Organization of the macaque monkey inferior parietal lobule based on multimodal receptor architectonics.

The macaque monkey inferior parietal lobe (IPL) is a structurally heterogeneous brain region, although the number of areas it contains and the anatomical/functional relationship of identified subdivisions remains controversial. Neurotransmitter receptor distribution patterns not only reveal the position of the cortical borders, but also segregate areas associated to different functional systems. Thus we carried out a multimodal quantitative analysis of the cyto- and receptor architecture of the macaque IPL to determine the number and extent of distinct areas it encompasses. We identified four areas on the IPL convexity arranged in a caudo-rostral sequence, as well as two areas in the parietal operculum, which we projected onto the Yerkes19 surface. We found rostral areas to have relatively smaller receptor fingerprints than the caudal ones, which is in an agreement with the functional gradient along the caudo-rostral axis described in previous studies. The hierarchical analysis segregated IPL areas into two clusters: the caudal one, contains areas involved in multisensory integration and visual-motor functions, and rostral cluster, encompasses areas active during motor planning and action-related functions. The results of the present study provide novel insights into clarifying the homologies between human and macaque IPL areas. The ensuing 3D map of the macaque IPL, and the receptor fingerprints are made publicly available to the neuroscientific community via the Human Brain Project and BALSA repositories for future cyto- and/or receptor architectonically driven analyses of functional imaging studies in non-human primates.

Seven-tesla quantitative magnetic resonance spectroscopy of glutamate, γ-aminobutyric acid, and glutathione in the posterior cingulate cortex/precuneus in patients with epilepsy.

OBJECTIVE: The posterior cingulate cortex (PCC)/precuneus is a key hub of the default mode network, whose function is known to be altered in epilepsy. Glutamate and γ-aminobutyric acid (GABA) are the main excitatory and inhibitory neurotransmitters in the central nervous system, respectively. Glutathione (GSH) is the most important free radical scavenging compound in the brain. Quantification of these molecules by magnetic resonance spectroscopy (MRS) up to 4 T is limited by overlapping resonances from other molecules. In this study, we used ultra-high-field (7 T) MRS to quantify their concentrations in patients with different epilepsy syndromes. METHODS: Nineteen patients with temporal lobe epilepsy (TLE) and 16 with idiopathic generalized epilepsy (IGE) underwent magnetic resonance imaging scans using a 7-T research scanner. Single-voxel (8 cm3 ) MRS, located in the PCC/precuneus, was acquired via stimulated echo acquisition mode. Their results were compared to 10 healthy volunteers. RESULTS: Mean concentrations of glutamate, GABA, and the glutamate/GABA ratio did not differ between the IGE, TLE, and healthy volunteer groups. The mean ± SD concentration of GSH was 1.9 ± 0.3 mmol·L-1 in healthy controls, 2.0 ± 0.2 mmol·L-1 in patients with TLE, and 2.2 ± 0.4 mmol·L-1 in patients with IGE. One-way analysis of variance with post hoc Tukey-Kramer test revealed a significant difference in the concentration of GSH between patients with IGE and controls (P = .03). Short-term seizure freedom in patients with epilepsy was predicted by an elevated concentration of glutamate in the PCC/precuneus (P = .01). In patients with TLE, the concentration of GABA declined with age (P = .03). SIGNIFICANCE: Patients with IGE have higher concentrations of GSH in the PCC/precuneus than healthy controls. There is no difference in the concentrations of glutamate and GABA, or their ratio, in the PCC/precuneus between patients with IGE, patients with TLE, and healthy controls. Measuring the concentration of glutamate in the PCC/precuneus may assist with predicting drug response.

UTE-SPECIAL for3D localization at an echo time of 4 ms on a clinical 3 T scanner.

Reducing the echo time of magnetic resonance spectroscopy experiments is appealing because it increases the available signal and reduces J-evolution of coupled metabolites. In this manuscript a novel sequence, referred to as Ultrashort echo TimE, SPin ECho, full Intensity Acquired Localized (UTE-SPECIAL), is described which is able to achieve ultrashort echo times (4 ms) on a standard clinical 3 T MR system while recovering the entirety of the available magnetization. UTE-SPECIAL obtains full 3D spatial localization through a 2D adiabatic inversion pulse which is cycled "on" and "off" every other repetition, in combination with a slice-selective excitation pulse. In addition to an ultrashort echo time, UTE-SPECIAL has negligible chemical shift displacement artefact and, because it uses no slice-selective refocusing pulse, has no signal cancellation at the borders for J-coupled metabolites. Spectra with an ultrashort echo time of 4 ms are demonstrated in vivo at 3 T, as well as J-resolved spectra obtained in a phantom and a healthy volunteer.

Brain N-Acetyl Aspartate and associations with cognitive impairment in alcohol dependent patients.

Introduction: Chronic alcohol consumption has been observed to be associated with a range of cognitive impairments that impact on treatment management. In this spectroscopy study, we examined the association of N-Acetyl Aspartate (NAA), a marker of neuronal integrity, and cognitive impairment in alcohol dependent patients.Method: Using in vivo proton magnetic resonance spectroscopy (1H-MRS), we examined brain metabolite levels in 31 alcohol dependent individuals. 1H-MRS from the parietal lobe were analyzed to yield absolute concentrations of NAA. Alcohol history, neurocognitive function including Clock Drawing Test (CDT), Mini Mental State Exam (MMSE), Trial Making Test (TMT) and Balloon Analogue Risk Task (BART) were also assessed. Covariates included concurrent medication, age and recent alcohol consumption.Results: There were statistically significant bivariate associations between NAA and the variables age, CDT and BART (r = -.45, P = 01; r = -.53, P = .01; r = .49, P = .02) respectively) but there were no statistically significant associations with other measures of cognitive function. Controlling for age, concurrent medication and recent alcohol consumption, multiple linear regression revealed a negative association between parietal NAA (Model: F = 6.96, R2 = .66, P = .001) and CDT scores (B = -.35, P = .03), a positive association with BART scores (B = .47, P = .02).Conclusion: These results demonstrate that in alcohol dependent patients lower NAA/Cr is associated with reduced cognitive functioning and increased risk-taking.

Voxel-based quantitative susceptibility mapping in Parkinson's disease with mild cognitive impairment.

OBJECTIVE: Brain iron accumulation has been proposed as one of the pathomechanisms in Parkinson's disease (PD). This study aimed to examine the whole-brain pattern of iron accumulation associated with cognitive impairment in patients with PD using voxel-based quantitative susceptibility mapping analysis. METHODS: We enrolled 24 patients with PD and mild cognitive impairment, 22 patients with PD and normal cognition, and 20 age-matched healthy controls in this cross-sectional study. All participants underwent global cognitive and physical assessments and brain MRI. Using a combined method of voxel-based morphometry and quantitative susceptibility mapping, we compared the voxel-wise magnetic susceptibility of the whole brain between the groups and analyzed its correlation with the cognitive and behavioral data. RESULTS: The PD and mild cognitive impairment group had lower Montreal Cognitive Assessment (MoCA) score than the PD and normal cognition and healthy control groups. There were no gray matter volumetric differences between the groups. In contrast, the voxel-based quantitative susceptibility mapping analysis showed that the PD and mild cognitive impairment group had significantly higher quantitative susceptibility mapping values in the cuneus, precuneus, caudate head, fusiform gyrus, and orbitofrontal cortex than did the PD and normal cognition group. These quantitative susceptibility mapping values were negatively correlated with the MoCA scores in the PD patients (cuneus: r = -0.510, P < .001; caudate head: r = -0.458, P = 0.002). CONCLUSIONS: This study suggests that cognitive impairment in PD is associated with cerebral iron burden and highlights the potential of quantitative susceptibility mapping as an auxiliary biomarker for early evaluation of cognitive decline in patients with PD. © 2019 International Parkinson and Movement Disorder Society.

Rostro-caudal Connectional Heterogeneity of the Dorsal Part of the Macaque Prefrontal Area 46.

Based on neural tracer injections we found evidence for 3 connectionally distinct sectors of the dorsal part of the macaque prefrontal area 46 (46d), located at different rostro-caudal levels. Specifically, a rostral sector displayed an almost exclusive and extensive intraprefrontal connectivity and extraprefrontal connections limited to superior temporal areas and the caudal cingulate area 31. Conversely, both a middle and a caudal sector were characterized by robust, topographically organized connections with parietal and frontal sensorimotor areas. Both these sectors shared connections with caudal and medial superior parietal areas (V6A and PGm) where visuospatial information is combined with gaze- and arm-related signals for visuomotor control of arm reaching and/or eye movements. However, the caudal sector was preferentially connected to parietal and frontal oculomotor areas, whereas the middle one was preferentially connected to skeletomotor, mostly arm-related, parietal and premotor areas. The present study provides evidence for a rostro-caudal organization of area 46d similar to that described for the ventrolateral prefrontal cortex, in which more caudal areas are relatively more directly involved in controlling different aspects of motor behavior and more rostral areas are most likely involved in higher order, possibly more abstract, cognitive functions.

Partitioning of the primate intraparietal cortex based on connectivity pattern and immunohistochemistry for Cat-301 and SMI-32.

We propose a partitioning of the primate intraparietal sulcus (IPS) using immunoarchitectural and connectivity criteria. We studied the immunoarchitecture of the IPS areas in the capuchin monkey using Cat-301 and SMI-32 immunohistochemistry. In addition, we investigated the IPS projections to areas V4, TEO, PO, and MT using retrograde tracer injections in nine hemispheres of seven animals. The pattern and distribution of Cat-301 and SMI-32 immunostaining revealed multiple areas in the IPS, in the adjoining PO cleft and in the annectant gyrus, with differential staining patterns found for areas V3d, DM, V3A, DI, PO, POd, CIP-1, CIP-2, VIPa, VIPp, LIPva, LIPvp, LIPda, LIPdp, PIPv, PIPd, MIPv, MIPd, AIPda, AIPdp, and AIPv. Areas V4, TEO, PO, MT, which belong to different cortical streams of visual information processing, receive projections from at least twenty different areas within the IPS and adjoining regions. In six animals, we analyzed the distribution of retrogradely labeled cells in tangential sections of flat-mount IPS preparations. The lateral bank of the IPS projects to regions belonging both to the ventral (V4 and TEO) and dorsal (PO and MT) streams. The region on the floor of the IPS (i.e., VIP) projects predominantly to dorsal stream areas. Finally, the medial bank of the IPS (i.e., MIP) projects solely to the dorsalmedial stream (PO). Therefore, our data suggest that ventral and dorsal streams remain segregated within the IPS, and that its projections to the dorsal stream can be further segregated based on those targeting the dorsolateral versus the dorsomedial subdivisions.

Increased Hyaluronan and TSG-6 in Association with Neuropathologic Changes of Alzheimer's Disease.

Little is known about the extracellular matrix (ECM) during progression of AD pathology. Brain ECM is abundant in hyaluronan (HA), a non-sulfated glycosaminoglycan synthesized by HA synthases (HAS) 1-3 in a high molecular weight (MW) form that is degraded into lower MW fragments. We hypothesized that pathologic severity of AD is associated with increases in HA and HA-associated ECM molecules. To test this hypothesis, we assessed HA accumulation and size; HA synthases (HAS) 1-3; and the HA-stabilizing hyaladherin, TSG-6 in parietal cortex samples from autopsied research subjects with not AD (CERAD = 0, Braak = 0- II, n = 12-21), intermediate AD (CERAD = 2, Braak = III-IV, n = 13-18), and high AD (CERAD = 3, Braak = V-VI, n = 32-40) neuropathologic change. By histochemistry, HA was associated with deposits of amyloid and tau, and was also found diffusely in brain parenchyma, with overall HA quantity (measured by ELSA) significantly greater in brains with high AD neuropathology. Mean HA MW was similar among the samples. HAS2 and TSG-6 mRNA expression, and TSG-6 protein levels were significantly increased in high AD and both molecules were present in vasculature, NeuN-positive neurons, and Iba1-positive microglia. These results did not change when accounting for gender, advanced age (≥ 90 years versus <90 years), or the clinical diagnosis of dementia. Collectively, our results indicate a positive correlation between HA accumulation and AD neuropathology, and suggest a possible role for HA synthesis and metabolism in AD progression.

Correlation Between Extravasation and Alterations of Cerebrovascular Laminin and ß-Dystroglycan Immunoreactivity Following Cryogenic Lesions in Rats.

The blood-brain barrier becomes "leaky" following lesions. Former studies revealed that following lesions the immunoreactivity of cerebrovascular laminin becomes detectable whereas that of ß-dystroglycan disappears. These alterations may be indicators of glio-vascular decoupling that may result in the impairment of the blood-brain-barrier. This study investigates correlation between the post-lesion extravasation and the above-mentioned immunohistochemical alterations. Following cryogenic lesions, the survival periods lasted 5, 10, 30 minutes, 1 or 12 hours, or 1 day. Some brains were fixed immediately post-lesion. Immunofluorescent reactions were performed in floating sections. The extravasation was detected with immunostaining for plasma fibronectin and rat immunoglobulins. When the survival period was 30 minutes or longer, the area of extravasation corresponded to the area of altered laminin and ß-dystroglycan immunoreactivities. Following immediate fixation some laminin immunoreactivity was already detected. The extravasation seemed to precede this early appearance of laminin immunoreactivity. The ß-dystroglycan immunoreactivity disappeared later. When the extravasation spread into the corpus callosum, vascular laminin immunoreactivity appeared but the ß-dystroglycan immunoreactivity persisted. It seems that extravasation separates the glial and vascular basal laminae, which results in the appearance of laminin immunoreactivity. The disappearance of ß-dystroglycan immunoreactivity is neither a condition nor an inevitable consequence of the 2 other phenomena.

Evaluation of structural connectivity changes in betel-quid chewers using generalized q-sampling MRI.

RATIONALE: Betel quid (BQ) is a common addictive substance in many Asian countries. However, few studies have focused on the influences of BQ on the brain. It remains unclear how BQ can affect structural brain abnormalities in BQ chewers. OBJECTIVES: We aimed to use generalized q-sampling imaging (GQI) to evaluate the impact of the neurological structure of white matter caused by BQ. METHODS: The study population comprised 16 BQ chewers, 15 tobacco and alcohol controls, and 17 healthy controls. We used GQI with voxel-based statistical analysis (VBA) to evaluate structural brain and connectivity abnormalities in the BQ chewers compared to the tobacco and alcohol controls and the healthy controls. Graph theoretical analysis (GTA) and network-based statistical (NBS) analysis were also performed to identify the structural network differences among the three groups. RESULTS: Using GQI, we found increases in diffusion anisotropy in the right anterior cingulate cortex (ACC), the midbrain, the bilateral angular gyrus, the right superior temporal gyrus (rSTG), the bilateral superior occipital gyrus, the left middle occipital gyrus, the bilateral superior and inferior parietal lobule, and the bilateral postcentral and precentral gyrus in the BQ chewers when compared to the tobacco and alcohol controls and the healthy controls. In GTA and NBS analyses, we found more connections in connectivity among the BQ chewers, particularly in the bilateral anterior cingulum. CONCLUSIONS: Our results provided further evidence indicating that BQ chewing may lead to brain structure and connectivity changes in BQ chewers.

In vivo functional neurochemistry of human cortical cholinergic function during visuospatial attention.

Cortical acetylcholine is involved in key cognitive processes such as visuospatial attention. Dysfunction in the cholinergic system has been described in a number of neuropsychiatric disorders. Levels of brain acetylcholine can be pharmacologically manipulated, but it is not possible to directly measure it in vivo in humans. However, key parts of its biochemical cascade in neural tissue, such as choline, can be measured using magnetic resonance spectroscopy (MRS). There is evidence that levels of choline may be an indirect but proportional measure of acetylcholine availability in brain tissue. In this study, we measured relative choline levels in the parietal cortex using functional (event-related) MRS (fMRS) during performance of a visuospatial attention task, with a modelling approach verified using simulated data. We describe a task-driven interaction effect on choline concentration, specifically driven by contralateral attention shifts. Our results suggest that choline MRS has the potential to serve as a proxy of brain acetylcholine function in humans.

Immunohistochemical study of Metallothionein in patients with temporal lobe epilepsy.

Epilepsy is characterized by spontaneous recurrent seizures and temporal lobe epilepsy (TLE) is the most common serious neurological example of acquired and frequent epilepsy. Oxidative stress is recognized as playing a contributing role in several neurological disorders, and most recently have been implicated in acquired epilepsies. The MTs occur in several brain regions and may serve as neuroprotective proteins against reactive oxygen species causing oxidative damage and stress. The main aim of this work was to describe the immunohistochemical localization of MT in the specimens derived from the patients affected by TLE. Histopathological examination showed NeuN, GFAP and MT immunopositive cells that were analyzed for determinate in hippocampal and parietal cortex samples. An increase in the reactive gliosis associated with increased MT expression was observed in patients with TLE.

Case Report: Next generation sequencing identifies a NAB2-STAT6 fusion in Glioblastoma.

BACKGROUND: Molecular profiling has uncovered genetic subtypes of glioblastoma (GBM), including tumors with IDH1 mutations that confer increase survival and improved response to standard-of-care therapies.  By mapping the genetic landscape of brain tumors in routine clinical practice, we enable rapid identification of targetable genetic alterations. CASE PRESENTATION: A 29-year-old male presented with new onset seizures prompting neuroimaging studies, which revealed an enhancing 5 cm intra-axial lesion involving the right parietal lobe. He underwent a subtotal resection and pathologic examination revealed glioblastoma with mitoses, microvascular proliferation and necrosis. Immunohistochemical (IHC) analysis showed diffuse expression of GFAP, OLIG2 and SOX2 consistent with a tumor of glial lineage. Tumor cells were positive for IDH1(R132H) and negative for ATRX. Clinical targeted-exome sequencing (DFBWCC Oncopanel) identified multiple functional variants including IDH1 (p.R132H), TP53 (p.Y126_splice), ATRX (p.R1302fs*), HNF1A (p.R263H) and NF1 (p.H2592del) variants and a NAB2-STAT6 gene fusion event involving NAB2 exon 3 and STAT6 exon 18. Array comparative genomic hybridization (aCGH) further revealed a focal amplification of NAB2 and STAT6.  IHC analysis demonstrated strong heterogenous STAT6 nuclear localization (in 20 % of tumor cells). CONCLUSIONS: While NAB2:STAT6 fusions are common in solitary fibrous tumors (SFT), we report this event for the first time in a newly diagnosed, secondary-type GBM or any other non-SFT. Our study further highlights the value of comprehensive genomic analyses in identifying patient-specific targetable mutations and rearrangements.

Malignant melanoma mimicking giant cell variant of glioblastoma multiforme: a case report and review of literature.

We present a case of metastatic malignant melanoma in a patient initially diagnosed with glioblastoma multiforme, giant cell variant. A forty year old female presented to our institution for a re-resection of a recurrent right parietal lobe mass, presumed to be recurrent glioblastoma multiforme. PET scan during preoperative evaluation revealed a 3 cm left lower lobe lung mass. Metastatic glioblastoma to lung was considered in the differential diagnosis. Resection of the brain mass revealed a highly pleomorphic giant and spindle cell lesion with an immunophenotype strongly supportive of melanoma. Immunostains for melanocytic markers were subsequently performed on the lung biopsy specimen, and demonstrated diffuse staining of the atypical cells, supporting the diagnosis of malignant melanoma in the lung. This case demonstrates the importance of considering melanoma in the differential in any tumor with high grade features.

Carbon-11 radiolabelling of organosulfur compounds: (11) C synthesis of the progesterone receptor agonist tanaproget.

Herein a new (11) C radiolabelling strategy for the fast and efficient synthesis of thioureas and related derivatives using the novel synthon, (11) CS2 , is reported. This approach has enabled the facile labelling of a potent progesterone receptor (PR) agonist, [(11) C]Tanaproget, by the intramolecular reaction of the acyclic aminohydroxyl precursor with (11) CS2 , which has potential applications as a positron emission tomography radioligand for cancer imaging.

Expression of ZNF804A in human brain and alterations in schizophrenia, bipolar disorder, and major depressive disorder: a novel transcript fetally regulated by the psychosis risk variant rs1344706.

IMPORTANCE: The single-nucleotide polymorphism rs1344706 in the zinc finger protein 804A gene (ZNF804A) shows genome-wide association with schizophrenia and bipolar disorder. Little is known regarding the expression of ZNF804A and the functionality of rs1344706. OBJECTIVES: To characterize ZNF804A expression in human brain and to investigate how it changes across the life span and how it is affected by rs1344706, schizophrenia, bipolar disorder, and major depressive disorder. DESIGN, SETTING, AND PARTICIPANTS: Molecular and immunochemical methods were used to study ZNF804A messenger RNA (mRNA) and ZNF804A protein, respectively. ZNF804A transcripts were investigated using next-generation sequencing and polymerase chain reaction-based methods, and ZNF804A protein was investigated using Western blots and immunohistochemistry. Samples of dorsolateral prefrontal cortex and inferior parietal lobe tissue were interrogated from 697 participants between 14 weeks' gestational age and age 85 years, including patients with schizophrenia, bipolar disorder, or major depressive disorder. MAIN OUTCOMES AND MEASURES: Quantitative measurements of ZNF804A mRNA and immunoreactivity, and the effect of diagnosis and rs1344706 genotype. RESULTS: ZNF804A was expressed across the life span, with highest expression prenatally. An abundant and developmentally regulated truncated ZNF804A transcript was identified, missing exons 1 and 2 (ZNF804AE3E4) and predicted to encode a protein lacking the zinc finger domain. rs1344706 influenced expression of ZNF804AE3E4 mRNA in fetal brain (P = .02). In contrast, full-length ZNF804A showed no association with genotype (P > .05). ZNF804AE3E4 mRNA expression was decreased in patients with schizophrenia (P = .006) and increased in those with major depressive disorder (P < .001), and there was a genotype-by-diagnosis interaction in bipolar disorder (P = .002). ZNF804A immunoreactivity was detected in fetal and adult human cerebral cortex. It was localized primarily to pyramidal neurons, with cytoplasmic as well as dendritic and nuclear staining. No differences in ZNF804A-immunoreactive neurons were seen in schizophrenia or related to rs1344706 (P > .05). CONCLUSIONS AND RELEVANCE: rs1344706 influences the expression of ZNF804AE3E4, a novel splice variant. The effect is limited to fetal brain and to this isoform. It may be part of the mechanism by which allelic variation in ZNF804A affects risk of psychosis. ZNF804A is translated in human brain, where its functions may extend beyond its predicted role as a transcription factor.

Measuring the longitudinal relaxation time of GABA in vivo at 3 Tesla.

PURPOSE: To measure the in vivo longitudinal relaxation time T1 of GABA at 3 Tesla (T). MATERIALS AND METHODS: J-difference edited single-voxel MR spectroscopy was used to isolate γ-aminobutyric acid (GABA) signals. An increased echo time (80 ms) acquisition was used, accommodating the longer, more selective editing pulses required for symmetric editing-based suppression of co-edited macromolecular signal. Acquiring edited GABA measurements at a range of relaxation times in 10 healthy participants, a saturation-recovery equation was used to model the integrated data. RESULTS: The longitudinal relaxation time of GABA was measured as T(1,GABA) = 1.31 ± 0.16 s. CONCLUSION: The method described has been successfully applied to measure the T1 of GABA in vivo at 3T.

Neuroprotective effect of erythropoietin on nandrolone decanoate-induced brain injury in rats.

Anabolic-androgenic steroids (AAS) are used in the medical treatment of many disorders. Erythropoietin (EPO) is a hematopoietic cytokine that has anti-apoptotic, anti-oxidative, and anti-inflammatory effects. The aim of the present study is to investigate the neuroprotective effects of EPO in the hippocampus, parietal cortex and prefrontal cortex, in brain damage due to nandrolone decanoate. 35 Wistar male rats were randomly divided into: (1) control group, (2) sham group, (3) nandrolone decanoate group (ND, intramuscular, 10 mg/(kg week), 8 weeks), (4) ND+low dose EPO treated group (ND+L-EPO) and (5) ND+high dose EPO treated group (ND+H-EPO). EPO was administrated by intraperitoneal injection at a dose of 100 U/(kg day) for L-EPO treatment and at a dose of 500 U/(kg day) for H-EPO treatment during 8 weeks. The number of neurons of CA1, CA2, CA3 and dentate gyrus of hippocampus, parietal cortex and prefrontal cortex were significantly less in the ND group compared with the control group. Treatment with H-EPO significantly preserved the number of neurons in hippocampus when compared with ND administrated. Besides, H-EPO treatment decreased the number of TUNEL-positive and active caspase-3 positive cells and MDA levels and increased GPx levels when compared to ND group. In conclusion, abuse of AAS causes reduction in the number of neurons in hippocampus, parietal cortex and prefrontal cortex regions and increases oxidative damage and therefore H-EPO may be useful as a neuroprotective agent in brain injury.

Regional differences in cortical benzodiazepine receptors of Alzheimer, vascular, and mixed dementia patients.

OBJECTIVE: We examined regional benzodiazepine receptors (rBZR) using single photon emission CT (SPECT) in patients with Alzheimer disease (AD), vascular dementia (VaD), and mixed AD/VaD dementia (MD) and compared the changes in the availability of rBZR with those of regional cerebral blood flow (rCBF). METHODS: A total of 7 patients with AD, 6 with MD, and 9 with VaD underwent SPECT studies with N-isopropyl-p-[(123)I] iodoamphetamine and (123)I-iomazenil to measure rCBF and rBZR. The ratios of rCBF and rBZR uptake in brain subregions to the average global activity were compared among these diseases. In addition, we acquired z-score maps using 3-dimensional stereotactic surface projections of SPECT data. RESULTS: Compared with AD, VaD and MD showed rCBF and rBZR reduction predominantly in the frontal lobe, but rBZR images revealed more extensive and severe defects than rCBF images. In contrast, AD showed rCBF and rBZR reduction predominantly in the parietotemporal lobe compared with VaD and MD, but rCBF images revealed more extensive defects than rBZR images. CONCLUSION: rCBF imaging can detect parietotemporal abnormalities in AD, while rBZR imaging may enable the demonstration of underlying pathophysiological differences in the frontal lobe between VaD, MD and AD, reflecting neuronal integrity in the cerebral cortex.

AD synapses contain abundant Aß monomer and multiple soluble oligomers, including a 56-kDa assembly.

Much evidence indicates that soluble amyloid beta (Aß) oligomers are key mediators of early cognitive loss, but the localization and key peptide species remain unclear. We have used flow cytometry analysis to demonstrate that surviving Alzheimer's disease (AD) synapses accumulate both Aß and phosphorylated tau (p-tau). The present experiments use peptide-specific X-map assays and Western blot analyses to identify the Aß peptide species in synaptosome-enriched samples from normal human subjects, neurologic controls, and AD cases. Aß40 peptide levels did not vary, but both Aß42 and Aß oligomers were increased in soluble AD extracts, with oligomer levels 20-fold higher in aqueous compared with detergent extracts. In Western blot analysis, a ladder of sodium dodecyl sulfate (SDS)-stable oligomers was observed in AD cases, varying in size from monomer, the major peptide observed, to larger assemblies up to about 200 kDa and larger. Multiple oligomers, including monomer, small oligomers, a 56-kDa assembly, and amyloid precursor protein (APP) were correlated with the Aß level measured in flow cytometry-purified synaptosomes. These results suggest that multiple amyloid precursor protein processing pathways are active in AD synapses and multiple soluble oligomeric assemblies may contribute to synaptic dysfunction.