Working memory processing of traumatic material in women with posttraumatic stress disorder

Background

Posttraumatic stress disorder (PTSD) is associated with medial frontal and amygdala functional alterations during the processing of traumatic material and frontoparietal dysfunctions during working memory tasks. This functional magnetic resonance imaging (fMRI) study investigated the effects of trauma-related words processing on working memory in patients with PTSD.

Methods

We obtained fMRI scans during a 3-back task and an identity task on both neutral and trauma-related words in women with PTSD who had been sexually abused and in healthy, nonexposed pair-matched controls.

Results

Seventeen women with PTSD and 17 controls participated in the study. We found no behavioural working memory deficit for the PTSD group. In both tasks, deactivation of posterior parietal midline regions was more pronounced in patients than controls. Additionally, patients with PTSD recruited the left dorsolateral frontal sites to a greater extent during the processing of trauma-related material than neutral material.

Limitations

This study included only women and did not include a trauma-exposed non-PTSD control group; the results may, therefore, have been influenced by sex or by effects specific to trauma exposure.

Conclusion

Our results broadly confirm frontal and parietal functional variations in women with PTSD and suggest a compensatory nature of these variations with regard to the retreival of traumatic memories and global attentional deficits, respectively, during cognitively challenging tasks.     

Alterations in White Matter Evident Before the Onset of Psychosis

Background

Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness.

Methods

Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis.

Results

At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition.

Conclusions

People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.     

Nightmares in Patients With Psychosis: The Relation With Sleep,Psychotic, Affective,and Cognitive Symptoms

Objective:

To examine the prevalence of nightmares in people with psychosis and to describe the link between nightmares and sleep quality, psychotic, affective, and cognitive symptoms.

Methods:

Forty participants with psychotic symptoms completed an assessment of nightmares, sleep quality, positive symptoms of psychosis, affect, posttraumatic stress, social functioning, and working memory.

Results:

Among the patients, 55% reported weekly distressing nightmares. Experience of more frequent nightmares was related to poorer sleep quality and sleep efficiency. More distressing nightmares were positively associated with greater delusional severity, depression, anxiety, stress, and difficulties with working memory.

Conclusions:

Nightmares might be common in those with psychosis and are associated with increased day- and nighttime impairment. Future research should investigate treatments for nightmares, for people presenting with psychotic symptoms.     

Knockdown of phospholipase C-β1 in the medial prefrontal cortex of male mice impairs working memory among multiple schizophrenia endophenotypes

Background

Decreased expression of phospholipase C-β1 (PLC-β1) has been observed in the brains of patients with schizophrenia, but, to our knowledge, no studies have shown a possible association between this altered PLC-β1 expression and the pathogenesis of schizophrenia. Although PLC-β1-null (PLC-β1^−/−) mice exhibit multiple endophenotypes of schizophrenia, it remains unclear how regional decreases in PLC-β1 expression in the brain contribute to specific behavioural defects.

Methods

We selectively knocked down PLC-β1 in the medial prefrontal cortex (mPFC) using a small hairpin RNA strategy in mice.

Results

Silencing PLC-β1 in the mPFC resulted in working memory deficits, as assayed using the delayed non-match-to-sample T-maze task. Notably, however, other schizophrenia- related behaviours observed in PLC-β1^−/− mice, including phenotypes related to locomotor activity, sociability and sensorimotor gating, were normal in PLC-β1 knockdown mice.

Limitations

Phenotypes of PLC-β1 knockdown mice, such as locomotion, anxiety and sensorimotor gating, have already been published in our previous studies. Further, the neural mechanisms underlying the working memory deficit in mice may be different from those in human schizophrenia.

Conclusion

These results indicate that PLC-β1 signalling in the mPFC is required for working memory. Importantly, these results support the notion that the decrease in PLC-β1 expression in the brains of patients with schizophrenia is a pathogenically relevant molecular marker of the disorder.     

Changes in Effective Connectivity According to Working Memory Load: An fMRI Study of Face and Location Working Memory Tasks

Objective

The functional strategic mechanisms in the brain during performing visuospatial working memory tasks, especially tasks with heavy load, are controversial. We conducted the functional magnetic resonance imaging (fMRI) while sixteen subjects were performing face- and location-matching n-back tasks to examine causal relations within the frontoparietal networks.

Methods

We applied a sophisticated method, the structural equation modeling (SEM), to the fMRI data. The imaging data were analyzed by extracting the task-related eigenseries using the principal component analysis (PCA) and then by applying a form of data-driven model called the automated search method.

Results

The SEM analyses revealed a functional shift of network connectivity from the right to the left hemisphere with increasing load in the face-matching n-back tasks while the location-matching tasks required bilateral activation. In the locating matching n-back tasks, a pattern of parallel processing was observed in the left phonological loop and the right inferior parietal regions. Furthermore, object working memory-related activities in the left hemisphere reliably contributed to performance of both the face- and location-matching 2-back tasks.

Conclusion

Our results are consistent with previous reports in terms of demonstrating parallel and distributed information processing during performing working memory tasks with heavy loads. Our results additionally suggest a dynamic shift between the fast imagery circuit (right hemisphere) and the stable verbal circuit (left hemisphere), depending on task load.     

Elevated Levels of α-Synuclein Oligomer in the Cerebrospinal Fluid of Drug-Na?ve Patients with Parkinson's Disease

Background and Purpose

The detection of α-synuclein in the body fluids of patients with synucleinopathy has yielded promising but inconclusive results, in part because of conformational changes of α-synuclein in response to environmental conditions. The aim of this study was to determine the feasibility of using α-synuclein as a biological marker for Parkinson''s disease (PD).

Methods

Twenty-three drug-naïve patients with PD (age 62.4±12.7 years, mean±SD; 11 males) and 29 age- and sex-matched neurologic control subjects (age 60.1±16.2 years; 16 males) were recruited. The levels of oligomeric and total α-synuclein in the cerebrospinal fluid (CSF) and plasma were measured using two simultaneous enzyme-linked immunosorbent assays.

Results

The level of α-synuclein oligomer in the CSF of PD patients was significantly higher in PD patients than in neurological controls, but other findings (plasma α-synuclein oligomer and total α-synuclein in CSF and plasma) did not differ significantly between the two groups. When the control subjects were divided into a symptomatic control group (11 patients who complained of parkinsonian symptoms and were diagnosed with hydrocephalus and drug-induced or vascular parkinsonism) and a neurologic control group (10 normal subjects and 8 patients with diabetic ophthalmoplegia), the level of α-synuclein oligomer in the CSF was still significantly higher in PD patients than in both of the control subgroups.

Conclusions

These findings provide further evidence for a pathogenic role of the α-synuclein oligomer and suggest that CSF levels of α-synuclein oligomer can be a reliable marker for PD.     

Increased glycogen synthase kinase-3β mRNA level in the hippocampus of patients with major depression: a study using the stanley neuropathology consortium integrative database

Objective

Glycogen synthase kinase-3β (GSK-3β) has become recognized as a broadly influential enzyme affecting diverse range of biological functions, including gene expression, cellular architecture, and apoptosis. The results of previous studies suggest that GSK-3β activity may be increased in the brain of patients with major depressive disorders (MDD). A recent animal study reported increased GSK-3β messenger ribonucleic acid (mRNA) level in the hippocampus of those with depression. However, few studies have investigated GSK-3β activity in the brain of patients with MDD.

Methods

In order to test whether patients with MDD have an increase in GSK-3β activity in the brain compared to normal controls, we explored GSK-3β expression level in all brain regions by using the Stanley Neuropathology Consortium Integrative Database (SNCID), which is a web-based method of integrating the Stanley Medical Research Institute data sets.

Results

The level of GSK-3β mRNA expression in the hippocampus was significantly increased in the MDD group (n=8) compared with the control group (n=12, p<0.05). Spearman''s test also reveals that GSK-3β mRNA expression levels were significantly correlated with nitric oxide synthase 1 (NOS1)(ρ=0.70, p<0.0001) and stathmin-like 3 (STMN3)(ρ=0.70, p<0.0001) in the hippocampus.

Conclusion

Our results correspond with the results of previous animal studies that reported increased GSK-3β activity in the hippocampus of those with depression. Our findings also suggest that oxidative stress-induced neuronal cell death and abnormal synaptic plasticity in the hippocampus may play important roles in the pathophysiology of major depression.     

Association of the PPAR-γ Gene with Altered Glucose Levels and Psychosis Profile in Schizophrenia Patients Exposed to Antipsychotics

Objective

Metabolic abnormalities, e.g., diabetes, are common among schizophrenia patients. Peroxisome proliferator activated receptor-γ (PPAR-γ) regulates glucose/lipid metabolisms, and schizophrenia like syndrome may be induced by actions involving retinoid X receptor-α/PPAR-γ heterodimers. We examined a possible role of the PPAR-γ gene in metabolic traits and psychosis profile in schizophrenia patients exposed to antipsychotics.

Methods

Single nucleotide polymorphisms (SNPs) of the PPAR-γ gene and a serial of metabolic traits were determined in 394 schizophrenia patients, among which 372 were rated with Positive and Negative Syndrome Scale (PANSS).

Results

SNP-10, -12, -18, -19, -20 and -26 were associated with glycated hemoglobin (HbA1c) whereas SNP-18, -19, -20 and -26 were associated with fasting plasma glucose (FPG). While SNP-23 was associated with triglycerides, no associations were identified between the other SNPs and lipids. Further haplotype analysis demonstrated an association between the PPAR-γ gene and psychosis profile.

Conclusion

Our study suggests a role of the PPAR-γ gene in altered glucose levels and psychosis profile in schizophrenia patients exposed to antipsychotics. Although the Pro12Ala at exon B has been concerned an essential variant in the development of obesity, the lack of association of the variant with metabolic traits in this study should not be treated as impossibility or a proof of error because other factors, e.g., genes regulated by PPAR-γ, may have complicated the development of metabolic abnormalities. Whether the PPAR-γ gene modifies the risk of metabolic abnormalities or psychosis, or causes metabolic abnormalities that lead to psychosis, remains to be examined.     

Persistent Infection by HSV-1 Is Associated With Changes in Functional Architecture of iPSC-Derived Neurons and Brain Activation Patterns Underlying Working Memory Performance

Background:

Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.

Methods:

Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.

Results:

HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 × 10^{− 4}; 2-back, P = 1.39 × 10^{− 5}) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.

Conclusions:

The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.Key words: memory, induced pluripotent stem cells, herpes simplex virus type 1, fMRI, herpes     

Voxel-wise meta-analysis of fMRI studies in patients at clinical high risk for psychosis

Background

Reliable neurofunctional markers of increased vulnerability to psychosis are needed to improve the predictive value of psychosis risk syndrome and inform preventive interventions.

Methods

I performed a signed differential mapping (SDM) voxel-wise meta-analysis of functional magnetic resonance imaging (fMRI) studies of patients at clinical high risk for psychosis.

Results

Ten studies were included in the analysis. Compared with controls, high-risk patients showed reduced neural activation in the left inferior frontal gyrus (Brodmann area [BA] 9) and in a cluster spanning the bilateral medial frontal gyrus (BA 8,6), bilateral superior frontal gyrus (BA 8,6) and the left anterior cingulate (BA 32). There was no publication bias. Heterogeneity across studies was low. Sensitivity analysis confirmed the robustness of the findings.

Limitations

The cross-sectional nature of the included studies prevented the comparison of high-risk patients who later experienced a psychotic episode with those who did not. Other caveats are reflected in methodologic heterogeneity across tasks employed by different individual imaging studies.

Conclusion

Reduced neurofunctional activation in prefrontal regions may represent a neurophysiologic correlate of increased vulnerability to psychosis.     

Interaction between Neuronal Depolarization and MK-801 in SH-SY5Y Cells and the Rat Cortex

Objective

The interaction between MK-801, a model of psychosis and KCl-induced depolarization or electroconvulsive shock (ECS), a therapeutic model of electroconvulsive therapy (ECT), was investigated in SH-SY5Y cells and the rat frontal cortex.

Methods

SH-SY5Y cells were pretreated with 1 µM MK-801 for 15 min, followed by cotreatment with 100 mM KCl for 5 min. MK-801 was reintroduced after the KCl was washed out, and the samples were incubated before harvesting. For the experiments in rats, male Sprague-Dawley rats were treated with MK-801 followed by ECS. Immunoblot analyses of glycogen synthase kinase 3β (GSK3β) (Ser9), AKT (Ser473) and extracellular legulated kinase (ERK)1/2 in SH-SY5Y cells and the rat frontal cortex were performed.

Results

KCl-induced neuronal depolarization resulted in the transient dephosphorylation of AKT (Ser473) and GSK3β (Ser9), followed by increased phosphorylation of the enzymes in SH-SY5Y cells. Cotreatment with MK-801 and KCl inhibited the initial dephosphorylation of AKT and GSK3β produced by KCl-induced neuronal depolarization. Similarly, ECS resulted in the transient dephosphorylation of AKT (Ser473) and GSK3β (Ser9), whereas cotreatment with MK-801 inhibited the initial dephosphorylation of AKT (Ser473) and GSK3β (Ser9) produced by ECS in the rat frontal cortex. No significant interaction was observed between MK-801 and KCl in the dephosphorylation of ERK1/2.

Conclusion

These results suggest that an antagonistic interplay between MK-801 and neuronal depolarization by KCl or ECS is involved the regulation of AKT (Ser473) and GSK3β (Ser9) phosphorylation.     

Pathways to First-Episode Care for Psychosis in African-, Caribbean-, and European-Origin Groups in Ontario

Objective:

To compare the pathways to care and duration of untreated psychosis (DUP) for people of Black-African, Black-Caribbean, or White-European origin with first-episode psychosis (FEP).

Methods:

We recruited a sample of 171 patients with FEP of Black-African, Black-Caribbean, and White-European origin from hospital- and community-based early intervention services (EIS) in the cities of Toronto and Hamilton. We compared the 3 groups on DUP and key indicators of the pathway to care.

Results:

We observed differences in pathways to care across the 3 groups. Black-Caribbean participants had an increased odds of referral from an inpatient unit to EIS (OR 3.33; 95% CI 1.46 to 7.60) and a decreased odds of general practitioner involvement on the pathway to care (OR 0.17; 95% CI 0.07 to 0.46), as well as fewer total contacts (exp[β] 0.77; 95% CI 0.60 to 0.99) when compared with White-European participants. Black-African participants had an increased odds of contact with the emergency department at first contact (OR 3.78; 95% CI 1.31 to 10.92). The differences in the DUP between groups were not statistically significant.

Conclusions:

Our findings suggest that there are significant differences in the pathways to EIS for psychosis for people of African and Caribbean origin in our Canadian context. It is essential to gain a comprehensive understanding of the pathways that different population groups take to mental health services, and the reasons behind observed differences, to inform the development of equitable services, targeting patients in the critical early stages of psychotic disorder.     

Clinical significance of detection of antibodies to fetal and adult acetylcholine receptors in myasthenia gravis

Objective To evaluate the frequency, distribution and clinical significance of the antibodies to the fetal and/or adult acetylcholine receptor (AChR) in patients with myasthenia gravis (MG). Methods AChR antibodies were detected by cell-based assay in the serum of ocular MG (OMG) (n = 90) and generalized MG (GMG) patients (n = 110). The fetal-type (2α: β: γ: δ) and adult-type (2α: β: ε: δ) AChR were used as antigens, and their relevance to disease presentation was assessed. Results The overall frequencies of anti-adult and anti-fetal AChR antibodies were similar in all 200 patients examined, with 14 having serum specific to the AChR-γ subunit, and 22 to the AChR-ε subunit. The overall sensitivity when using the fetal and adult AChR antibodies was higher than that when using the fetal AChR antibody only (P = 0.015). Compared with OMG patients, the mean age at disease onset and the positive ratio of antibodies to both isoforms of the AChR were significantly higher in patients who subsequently progressed to GMG. Older patients and patients with both anti-fetal and anti-adult AChR antibodies had a greater risk for developing generalized disease [odds ratio (OR), 1.03; 95% confidence interval (CI), 1.01-1.06 and OR, 5.09; 95% CI, 2.23-11.62]. Conclusion Using both fetal-and adult-type AChRs as the antigens may be more sensitive than using either subtype. Patients with serum specific to both isoforms are at a greater risk of progressing to GMG. Patients with disease onset at an advanced age appear to have a higher frequency of GMG conversion.     

Associated factors of quality of life in first-episode schizophrenia patients

Objective

Improving quality of life is an important goal in the treatment of schizophrenia. In previous research, quality of life has been reported to be compromised in patients with schizophrenia. The aim of this study was to investigate whether quality of life may be impaired in first-episode schizophrenia patients and to identify the associated factors of quality of life in first-episode schizophrenia.

Methods

Forty-eight patients with first-episode schizophrenia and 20 normal controls were recruited. Quality of life was measured by using the Quality of Life scale (QLS). General and social self-efficacy, perceived social support were measured by using the self-report scales. The clinical assessments and comprehensive neurocognitive battery were also administered.

Results

First-episode group showed significantly decreased QLS total and QLS subscale scores compared to normal controls group. The key associated factors of quality of life in patients with first-episode schizophrenia were the negative symptoms and social self-efficacy.

Conclusion

This finding implies that compromised quality of life may be already emerged in schizophrenia in their first-episode and the psychosocial interventions should be targeting the negative symptoms and the psychosocial protective factors including self-efficacy in addition to simply ameliorating the positive symptoms to foster social reintegration and recovery of first-episode patients.     

Normal Birth Weight Variation Is Related to Cortical Morphology Across the Psychosis Spectrum

Background:

Normal birth weight variation affects schizophrenia risk and cognitive performance in schizophrenia patients and healthy controls. Brain cortical anatomy is altered in psychotic disorders and in low birth weight subjects, but if birth weight variation relates to cortical morphology across the psychosis spectrum is not known.

Methods:

Magnetic Resonance Imaging brain scans and clinical-, neurocognitive-, and medical birth registry data were collected from 359 adults including patients with a DSM-IV diagnosis of schizophrenia (n = 90, mean age 29.4±10.2 [95% CI], 62% male), bipolar disorder (n = 79, age 29.4±11.8, 39% male) or other psychosis (n = 40, age 26.3±10.0, 56% male), and healthy controls (n = 140, age 30.8±12.0,53% male). We explored the relationship between whole-range birth weight variation and cortical surface area and thickness and their possible associations to cognitive performance.

Results:

Across all groups, lower birth weight was associated with smaller total surface area (t = 3.87, P = .0001), within specific regions of the temporal, parietal, and frontal cortex bilaterally. There were no associations between birth weight and cortical thickness, and no diagnosis by birth weight interaction effects on cortical thickness or surface area. Smaller cortical area (t = 2.50, P = .013) and lower birth weight (t = 2.53, P = .012) were significantly related to poorer working memory performance in all diagnostic groups except schizophrenia.

Conclusion:

Birth weight relates to adult cortical surface area, but not cortical thickness, in patients across the psychosis spectrum and in healthy controls. Cortical area appears to be a diagnosis-independent general marker of early neurodevelopment, with a dose-response association to normal birth weight variation.Key words: Magnetic Resonance Imaging, cortical area, neurodevelopment, schizophrenia, IQ, working memory     

Prefrontal Brain Network Connectivity Indicates Degree of Both Schizophrenia Risk and Cognitive Dysfunction

Objective:

Cognitive dysfunction is a core feature of schizophrenia, and persons at risk for schizophrenia may show subtle deficits in attention and working memory. In this study, we investigated the relationship between integrity of functional brain networks and performance in attention and working memory tasks as well as schizophrenia risk.

Methods:

A total of 235 adults representing 3 levels of risk (102 outpatients with schizophrenia, 70 unaffected first-degree relatives of persons with schizophrenia, and 63 unrelated healthy controls [HCs]) completed resting-state functional magnetic resonance imaging and a battery of attention and working memory tasks (Brief Test of Attention, Hopkins Verbal Learning Test, and Brief Visuospatial Memory Test) on the same day. Functional networks were defined based on coupling with seeds in the dorsal anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), medial prefrontal cortex (MPFC), and primary visual cortex. Networks were then dissected into regional clusters of connectivity that were used to generate individual interaction matrices representing functional connectivity within each network.

Results:

Both patients with schizophrenia and their first-degree relatives showed cognitive dysfunction compared with HCs. First canonicals indicated an inverse relationship between cognitive performance and connectivity within the DLPFC and MPFC networks. Multivariate analysis of variance revealed multivariate main effects of higher schizophrenia risk status on increased connectivity within the DLPFC and MPFC networks.

Conclusions:

These data suggest that excessive connectivity within brain networks coupled to the DLPFC and MPFC, respectively, accompany cognitive deficits in persons at risk for schizophrenia. This might reflect compensatory reactions in neural systems required for cognitive processing of attention and working memory tasks to brain changes associated with schizophrenia.Key words: resting state, fMRI, default-mode network, attention, working memory     

Complementary diffusion tensor imaging study of the corpus callosum in patients with first-episode and chronic schizophrenia

Background

Abnormalities in the corpus callosum have long been implicated in schizophrenia. Previous diffusion tensor imaging (DTI) studies in patients with different durations of schizophrenia yielded inconsistent results. By comparing patients with different durations of schizophrenia, we investigated if white matter abnormalities of the corpus callosum emerge at an early stage in the illness or result from pathological progression.

Methods

We recruited patients with first-episode schizophrenia, patients with chronic schizophrenia and age-, sex-and handedness-matched healthy controls. We used 2 DTI techniques (voxel-based and fibre-tracking DTI) to investigate differences in corpus callosum integrity among the 3 groups.

Results

With both DTI techniques, significantly decreased fractional anisotropy values were identified in the genu of corpus callosum in patients with chronic schizophrenia, but not first-episode schizophrenia, compared with healthy controls.

Limitations

This study was cross-sectional, and the sample size was relatively small.

Conclusion

Abnormalities in the genu of the corpus callosum might be a progressive process in schizophrenia, perhaps related to disease severity and prognosis.     

Alpha4beta2 nicotinic receptor status in Alzheimer's disease using 123I-5IA-85380 single-photon-emission computed tomography

Background

Loss of the α4β2 nicotinic receptor subtype is found at autopsy in Alzheimer''s disease.

Objective

To investigate in vivo changes in this receptor using single‐photon‐emission CT (SPECT) with ¹²³I‐5‐iodo‐3‐[2(S)‐2‐azetidinylmethoxy] pyridine (5IA‐85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the α4β2 receptor.

Methods

32 non‐smoking subjects (16 with Alzheimer''s disease and 16 normal elderly controls) underwent ¹²³I‐5IA‐85380 and perfusion (^99mTc‐hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation.

Results

Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both ¹²³I‐5IA‐85380 and ^99mTc‐HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD.

Conclusion

Using ¹²³I‐5IA‐85380 SPECT we found changes consistent with significant reductions in the nicotinic α4β2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.Nicotinic acetylcholine receptors (nAChRs) are known to be associated with important neurophysiological processes such as memory and learning.¹ Reductions in nAChR have been shown in a number of neurodegenerative disorders, including Alzheimer''s disease, dementia with Lewy bodies (DLB) and Parkinson''s disease.^2,3,4 Loss of nAChR binding sites has been identified in frontal⁵ and other cortical areas in brain tissue of patients with AD compared to controls using the nicotinic receptor ligand ³H‐nicotine.⁶ Temporal archicortical regions including the parahippocampal gyrus have also been shown to be affected in the postmortem examination of the brain of patients with AD.³ Nicotinic‐agonist (³H‐nicotine, ³H‐epibatidine and ³H‐cytisine) deficits have been demonstrated in the temporal brain cortex in the brain of patients with AD compared to age‐matched controls.^7,8 nAChRs consist of eight α (α2–α9) and three β (β2–β4) subunits,⁹ of which the most abundant varieties in the mammalian brain are the α4β2 and α7 subtypes.¹The marker ¹²⁵I‐5‐iodo‐3‐[2(S)‐2‐azetidinylmethoxy] pyridine (5IA‐85380) has been used to assess the nicotinic α4β2 subtype receptor status in the postmortem examination of brain tissue of patients with AD, where receptor loss was shown in tissues of the striatum and entorhinal cortex compared to age‐matched controls.¹⁰ In addition, a ligand with high affinity to the β2 subtype, ¹⁸F‐2‐fluoro‐3‐[2(S)‐2‐azetidinylmethoxy] pyridine (2FA‐85380), revealed a 36% reduction in both the thalamus and occipital cortex in the brains of patients with AD compared to elderly controls.¹¹ Although important in providing information about the mechanism of the receptor–ligand interaction and establishing suitability for specific receptor studies, one limitation of in vitro investigations with tissue postmortem examination is that the results generally reflect end‐stage disease and information regarding early pathological states is limited. By contrast, molecular in vivo imaging can provide data from living patients at various stages of illness and has the potential to investigate clinical correlates and the effects of medication.¹ One previous imaging study using ¹¹C‐nicotine positron emission tomography (PET) investigated the nicotinic receptor status in vivo in patients with AD, showing deficits in frontal, temporal and hippocampal regions compared to controls.¹² Imaging studies, to date, are limited by availability of nicotinic subtype‐specific ligands, although recently several studies showed that the single‐photon‐emission CT (SPECT) tracer ¹²³I‐5IA‐85380 was a suitable agent to quantify and image α4β2 nAChR in normal humans.^13,14,15 In this study we investigated, using a semiautomated region of interest (ROI) approach, differences in cortical and subcortical patterns of nAChR in vivo in patients with AD and in elderly normal controls using ¹²³I‐5IA‐85380 SPECT. ROI was chosen as it is robust, well‐validated and can provide important semiquantitative data for this novel ligand. The pattern of nACh receptor status for each group was also compared with their associated regional cerebral blood flow (rCBF) patterns obtained from ^99mTc‐hexamethylenepropyleneamine oxime (HMPAO) SPECT imaging.     

Hippocampal subdivision and amygdalar volumes in patients in an at-risk mental state for schizophrenia

Background

Accumulating evidence from postmortem and magnetic resonance imaging (MRI) studies suggests that abnormalities of medial temporal lobe structures are critically involved in the pathogenesis of schizophrenia. It is still unclear, however, whether certain abnormalities are already present in individuals at ultra high-risk (UHR) for transition into psychosis. Recent studies involving patients at UHR showed contradictory results for hippocampal volume, and only 1 study reported that amygdalar volume was unchanged between healthy patients and those at UHR. Furthermore, no subregions of the hippocampus have been investigated in people at UHR.

Methods

We recruited 29 UHR patients, 23 first-episode patients and 29 age-and sex-matched healthy controls. We measured hippocampal and amygdalar volumes from MRI scans by use of BRAINS2 to manually trace the regions of interest. The hippocampi were divided in 2 regions: head and corpus/tail.

Results

Patients at UHR had significantly smaller volumes of the hippocampus corpus and tail bilaterally, but not of the head, compared with healthy controls. Group differences for the right hippocampus corpus and tail volume remained significant after we controlled for whole brain volume and other covariates. We found that UHR patients who later developed psychosis had smaller right hippocampus corpus and tail volumes than did those who did not develop psychosis. First-episode patients had significantly smaller left amygdalar volumes than did healthy individuals or those at UHR.

Limitations

Our study had a small sample size, and we were unable to control for the effects of medication.

Conclusion

Our findings suggest that parts of the hippocampal–amygdalar complex are involved in the pathogenesis of schizophrenia. Reduction of hippocampus corpus and tail volumes may be indicative of the prodromal phase of schizophrenia and represent risk factors for transition into psychosis. Further investigations are needed to determine whether structural changes of the left amygdala play a role during transition from the prodromal phase to the first manifest episode of schizophrenia.