In Vivo Detection of Changes Related to Cortical Columnar Organization and Neuroinflammation Across the AD Continuum.

BACKGROUND: Alzheimer's disease (AD) neuropathology reveals progressive microstructural alterations of cortical architecture. Recent studies reported intriguing biphasic trajectories of cortical structural changes in the early stages of Alzheimer's disease (AD), comprising decreased mean diffusivity (MD) and increased cortical thickness in cognitively normal amyloid-positive individuals, ahead of increases and decreases, respectively, in subsequent disease stages. OBJECTIVE: To better understand the cytoarchitectural correlates of these observations, we assessed novel cortical diffusion tensor imaging (DTI) metrics that are correlated with disruption of cortical minicolumns and protein deposition. DESIGN: Cross-sectional and longitudinal analysis of whole brain and temporal lobe cortical diffusivity measures. Investigation of associations between baseline cortical diffusivity values and 24-month longitudinal structural-MRI changes. Investigations of the relationships between cortical diffusivity measures and biomarkers of neuroinflammation. SETTING: Alzheimer's Disease Neuroimaging Initiative (ADNI). PARTICIPANTS: Twenty-four amyloid-negative controls (CN-), 28 amyloid-positive controls (CN+), 46 amyloid-positive subjects with mild cognitive impairment (MCI+) and 22 amyloid-positive subjects with AD were included. MEASUREMENTS: 3DT1 and DTI scans at baseline and approximately 24-month follow-up were used to calculate cortical MD and three novel cortical diffusivity measures: the angle between the radial minicolumnar axis and the principal diffusion direction (AngleR); the diffusion components perpendicular to the minicolumns (PerpPD+), and the principal diffusion component parallel with the minicolumns (ParlPD). Cortical macrostructural measurements (cortical volume fraction and cortical thickness), were used to test the hypothesis that baseline cortical diffusivity values can predict change in structural MRI outcomes over approximately 24 months. CSF soluble TREM2 and progranulin (PGRN) concentrations were used to investigate associations with microglial activity and potentially other aspects of neuroinflammation. RESULTS: Cortical diffusivity metrics revealed a dependence on disease stage, with AngleR and PerpPD+ displaying biphasic relationships and ParlPD a monotonic relationship with clinical severity. The novel metrics were able to differentiate between Amyloid+ and Amyloid- controls (AngleR) and to differentiate among disease stages along the AD continuum (PerpPD+). Linear regression revealed significant associations between baseline cortical diffusivity values and subsequent 24-month longitudinal structural-MRI changes. AngleR values were significantly associated with CSF sTREM2 and PGRN concentrations. CONCLUSIONS: Cortical diffusivity parameters reflecting minicolumnar organization and neuroinflammation may provide a sensitive and biologically interpretable measurement of cortex quality and microstructure across the AD continuum.

Using diffusion tensor imaging to detect cortical changes in fronto-temporal dementia subtypes.

Fronto-temporal dementia (FTD) is a common type of presenile dementia, characterized by a heterogeneous clinical presentation that includes three main subtypes: behavioural-variant FTD, non-fluent/agrammatic variant primary progressive aphasia and semantic variant PPA. To better understand the FTD subtypes and develop more specific treatments, correct diagnosis is essential. This study aimed to test the discrimination power of a novel set of cortical Diffusion Tensor Imaging measures (DTI), on FTD subtypes. A total of 96 subjects with FTD and 84 healthy subjects (HS) were included in the study. A "selection cohort" was used to determine the set of features (measurements) and to use them to select the "best" machine learning classifier from a range of seven main models. The selected classifier was trained on a "training cohort" and tested on a third cohort ("test cohort"). The classifier was used to assess the classification power for binary (HS vs. FTD), and multiclass (HS and FTD subtypes) classification problems. In the binary classification, one of the new DTI features obtained the highest accuracy (85%) as a single feature, and when it was combined with other DTI features and two other common clinical measures (grey matter fraction and MMSE), obtained an accuracy of 88%. The new DTI features can distinguish between HS and FTD subgroups with an accuracy of 76%. These results suggest that DTI measures could support differential diagnosis in a clinical setting, potentially improve efficacy of new innovative drug treatments through effective patient selection, stratification and measurement of outcomes.

The neuropathology of schizophrenia: A selective review of past studies and emerging themes in brain structure and cytoarchitecture.

Schizophrenia is a devastating mental illness. Although its etiology is still largely unknown, strides have been taken throughout the last several decades to elucidate the nature of the neuropathology behind this disorder. The advent of neuroimaging technologies such as computerized axial tomography and magnetic resonance imaging have progressed knowledge about the macroscopic brain changes that occur in schizophrenia, including the characteristic enlarged ventricle size and reductions in gray matter volume, whole-brain volume, and white matter anisotropy. Although this review presents a broad outline of current and historical neuropathological research, the focus is primarily on the quantitative neuropathology of the cerebral cortex in schizophrenia, which may underlie many of the larger scale changes observed. The reduced neuropil hypothesis has been suggested as a microanatomical explanation to account for these macroscopic changes, although the present review finds that evidence does not always support this. A quantitative meta-analytic summary of these studies, focused on neuron density, provides support for the finding of increased neuron density in schizophrenia, with variation dependent on age. This is consistent with neuroimaging data and implicates an altered aging trajectory as a factor in the pathogenesis of schizophrenia. Combined with evidence from other neuroanatomical studies reviewed here, as well as studies in childhood-onset schizophrenia, the evidence converges on a progressive neurodevelopmental model of schizophrenia related to altered neuroplasticity. The evidence also supports a particular vulnerability of inhibitory cortical circuits with markers of interneurons showing some of the more consistent reductions in schizophrenia.

The relationship between callosal axons and cortical neurons in the planum temporale: alterations in schizophrenia.

The relationship between "connectivity" measures such as DTI and the cellular alterations in the cortex that give rise to those connections remains unclear. Cytoarchitectural changes in the planum temporale (PT) suggest impaired layer III feedforward projection neurons in schizophrenia. Altered hemispheric asymmetry of the PT has been reported in patients, along with altered white matter density in the corpus callosum, and there is anomalous activation of the PT during auditory hallucinations. We measured layer III cell density and pyramidal neuron size in PT of both hemispheres of post-mortem brains from patients with schizophrenia (n=16) and control subjects (n=16). We found reduced cell density and the loss of a correlation between magnopyramidal neuron density and axon number in the isthmus of the corpus callosum in schizophrenia. The normal asymmetry indicated that magnopyramidal neurons tend towards being larger and denser in the left PT but this asymmetry is significantly reduced in schizophrenia. The findings offer cytoarchitectural insight into the relationship between PT cortex and callosal white matter abnormalities in schizophrenia.

Callosal misconnectivity and the sex difference in psychosis.

The sex difference in age of onset in schizophrenia is paradoxical in the sense that the brain is developing faster in females but onsets are earlier in males. Therefore if schizophrenia, as widely believed, is a disorder of development, the difference is in the wrong direction. Here we attempt to resolve the paradox with the hypothesis that psychosis is an anomaly of development of cerebral asymmetry and the following assumptions: (1) asymmetry (the torque) confers directionality on the 'language circuit'--failure to develop asymmetry leads to the risk of reverse transmission, a putative mechanism of psychotic symptoms; (2) the corpus callosum goes on developing in an antero-posterior direction into the third and fourth decades of life; (3) a sex difference in structure and development of the corpus callosum (with some anterior components greater in males and posterior components greater in females) reflects stronger, faster lateralization in females; (4) because of the inverse relationship between asymmetry and interhemispheric connections, females, by developing faster, avoid the misconnectivity phenomena in the frontal lobes that males, developing more slowly, may encounter at a younger age with particular risk of negative symptoms.

Subtle changes in the ageing human brain.

Subtle changes in the human brain constitute a third element in addition to plaques and tangles as markers of vulnerability to Alzheimer's disease (AD). Neurofibrillary tangle (NFT) distribution shows the closest relationship to the severity of dementia. Two features of the distribution (regional selectivity and columnar clustering) provide clues about the structural changes due to normal ageing that may precede tangle formation. It is hypothesized that the columnar organization of the cortex, determines the pattern of pathological spread in AD and, consequently, the pattern of function loss. Minicolum thinning occurs in normal ageing and echoes the selective regional distribution of NFT formation in AD. NFT vulnerability appears to emerge from hierarchical variation in neural plasticity associated with the hierarchical variation in size and spacing of mini and macro-columns in the cortex. Regional differences may involve regional variation in gene expression. Dietary Omega 3 fatty acid intake has been shown to have neuroprotective effects on the cytoarchitectural features that contribute to this cortical hierarchy.

Minicolumnar structure in Heschl's gyrus and planum temporale: Asymmetries in relation to sex and callosal fiber number.

AIM: To investigate the cytoarchitectural basis of asymmetries in human auditory cortex. Minicolumn spacing and number, and regional cortical volume and surface area were measured in the primary auditory region (Heschl's gyrus, HG) and posterior auditory association region (planum temporale, PT) in 17 neurologically normal adults (10 female, seven male). PT surface area, minicolumn spacing and minicolumn number were greater in the left hemisphere. HG surface area was larger in the left hemisphere. Asymmetries of minicolumn number in primary and association auditory regions correlated with axonal fiber numbers in the subregions of the corpus callosum through which they project. PT minicolumn number was more asymmetrical in men than women but total number was similar in the two sexes. We conclude that asymmetry of the surface area of the PT is a function of minicolumn spacing. Fewer callosal projections between the plana are found when the minicolumn spacing is more asymmetrical.

Neocortical neuronal, synaptic, and glial loss in multiple sclerosis.

BACKGROUND: Recent pathologic investigations have shown that neocortical lesions are frequent in multiple sclerosis (MS). Structural MRI has shown that neocortical atrophy occurs early and can be substantial, but the specific substrate for this atrophy has not been defined quantitatively. OBJECTIVE: To investigate cortical thickness as well as neuronal, glial, and synaptic densities in MS. METHODS: We studied brain samples from 22 patients with MS and 17 control subjects. Neocortical lesions and cortical thickness were assessed on sections stained for myelin basic protein. Neuronal, glial, and synaptic densities were measured in type I leukocortical lesions, nonlesional neocortex, and non-MS control cortex. Immunoautoradiography was used to quantify synaptic densities. RESULTS: Neocortical lesions were common in patients with MS. Subpial type III (44%) and leukocortical type I (38%) lesions were more abundant than intracortical type II (18%) lesions. An overall relative neocortical thinning of 10% (p = 0.016) was estimated for the patients. Within the type I lesions, we found evidence for substantial cell (glial, 36%, p = 0.001; neuronal, 10%, p = 0.032) and synaptic (47% decrease in synaptophysin, p = 0.001) loss. Nonlesional neocortex did not show significant relative changes in neuronal, glial, or synaptic density. CONCLUSIONS: Neocortical neuronal and glial degeneration is significant in multiple sclerosis. Synaptic loss was particularly striking in the neocortical lesions, which should make a major independent contribution to the expression of pathology. New therapies should be directed toward limiting this damage.

Vulnerability to Alzheimer's pathology in neocortex: the roles of plasticity and columnar organization.

Two principal findings in the Pearson et al. paper are commented on here. The first is the regional selectivity within the cerebrum of neurofibrillary tangle (NFT) formation in Alzheimer's disease (AD) which targets association cortex and the primary olfactory cortex alone among regions of primary sensory cortex. The second finding is the clustering of NFT in columns of supra- and infra-granular layers of association cortex. We review recent evidence confirming these findings and comment on their possible significance. We consider that the most attractive hypothesis to explain the vulnerability of the olfactory system and association cortex is the persistent neural plasticity of these regions. On this basis there would be no need to postulate a progressive spreading process. The columnar distribution of clustered NFT can be well understood in the context of recent concepts of columnar organization of the cerebral cortex. The original interpretation that this distribution of NFT reflects pathology in neurons subserving cortico-cortical and cortico-subcortical connections seems to us to have stood the test of time.

Reduced density of calbindin-immunoreactive interneurons in the planum temporale in schizophrenia.

Reduced density of calbindin-containing interneurons in the prefrontal cortex in schizophrenia has been reported (Beasley et al 2002; Biol Psych 52:708-715). Calbindin is a calcium-binding protein (CBP) present in a subpopulation of GABAergic neurons restricted mainly to layer II of the cortex. A paraffin-embedded, 10-mum-thick section from the planum temporale (PT) of each hemisphere was prepared from 12 patients with schizophrenia and 12 controls. Calbindin-containing cells were stained using an antibody (D-28K). Counting frames were superimposed to sample within layer II of the PT. A bilateral reduction (20%) in calbindin cell density was found in patients (controlling for fixation time). Furthermore, mean calbindin cell cross-sectional area was increased in female patients and reduced in male patients. Reduced CBP expression (reducing the excitability of interneurons) or reduced number of CBP-containing cells may cause disinhibition of pyramidal cells. The majority of calbindin-containing cells in the mature brain are double-bouquet cells with vertically oriented dendrites and axon bundles. By exercising inhibitory modulation of pyramidal cells in a columnar arrangement, they make possible cohesive vertical inhibition of minicolumns. Loss of columnar inhibition may result in reduced minicolumnar segregation and altered cell size may reflect altered minicolumn size.

The cytoarchitecture of sulcal folding in Heschl's sulcus and the temporal cortex in the normal brain and schizophrenia: lamina thickness and cell density.

Developmental and psychiatric disorders, including schizophrenia, may be associated with altered cortical thickness and folding. Two studies were performed: (1) to assess cortical layering around a sulcus; cortical thickness, relative thickness of the supragranular (I-III):infragranular (IV-VI) layers, and cell density were assessed at anatomically defined points around Heschl's sulcus in tissue from 10 controls and 10 schizophrenia patients. (2) To sample sulci of contrasting prominence; sulcal depth, width, lamina thickness, and cell density from laminae II-VI were taken from various sulci within the temporal lobes from another group of 6 controls and 10 patients. Reduced cell density was found in the fundi of sulci in schizophrenia. Independent of diagnosis; increased sulcal prominence in temporal cortex accompanies reduced lamina thickness (particularly layers V and VI), deep layers show negative relationships between cell density and layer thickness, and total cortex width in Heschl's sulcus reduces by half at the bottom compared to the top. Furthermore, compared to the supragranular layers, the infragranular division is relatively thicker at the top of a gyrus, equal in the wall of the sulcus and relatively thinner at the bottom. Many effects of sulcal folding on laminar proportions in controls are similar in schizophrenia. However, cell density is less at the bottom of some sulci in the temporal lobe in schizophrenia. Sampling methods should consider that cortical folding affects cell and lamina distribution in the sampled region in a highly localised manner.

Fiber content of the fornix in schizophrenia: lack of evidence for a primary limbic encephalopathy.

OBJECTIVE: There have been claims that schizophrenia is a disease of the limbic circuit and that the volume of the hippocampus and its content of neurons are low in schizophrenia. The fornix is a major pathway through which neurons project to and from the hippocampus. The authors investigated whether the fiber number or structure of the fornix is abnormal in schizophrenia, as was suggested by an earlier MRI study. METHOD: A section of fornix was removed from each hemisphere of postmortem brains of 16 male and 13 female schizophrenic patients and a comparison group of 19 men and 14 women. Cross-sectional area, fiber density, and total fiber number were examined for differences between diagnostic groups and between genders. RESULTS: The men had a lower fiber density in the fornix than the women. Fiber density on the left side was greater in the schizophrenic men than in the comparison men. For total fiber number (density multiplied by area) there were no differences between groups. Density was found to decrease with increasing area, suggesting that these measures may be affected by degree of myelination. CONCLUSIONS: The fornix does not show the abnormalities in cross-sectional area or total fiber number that would be expected if the primary impact of schizophrenia is on the hippocampus and limbic system. The greater density on the left in schizophrenic men suggests an effect of schizophrenia on myelination related to sex and asymmetry, which may reflect one aspect of a global delay in brain development.

The performance of students with disabilities in a norm-referenced, statewide standardized testing program.

Hawaii uses the Stanford Achievement Test, 8th Edition (Stanford 8), to assess the academic performance of students in Grades 3, 6, 8, and 10. Three longitudinal cohorts were analyzed for achievement performance among Grades 3 to 6, 6 to 8, and 8 to 10. ANOVAs indicated significant differences in overall performance between nondisabled students and three high-incidence categories of students with disabilities (specific learning disability, emotional impairment, and mild mental retardation). Local subgroup norms were developed on the basis of Stanford 8 reading and mathematics results from 1992 to 1996 to supplement the national norms and provide an additional means of comparison to evaluate performance for these categories. The longitudinal cohorts of students with disabilities made greater gains in achievement from third to sixth grade than their national counterparts and cohort of nondisabled students in Hawaii. Between 8th and 10th grade, students with learning disabilities and emotional impairments made gains equal to or greater than their national counterparts'.