Verbal fluency performance in amnestic MCI and older adults with cognitive complaints

Verbal fluency tests are employed regularly during neuropsychological assessments of older adults, and deficits are a common finding in patients with Alzheimer's disease (AD). Little extant research, however, has investigated verbal fluency ability and subtypes in preclinical stages of neurodegenerative disease. We examined verbal fluency performance in 107 older adults with amnestic mild cognitive impairment (MCI, n = 37), cognitive complaints (CC, n = 37) despite intact neuropsychological functioning, and demographically matched healthy controls (HC, n = 33). Participants completed fluency tasks with letter, semantic category, and semantic switching constraints. Both phonemic and semantic fluency were statistically (but not clinically) reduced in amnestic MCI relative to cognitively intact older adults, indicating subtle changes in the quality of the semantic store and retrieval slowing. Investigation of the underlying constructs of verbal fluency yielded two factors: Switching (including switching and shifting tasks) and Production (including letter, category, and action naming tasks), and both factors discriminated MCI from HC albeit to different degrees. Correlational findings further suggested that all fluency tasks involved executive control to some degree, while those with an added executive component (i.e., switching and shifting) were less dependent on semantic knowledge. Overall, our findings highlight the importance of including multiple verbal fluency tests in assessment batteries targeting preclinical dementia populations and suggest that individual fluency tasks may tap specific cognitive processes.     

Clinical significance of corpus callosum atrophy in a mixed elderly population

Corpus callosum (CC) is the main tract connecting the hemispheres, but the clinical significance of CC atrophy is poorly understood. The aim of this work was to investigate clinical and functional correlates of CC atrophy in subjects with age-related white matter changes (ARWMC). In 569 elderly subjects with ARWMC from the Leukoaraiosis And DISability (LADIS) study, the CC was segmented on the normalised mid-sagittal magnetic resonance imaging (MRI) slice and subdivided into five regions. Correlations between the CC areas and subjective memory complaints, mini mental state examination (MMSE) score, history of depression, geriatric depression scale (GDS) score, subjective gait difficulty, history of falls, walking speed, and total score on the short physical performance battery (SPPB) were analyzed. Significant correlations between CC atrophy and MMSE, SPPB, and walking speed were identified, and the CC areas were smaller in subjects with subjective gait difficulty. The correlations remained significant after correction for ARWMC grade. In conclusion, CC atrophy was independently associated with impaired global cognitive and motor function in subjects with ARWMC.     

Assessing motor and cognitive regulation in AD, MCI, and controls using the Behavioral Dyscontrol Scale.

The objective of this study was to evaluate the utility of the Behavioral Dyscontrol Scale (BDS) as a measure of behavioral regulation in Alzheimer's disease (AD) and mild cognitive impairment (MCI). Two patients groups (n=40 MCI and 40 AD) recruited from a memory clinic and an elderly control (EC) group (n=40) recruited from the community were administered a battery of neuropsychological tests including the BDS and a measure of functioning of activities of daily living (ADLs). Results of ROC analyses revealed that performance on the BDS discriminated between the AD group and the MCI and EC groups but did not discriminate between the MCI and EC groups. Performance on the BDS was an independent predictor of ADLs in patient groups after controlling for the effects of performance on a memory measure.     

Partial agenesis of the corpus callosum, hippocampal atrophy, and stable intellectual disability associated with Roifman syndrome

In 2006, we reported the cognitive and behavioral phenotype of the seventh case of Roifman syndrome (OMIM 300258). Aged 11 years 6 months, the patient displayed significant intellectual disability with proportionate impairments in attentional-executive, memory, and visuo-spatial abilities despite appearing socially "able." This discrepancy may be explained by good social-emotional skills masking his intellectual disability, by decline in cognitive abilities over time, or by unusual neuroradiological abnormalities not previously examined in Roifman syndrome. Here, we present results from a structural MRI scan, neurocognitive evaluations repeated 2 and 5 years post-baseline and assessments of face and emotional processing. The MRI revealed partial agenesis of the corpus callosum, bilateral hypoplastic hippocampi but bilaterally intact amygdala. No evidence was found for decline in the patient's neurocognitive profile. Emotional processing data indicated an age-appropriate pattern of reactivity to emotional stimuli and preserved facial identity recognition abilities, but impairments in recognition of negative facial expressions. The results confirmed a stable pattern of intellectual disability, and indicated that Roifman syndrome may be associated with major structural neuro-anatomical abnormalities. We suggest that the relative strengths in emotion and face processing are consistent with the patient's apparently able social behavior, and with intact amygdalar function.     

Correlation between corpus callosum shape and cognitive performance in healthy young adults

Corpus callosum (CC) might be related to cognitive performance because of its role in interhemispheric communication. Previous research has focused mainly on volumetric analyses of the CC, yielding contradictory results to some extent. Shape is an approach that integrates and extends the data obtained with the volumetric methodology. Here, we analyze the relationships between midsagittal CC shape variation and several cognitive measures. 2D coordinates from 102 MRI-scanned young adult human CCs were superimposed through a Procrustes approach. The residual variation was regressed onto 21 cognitive measures completed by the participants. Most of these measures (including general intelligence, working memory, executive functioning, and mental speed) were unrelated to midsagittal CC morphology. However, attentional control did show consistent and significant correlations with CC shape variation. Slower responses in attentional control were systematically associated with more curved and thinner CC, with consequent rotation of the splenium and the genu. Although the magnitude of the correlations suggests a small relationship of midsagittal CC geometry and attention, the results provide interesting clues regarding the links between brain anatomical configuration and human cognitive function.     

Self- and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints.

Amnestic mild cognitive impairment (MCI) is characterized by impaired episodic memory, although subtle executive problems have been noted on neuropsychological tests. Recent research also has described a group of healthy, non-depressed older adults with significant cognitive complaints (CC) but normal performance on neuropsychological testing. These individuals show structural and functional brain changes intermediate between those seen in MCI and healthy older adults without such complaints (HC). We evaluated executive functions in MCI and CC using the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A), a newly developed self- and informant report questionnaire in 29 patients with amnestic MCI, 28 CCs, and 30 demographically matched HCs. MCI and CC participants reported significant difficulties with selective aspects of executive functioning relative to HCs despite clinically normal performance on neuropsychological tests of this cognitive domain. Scores were generally in the pattern of MCI>CC>HC, and findings were most pronounced for working memory. Additionally, MCI and CC participants were more likely than their informants to report clinically meaningful executive problems, though informants identified a similar pattern of difficulty overall. Results failed to reveal strong relations between the BRIEF-A and standardized neuropsychological tests of executive function. Overall findings indicate that the BRIEF-A is sensitive to subtle executive changes in MCI and CC and suggest the need for research to determine if executive complaints are predictive of clinical course.     

Loss of interhemispheric inhibition in patients with multiple sclerosis is related to corpus callosum atrophy

Axonal injury and loss in the corpus callosum (CC) is characteristic of the pathology of multiple sclerosis (MS). Functional magnetic resonance imaging (fMRI) potentially allows neurophysiological consequences of this interhemispheric axonal loss to be defined quantitatively. Here we have used 3T fMRI to study the activation in the contralateral primary sensorimotor cortex and deactivation (mediated by transcallosal tracts) in the homologous ipsilateral region in 14 patients with MS and in 14 matched healthy controls during a simple hand-tapping task. Both healthy controls and MS patients showed similar activation in the motor cortex contralateral to the hand moved, but the patients showed a significantly smaller relative deactivation in the ipsilateral motor cortex (P = 0.002). The difference was accounted for by the sub-group of MS patients who previously had impairment of motor function of the hand tested (MS-phd). The CC of the whole patient group was significantly thinner than for the controls (P = 0.001). Atrophy of the CC was correlated with loss of deactivation for the whole patient group (r = −0.50, P = 0.035), but particularly for MS-phd (r = −0.914, P = 0.004). Interhemispheric physiological inhibition thus is impaired in patients with MS, potentially contributing to impairment of motor control. This work suggests one way in which FMRI monitoring of the transcallosal interactions in motor cortex could become a tool for evaluation of therapies that may enhance function in reversibly impaired pathways.     

A nonsense variant in HERC1 is associated with intellectual disability,megalencephaly, thick corpus callosum and cerebellar atrophy

Megalencephaly is a congenital condition characterized by severe overdeveloped brain size. This phenotype is often caused by mutations affecting the RTK/PI3K/mTOR (receptor tyrosine kinase-phosphatidylinositol-3-kinase-AKT) signaling and its downstream pathway of mammalian target of rapamycin (mTOR). Here, using a whole-exome sequencing in a Moroccan consanguineous family, we show that a novel autosomal-recessive neurological condition characterized by megalencephaly, thick corpus callosum and severe intellectual disability is caused by a homozygous nonsense variant in the HERC1 gene. Assessment of the primary skin fibroblast from the proband revealed complete absence of the HERC1 protein. HERC1 is an ubiquitin ligase that interacts with tuberous sclerosis complex 2, an upstream negative regulator of the mTOR pathway. Our data further emphasize the role of the mTOR pathway in the regulation of brain development and the power of next-generation sequencing technique in elucidating the genetic etiology of autosomal-recessive disorders and suggest that HERC1 defect might be a novel cause of autosomal-recessive syndromic megalencephaly.     

Polyasplenia, caudal deficiency, and agenesis of the corpus callosum

Fullana et al. [Am J Med Genet (suppl. 2): 23-29, 1986] reported on 2 sibs with an autosomal recessive syndrome of caudal deficiency and polyasplenia anomalies. We report on a similar patient in which agenesis of the corpus callosum (ACC) was also found. Such an association has not been reported previously. This finding of ACC is to be interpreted as another midline anomaly rather than as a causally independent malformation.     

Agenesis of the corpus callosum and hepatoblastoma

Agenesis of the corpus callosum is a congenital brain malformation that can occur in isolation or as a component of a congenital syndrome. Hepatoblastoma (HB) is a rare tumor that comprises two thirds of primary hepatic neoplasms in children and adolescents. Up to 20% of children with HB have associated congenital anomalies. In addition to defined genetic syndromes such as Familial Adenomatous Polyposis, Beckwith–Wiedemann syndrome, Trisomy 13, and Trisomy 18, HB is significantly associated with kidney/bladder abnormalities. We present two children with multiple congenital anomalies, including agenesis of the corpus callosum, who were subsequently diagnosed with HB. Review of the literature revealed two patients with clinically‐diagnosed Aicardi syndrome and HB. Due to the rarity of both agenesis of the corpus callosum and HB, this is likely a true association. Further investigation into the underlying genetic and molecular basis of this probable association is warranted.     

大鼠胼胝体体积和胼胝体额区有髓神经纤维老年改变

目的:探讨老年大鼠大脑胼胝体体积及胼胝体额区有髓神经纤维的改变.方法:运用透射电子显微镜和新的体视学方法分别对年轻组、中老年组和老年组雌性Long-Evans大鼠胼胝体体积及胼胝体额区有髓神经纤维进行定量研究.结果:与年轻组比较,中老年和老年的胼胝体体积和胼胝体额区体积均存在显著性降低,胼胝体额区体积的老年性改变出现更早,老年改变程度更大.老年大鼠胼胝体额区有髓神经纤维总体积较年轻大鼠有下降趋势;有髓神经纤维总长度较年轻大鼠下降19.5%,直径在0.4～0.6 μm范围的有髓神经纤维长度下降28.1%.结论:胼胝体存在显著性老年萎缩,老年胼胝体额区具有选择易损性,胼胝体额区的老年改变可能与老年大脑额叶功能下降有关.     

Agenesis of the corpus callosum and macrocephaly in siblings

A brother and sister with developmental delay, relative macrocephaly and agenesis of the corpus callosum are described. The brother also had unilateral cerebellar hypoplasia and malrotation of the large bowel. Published cases of familial agenesis of the corpus callosum are reviewed and the value of ultrasonography in demonstrating agenesis of the corpus callosum in the neonate is emphasised.     

Morphology of the corpus callosum in human fetuses

Shape and size of the human fetal corpus callosum of a relatively racially homogeneous southern Indian sample population were studied in midsagittal sections of formalin fixed brains. Length of corpus callosum and width of its genu, body, and splenium were measured and the data statistically analyzed. Presence of an isthmus between the body and splenium did not correlate with the measured variables. There was no significant gender difference. The variables correlated significantly among each other but only callosal length and genu width correlated with gestation age. Significant absolute increase occurred in callosal length and genu width, whereas body and splenium widths remained the same. Simple regression equations to estimate the callosal length and genu width for a given age are derived. Clin. Anat. 10:22–26 © 1997 Wiley-Liss, Inc.     

Frontonasal dysplasia, lipoma of the corpus callosum and tetralogy of Fallot

Meguid NA. Frontonasal dysplasia, lipoma of the corpus callosum and tetralogy of Fallot.
Clin Genet 1993: 44: 95–97. © Munksgaard, 1993
A 6-year-old Egyptian boy with frontonasal dysplasia (FND) and lipoma of the corpus callosum associated with tetralogy of Fallot is reported. The main features were severe hypertelorism, downward slanted palpebral fissures, bilateral epicanthal folds, a grossly deformed nose with notched alae nasi, absent nasal tip and long philtrum. A computerized tomography (CT) scan of the brain showed cerebral atrophy and lipoma of the corpus callosum. While marked neurological symptoms have been reported in cases with lipoma of the corpus callosum in the absence of FND, the present case and previous reports showed minor neurological alterations when lipoma of the corpus callosum was associated with FND. From the findings in this case and previous reports, it is possible to conclude that lipoma of the corpus callosum associated with FND is always located in the anterior part of the corpus callosum. The etiology of FND remains uncertain. While multifactorial inheritance has been proposed, parental consanguinity with young parental age in the present case cannot exclude autosomal recessive inheritance.     

Agenesis of corpus callosum in three sibs

Summary We report on a rare familial cases with complete agenesis of the corpus callosum found in three sibs, in which autosomal recessive mode of inheritance was suggested.