matter Sexual Dimorphism of the Adult Human Brain.

Sex-biased psychophysiology, behavior, brain function, and conditions are extensive, yet underlying structural brain mechanisms remain unclear. There is contradicting evidence regarding sexual dimorphism when it comes to brain structure, and there is still no consensus on whether or not there exists such a dimorphism for brain white matter. Therefore, we conducted a voxel-based morphometry (VBM) analysis along with global volume analysis for white matter across sex. We analyzed 384 T1-weighted MRI brain images (192 male, 192 female) to investigate any differences in white matter (WM) between males and females. In the VBM analysis, we found males to have larger WM, compared to females, in occipital, temporal, insular, parietal, and frontal brain regions. In contrast, females showed only one WM region to be significantly larger than males: the right postcentral gyrus in the parietal lobe region. Although, on average, males showed larger global WM volume, we did not find any significant difference in global WM volume between males and females.

The role of semantic distance in category-specific impairments for living things: evidence from a case of semantic dementia.

In this paper, we describe a patient (LI) suffering from semantic dementia who showed a category-specific naming impairment for living things over and above the effects of several nonsemantic confounding variables. We investigated the characteristics of LI's impairment to address the following three issues raised in three different accounts of category-specific impairments: (i) the role of an imbalance in the loss of sensory compared to nonsensory features (assumed by the Sensory Functional Theory [Warrington, E. K., & Shallice, T. (1984). Category-specific semantic impairments. Brain, 107, 829-859]); (ii) the role of cross domain differences in Feature Correlation (assumed by the Conceptual Structure Account [Moss, H., Tyler, L. K., & Devlin, J. T. (2002). The emergence of category-specific deficits in a distributed semantic system. In: E. M. E. Forde & G. W. Humphreys (Eds.), Category Specificity in Brain and Mind (pp. 115-147). New York: Psychology Press]); (iii) the role of semantic distance (proposed by Cree and McRae [Cree, G. S., & McRae, K. (2003). Analyzing the factors underlying the structure and computation of the meaning of chipmunk, cherry, chisel, cheese, and cello (and many other such concrete nouns). Journal of Experimental Psychology: General, 132, 163-201]). We found that semantic distance was the only factor causally linked to LI's poorer performance on living things. In fact, her naming performance was less accurate on items that had many semantic neighbours, which is typical of living things. On the contrary, a feature listing task revealed that the features available to LI were not predicted by their level of correlation, as expected by the Conceptual Structure Account. Finally, at variance with the Sensory Functional Theory, although LI quoted sensory features less accurately than nonsensory ones, this did not give rise to a disproportionate loss of semantic features in the living domain.

Major Superficial White Matter Abnormalities in Huntington's Disease.

BACKGROUND: The late myelinating superficial white matter at the juncture of the cortical gray and white matter comprising the intracortical myelin and short-range association fibers has not received attention in Huntington's disease. It is an area of the brain that is late myelinating and is sensitive to both normal aging and neurodegenerative disease effects. Therefore, it may be sensitive to Huntington's disease processes. METHODS: Structural MRI data from 25 Pre-symptomatic subjects, 24 Huntington's disease patients and 49 healthy controls was run through a cortical pattern-matching program. The surface corresponding to the white matter directly below the cortical gray matter was then extracted. Individual subject's Diffusion Tensor Imaging (DTI) data was aligned to their structural MRI data. Diffusivity values along the white matter surface were then sampled at each vertex point. DTI measures with high spatial resolution across the superficial white matter surface were then analyzed with the General Linear Model to test for the effects of disease. RESULTS: There was an overall increase in the axial and radial diffusivity across much of the superficial white matter (p < 0.001) in Pre-symptomatic subjects compared to controls. In Huntington's disease patients increased diffusivity covered essentially the whole brain (p < 0.001). Changes are correlated with genotype (CAG repeat number) and disease burden (p < 0.001). CONCLUSIONS: This study showed broad abnormalities in superficial white matter even before symptoms are present in Huntington's disease. Since, the superficial white matter has a unique microstructure and function these abnormalities suggest it plays an important role in the disease.

Changes in white matter in long-term survivors of severe non-missile traumatic brain injury: a computational analysis of magnetic resonance images.

The aim of this study was to investigate long-term consequences of severe non-missile traumatic brain injury (nmTBI) in patients without macroscopic focal brain lesions (>1.6 cm(3)) on regional white-matter density (WMd), and possible correlations with days of coma and memory performances. T1-weighted magnetic-resonance images (MRI) were acquired in 19 nmTBI patients, 3-113 months following the injury, and in 19 control subjects matched for age and gender. In addition, nmTBI patients underwent a battery of standardised memory tests. The MRIs were processed in a fully automatic system using voxel-by-voxel methods. Corpus callosum, fornix, anterior limb of the internal capsule, superior frontal gyrus, para-hippocampal gyrus, optic radiation and chiasma showed significant WMd reduction in nmTBI when compared to control subjects. None of the correlations between days of coma and memory performance scores with nmTBI voxels value that showed WMd reduction reached significance, with the exception of a significant negative correlation between WMd in the mid body of corpus callosum and short-story delayed recall. We detected reductions in WM density in several brain locations similar to those described in previous post mortem investigations. In addition, we observed WMd reduction in the optic chiasma and in the optic radiations; this finding may reflect transneural degeneration along the visual pathway. The weak correlations between specific anatomical sites of the reduced WMd and behavior may reflect the diffuse nature of the brain damage and/or the different time of onset between behavioral manifestations and neuropathological modifications occurring in nmTBI.

Corpus Callosum Structure is Topographically Correlated with the Early Course of Cognition and Depression in Alzheimer's Disease.

Corpus callosum (CC) abnormalities may cause cognitive and neuropsychiatric complications due to reduced hemispheric integration. Over a one-year period, we investigated whether the CC structure of 20 patients with mild Alzheimer's disease (AD) was linked to the evolution of cognitive and neuropsychiatric symptoms. We also investigated whether this anatomical-clinical relationship was localized topographically on the CC by combining voxel-based morphometry and diffusion tensor imaging approaches. We assessed patients' global cognitive deterioration and neuropsychiatric symptoms with the Mini-Mental State Examination and the Neuropsychiatric Inventory. Increased global cognitive deterioration during the early course of AD was significantly related to reduced white matter density (p = 0.004) and fractional anisotropy (FA) (p = 0.012) and increased mean diffusivity (MD) (p = 0.017) at the level of the CC isthmus/splenium. Further, increased depression severity was significantly related to reduced FA (p = 0.008) and increased MD (p = 0.018) at the level of the CC rostrum. These results indicate that changes in early myelinated CC fibers, which subserve the lateral temporal and parietal cortices and are less vulnerable to damage, may be related to cognitive impairment. Furthermore, changes in late myelinated CC fibers, which connect the orbitofrontal cortices and are more vulnerable to damage, may be related to the earliest neuropsychiatric symptoms of AD, such as depression.