Prefrontal Cortex White Matter Research Articles

Reduced length of nodes of Ranvier and altered proteoglycan immunoreactivity in prefrontal white matter in major depressive disorder and chronically stressed rats

Major depressive disorder (MDD) and chronic unpredictable stress (CUS) in animals feature comparable cellular and molecular disturbances that involve neurons and glial cells in gray and white matter (WM) in prefrontal brain areas. These same areas demonstrate disturbed connectivity with other brain regions in MDD and stress-related disorders. Functional connectivity ultimately depends on signal propagation along WM myelinated axons, and thus on the integrity of nodes of Ranvier (NRs) and their environment. Various glia-derived proteoglycans interact with NR axonal proteins to sustain NR function. It is unclear whether NR length and the content of associated proteoglycans is altered in prefrontal cortex (PFC) WM of human subjects with MDD and in experimentally stressed animals. The length of WM NRs in histological sections from the PFC of 10 controls and 10 MDD subjects, and from the PFC of control and CUS rats was measured. In addition, in WM of the same brain region, five proteoglycans, tenascin-R and NR protein neurofascin were immunostained or their levels measured with western blots. Analysis of covariance and t-tests were used for group comparisons. There was dramatic reduction of NR length in PFC WM in both MDD and CUS rats. Proteoglycan BRAL1 immunostaining was reduced at NRs and in overall WM of MDD subjects, as was versican in overall WM. Phosphacan immunostaining and levels were increased in both in MDD and CUS. Neurofascin immunostaining at NRs and in overall WM was significantly increased in MDD. Reduced length of NRs and increased phosphacan and neurocan in MDD and stressed animals suggest that morphological and proteoglycan changes at NRs in depression may be related to stress exposure and contribute to connectivity alterations. However, differences between MDD and CUS for some NR related markers may point to other mechanisms affecting the structure and function of NRs in MDD.

Diffusion tensor imaging of superficial prefrontal white matter in healthy aging

The prefrontal cortex (PFC) is a heterogenous structure that is highly susceptible to the effects of aging. Few studies have investigated age effects on the superficial white matter (WM) contained within the PFC using in-vivo magnetic resonance imaging (MRI). This study used diffusion tensor imaging (DTI) tractography to examine the effects of age, sex, and intracranial volume (ICV) on superficial WM within specific PFC subregions, and to model the relationships with age using higher order polynomial regression modelling. PFC WM of 140 healthy individuals, aged 18–85, was segmented into medial and lateral orbitofrontal, medial prefrontal, and dorsolateral prefrontal subregions. Differences due to age in microstructural parameters such as fractional anisotropy (FA), axial and radial diffusivities, and macrostructural measures of tract volumes, fiber counts, average fiber lengths, and average number of fibers per voxel were examined. We found that most prefrontal subregions demonstrated age effects, with decreases in FA, tract volume, and fiber counts, and increases in all diffusivity measures. Age relationships were mostly non-linear, with higher order regressions chosen in most cases. Declines in PFC FA began at the onset of adulthood while the greatest changes in diffusivity and volume did not occur until middle age. The effects of age were most prominent in medial tracts while the lateral orbitofrontal tracts were less affected. Significant effects of sex and ICV were also observed in certain parameters. The patterns mostly followed myelination order, with late-myelinating prefrontal subregions experiencing earlier and more pronounced age effects, further supporting the frontal theory of aging.

Mapping frontostriatal white matter tracts and their association with reward-related ventral striatum activation in adolescence

The ventral striatum (VS) is implicated in reward processing and motivation. Human and non-human primate studies demonstrate that the VS and prefrontal cortex (PFC), which comprise the frontostriatal circuit, interact to influence motivated behavior. However, there is a lack of research that precisely maps and quantifies VS–PFC white matter tracts. Moreover, no studies have linked frontostriatal white matter to VS activation. Using a multimodal neuroimaging approach with diffusion MRI (dMRI) and functional MRI (fMRI), the present study had two objectives: 1) to chart white matter tracts between the VS and specific PFC structures and 2) assess the association between the degree of VS–PFC white matter tract connectivity and VS activation in 187 adolescents. White matter connectivity was assessed with probabilistic tractography and functional activation was examined with two fMRI tasks (one task with social reward and another task using monetary reward). We found widespread but variable white matter connectivity between the VS and areas of the PFC, with the anterior insula and subgenual cingulate cortex demonstrating the greatest degree of connectivity with the VS. VS–PFC structural connectivity was related to functional activation in the VS though activation depended on the specific PFC region and reward task.

Expression of Oligodendrocyte and Oligoprogenitor Cell Proteins in Frontal Cortical White and Gray Matter: Impact of Adolescent Development and Ethanol Exposure.

Adolescent development of prefrontal cortex (PFC) parallels maturation of executive functions as well as increasing white matter and myelination. Studies using MRI and other methods find that PFC white matter increases across adolescence into adulthood in both humans and rodents. Adolescent binge drinking is common and has been found to alter adult behaviors and PFC functions. This study examines development of oligoprogenitor (OPC) and oligodendrocytes (OLs) in Wistar rats from adolescence to adulthood within PFC white matter, corpus callosum forceps minor (fmi), PFC gray matter, and the neurogenic subventricular zone (SVZ) using immunohistochemistry for marker proteins. In addition, the effects of adolescent intermittent ethanol exposure [AIE; 5.0 g/kg/day, intragastric, 2 days on/2 days off on postnatal day (P)25–54], which is a weekend binge drinking model, were determined. OPC markers NG2+, PDGFRα+ and Olig2+IHC were differentially impacted by both age and PFC region. In both fmi and SVZ, NG2+IHC cells declined from adolescence to adulthood with AIE increasing adult NG2+IHC cells and their association with microglial marker Iba1. PFC gray matter decline in NG2+IHC in adulthood was not altered by AIE. Both adult maturation and AIE impacted OL expression of PLP+, MBP+, MAG+, MOG+, CNPase+, Olig1+, and Olig2+IHC in all three PFC regions, but in region- and marker-specific patterns. These findings are consistent with PFC region-specific changes in OPC and OL markers from adolescence to adulthood as well as following AIE that could contribute to lasting changes in PFC function.

WITHDRAWN:Childhood violence exposure and social deprivation predict adolescent amygdala-orbitofrontal cortex white matter connectivity

Childhood adversity is heterogeneous with potentially distinct dimensions of violence exposure and social deprivation. These dimensions may differentially shape emotion-based neural circuitry, such as amygdala–prefrontal cortex (PFC) white matter connectivity. Amygdala–orbitofrontal cortex (OFC) white matter connectivity has been linked to regulation of the amygdala’s response to emotional stimuli. Using a preregistered analysis plan, we prospectively examined the effects of childhood exposure to two dimensions of adversity, violence exposure and social deprivation, on the adolescent amygdala–PFC white matter connectivity. We also reproduced the negative correlation between amygdala–PFC white matter connectivity and amygdala activation to threat faces. 183 15–17-year-olds were recruited from the Fragile Families and Child Wellbeing Study — a longitudinal, birth cohort, sample of predominantly low-income youth. Probabilistic tractography revealed that childhood violence exposure and social deprivation interacted to predict the probability of adolescent right hemisphere amygdala–OFC white matter connectivity. High violence exposure with high social deprivation related to less amygdala–OFC white matter connectivity. Violence exposure was not associated with white matter connectivity when social deprivation was at mean or low levels (i.e., relatively socially supportive contexts). Therefore, social deprivation may exacerbate the effects of childhood violence exposure on the development of white matter connections involved in emotion processing and regulation. Conversely, social support may buffer against them.

Selectively Impaired Vasodilation of Human White Matter Penetrating Cerebral Arterioles in Microvascular Brain Injury and Alzheimer's disease

Microvascular brain injury (mVBI) is a common pathologic correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter (WM) injury. VCID appears to arise from chronic recurrent WM ischemia. We hypothesized that in mVBI WM injury is specifically attributed to vasodilator dysfunction of WM penetrating arterioles. We analyzed 38 cases of mVBI with low and high Alzheimer's disease (AD) neuropathologic changes in prefrontal cortex WM from rapid autopsies in a population‐based cohort where VCID and AD frequently occur. Arteriolar vasodilator function was quantified by videomicroscopy. Acetylcholine‐mediated arteriolar dilation in mVBI with low AD pathology was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis‐defined WM injury was associated with impaired vasodilator function of WM penetrating arterioles. In mVBI with high AD pathology vasodilator function of WM penetrating arterioles was further diminished. Presence of moderate/frequent neuritic plaques and cerebral amyloid angiopathy were associated with impaired dilation in WM penetrating, but not in pial arterioles. In conclusion, we successfully assessed vasodilator function of human WM penetrating arterioles in postmortem rapid autopsy samples. We found that selectively impaired vasodilator function of WM penetrating arterioles in mVBI occurs in association with WM injury and AD neuropathologic change.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vasodilator dysfunction and oligodendrocyte dysmaturation in aging white matter.

Microvascular brain injury (mVBI) is a common pathological correlate of vascular contributions to cognitive impairment and dementia (VCID) that leads to white matter (WM) injury (WMI). VCID appears to arise from chronic recurrent white matter ischemia that triggers oxidative stress and an increase in total oligodendrocyte lineage cells. We hypothesized that mVBI involves vasodilator dysfunction of white matter penetrating arterioles and aberrant oligodendrocyte progenitor cell (OPC) responses to WMI. We analyzed cases of mVBI with low Alzheimer's disease neuropathological change in prefrontal cortex WM from rapid autopsies in a population-based cohort where VCID frequently occurs. Arteriolar vasodilator function was quantified by videomicroscopy. OPC maturation was quantified using lineage specific markers. Acetylcholine-mediated arteriolar dilation in mVBI was significantly reduced in WM penetrators relative to pial arterioles. Astrogliosis-defined WMI was positively associated with increased OPCs and was negatively associated with decreased mature oligodendrocytes. Selectively impaired vasodilator function of WM penetrating arterioles in mVBI occurs in association with aberrant differentiation of OPCs in WMI, which supports that myelination disturbances in VCID are related to disrupted maturation of myelinating oligodendrocytes. Ann Neurol 2018;83:142-152.

Developmental trajectory of the prefrontal cortex: a systematic review of diffusion tensor imaging studies.

Fluctuations in gray and white matter volumes in addition to the fibers' reorganization and refinement of synaptic connectivity apparently happen in a particular temporo-spatial sequence during the dynamic and prolonged process of cerebral maturation. These developmental events are associated with regional modifications of brain tissues and neural circuits, contributing to networks' specialization and enhanced cognitive processing. According to several studies, improvements in cognitive processes are possibly myelin-dependent and associated to white matter maturation. Of particular interest is the developmental pattern of the prefrontal cortex (PFC), more specifically the PFC white matter, due to its role in high-level executive processes such as attention, working memory and inhibitory control. A systematic review of the literature was conducted using the Web of Science, PubMed and Embase databases to analyze the development of PFC white matter using Diffusion Tensor Imaging (DTI), a widely used non-invasive technique to assess white matter maturation. Both the research and reporting of results were based on Cochrane's recommendations and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. Information extracted from 27 published studies revealed an increased myelination, organization and integrity of frontal white matter with age, as revealed by DTI indexes (fractional anisotropy [FA], mean diffusivity [MD], radial diffusivity [RD] and axial diffusivity [AD]). These patterns highlight the extended developmental course of the frontal structural connectivity, which parallels the improvements in higher-level cognitive functions observed between adolescence and early adulthood.

Myelin vs Axon Abnormalities in White Matter in Bipolar Disorder

White matter (WM) abnormalities are among the most commonly reported neuroimaging findings in bipolar disorder. Nonetheless, the specific nature and pathophysiology of these abnormalities remain unclear. Use of a combination of magnetization transfer ratio (MTR) and diffusion tensor spectroscopy (DTS) permits examination of myelin and axon abnormalities separately. We aimed to examine myelination and axon geometry in euthymic patients with bipolar disorder with psychosis (BDP) by combining these two complementary noninvasive MRI techniques. We applied a combined MRI approach using MTR to study myelin content and DTS to study metabolite (N-acetylaspartate, NAA) diffusion within axons in patients with BDP (n=21) and healthy controls (n=24). Data were collected from a 1 × 3 × 3-cm voxel within the right prefrontal cortex WM at 4 Tesla. Clinical and cognitive data were examined in association with MTR and DTS data. MTR was significantly reduced in BDP, suggesting reduced myelin content. The apparent diffusion coefficient of NAA did not differ from healthy controls, suggesting no changes in axon geometry in patients with BDP. These findings suggest that patients with BDP exhibit reduced myelin content, but no changes in axon geometry compared with controls. These findings are in contrast with our recent findings, using the same techniques, in patients with schizophrenia (SZ), which suggest both myelination and axon abnormalities in SZ. This difference may indicate that alterations in WM in BDP may have unique causes and may be less extensive than WM abnormalities seen in SZ.

E17 Diffusion Weighted Imaging Study Of Prefrontal Cortex White Matter In Prodromal Huntington Disease

<h3>Background</h3> There is considerable interest in finding reliable indicators of Huntington’s disease (HD) progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterising diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connexions and documented role in executive function. <h3>Aims</h3> The primary goal is to assess alterations in the white matter tracts of HD gene-positive individuals using DWI and examine its association with motor, cognitive, psychiatric, demographic and genetic variables. <h3>Methods</h3> Imaging and clinical data were collected from 15 PREDICT-HD sites. This study uses DWI to characterise diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. A streamline-specific alteration was assessed in four major PFC WM tracts: forceps minor (FM), anterior thalamic radiations (ATR), inferior fronto-occipital fasciculi (IFO), uncinate fasciculi (UNC). <h3>Results</h3> Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. White matter alterations in FM, ATR, and IFO showed robust associations with neuropsychological measures of executive functioning. <h3>Conclusions</h3> The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression with increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals. Our tract study also suggests that long-range tracts that are essential for cross-region information that shows early vulnerability in HD and may help to explain cognitive problems in the prodromal stage. <h3>Funding</h3> National Institutes for Health, National Institute of Neurological Disorders and Stroke 040068, and CHDI Foundation, Inc. <h3>Reference</h3> Matsui JT, Vaidya JG, Johnson HJ, <i>et al</i>. Diffusion weighted imaging of prefrontal cortex in prodromal huntington’s disease. <i>Human Brain Mapping</i>2013;1–12:doi:10.1002/hbm.22273

Diffusion weighted imaging of prefrontal cortex in prodromal huntington's disease

Huntington's disease (HD) is a devastating neurodegenerative disease with no effective disease-modifying treatments. There is considerable interest in finding reliable indicators of disease progression to judge the efficacy of novel treatments that slow or stop disease onset before debilitating signs appear. Diffusion-weighted imaging (DWI) may provide a reliable marker of disease progression by characterizing diffusivity changes in white matter (WM) in individuals with prodromal HD. The prefrontal cortex (PFC) may play a role in HD progression due to its prominent striatal connections and documented role in executive function. This study uses DWI to characterize diffusivity in specific regions of PFC WM defined by FreeSurfer in 53 prodromal HD participants and 34 controls. Prodromal HD individuals were separated into three CAG-Age Product (CAP) groups (16 low, 22 medium, 15 high) that indexed baseline progression. Statistically significant increases in mean diffusivity (MD) and radial diffusivity (RD) among CAP groups relative to controls were seen in inferior and lateral PFC regions. For MD and RD, differences among controls and HD participants tracked with baseline disease progression. The smallest difference was for the low group and the largest for the high group. Significant correlations between Trail Making Test B (TMTB) and mean fractional anisotropy (FA) and/or RD paralleled group differences in mean MD and/or RD in several right hemisphere regions. The gradient of effects that tracked with CAP group suggests DWI may provide markers of disease progression in future longitudinal studies as increasing diffusivity abnormalities in the lateral PFC of prodromal HD individuals.

Myelin and Axon Abnormalities in Schizophrenia Measured with Magnetic Resonance Imaging Techniques

In schizophrenia (SZ), disturbances in integration of activity among brain regions seem to be as important as abnormal activity of any single region. Brain regions are connected through white matter (WM) tracts, and diffusion tensor imaging has provided compelling evidence for WM abnormalities in SZ. However, diffusion tensor imaging alone cannot currently pinpoint the biological basis of these abnormalities. In this study, we combined a myelin-specific and an axon-specific magnetic resonance imaging approach to examine potentially distinct abnormalities of WM components in SZ. Magnetization transfer ratio (MTR) provides information on myelin content, whereas diffusion tensor spectroscopy provides information on metabolite diffusion within axons. We collected data from a 1 × 3 × 3 cm voxel within the right prefrontal cortex WM at 4 Tesla and studied 23 patients with SZ and 22 age- and sex-matched healthy control participants. The MTR was significantly reduced in SZ, suggesting reduced myelin content. By contrast, the apparent diffusion coefficient of N-acetylaspartate (NAA) was significantly elevated, suggesting intra-axonal abnormalities. Greater abnormality of both MTR and the apparent diffusion coefficient of NAA correlated with more adverse outcomes in the patient group. The results suggest that WM abnormalities in SZ include both abnormal myelination and abnormal NAA diffusion within axons. These processes might be associated with abnormal signal transduction and abnormal information processing in SZ.

Evidence for a detrimental relationship between hypertension history, prospective memory, and prefrontal cortex white matter in cognitively normal older adults.

Hypertension affects many older adults and is associated with impaired neural and cognitive functioning. We investigated whether a history of hypertension was associated with impairments to prospective memory, which refers to the ability to remember to perform delayed intentions, such as remembering to take medication. Thirty-two cognitively normal older adult participants with or without a history of hypertension (self-reported) performed two laboratory prospective memory tasks, one that relied more strongly on executive control (nonfocal prospective memory) and one that relied more strongly on spontaneous memory retrieval processes (focal prospective memory). We observed hypertension-related impairments for nonfocal, but not focal, prospective memory. To complement our behavioral approach, we conducted a retrospective analysis of available structural magnetic resonance imaging data. Lower white matter volume estimates in the anterior prefrontal cortex were associated with lower nonfocal prospective memory and with a history of hypertension. A history of hypertension may be associated with worsened executive control and lower prefrontal white matter volume. The translational implication is that individuals who must remember to take antihypertensive medications and to monitor their blood pressure at home may be impaired in the executive control process that helps to support these prospective memory behaviors.

White matter lesions defined by diffusion tensor imaging in older adults

The cellular and molecular mechanisms underlying magnetic resonance imaging-defined white matter (WM) changes associated with age-related cognitive decline remain poorly defined. We tested the hypothesis that WM lesions in older adults, defined by diffusion tensor imaging (DTI), arise in the setting of vascular brain injury (VBI) and are characterized by increased free radical injury and aberrant oligodendrocyte lineage (OL) cell response to injury. We undertook a multimodal analysis of prefrontal cortex (PFC) WM from 25 autopsies derived from a population-based cohort where VBI and Alzheimer disease (AD) frequently coincide. Ex vivo high field strength DTI measurements of fractional anisotropy (FA), apparent diffusion coefficient, and axial and radial (D(⊥) ) diffusivity were measured at high magnetic field strength (11.7T) and analyzed relative to quantitative in vivo biomarkers of free radical injury, an OL-specific marker Olig2, and histologic evaluation of hyaluronan (HA), an inhibitor of OL maturation. Coincident AD and VBI showed significant association with lower FA and a robust relationship between decreasing FA and increasing D(⊥) . Free radical injury to docosahexaenoate and adrenate in PFC WM was significantly elevated in cases with VBI independent of AD, and was inversely correlated with FA. Similarly, increased density of Olig2-immunoreactive cells in PFC WM was significantly associated with VBI independent of AD and colocalized with regions enriched in HA. DTI-defined PFC WM lesions in older individuals are characterized by free radical injury to myelin and neuroaxonal elements that coincides with pronounced expansion of the pool of OL cells in HA-rich regions.

Factors underlying prefrontal and insula structural alterations in smokers

Based upon previous reports of alterations in white matter integrity and gray matter density in smokers, we examined these markers in a large, well-matched sample of smokers and non-smokers. We further investigated the effect of heavy cigarette exposure by using pack-years and the effects of two relatively stable, highly heritable traits in smokers (Fagerström Test of Nicotine Dependence (FTND), a measure of severity of nicotine dependence and Toronto Alexithymia Scale (TAS-20), a stable personality trait related to smoking). Forty-eight nicotine-dependent subjects and 48 matched controls were included in the analyses, with smokers also subdivided into high/low dependence and high/low pack-years smokers. White matter integrity (fractional anisotropy (FA)) and gray matter density (voxel-based morphometry (VBM)) were measured and compared across groups. Gray matter density was lower in left prefrontal cortex (PFC) in high pack-years smokers and was inversely related to pack-years. In contrast, left insular cortex gray matter density was higher in smokers and associated with TAS-20 total score and with difficulty-identifying-feelings factor. Further, the most highly dependent smokers showed lower prefrontal FA, which was negatively correlated with FTND. There was no correlation between pack-years and FTND in our smoker population. These data suggest chronic tobacco use is correlated with prefrontal gray matter damage , while differences in insula gray matter and PFC white matter appear to reflect stable and heritable differences between smokers and non-smokers.

Prefrontal Cortex Volumes in Adolescents With Alcohol Use Disorders: Unique Gender Effects

Adolescents with alcohol use disorders (AUD) have shown smaller prefrontal cortex (PFC) volumes compared with healthy controls; however, differences may have been due to comorbid disorders. This study examined PFC volumes in male and female adolescents with AUD who did not meet criteria for comorbid mood or attention disorders. Participants were adolescents aged 15 to 17 who met criteria for AUD (n = 14), and demographically similar healthy controls (n = 17). Exclusions included any history of a psychiatric or neurologic disorder other than AUD or conduct disorder. Magnetic resonance imaging scans occurred after at least 5 days of abstinence from alcohol or drugs. Overall PFC volumes and white matter PFC volumes were compared between groups. After controlling for conduct disorder, gender, and intracranial volume, AUD teens demonstrated marginally smaller anterior ventral PFC volumes (p = 0.09) than controls, and significant interactions between group and gender were observed (p < 0.001 to p < 0.03). Compared with same-gender controls, females with AUD demonstrated smaller PFC volumes, while males with AUD had larger PFC volumes. The same pattern was observed for PFC white matter volumes. Consistent with adult literature, alcohol use during adolescence is associated with prefrontal volume abnormalities, including white matter differences. However, adolescents with AUD demonstrated gender-specific morphometric patterns. Thus, it is possible that gender may moderate the impact of adolescent alcohol use on prefrontal neurodevelopment, and the neurodevelopmental trajectories of heavy drinking boys and girls should be evaluated separately in longitudinal studies.

Metabotropic Glutamate Receptor 2 and 3 Gene Expression in The Human Prefrontal Cortex and Mesencephalon in Schizophrenia

Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in schizophrenia. We characterized mGluR2 and 3 mRNA in the human prefrontal cortex (PFC) and mesencephalon, and then compared cases with schizophrenia to matched controls. In the human brain, both receptors were expressed in the PFC and, unlike the rodent, in dopaminergic (DA) cell groups. In schizophrenia, we found significantly higher levels of mGluR2 mRNA in the PFC white matter. The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia.

Increased Prefrontal Gyrification in a Large High-Risk Cohort Characterizes Those Who Develop Schizophrenia and Reflects Abnormal Prefrontal Development

In our cohort considered at high risk (HR) of developing schizophrenia, we previously found a significant difference in extent of right prefrontal cortical folding between those who subsequently developed schizophrenia and a matched group who remained well. This study aimed to determine if this preexisting difference distinguished 17 individuals who developed schizophrenia from the 128 HR individuals in the cohort who remained well and to explore possible underlying differences in cortical composition. Prefrontal cortical folding was measured by an automated version of the Gyrification Index (A-GI), a ratio reflecting extent of folding. Multivariate logistic regression assessed the probability that prefrontal A-GI predicts diagnostic outcome and subsequently assessed the effect on A-GI of regional cerebrospinal fluid and gray and white matter. High-risk individuals who subsequently developed schizophrenia were distinguished from the remaining cohort by increased right prefrontal cortex (PFC) A-GI. Mean right PFC gray matter volume also differed between groups, but white matter volume did not. Correlations of age with gray and white matter further distinguished groups and a linear regression analysis showed a significant interaction between age and diagnosis on mean volume of right PFC white matter. Increased A-GI appears to indicate abnormal right prefrontal development in those who develop schizophrenia.

Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer disease.

The prefrontal cortex (PFC) is a heterogeneous cortical structure that supports higher cognitive functions, including working memory and verbal abilities. The PFC is vulnerable to neurodegeneration with healthy aging and Alzheimer disease (AD). We used volumetric magnetic resonance imaging to determine whether any region within the PFC is more vulnerable to deterioration with late aging or AD. Volumetric analysis of PFC regions was performed on younger healthy elderly subjects (n = 26; 14 men and 12 women [mean age, 71.7 years] for aging analysis; 12 men and 14 women [mean age, 71.4 years] for AD analysis), oldest healthy elderly (OHE) subjects (n = 22 [11 men and 11 women]; mean age, 88.9 years), and patients with AD (n = 22 [12 men and 10 women]; mean age, 69.8 years). The OHE subjects had less PFC white matter than did young healthy elderly subjects. The orbital region was selectively preserved relative to other PFC regions in the OHE subjects. Subjects with AD had less total PFC gray matter than did age-matched healthy subjects and significantly less volume in the inferior PFC region only. Orbital PFC is selectively preserved in OHE subjects. In contrast, degeneration within the PFC with AD is most prominent in the inferior PFC region. Thus, degeneration within the PFC has a regionally distinct pattern in healthy aging and AD.