Executive dysfunction in mild cognitive impairment is associated with changes in frontal and cingulate white matter tracts

Mild cognitive impairment (MCI) may affect multiple neuropsychological domains. While amnestic MCI is associated with Alzheimer's disease, patterns of brain pathology in non-amnestic subtypes have been less studied. Twenty-three patients with attention/executive MCI (a/e MCI), seen at a university-based memory clinic, and 23 normal controls, matched according to age, gender, and education, were included in this study. All subjects were assessed with a neuropsychological test battery, including tests of memory, attention and executive function, and underwent magnetic resonance imaging. Diffusion tensor imaging derived white matter (WM) tract radial and mean diffusivity (DR and MD) were assessed using Tract-Based Spatial Statistics, and cortical thickness (CTH) was assessed using FreeSurfer. This study investigated changes of WM DR/MD and CTH in subjects with a/e MCI, and associations between these changes and different a/e subfunctions. WM DR/MD underlying rostral middle frontal, medial orbitofrontal, caudal anterior cingulate, posterior cingulate, retrosplenial and entorhinal cortices was higher for the a/e MCI than the control group, but CTH was not different from controls in any of the regions. WM DR/MD underlying superior frontal, rostral middle frontal, lateral/medial orbitofrontal and retrosplenial cortices were significantly associated with inhibition/switching performance, while caudal middle frontal CTH was significantly associated with attention and divided attention in the patient group. We conclude that increased WM DR/MD in frontal and cingulate regions and cortical thinning in caudal middle frontal region are both associated with executive dysfunction in MCI.     

Longitudinal white matter changes in frontotemporal dementia subtypes

Frontotemporal dementia is a degenerative brain condition characterized by focal atrophy affecting the frontal and temporal lobes predominantly. Changes in white matter with disease progression and their relationship to grey matter atrophy remain unknown in FTD. This study aimed to establish longitudinal white matter changes and compare these changes to regional grey matter atrophy in the main FTD subtypes. Diffusion and T₁‐weighted images were collected from behavioral‐variant FTD (bvFTD: 12), progressive non‐fluent aphasia (PNFA: 10), semantic dementia (SD: 11), and 15 controls at baseline and 12 months apart. Changes in white matter integrity were established by fractional anisotropy, mean, axial and radial diffusivity measurements using tract‐based spatial statistics. Patterns of cortical grey matter atrophy were measured using voxel‐based morphometry. At baseline, bvFTD showed severe cross‐sectional changes in orbitofrontal and anterior temporal tracts, which progressed to involve posterior temporal and occipital white matter over the 12‐month. In PNFA, cross‐sectional changes occurred bilaterally in frontotemporal white matter (left > right), with longitudinal changes more prominent on the right. Initial white matter changes in SD were circumscribed to the left temporal lobe, with longitudinal changes extending to bilateral frontotemporal tracts. In contrast, progression of grey matter change over time was less pronounced in all FTD subtypes. Mean diffusivity was most sensitive in detecting baseline changes while fractional anisotropy and radial diffusivity revealed greatest changes over time, possibly reflecting different underlying pathological processes with disease progression. Our results indicate that investigations of white matter changes reveal important differences across FTD syndromes with disease progression. Hum Brain Mapp 35:3547–3557, 2014. © 2013 Wiley Periodicals, Inc .     

Profiles of white matter tract pathology in frontotemporal dementia

Despite considerable interest in improving clinical and neurobiological characterisation of frontotemporal dementia and in defining the role of brain network disintegration in its pathogenesis, information about white matter pathway alterations in frontotemporal dementia remains limited. Here we investigated white matter tract damage using an unbiased, template‐based diffusion tensor imaging (DTI) protocol in a cohort of 27 patients with the behavioral variant of frontotemporal dementia (bvFTD) representing both major genetic and sporadic forms, in relation both to healthy individuals and to patients with Alzheimer's disease. Widespread white matter tract pathology was identified in the bvFTD group compared with both healthy controls and Alzheimer's disease group, with prominent involvement of uncinate fasciculus, cingulum bundle and corpus callosum. Relatively discrete and distinctive white matter profiles were associated with genetic subgroups of bvFTD associated with MAPT and C9ORF72 mutations. Comparing diffusivity metrics, optimal overall separation of the bvFTD group from the healthy control group was signalled using radial diffusivity, whereas optimal overall separation of the bvFTD group from the Alzheimer's disease group was signalled using fractional anisotropy. Comparing white matter changes with regional grey matter atrophy (delineated using voxel based morphometry) in the bvFTD cohort revealed co‐localisation between modalities particularly in the anterior temporal lobe, however white matter changes extended widely beyond the zones of grey matter atrophy. Our findings demonstrate a distributed signature of white matter alterations that is likely to be core to the pathophysiology of bvFTD and further suggest that this signature is modulated by underlying molecular pathologies. Hum Brain Mapp 35:4163–4179, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

Orbitofrontal dysfunction related to both apathy and disinhibition in frontotemporal dementia

Orbitofrontal metabolic impairment is characteristic of the frontal variant of frontotemporal dementia (fv-FTD), as are early changes in emotional and social conduct. Two main types of behavioral disturbances have been distinguished in fv-FTD patients: apathetic and disinhibited manifestations. In this study, we searched for relationships between brain metabolism and presence of apathetic or disinhibited behavior. Metabolic activity and behavioral data were collected in 41 fv-FTD patients from European PET centers. A conjunction analysis of the PET data showed an expected impairment of metabolic activity in the anterior cingulate, ventromedial and orbital prefrontal cortex, the dorsolateral prefrontal cortex and the left anterior insula in fv-FTD subjects compared to matched controls. A correlation was observed between disinhibition scores on the Neuropsychiatric Inventory scale and a cluster of voxels located in the posterior orbitofrontal cortex (6, 28, -24). Comparison of brain activity between apathetic and nonapathetic fv-FTD patients from two centers also revealed a specific involvement of the posterior orbitofrontal cortex in apathetic subjects (4, 22, -22). The results confirm that the main cerebral metabolic impairment in fv-FTD patients affects areas specializing in emotional evaluation and demonstrate that decreased orbitofrontal activity is related to both disinhibited and apathetic syndromes in fv-FTD.     

Microstructural abnormalities of short-distance white matter tracts in autism spectrum disorder

Recent functional connectivity magnetic resonance imaging and diffusion tensor imaging (DTI) studies have suggested atypical functional connectivity and reduced integrity of long-distance white matter fibers in autism spectrum disorder (ASD). However, evidence for short-distance white matter fibers is still limited, despite some speculation of potential sparing of local connectivity in ASD. Short-distance U-fibers are an important component of neural networks and are thought to play a crucial role in cognitive function. In the present study, we applied tract-based spatial statistics to derive short- and long-distance white matter tracts in frontal, parietal, and temporal lobes in both hemispheres. DTI data were acquired from 26 children with ASD and 24 typically developing (TD) children. A mean fractional anisotropy (FA) image was created and thinned to represent centers of all common tracts. Evidence of compromised short-distance tracts for the ASD group was found in frontal lobe (reduced FA, increased mean diffusivity [MD] and radial diffusivity) as well as in temporal and parietal lobes (increased MD and radial diffusivity). Significant positive correlations between age and FA and negative correlations between age and MD and radial diffusivity were also found for short-distance tracts in each lobe in the TD, but not the ASD group. These results suggest white matter compromise in short-distance tracts in ASD. Absence of typical age-related correlations with DTI indices may reflect altered maturation of short-distance tracts in ASD. Our results are inconsistent with a notion of selective sparing of short-distance connectivity in ASD.     

Evidence of white matter changes on diffusion tensor imaging in frontotemporal dementia

BACKGROUND: Two major clinical variants of frontotemporal dementia (FTD) have been described: frontal variant (fvFTD) and temporal variant (tvFTD). OBJECTIVE: To analyze white matter (WM) and gray matter (GM) tissue organization in patients with fvFTD and tvFTD by means of diffusion tensor imaging and voxel-based morphometry, and the correlations with neuropsychological and behavioral variables. DESIGN AND SETTING: Frontotemporal dementia clinic-based cohort and structural magnetic resonance imaging acquisition for voxel-based morphometry and diffusion tensor imaging measurements. Abnormalities were detected by a comparison with healthy control subjects. These variables were also correlated with clinical scores. Patients Thirty-six patients (28 with fvFTD and 8 with tvFTD) in early disease stage and 23 healthy controls who underwent standardized clinical and neuropsychological evaluation and magnetic resonance imaging. INTERVENTIONS: Diffusion tensor imaging and voxel-based morphometry. MAIN OUTCOME MEASURES: Neuroimaging analyses resulted in localized GM atrophy and reductions of white matter densities; the latter correlated with behavioral scores. RESULTS: Voxel-based morphometry analysis showed separate patterns of GM atrophy in the 2 groups. Diffusion tensor imaging showed different WM reduction patterns in patients with fvFTD and tvFTD. The fvFTD group showed a selective WM reduction in the superior longitudinal fasciculus, interconnecting the frontal and occipital and the temporal and parietal regions. Conversely, patients with tvFTD were characterized by WM reductions in the inferior longitudinal fasciculus, which affected the connections between anterior temporal and frontal regions. The WM reductions in fvFTD paralleled both behavioral disturbances measured by Frontal Behavioral Inventory and neuropsychological deficits affecting frontal functions. CONCLUSIONS: The fvFTD and tvFTD variants are associated not only with selective local GM reductions but also with significant WM damage in early disease phase. The different WM patterns contribute to the different clinical syndromes in FTD and could be responsible for the further progression of atrophy in the later disease stages.     

Subcortical white matter abnormalities related to drug resistance in Wilson disease

Wilson disease (WD) produces typical lesions in the brain, which can aid in diagnosis and therapy. The authors present a drug-resistant WD case with atypical cerebral lesions with marked involvement of white matter as visualized on MRI scans. The diagnosis was confirmed by identification of mutations in the ATP7B gene. The case demonstrates an uncommon pathology-related cerebral copper accumulation and emphasizes the importance of genetic screening in the diagnosis of WD.     

Abnormal frontal white matter tracts in bipolar disorder: a diffusion tensor imaging study

OBJECTIVES: Prefrontal white matter has been hypothesized to be integral to the pathophysiology of bipolar disorder. Recent morphometric studies however, have not observed changes in white matter in bipolar patients. We hypothesized that changes in prefrontal function in bipolar disorder, widely reported in the literature, may be related to a loss of white matter tract integrity with a resultant dysconnectivity syndrome. In this study we utilized diffusion tensor imaging (DTI) to examine prefrontal white matter in patients with bipolar disorder. METHODS: Nine patients with bipolar disorder and nine healthy controls were recruited. DTI and localizing anatomic data were acquired, and regions of interest (ROIs) identified in the prefrontal white matter at 15, 20, 25, and 30 mm superior to the anterior commissure (AC). Fractional anisotropy (FA) and trace apparent diffusion coefficient (TADC) were compared by ROI between study groups. RESULTS: The FA of ROIs 25 and 30 mm above the AC was significantly reduced in patients with bipolar disorder; FA of all ROIs showed high-medium to large effect sizes. No significant group differences were identified in TADC. CONCLUSIONS: Our findings suggest that a loss of bundle coherence is present in prefrontal white matter. This loss of coherence may contribute to prefrontal cortical pathology in patients with bipolar disorder.     

Structural abnormalities in frontal, temporal, and limbic regions and interconnecting white matter tracts in schizophrenic patients with prominent negative symptoms

OBJECTIVE: Imaging studies of schizophrenia have repeatedly demonstrated global abnormalities of cerebral and ventricular volumes. However, pathological changes at more local levels of brain organization have not yet been so clearly characterized because of the few brain regions of interest heretofore included in morphometric analyses as well as heterogeneity of patient samples. METHOD: Dual echo magnetic resonance imaging (MRI) data were acquired at 1.5 T from 27 right-handed patients who met DSM-IV criteria for schizophrenia with enduring negative symptoms and from 27 healthy comparison subjects. Between-group differences in gray and white matter volume were estimated at each intracerebral voxel after registration of the images in standard space. The relationship between clinical symptom scores and brain structure was also examined within the patient group. Spatial statistics and permutation tests were used for inference. RESULTS: Significant deficits of gray matter volume in the patient group were found at three main locations: 1) the left superior temporal gyrus and insular cortex, 2) the left medial temporal lobe (including the parahippocampal gyrus and hippocampus), and 3) the anterior cingulate and medial frontal gyri. The volume of these three regions combined was 14% lower in the patients relative to the comparison subjects. White matter deficits were found in similar locations in the left temporal lobe and extended into the left frontal lobe. The patient group showed a relative excess of gray matter volume in the basal ganglia. Within the patient group, basal ganglia gray matter volume was positively correlated with positive symptom scores. CONCLUSIONS: Anatomical abnormalities in these schizophrenic patients with marked negative symptoms were most evident in left hemispheric neocortical and limbic regions and related white matter tracts. These data are compatible with models that depict schizophrenia as a supraregional disorder of multiple, distributed brain regions and the axonal connections between them.     

Executive control deficits correlate with reduced frontal white matter volume in multiple sclerosis

Introduction: Executive control deficits are frequently reported in patients with multiple sclerosis (MS). We have previously proposed that in the context of competing automatic and volitional processes, such deficits may in part reflect poor resolution of response conflict. This study aimed to investigate the neuropathological underpinnings of executive control deficits in MS, focusing on the frontostriatal system proposed to mediate executive control.

Method: Forty-one MS patients and 25 healthy controls completed measures of executive control that have previously been used to characterize deficit in MS: antisaccade and endogenously cued saccade paradigms, and the Stroop color and word test. Relationships between task performance and volumetric measures of frontal white matter, frontal gray matter, striatum, and pallidum were investigated.

Results: MS participants performed significantly more poorly on the Stroop and antisaccade tasks than controls. For MS patients, higher erroneous responding on the antisaccade task was related to reduced frontal white matter volume.

Conclusion: These findings suggest that loss of frontal white matter may underlie executive control deficits in MS, and provides information that may inform the development of targeted cognitive training strategies in MS.     

Reduced white matter integrity is related to cognitive instability

Increased performance variability has been demonstrated in several groups and conditions, including aging and cognitive decline. Structural brain characteristics underlying this phenomenon have so far been elusive. However, there is reason to expect that disconnectivity in associative pathways, whether caused by immature or degraded white matter (WM) tracts, will increase performance variability by neural noise. The aim of this study was to test whether the quality of WM, measured by diffusion tensor imaging, is related to performance variability in healthy adults. Intraindividual standard deviation of the reaction time (sdRT) across trials and median reaction time (mRT) from 270 participants were obtained from a speeded continuous performance task (Eriksen flanker task) with two conditions (congruent, incongruent). Tract-based spatial statistics was used to test the relationship with diffusion characteristics [fractional anisotropy (FA), mean diffusion (MD), radial diffusion (RD), axial diffusion (AD)]. Robust relationships between sdRT and all diffusion measures were found in most WM areas, independently of mRT, age, and sex. The effects were anatomically more widespread in the congruent than the incongruent condition, covering almost 50% of the voxels for RD and MD, and >25% of the voxels for FA and AD. Partial betas were in the range 0.45-0.55, and the strength of the relationships increased significantly with age. For mRT, the effects were smaller and unstable across condition. We concluded that performance variability is a likely consequence of individual differences in WM integrity, and that it is a promising behavioral correlate of individual differences in WM microstructure.     

Alzheimer's disease and frontal variant of frontotemporal dementia

The aim of this study was to investigate whether a brief neuropsychological battery consisting of a limited number of cognitive tests and an evaluation of the behavioural domains intended to discriminate between frontotemporal dementia (fv–FTD) and Alzheimer's disease (AD), constitutes a useful instrument for making a differential clinical diagnosis between these two pathologies. Nineteen fv–FTD and 39 AD patients were compared on cognitive tasks (assessing memory, executive functions, language and constructional praxis) and on the NPI behavioural assessment. A stepwise discriminant analysis was performed to identify the linear combination of cognitive and behavioural measures able to best discriminate between the two groups. One test for each of the investigated cognitive domains (Delayed Prose Recall, FAS verbal fluency, Boston naming test, Rey's Figure A Copy) and the four subscales of the Neuropsychiatry Inventory (NPI) which best differentiated between fv–FTD and AD patients (apathy, disinhibition, euphoria, aberrant motor behaviour) were used. The analysis selected Rey's Figure A Copy, FAS verbal fluency and NPI apathy subscale as the best discriminants between fv–FTD and AD patients. The final equation assigned 73.7% of the fv–FTD patients and 94.7% of the AD patients to the correct diagnostic group. A validation study conducted on a new independent sample of 11 fv–FTD and 22 AD patients confirmed the high sensitivity (82.6 %) and specificity (81.8%) of the diagnostic equation in assigning fv–FTD and AD patients to the correct dementia group. Although both cognitive and behavioural differences exist between FTD and AD, previous studies have aimed at differentiating the two pathologies by considering the two aspects separately and discriminant analyses were focused only on neuropsychological or neuropsychiatric evaluations. The present results emphasise the importance of rating both cognitive and behavioural clinical features of the two syndromes as objectively as possible to improve differential diagnostic accuracy.     

Pathological correlates of white matter hyperintensities in a case of progranulin mutation associated frontotemporal dementia

White matter hyperintensities (WMH) are often seen on MRI brain scans in frontotemporal dementia (FTD) due to progranulin (GRN) mutations, but their pathological correlates are unknown. We examined the histological changes underlying WMH in a patient with GRN mutation associated behavioral variant FTD. In vivo and cadaveric MRI showed progressive, asymmetric frontotemporal and parietal atrophy, and asymmetrical WMH predominantly affecting frontal mid-zones. We first performed segmentation and localization analyses of WMH present on cadaveric MRI FLAIR images, then selected five different brain regions directly matched to differing severities of WMH for histological analysis. We used immunohistochemistry to assess vascular pathology, degree of spongiosis, neuronal and axonal loss, TDP-43, demyelination and astrogliosis, and microglial burden and morphology. Brain regions with significant WMH displayed severe cortical and white matter pathology, and prominent white matter microglial activation and microglial dystrophy, but only mild axonal loss and minimal vascular pathology. Our study suggests that WMH in GRN mutation carriers are not secondary to vascular pathology. Whilst cortical pathology induced axonal degeneration could contribute to white matter damage, individuals with GRN mutations could develop selective white matter vulnerability and myelin loss due to chronic, regional microglial dysfunction arising from GRN haploinsufficiency.     

Face and emotion processing in frontal variant frontotemporal dementia.

Lavenu et al. [Alzheimer Dis. Assoc. Disorder 5 (1999) 96] have shown that patients with frontotemporal dementia (FTD) show impaired recognition of facial expressions. It is not clear, however, whether these deficits arise from an impairment affecting face processing generally, emotion processing generally, or facial expression recognition alone. We address this issue by testing six patients with frontal variant frontotemporal dementia (fvFTD) on a series of face perception tasks (including facial identity and facial expression recognition), and a test of vocal emotion recognition. In general, the fvFTD participants showed impaired recognition of facial expressions in the context of preserved recognition of facial identity. In addition, however, deficits were also observed for the vocal emotion recognition task. These results are consistent with the idea that fvFTD affects the recognition of emotional signals from multiple modalities rather than facial expression processing alone. It is plausible that the emotion recognition impairments observed contribute to the abnormal social behaviour that is characteristic of this condition.     

Amyloid Abeta40 CSF concentrations correlate to frontal lobe atrophy in frontotemporal dementia

We wanted to further study amyloid Abeta protein alterations in non-AD neurodegenerative diseases. Cerebrospinal fluid concentrations of the amyloid Abeta protein with 40 (Abeta40) and 42 (Abeta42) amino acid residues were measured in eleven patients with frontotemporal dementia (FTD). Abeta40 and Abeta42 concentrations were related to the degree of frontal lobe atrophy as assessed with MRI volumetry. Abeta40 concentrations showed a statistically significant linear correlation with degree of frontal lobe atrophy (r = -0.77, p<0.02). Similar results have not been found in previous studies of CSF Abeta40 concentrations and atrophy in patients with AD which suggest that the role of Abeta40 differs between the pathological processes of FTD and AD.