In Vivo Assessment of Astrocyte Reactivity in Patients with Progressive Supranuclear Palsy.

OBJECTIVE: Although astrocytic pathology is a pathological hallmark of progressive supranuclear palsy (PSP), its pathophysiological role remains unclear. This study aimed to assess astrocyte reactivity in vivo in patients with PSP. Furthermore, we investigated alterations in brain lactate levels and their relationship with astrocyte reactivity. METHODS: We included 30 patients with PSP-Richardson syndrome and 30 healthy controls; in patients, tau deposition was confirmed through 18F-florzolotau positron emission tomography. Myo-inositol, an astroglial marker, and lactate were quantified in the anterior cingulate cortex through magnetic resonance spectroscopy. We measured plasma biomarkers, including glial fibrillary acidic protein as another astrocytic marker. The anterior cingulate cortex was histologically assessed in postmortem samples of another 3 patients with PSP with comparable disease durations. RESULTS: The levels of myo-inositol and plasma glial fibrillary acidic protein were significantly higher in patients than those in healthy controls (p < 0.05); these increases were significantly associated with PSP rating scale and cognitive function scores (p < 0.05). The lactate level was high in patients, and correlated significantly with high myo-inositol levels. Histological analysis of the anterior cingulate cortex in patients revealed reactive astrocytes, despite mild tau deposition, and no marked synaptic loss. INTERPRETATION: We discovered high levels of astrocyte biomarkers in patients with PSP, suggesting astrocyte reactivity. The association between myo-inositol and lactate levels suggests a link between reactive astrocytes and brain energy metabolism changes. Our results indicate that astrocyte reactivity in the anterior cingulate cortex precedes pronounced tau pathology and neurodegenerative processes in that region, and affects brain function in PSP. ANN NEUROL 2024;96:247-261.

The behavioral variant of Alzheimer's disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex.

BACKGROUND: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer's disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. METHODS: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. RESULTS: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. DISCUSSION: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants.

Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

Socioeconomic Disparities in Chronic Physiologic Stress Are Associated With Brain Structure in Children.

BACKGROUND: Socioeconomic factors have been consistently linked with the structure of children's hippocampus and anterior cingulate cortex (ACC). Chronic stress-as indexed by hair cortisol concentration-may represent an important mechanism underlying these associations. Here, we examined associations between hair cortisol and children's hippocampal and ACC structure, including across hippocampal subfields, and whether hair cortisol mediated associations between socioeconomic background (family income-to-needs ratio, parental education) and the structure of these brain regions. METHODS: Participants were 5- to 9-year-old children (N = 94; 61% female) from socioeconomically diverse families. Parents and children provided hair samples that were assayed for cortisol. High-resolution, T1-weighted magnetic resonance imaging scans were acquired, and FreeSurfer 6.0 was used to compute hippocampal volume and rostral and caudal ACC thickness and surface area (n = 37 with both child hair cortisol and magnetic resonance imaging data; n = 41 with both parent hair cortisol and magnetic resonance imaging data). RESULTS: Higher hair cortisol concentration was significantly associated with smaller CA3 and dentate gyrus hippocampal subfield volumes but not with CA1 or subiculum volume. Higher hair cortisol was also associated with greater caudal ACC thickness. Hair cortisol significantly mediated associations between parental education level and CA3 and dentate gyrus volumes; lower parental education level was associated with higher hair cortisol, which in turn was associated with smaller volume in these subfields. CONCLUSIONS: These findings point to chronic physiologic stress as a potential mechanism through which lower parental education level leads to reduced hippocampal volume. Hair cortisol concentration may be an informative biomarker leading to more effective prevention and intervention strategies aimed at childhood socioeconomic disadvantage.

Anxiety symptoms are associated with smaller insular and orbitofrontal cortex volumes in late-life depression.

BACKGROUND: Increasing understanding of the neural correlates of anxiety symptoms in late-life depression (LLD) could inform the development of more targeted and effective treatments. METHODS: Grey matter volume (GMV) was assessed with volumetric magnetic resonance imaging in a sample of 113 adults ≥60 years with MDD using the following regions of interest: amygdala, anterior cingulate cortex (ACC), insula, orbitofrontal cortex (OFC), and temporal cortex. RESULTS: After controlling for demographic (age, sex, education) and clinical variables (antidepressant use, anxiolytic use, duration of illness, medical comorbidity, cognitive functioning), greater severity of anxiety symptoms was associated with lower GMV bilaterally in the insula, F(1,102) = 6.63, p = 0.01, and OFC, F(1,102) = 8.35, p = 0.005. By contrast, depressive symptom severity was significantly associated with lower bilateral insula volumes, F(1,102) = 6.43, p = 0.01, but not OFC volumes, F(1,102) = 5.37, p = 0.02. LIMITATIONS: Limitations include (1) the relatively mild nature of anxiety symptoms in our sample; (2) the cross-sectional research design, which prohibits inferences of directionality; (3) the relatively homogenous demographic of the sample, and (4) the exclusion of participants with significant psychiatric comorbidity, suicidality, or cognitive impairment. CONCLUSIONS: Decreased OFC volumes may serve as a unique biomarker of anxiety symptoms in LLD. Future longitudinal and clinical studies with long-term follow up and more diverse samples will help further elucidate the biological, psychological, and social factors affecting associations between anxiety and brain morphology in LLD.

Von Economo neurons are part of a larger neuronal population that are selectively vulnerable in C9orf72 frontotemporal dementia.

AIMS: The behavioural variant of frontotemporal dementia with a C9orf72 expansion (C9-bvFTD) is characterised by early changes in social-emotional cognition that are linked to the loss of von Economo neurons (VENs). Together with a subset of neighbouring pyramidal neurons, VENs express the GABA receptor subunit theta (GABRQ). It is not known if the selective vulnerability of VENs in C9-bvFTD also includes this GABRQ-expressing population. METHODS: We quantified VENs and GABRQ immunopositive neurons in the anterior cingulate cortex (ACC) in C9-bvFTD (n = 16), controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we assessed VENs and GABRQ-expressing populations in relation to the clinicopathological profiles. RESULTS: We found the number of VENs and GABRQ-expressing neurons and their ratio over the total layer 5 neuronal population was lower in C9-bvFTD compared to control and AD. C9-bvFTD donors with underlying TDP43 type A pathology in the ACC showed the highest loss of GABRQ-expressing neurons. C9-bvFTD donors that did not present with motor neuron disease (MND) symptoms in the first half of their disease course showed a prominent loss of GABRQ-expressing neurons compared to controls. C9-bvFTD donors with no symptoms of psychosis showed a higher loss compared to controls. Across all donors, the number of VENs correlated strongly with the number of GABRQ-expressing neurons. CONCLUSION: We show that VENs, together with GABRQ-expressing neurons, are selectively vulnerable in C9-bvFTD but are both spared in AD. This suggests they are related and that this GABRQ-expressing population of VENs and pyramidal neurons, is a key modulator of social-emotional functioning.

Semiautomated Assessment of the Anterior Cingulate Cortex in Alzheimer's Disease.

BACKGROUND AND PURPOSE: The anterior cingulate cortex (ACC) is involved in several cognitive processes including executive function. Degenerative changes of ACC are consistently seen in Alzheimer's disease (AD). However, volumetric changes specific to the ACC in AD are not clear because of the difficulty in segmenting this region. The objectives of the current study were to develop a precise and high-throughput approach for measuring ACC volumes and to correlate the relationship between ACC volume and cognitive function in AD. METHODS: Structural T1 -weighted magnetic resonance images of AD patients (n = 47) and age-matched controls (n = 47) at baseline and at 24 months were obtained from the Alzheimer's disease neuroimaging initiative (ADNI) database and studied using a custom-designed semiautomated segmentation protocol. RESULTS: ACC volumes obtained using the semiautomated protocol were highly correlated to values obtained from manual segmentation (r = .98) and the semiautomated protocol was considerably faster. When comparing AD and control subjects, no significant differences were observed in baseline ACC volumes or in change in ACC volumes over 24 months using the two segmentation methods. However, a change in ACC volume over 24 months did not correlate with a change in mini-mental state examination scores. CONCLUSIONS: Our results indicate that the proposed semiautomated segmentation protocol is reliable for determining ACC volume in neurodegenerative conditions including AD.

Transcriptomic Landscape of von Economo Neurons in Human Anterior Cingulate Cortex Revealed by Microdissected-Cell RNA Sequencing.

The von Economo neurons (VENs) are specialized large bipolar projection neurons with restricted distribution in the human brain, and they are far more abundant in humans than in non-human primates. However, VEN functions remain elusive due to the difficulty of isolating VENs and dissecting their connections in the brain. Here, we combined laser-capture-microdissection with RNA sequencing to describe the transcriptomic profile of VENs from human anterior cingulate cortex (ACC). Using pyramidal neurons as reference cells, we identified 344 genes with VEN-associated expression differences, including 215 higher and 129 lower expression genes. Functional enrichment and protein-protein interaction network analyses showed that these genes with VEN-associated expression differences are involved in VEN morphogenesis and functions, such as dendrite branching and axon myelination, and many of them are associated with human social-emotional disorders. With the use of in situ hybridization and immunohistochemistry assays, we validated four novel VEN markers (VAT1L, CHST8, LYPD1, and SULF2). Collectively, we generated a full-spectrum expression profile of VENs from human ACC, greatly enlarging the pool of genes with VEN-associated expression differences that can help researchers to understand the role of VENs in normal and disordered human brains.

Migraine improvement correlates with posterior cingulate cortical thickness reduction.

Objective The main goal of this study was to correlate migraine improvement, after prophylactic therapy, with cortical thickness changes. Methods Cortical thickness maps were obtained with magnetic resonance imaging (MRI) from 19 patients with migraine before (first scan) and after (second scan) prophylactic treatment, and these were compared with controls using the FreeSurfer MRI tool. Cortical changes were correlated with the headache index (HI). Results Anincrease incortical thickness was found in the right cuneus and precuneus, somatosensory and superior parietal cortices in both patient scans, compared with the controls. No changes were observed in the left hemisphere. Following correction for multiple comparisons, no areas changed from the first to the second scan. Regression analysis showed a significant negative correlation between the HI improvement and cortical thickness changes in the left posterior cingulate, a region involved with nociception and, possibly, the development of chronic pain. Conclusion There were changes in cortical thickness in patients with migraine relative to controls in areas involved with vision and pain processing. Left posterior cingulate cortical changes correlated with headache frequency and intensity.

Migraine improvement correlates with posterior cingulate cortical thickness reduction / Variação da espessura cortical no cíngulo posterior em pacientes com enxaqueca. Correlação com a melhora pós-tratamento profilático

ABSTRACT Objective The main goal of this study was to correlate migraine improvement, after prophylactic therapy, with cortical thickness changes. Methods Cortical thickness maps were obtained with magnetic resonance imaging (MRI) from 19 patients with migraine before (first scan) and after (second scan) prophylactic treatment, and these were compared with controls using the FreeSurfer MRI tool. Cortical changes were correlated with the headache index (HI). Results Anincrease incortical thickness was found in the right cuneus and precuneus, somatosensory and superior parietal cortices in both patient scans, compared with the controls. No changes were observed in the left hemisphere. Following correction for multiple comparisons, no areas changed from the first to the second scan. Regression analysis showed a significant negative correlation between the HI improvement and cortical thickness changes in the left posterior cingulate, a region involved with nociception and, possibly, the development of chronic pain. Conclusion There were changes in cortical thickness in patients with migraine relative to controls in areas involved with vision and pain processing. Left posterior cingulate cortical changes correlated with headache frequency and intensity.

RESUMO Objetivos Correlacionar a melhora de pacientes enxaquecosos após tratamento preventivo com alterações na espessura do córtex cerebral. Métodos Espessura cortical foi determinada a partir de imagens de ressonância magnética (RM)em 19 pacientes com enxaqueca, antes (1ᵃ RM) e após (2ᵃ RM) o tratamento profilático, e comparada com controles, usando o programa FreeSurfer. Mudanças corticais foram correlacionadas com o índice de cefaleia (HI). Resultados O hemisfério direito apresentou aumento da espessura no córtex do cúneus e pré-cúneus, parietal superior e somatossensitivo na primeira RM e na segunda RM, em comparação aos controles. Após correção para comparações múltiplas, nenhuma região cortical se mostrou estatisticamente diferente entre a primeira e a segunda RM. A regressão mostrou correlação (negativa) significativa entre melhora do HI e mudanças na espessura cortical do cíngulo posterior esquerdo. Conclusão Existem alterações de espessura cortical em pacientes com enxaqueca em relação a controles em áreas envolvidas com processamento visual e com a dor. As alterações corticais no cíngulo posterior esquerdo variaram de acordo com a frequência e intensidade das crises.

Von Economo neurons of the anterior cingulate across the lifespan and in Alzheimer's disease.

BACKGROUND: Throughout the human aging lifespan, neurons acquire an unusually high burden of wear and tear; this is likely why age is considered the strongest risk factor for the development of Alzheimer's Disease (AD). Von Economo neurons (VENs) are rare, spindle-shaped cells mostly populated in anterior cingulate cortex. In a prior study, "SuperAgers" (individuals older than 80 years of age with outstanding memory ability) showed higher VEN densities compared to elderly controls with average memory, and those with amnestic Mild Cognitive Impairment (aMCI). The intrinsic vulnerabilities of these neurons are unclear, and their contribution to neurodegeneration is unknown. The current study investigated the influence of age and the severity of Alzheimer's disease (AD) on VEN density. METHODS: VEN and total neuronal densities were quantitated using unbiased stereological methods in the anterior cingulate cortex of postmortem samples from the following subject groups: younger controls (age 20-60), SuperAgers, cognitively average elderly controls (age 65+), individuals diagnosed antemortem with aMCI, and individuals diagnosed antemortem with dementia of AD (N = 5, per group). RESULTS: The AD group showed significantly lower VEN density compared to younger and older controls (p < .05), but not compared to the aMCI group, and VENs bearing neurofibrillary tangles were discovered in AD cases. The aMCI group showed lower VEN density than elderly controls, but this was not significant. There was a significant negative correlation between VEN density and Braak stages of AD (p < .001). Consistent with prior findings, SuperAgers showed highest mean VEN density, even when compared to younger cases. CONCLUSIONS: VENs in human anterior cingulate cortex are vulnerable to AD pathology, particularly in later stages of pathogenesis. Their densities do not change throughout aging in individuals with average cognition, and they are more numerous in SuperAgers.

Ultrastructural Alterations of Von Economo Neurons in the Anterior Cingulate Cortex in Schizophrenia.

Von Economo neurons (VENs) are large bipolar projection neurons mainly located in layer Vb of anterior cingulate cortex (ACC) and anterior insula. Both regions are involved in cognitive and emotional procedures and are functionally and anatomically altered in schizophrenia. Although the detailed function of VEN remains unclear, it has been suggested that these neurons are involved in the pathomechanism of schizophrenia. Here, we were interested in the question whether or not the VEN of schizophrenia patients would show abnormalities at the ultrastructural level. Accordingly, we examined the amount of lysosomal aggregations of the VEN in post-mortem tissue of patients with schizophrenia, bipolar disorder and psychologically unaffected individuals, and compared the findings with aggregations in adjacent pyramidal cells in layer Vb of the ACC. VEN of patients with schizophrenia, and to a lesser degree individuals with bipolar disorder contained significantly more lysosomal aggregations compared with tissue from unaffected controls. Specifically, the larger amount of lysosomal aggregations in schizophrenia seemed to be selective for VEN, with no differences occurring in pyramidal cells. These findings may indicate that the VEN of schizophrenia patients are selectively vulnerable to neuronal damage. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:2017-2024, 2017. © 2017 Wiley Periodicals, Inc.

Assessment of Anterior Cingulate Cortex (ACC) and Left Cerebellar Metabolism in Asperger's Syndrome with Proton Magnetic Resonance Spectroscopy (MRS).

PURPOSE: Proton magnetic resonance spectroscopy (1H MRS) is a noninvasive neuroimaging method to quantify biochemical metabolites in vivo and it can serve as a powerful tool to monitor neurobiochemical profiles in the brain. Asperger's syndrome (AS) is a type of autism spectrum disorder, which is characterized by impaired social skills and restrictive, repetitive patterns of interest and activities, while intellectual levels and language skills are relatively preserved. Despite clinical aspects have been well-characterized, neurometabolic profiling in the brain of AS remains to be clear. The present study used proton magnetic resonance spectroscopy (1H MRS) to investigate whether pediatric AS is associated with measurable neurometabolic abnormalities that can contribute new information on the neurobiological underpinnings of the disorder. METHODS: Study participants consisted of 34 children with AS (2-12 years old; mean age 5.2 (±2.0); 28 boys) and 19 typically developed children (2-11 years old; mean age 5.6 (±2.6); 12 boys) who served as the normal control group. The 1H MRS data were obtained from two regions of interest: the anterior cingulate cortex (ACC) and left cerebellum. RESULTS: In the ACC, levels of N-acetylaspartate (NAA), total creatine (tCr), total choline-containing compounds (tCho) and myo-Inositol (mI) were significantly decreased in children with AS compared to controls. On the other hand, no significant group differences in any of the metabolites were found in the left cerebellum. Neither age nor sex accounted for the metabolic findings in the regions. CONCLUSION: The finding of decreased levels of NAA, tCr, tCho, and mI in the ACC but not in left cerebellar voxels in the AS, suggests a lower ACC neuronal density in the present AS cohort compared to controls.

Biochemical assessment of precuneus and posterior cingulate gyrus in the context of brain aging and Alzheimer's disease.

Defining the biochemical alterations that occur in the brain during "normal" aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1) young adult individuals, average age 26 years (n = 9); 2) middle-aged subjects, average age 59 years (n = 5); 3) oldest-old individuals, average age 93 years (n = 6). Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer's disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.

von Economo neurones are selectively targeted in frontotemporal dementia.

BACKGROUND: von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population. AIM: A previous study has shown a selective loss of VEN in FTD above other neurones in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology. METHODS: VEN and neighbouring neurones (NN) were quantified in layers Va and Vb of the right dorsal ACC in 21 cases of bvFTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC). RESULTS: A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n = 13), VEN/10,000 NN was significantly reduced by 53% compared with NDC (P < 0.001) and 41% compared with AD (P = 0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10,000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups. DISCUSSION: In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process.

Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities.

AIMS: The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data, however, are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development. METHODS: We investigated the dorsal anterior cingulate cortex (dACC) in 13 men with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neurone and glial numbers, and glia/neurone index (GNI) in both layers II-III and V-VI. RESULTS: We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neurone numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development. CONCLUSIONS: Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post mortem histopathological studies and in vivo brain imaging findings in patients.

Microvascular changes in late-life schizophrenia and mood disorders: stereological assessment of capillary diameters in anterior cingulate cortex.

AIMS: Previous neuroimaging reports described morphological and functional abnormalities in anterior cingulate cortex (ACC) in schizophrenia and mood disorders. In earlier neuropathological studies, microvascular changes that could affect brain perfusion in these disorders have rarely been studied. Here, we analysed morphological parameters of capillaries in this area in elderly cases affected by these psychiatric disorders. METHODS: We analysed microvessel diameters in the dorsal and subgenual parts of the ACC in eight patients with schizophrenia, 10 patients with sporadic bipolar disorder, eight patients with sporadic major depression, and seven age- and gender-matched control cases on sections stained with modified Gallyas silver impregnation using a stereological counting approach. All individuals were drug-naïve or had received psychotropic medication for less than 6 months, and had no history of substance abuse. Statistical analysis included Kruskal-Wallis group comparisons with Bonferroni correction as well as multivariate regression models. RESULTS: Mean capillary diameter was significantly decreased in the dorsal and subgenual parts of areas 24 in bipolar and unipolar depression cases, both in layers III and V, whereas schizophrenia patients were comparable with controls. These differences persisted when controlling for age, local neuronal densities, and cortical thickness. In addition, cortical thickness was significantly smaller in both layers in schizophrenia patients. CONCLUSIONS: Our findings indicate that capillary diameters in bipolar and unipolar depression but not in schizophrenia are reduced in ACC. The significance of these findings is discussed in the light of the cytoarchitecture, brain metabolism and perfusion changes observed in ACC in mood disorders.

Selective frontoinsular von Economo neuron and fork cell loss in early behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) erodes complex social-emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region-specific neuronal targets in early bvFTD.

Neuroanatomical correlates of suicide in psychosis: the possible role of von Economo neurons.

Suicide is the most important incident in psychiatric disorders. Psychological pain and empathy to pain involves a neural network that involves the anterior cingulate cortex (ACC) and the anterior insula (AI). At the neuronal level, little is known about how complex emotions such as shame, guilt, self-derogation and social isolation, all of which feature suicidal behavior, are represented in the brain. Based on the observation that the ACC and the AI contain a large spindle-shaped cell type, referred to as von Economo neuron (VEN), which has dramatically increased in density during human evolution, and on growing evidence that VENs play a role in the pathophysiology of various neuropsychiatric disorders, including autism, psychosis and dementia, we examined the density of VENs in the ACC of suicide victims. The density of VENs was determined using cresyl violet-stained sections of the ACC of 39 individuals with psychosis (20 cases with schizophrenia, 19 with bipolar disorder). Nine subjects had died from suicide. Twenty specimen were available from the right, 19 from the left ACC. The density of VENs was significantly greater in the ACC of suicide victims with psychotic disorders compared with psychotic individuals who died from other causes. This effect was restricted to the right ACC. VEN density in the ACC seems to be increased in suicide victims with psychosis. This finding may support the assumption that VEN have a special role in emotion processing and self-evaluation, including negative self-appraisal.

Assessment of morbidity following resection of cingulate gyrus gliomas. Clinical article.

OBJECT: The morbidity associated with resection of tumors in the cingulate gyrus (CG) is not well established. The goal of the present study is to define the short- and long-term morbidity profile associated with resection of gliomas within this region. METHODS: Ninety consecutive patients with gliomas involving the CG were analyzed. Resections were classified by zones corresponding to functionally defined regions of the CG as follows: Zone I (perigenual, anterior), Zone II (midcingulate), Zone III (posterior), and Zone IV (retrosplenial). Basic demographic, imaging, operative details, and pre- and postoperative neurological examinations were recorded for each patient. Patients in whom neurological morbidity was documented during their initial postoperative examination who did not completely improve by the 6-month follow-up examination were considered to have a permanent deficit. For each patient with surgery-related morbidity, postoperative MR imaging and operative notes were reviewed, and the cortical regions incorporated in the surgical trajectory were recorded. The analysis was carried out for tumors confined to the CG (> 90% of tumor contained within the CG) as well as those involving the CG but extending into adjacent cortical structures. RESULTS: Analysis of the entire patient cohort demonstrated that 29% of patients experienced a new or worsened neurological deficit immediately after surgery. The most common deficits were supplementary motor area (SMA) syndrome (20%), weakness (6%), and sensory changes (2%). All patients with an SMA syndrome in our series had intentional resection of SMA as part of the surgical approach. Patients with resections including Zone II or III had a higher rate of total morbidity and SMA syndrome than patients with Zone I resections (p < 0.05). Only 4% of patients had a persistent neurological deficit at 6 months postoperatively. A similar morbidity profile was observed in the subset analysis of patients with tumors confined to the CG, with no additional morbidity related to known cingulate-specific functions. CONCLUSIONS: Resection of gliomas involving the CG can be performed with minimal, predictable long-term morbidity (< 5%). Surgical morbidity is primarily a function of surgical trajectory rather than the particular cingulate region resected.