Glycosylation spectral signatures for glioma grade discrimination using Raman spectroscopy.

BACKGROUND: Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific glioma biomarkers that would aid tumour subtyping and minimally invasive early diagnosis. Aberrant glycosylation is an important post-translational modification in cancer and is implicated in glioma progression. Raman spectroscopy (RS), a vibrational spectroscopic label-free technique, has already shown promise in cancer diagnostics. METHODS: RS was combined with machine learning to discriminate glioma grades. Raman spectral signatures of glycosylation patterns were used in serum samples and fixed tissue biopsy samples, as well as in single cells and spheroids. RESULTS: Glioma grades in fixed tissue patient samples and serum were discriminated with high accuracy. Discrimination between higher malignant glioma grades (III and IV) was achieved with high accuracy in tissue, serum, and cellular models using single cells and spheroids. Biomolecular changes were assigned to alterations in glycosylation corroborated by analysing glycan standards and other changes such as carotenoid antioxidant content. CONCLUSION: RS combined with machine learning could pave the way for more objective and less invasive grading of glioma patients, serving as a useful tool to facilitate glioma diagnosis and delineate biomolecular glioma progression changes.

Molecular changes in the absence of severe pathology in the pulvinar in dementia with Lewy bodies.

BACKGROUND: Dementia with Lewy bodies is characterized by transient clinical features, including fluctuating cognition and visual hallucinations, implicating dysfunction of cerebral hub regions, such as the pulvinar nuclei of the thalamus. However, the pulvinar is typically only mildly affected by Lewy body pathology in dementia with Lewy bodies, suggesting additional factors may account for its proposed dysfunction. METHODS: We conducted a comprehensive analysis of postmortem pulvinar tissue using whole-transcriptome RNA sequencing, protein expression analysis, and histological evaluation. RESULTS: We identified 321 transcripts as significantly different between dementia with Lewy bodies cases and neurologically normal controls, with gene ontology pathway analysis suggesting the enrichment of transcripts related to synapses and positive regulation of immune functioning. At the protein level, proteins related to synaptic efficiency were decreased, and general synaptic markers remained intact. Analysis of glial subpopulations revealed astrogliosis without activated microglia, which was associated with synaptic changes but not neurodegenerative pathology. DISCUSSION: These results indicate that the pulvinar, a region with relatively low Lewy body pathological burden, manifests changes at the molecular level that differ from previous reports in a more severely affected region. We speculate that these alterations result from neurodegenerative changes in regions connected to the pulvinar and likely contribute to a variety of cognitive changes resulting from decreased cortical synchrony in dementia with Lewy bodies. © 2018 International Parkinson and Movement Disorder Society.

Doublecortin expression in CD8+ T-cells and microglia at sites of amyloid-ß plaques: A potential role in shaping plaque pathology?

INTRODUCTION: One characteristic of Alzheimer's disease is the formation of amyloid-ß plaques, which are typically linked to neuroinflammation and surrounded by inflammatory cells such as microglia and infiltrating immune cells. METHODS: Here, we describe nonneurogenic doublecortin (DCX) positive cells, DCX being generally used as a marker for young immature neurons, at sites of amyloid-ß plaques in various transgenic amyloid mouse models and in human brains with plaque pathology. RESULTS: The plaque-associated DCX+ cells were not of neurogenic identity, instead most of them showed coexpression with markers for microglia (ionized calcium-binding adapter molecule 1) and for phagocytosis (CD68 and TREM2). Another subpopulation of plaque-associated DCX+ cells was negative for ionized calcium-binding adapter molecule 1 but was highly positive for the pan-leukocyte marker CD45. These hematopoietic cells were identified as CD3-and CD8-positive and CD4-negative T-cells. DISCUSSION: Peculiarly, the DCX+/ionized calcium-binding adapter molecule 1+ microglia and DCX+/CD8+ T-cells were closely attached, suggesting that these two cell types are tightly interacting and that this interaction might shape plaque pathology.

Specific patterns of neuronal loss in the pulvinar nucleus in dementia with lewy bodies.

BACKGROUND: Complex visual hallucinations occur in 70%-80% of dementia with Lewy bodies patients and significantly affect well-being. Despite the prevalence of visual hallucinations in dementia with Lewy bodies, the neuropathological basis of this phenomenon is poorly understood. The pulvinar nucleus of the thalamus has not previously been neuropathologically examined, but has been linked to visual hallucinations in dementia with Lewy bodies. The objective of this study was to investigate whether neuropathological or morphometric changes occur in the pulvinar nucleus in dementia with Lewy bodies cases that may contribute to visual hallucinations. METHODS: Postmortem pulvinar tissue was acquired from 8 individuals with dementia with Lewy bodies, 8 with Alzheimer's disease, and 8 control cases and was analyzed using stereological and quantitative neuropathological techniques. RESULTS: Lewy body pathology was present throughout the pulvinar in dementia with Lewy bodies but was most severe in the medial pulvinar. Neuronal loss was found in the lateral pulvinar in dementia with Lewy bodies and Alzheimer's disease but was more severe in dementia with Lewy bodies. CONCLUSIONS: The pulvinar has an important role in visual attention, visual target selection and affective visual perception. These functions are thought to be deficient in dementia with Lewy bodies and may contribute a vulnerability to visual hallucinations. Therefore, this study has demonstrated neuropathological changes that may promote the manifestation of visual hallucinations in dementia with Lewy bodies. © 2017 International Parkinson and Movement Disorder Society.

Quantitative neuropathology: an update on automated methodologies and implications for large scale cohorts.

A tissue microarray (TMA) has previously been developed for use in assessment of neurodegenerative diseases. We investigated the variation of pathology loads in semi-quantitative score categories and how pathology load related to disease progression. Post-mortem tissue from 146 cases were used; Alzheimer's disease (AD) (n = 36), Lewy body disease (LBD) (n = 56), mixed AD/dementia with Lewy bodies (n = 14) and controls (n = 40). TMA blocks (one per case) were constructed using tissue cores from 15 brain regions including cortical and subcortical regions. TMA tissue sections were stained for hyperphosphorylated tau (HP-T), ß amyloid and α-synuclein (αsyn), and quantified using an automated image analysis system. Cases classified as Braak stage VI displayed a wide variation in HP-T pathology in the entorhinal cortex (interquartile range 4.13-44.03%). The interquartile range for ß amyloid in frontal cortex in cases classified as Thal phase 5 was 6.75-17.03% and for αsyn in the cingulate in cases classified as McKeith neocortical LBD was 0.04-0.58%. In AD and control cases, HP-T load predicted the Braak stage (p < 0.001), ß amyloid load predicted Thal phase (p < 0.001) and αsyn load in LBD cases predicted McKeith type of LBD (p < 0.001). Quantitative data from TMA assessment highlight the range in pathological load across cases classified with 'severe' pathology and is beneficial to further elucidate the heterogeneity of neurodegenerative diseases. Quantifying pathology in multiple brain regions may allow identification of novel clinico-pathological phenotypes for the improvement of intra vitam stratification of clinical cohorts according to underlying pathologies.

Neuronal Loss and Α-Synuclein Pathology in the Superior Colliculus and Its Relationship to Visual Hallucinations in Dementia with Lewy Bodies.

OBJECTIVE: Patients with dementia with Lewy bodies (DLB) often experience visual hallucinations, which are related to decreased quality of life for patients and increased caregiver distress. The pathologic changes that contribute to visual hallucinations are not known, but several hypotheses implicate deficient attentional processing. The superior colliculus has a role in visual attention and planning eye movements and has been directly implicated in several models of visual hallucinations. Therefore, the present study sought to identify neurodegenerative changes that may contribute to hallucinations in DLB. METHODS: Postmortem superior colliculus tissue from 13 comparison, 10 DLB, and 10 Alzheimer disease (AD) cases was evaluated using quantitative neuropathologic methods. RESULTS: α-Synuclein and tau deposition were more severe in deeper layers of the superior colliculus. DLB cases had neuronal density reductions in the stratum griseum intermedium, an important structure in directing attention toward visual targets. In contrast, neuronal density was reduced in all laminae of the superior colliculus in AD. CONCLUSION: These findings suggest that regions involved in directing attention toward visual targets are subject to neurodegenerative changes in DLB. Considering several hypotheses of visual hallucinations implicating dysfunctional attention toward external stimuli, these findings may provide evidence of pathologic changes that contribute to the manifestation of visual hallucinations in DLB.

Changes to the lateral geniculate nucleus in Alzheimer's disease but not dementia with Lewy bodies.

AIMS: Complex visual hallucinations occur in 70% of dementia with Lewy bodies (DLB) cases and significantly affect patient well-being. Visuo-cortical and retinal abnormalities have been recorded in DLB and may play a role in visual hallucinations. The present study aimed to investigate the lateral geniculate nucleus (LGN), a visual relay centre between the retina and visual cortex, to see if changes to this structure underlie visual hallucinations in DLB. METHODS: Fifty-one [17 probable DLB, 19 control and 15 probable Alzheimer's disease (AD)] cases were recruited for a functional magnetic resonance imaging study, in which patients' response to a flashing checkerboard stimulus was detected and measured in the LGN, before comparison across experimental groups. Additionally, post mortem LGN tissue was acquired for a cross-sectional study using 20 (six DLB, seven control and seven AD) cases and analysed using stereology. α-Synuclein, phosphorylated tau and amyloid-ß pathology was also assessed in all cases. RESULTS: DLB cases did not significantly differ from controls on neuroimaging, morphometry or pathology. However, a significant increase in amyloid-ß pathology, a reduction in number of parvocellular neurones and magnocellular gliosis was found in AD cases compared with control and DLB cases. CONCLUSIONS: These findings suggest that the early visual system is relatively spared in DLB, which implies that upstream visual structures may be largely responsible for the generation of hallucinatory percepts. The significance of the degeneration of the LGN in AD cases is uncertain.

Pyramidal neurons of the prefrontal cortex in post-stroke, vascular and other ageing-related dementias.

Dementia associated with cerebrovascular disease is common. It has been reported that ∼30% of elderly patients who survive stroke develop delayed dementia (post-stroke dementia), with most cases being diagnosed as vascular dementia. The pathological substrates associated with post-stroke or vascular dementia are poorly understood, particularly those associated with executive dysfunction. Three separate yet interconnecting circuits control executive function within the frontal lobe involving the dorsolateral prefrontal cortex, anterior cingulate cortex and the orbitofrontal cortex. We used stereological methods, along with immunohistological and related cell morphometric analysis, to examine densities and volumes of pyramidal neurons of the dorsolateral prefrontal cortex, anterior cingulate cortex and orbitofrontal cortex in the frontal lobe from a total of 90 elderly subjects (age range 71-98 years). Post-mortem brain tissues from post-stroke dementia and post-stroke patients with no dementia were derived from our prospective Cognitive Function After Stroke study. We also examined, in parallel, samples from ageing controls and similar age subjects pathologically diagnosed with Alzheimer's disease, mixed Alzheimer's disease and vascular dementia, and vascular dementia. We found pyramidal cell volumes in layers III and V in the dorsolateral prefrontal cortex of post-stroke and vascular dementia and, of mixed and Alzheimer's disease subjects to be reduced by 30-40% compared to post-stroke patients with no dementia and controls. There were no significant changes in neuronal volumes in either the anterior cingulate or orbitofrontal cortices. Remarkably, pyramidal neurons within the orbitofrontal cortex were also found to be smaller in size when compared to those in the other two neocortical regions. To relate the cell changes to cognitive function, we noted significant correlations between neuronal volumes and total CAMCOG, orientation and memory scores and clinical dementia ratings. Total estimated neuronal densities were not significantly changed between patients with post-stroke dementia and post-stroke patients with no dementia groups or ageing controls in any of the three frontal regions. In further morphometric analysis of the dorsolateral prefrontal cortex, we showed that neither diffuse cerebral atrophy nor neocortical thickness explained the selective neuronal volume effects. We also noted that neurofilament protein SMI31 immunoreactivity was increased in post-stroke and vascular dementia compared with post-stroke patients with no dementia and correlated with decreased neuronal volumes in subjects with post-stroke dementia and vascular dementia. Our findings suggest selective regional pyramidal cell atrophy in the dorsolateral prefrontal cortex-rather than neuronal density changes per se-are associated with dementia and executive dysfunction in post-stroke dementia and vascular dementia. The changes in dorsolateral prefrontal cortex pyramidal cells were not associated with neurofibrillary pathology suggesting there is a vascular basis for the observed highly selective neuronal atrophy.

Cellular morphometry in late-life depression: a review of postmortem studies.

The impact of major depression in late life is considerable and set to intensify with a worldwide shift in demographic profile toward an elderly population. Although the precise neurobiological mechanisms are not fully understood, a significant body of clinical, epidemiological, and imaging data have suggested divergent pathophysiological pathways underlie depression in late life, when compared with younger patients. Neuroimaging studies have demonstrated significant increases in white matter hyperintensities in late-life depression in several key areas involved in affective circuitry. Postmortem cellular morphometry studies have played a vital role in the identification of discrete changes in the brain microstructure in depression. This review draws together such postmortem studies, which have utilized tissue from younger/mixed age and late-life depressed patients. These findings have suggested varying neuronal and glial cell pathology in depression between different age cohorts. This age-related disparity may suggest different pathophysiological basis for depression, with vascular factors playing a potentially greater role in late life.

Advancing Brain Research through Surface-Enhanced Raman Spectroscopy (SERS): Current Applications and Future Prospects.

Surface-enhanced Raman spectroscopy (SERS) has recently emerged as a potent analytical technique with significant potential in the field of brain research. This review explores the applications and innovations of SERS in understanding the pathophysiological basis and diagnosis of brain disorders. SERS holds significant advantages over conventional Raman spectroscopy, particularly in terms of sensitivity and stability. The integration of label-free SERS presents promising opportunities for the rapid, reliable, and non-invasive diagnosis of brain-associated diseases, particularly when combined with advanced computational methods such as machine learning. SERS has potential to deepen our understanding of brain diseases, enhancing diagnosis, monitoring, and therapeutic interventions. Such advancements could significantly enhance the accuracy of clinical diagnosis and further our understanding of brain-related processes and diseases. This review assesses the utility of SERS in diagnosing and understanding the pathophysiological basis of brain disorders such as Alzheimer's and Parkinson's diseases, stroke, and brain cancer. Recent technological advances in SERS instrumentation and techniques are discussed, including innovations in nanoparticle design, substrate materials, and imaging technologies. We also explore prospects and emerging trends, offering insights into new technologies, while also addressing various challenges and limitations associated with SERS in brain research.

Uncovering potential diagnostic and pathophysiological roles of α-synuclein and DJ-1 in melanoma.

BACKGROUND: Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma. METHODS: The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein-protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in vitro cellular models and ELISA immunoassays. RESULTS: α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cells induced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability. CONCLUSION: α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.

Hippocampal neuronal atrophy and cognitive function in delayed poststroke and aging-related dementias.

BACKGROUND AND PURPOSE: We have previously shown delayed poststroke dementia in elderly (≥75 years old) stroke survivors is associated with medial temporal lobe atrophy; however, the basis of the structural and functional changes is unknown. METHODS: Using 3-dimensional stereological methods, we quantified hippocampal pyramidal neuronal volumes and densities in a total of 95 postmortem samples from demented and nondemented poststroke survivors within our prospective Cognitive Function after Stroke study and subjects pathologically diagnosed with vascular dementia, Alzheimer disease, and mixed Alzheimer disease and vascular dementia syndrome. RESULTS: Hippocampal CA1 but not CA2 subfield neuron density was affected in poststroke, Alzheimer disease, vascular dementia, and mixed dementia groups relative to control subjects (P<0.05). Neuronal volume was reduced in the poststroke dementia relative to poststroke nondemented group in both CA1 and CA2, although there were no apparent differences in neuronal density. Poststroke nondemented neuronal volumes were similar to control subjects but greater than in all dementias (P<0.05). Neuronal volumes positively correlated with global cognitive function and memory function in both CA1 and CA2 in poststroke subjects (P<0.01). Degrees of neuronal atrophy and loss were similar in the poststroke dementia and vascular dementia groups. However, in the entorhinal cortex layer V, neuronal volumes were only impaired in the mixed and Alzheimer disease groups (P<0.05). CONCLUSIONS: Our results suggest hippocampal neuronal atrophy is an important substrate for dementia in both cerebrovascular and neurodegenerative disease.

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients.

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan-Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the 'MUC4/MMP9/EGFR axis' may play a vital role in glioblastoma diagnostics.

Morphometric analysis of neuronal and glial cell pathology in the caudate nucleus in late-life depression.

OBJECTIVE: To assess glial and neuronal density and neuronal volume in two areas of the caudate nucleus in late-life major depression. DESIGN: A postmortem study using the disector and nucleator methods to estimate neuronal density and volume and glial density of cells from human brain tissue from the anterior portion (dorsolateral and ventromedial aspects) of the caudate nucleus. SETTING: Brain tissues were obtained from the Newcastle Brain Tissue Resource at Newcastle University, UK. PARTICIPANTS: The study group consisted of 13 subjects with late-life major depression and nine comparison subjects of similar age. RESULTS: Evidence of moderate reductions in neuronal density was found in the depressed group in both the dorsolateral and ventromedial areas of the caudate nucleus. There were no significant changes in glial density or neuronal volume in either area nor was there any evidence of differences in depression in early and late-onset subgroups. CONCLUSIONS: Neuroimaging abnormalities in frontal and subcortical areas including ischemic hyperintensities and a reduction in volume and metabolism in the caudate nucleus have been reported in late-life depression, and previous morphometric studies have reported neuronal changes in prefrontal cortical areas. The findings in this study extend these morphometric investigations in late-life depression to the caudate nucleus, suggesting that neuronal abnormalities are present in this subcortical nucleus as well as in these related prefrontal areas.

Cellular pathology within the anterior cingulate cortex of patients with late-life depression: a morphometric study.

Previous imaging and morphometric studies have identified volumetric and cellular abnormalities in prefrontal areas in late-life depression. This study aimed to examine cellular morphology using stereological methodology in the supragenual region of the anterior cingulate cortex in late-life depressed patients compared with age-matched controls. Post-mortem tissue was acquired from nine patients with depression and 11 control patients and analyzed using the optical disector and nucleator methods. No changes were found in glial, non-pyramidal and pyramidal cell density, or in non-pyramidal or pyramidal cell volume within individual layers (2-5) or the supragenual anterior cortex as a whole. This study, therefore, does not provide further evidence for cellular abnormalities in late-life depression.

The immunohistochemical examination of GABAergic interneuron markers in the dorsolateral prefrontal cortex of patients with late-life depression.

BACKGROUND: The "vascular depression" hypothesis has sought to explain differences in etiology between early and late life depression, and has been reinforced by recent imaging and morphometric studies. Gamma-aminobutyric acid (GABA) is thought to play a major role in the neurobiology of depression. However, it is unclear whether there is an effect on GABA neuronal subpopulations in an elderly depressed cohort. This study therefore examined immunohistochemically two calcium-binding proteins, calretinin and parvalbumin, which have been demonstrated to bind to two distinct GABAergic interneuron subpopulations, within the dorsolateral prefrontal cortex (DLPFC) of elderly depressed patients, against age-matched controls. METHODS: Post-mortem tissue was obtained from nine controls and 11 depressed patients for the parvalbumin study and seven controls and 14 depressed patients in the calretinin study, and the mean percentage per area of immunohistochemical staining of the two antibodies was measured in individual layers and across the whole of the DLPFC. RESULTS: The study found a reduction in parvalbumin immunostaining in layer 6 (p = 0.05) of the DLFPC in elderly depressed patients. However, no significant changes were found in parvalbumin or calretinin immunostaining in the any other layer of the DLPFC in elderly depressed patients. CONCLUSION: The study does not suggest any change in GABA interneuron subpopulations, though significant reductions in layer 6 may represent subtle disturbance in GABA parvalbumin-expressing interneuron and glumatatergic pyramidal projection neuron regulation in late-life depression.

A morphometric examination of neuronal and glial cell pathology in the orbitofrontal cortex in late-life depression.

BACKGROUND: The orbitofrontal cortex has been implicated as a key component in depression by several imaging studies. This study aims to examine morphometrically glial cell and neuronal density and neuronal volume in the orbitofrontal cortex of late-life major depression patients. METHODS: Post mortem tissue from 13 patients with major depression and 11 matched controls was obtained and analyzed using the optical disector and nucleator methods. RESULTS: No changes were found in glial cell, pyramidal or non-pyramidal neuron density, or in non-pyramidal and pyramidal neuron volume in the orbitofrontal cortex. CONCLUSIONS: Based on previous findings, this study suggests variability in morphological changes within the orbitofrontal cortex, as well as the prefrontal cortex as a whole.

Examination of glucose transporter-1, transforming growth factor-ß and neuroglobin immunoreactivity in the orbitofrontal cortex in late-life depression.

AIMS: This study immunohistochemically examined the orbitofrontal cortex for three possible candidates in hypoxic/ischemic signaling: the cytokine transforming growth factor-ß, the glucose transporter-1 and the neuron-specific oxygen-binding protein neuroglobin. METHODS: Post-mortem tissue from 20 depressed and 20 non-depressed individuals was obtained and the expression of the three proteins was analyzed using image analysis software. RESULTS: No significant changes were found in transforming growth factor-ß or neuroglobin in the orbitofrontal cortex between depressed and non-depressed individuals. There was, however, a trend towards a reduction in glucose transporter-1 in the depressed group. CONCLUSIONS: This study does not clearly support the hypothesis that hypoxic/ischemic processes are behind the pathological deficits in the frontal-subcortical circuitry associated with depression and therefore does not provide evidence to support the 'vascular depression' hypothesis.

Neuronal densities and vascular pathology in the hippocampal formation in CADASIL.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary cerebral small vessel disease. Previous neuroimaging studies have suggested loss of hippocampal volume is a pathway for cognitive impairment in CADASIL. We used unbiased stereological methods to estimate SMI32-positive and total numbers and volumes of neurons in the hippocampal formation of 12 patients with CADASIL and similar age controls (young controls) and older controls. We found densities of SMI32-positive neurons in the entorhinal cortex, layer V, and cornu ammonis CA2 regions were reduced by 26%-50% in patients with CADASIL compared with young controls (p < 0.01), with a decreasing trend observed in older controls in the order of young controls> older controls ≥ CADASIL. These changes were not explained by any hippocampal infarct or vascular pathology or glial changes. Our results suggest notable loss of subsets of projection neurons within the hippocampal formation that may contribute to certain memory deficits in CADASIL, which is purely a vascular disease. It is likely that the severe arteriopathy leads to white matter damage which disconnects cortico-cortical and subcortical-cortical networks including the hippocampal formation.

Differential regulation of psychostimulant-induced gene expression of brain derived neurotrophic factor and the immediate-early gene Arc in the juvenile and adult brain.

Psychostimulant drugs are widely used in children for the treatment of attention-deficit/hyperactivity disorder. Recent animal studies have suggested that exposure to these agents in early life could be detrimental to brain development. Here, for the first time, the effect of methylphenidate (MPH) and D-amphetamine (AMPH) on the expression of two key genes for neuronal development and plasticity, brain-derived neurotrophic factor (bdnf) and the effector immediate early gene activity-regulated, cytoskeletal-associated protein (Arc), was examined in both juvenile and adult rats. Both MPH [2 mg/kg, intraperitoneal (i.p.)] and AMPH (0.5 mg/kg, i.p.) induced marked decreases of bdnf mRNA in hippocampal and cortical brain regions of juveniles, whereas effects in adults were significantly less (hippocampus) or opposite (frontal cortex). In comparison, Arc mRNA was decreased (hippocampus and parietal cortex), largely unaffected (frontal cortex) or increased (striatum) in juveniles, whereas in adults, Arc mRNA increased in most brain regions. MPH-induced locomotion was also measured, and showed a much smaller increase in juveniles than in adults. In summary, our data show that the effects of MPH and AMPH on expression of the neurodevelopmentally important genes, bdnf and Arc, differ markedly in juvenile and adult rats, with juveniles showing evidence of brain region-specific decreases in both genes. These age-dependent effects on gene expression may be linked with the reported long-term harmful effects of psychostimulants in animal models.