The psychotic phenomenon in probable Alzheimer's disease: a positron emission tomography study

Positron emission tomography was used to examine the mechanisms of the psychotic phenomenon in Alzheimer's disease (AD). Data from 2 patients with delusions and 2 with hallucinations were compared with those of 5 AD patients without psychosis. The patients with paranoid delusions had diminished relative regional cerebral blood flow (rel-CBF) in the left dorsolateral prefrontal and left medial temporal cortices. The patients with visual hallucinations showed diminished rel-CBF in the right parietal, left medial temporal, and left dorsolateral prefrontal cortices. These findings support the hypothesis that a frontal-temporal abnormality is associated with paranoid delusions in AD. By contrast, visual hallucinations are associated with parietal as well as frontal and temporal lobe dysfunction. In these patients, a left prefrontal-temporal cortex dysfunction appears to be a common denominator for the development of the psychotic phenomenon in AD.     

Relation between medial temporal atrophy and functional brain activity during memory processing in Alzheimer's disease: a combined MRI and SPECT study

OBJECTIVE: To investigate the relation between atrophy of the hippocampal region and brain functional patterns during episodic memory processing in Alzheimer's disease. PATIENTS AND METHODS: Whole brain structural magnetic resonance imaging (MRI) data and single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF) were obtained during a verbal recognition memory task in nine subjects with mild Alzheimer's disease and 10 elderly healthy controls. Using the statistical parametric mapping approach, voxel based comparisons were made on the MRI data to identify clusters of significantly reduced grey matter concentrations in the hippocampal region in the Alzheimer patients relative to the controls. The mean grey matter density in the voxel cluster of greatest hippocampal atrophy was extracted for each Alzheimer subject. This measure was used to investigate, on a voxel by voxel basis, the presence of significant correlations between the degree of hippocampal atrophy and the rCBF SPECT measures obtained during the memory task. RESULTS: Direct correlations were detected between the hippocampal grey matter density and rCBF values in voxel clusters located bilaterally in the temporal neocortex, in the left medial temporal region, and in the left posterior cingulate cortex during the memory task in the Alzheimer's disease group (p < 0.001). Conversely, measures of hippocampal atrophy were negatively correlated with rCBF values in voxel clusters located in the frontal lobes, involving the right and left inferior frontal gyri and the insula (p < 0.001). CONCLUSIONS: Hippocampal atrophic changes in Alzheimer's disease are associated with reduced functional activity in limbic and associative temporal regions during episodic memory processing, but with increased activity in frontal areas, possibly on a compensatory basis.     

An fMRI study of prefrontal dysfunction and symptomatic recovery in schizophrenia

Smee C, Krabbendam L, O’Daly O, Prins A‐M, Nalesnik N, Morley L, Samson G, Shergill S. An fMRI study of prefrontal dysfunction and symptomatic recovery in schizophrenia. Objective: Prefrontal cortical dysfunction has been implicated in the pathophysiology of schizophrenia but it is unclear to what extent these are related to changes in symptomatology as well as task demand. Method: We examined the neural correlates of symptom change and task demand during a longitudinal functional magnetic resonance imaging (fMRI) study using a verbal fluency task with differential task demands in patients with schizophrenia and matched healthy control subjects. The fMRI data were acquired using clustered acquisition technique, enabling ongoing monitoring of behavioural responses, in the patient group on two occasions separated by 6–8 weeks, and the control group at baseline. Results: Positive psychotic symptoms were significantly reduced over the 6–8‐week duration of the study. This change was associated with increased activation within the left middle frontal gyrus and decreased activation of the left precuneus. An interaction between symptom change and task demand was evident in the activation of the left middle frontal gyrus. The decrease in positive symptoms was associated with normalisation of activation in the dorsolateral prefrontal cortex and a decrease in parietal activation during the verbal fluency task. Conclusion: The data supports the role of dysfunctional prefronto‐parietal relationships in the genesis of positive psychotic symptoms.     

Alterations of rCBF and mitochondrial dysfunction in major depressive disorder: a case report

OBJECTIVE: A mitochondrial disease might be considered when depressive disorder is associated with diabetes mellitus or other symptoms commonly found in mitochondrial disease. Scattered regional cerebral blood flow (rCBF) decreases and increases have been reported in depressive and mitochondrial disorders. A 61-year-old male patient with early adult onset of depressive disorder and a slowly developing multiorgan syndrome including diabetes mellitus was investigated. METHOD: 99mTc-HMPAO rCBF SPECT and muscle biopsy to assess mitochondrial functions were performed in the patient. RESULTS: Alterations of rCBF were found in the patient, with the most pronounced decreases in the left dorsolateral frontal and inferior parietal lobes, and the most pronounced increases in the bilateral superior parietal lobes. Muscle biopsy revealed myopathy and decrease of mitochondrial adenosine triphosphate production rates (MAPRs). CONCLUSION: The MAPRs decreases support the suspicion of mitochondrial dysfunction in the patient. A subgroup of depressed patients may have mitochondrial dysfunctions.     

Neurobehaviors and psychotic symptoms in Alzheimer's disease.

Psychotic symptoms are common in Alzheimer's disease (AD) and clinicoanatomical and neuropsychological evidence indicate an association between these symptoms and frontal lobe dysfunction. Neuro-behaviors associated with frontal dysfunction were assessed in Alzheimer's disease (AD) patients with (n = 20) and without psychotic symptoms (n = 21) matched for mean age, education, gender, and dementia severity. The Frontal Lobe Personality Scale (FLOPs) was completed by patient caregivers to measure behaviors typically associated with frontal dysfunction. Findings indicated that AD patients with psychotic symptoms exhibited significantly greater neurobehavioral dysfunction (FLOPs M = 130.69, SD = 24.70) than AD patients without psychotic symptoms (FLOPs M = 111.10, SD = 25.83). Subscale analyses indicated that psychotic AD patients were more dis-inhibited (M = 28.28, SD = 7.54) than patients without psychotic symptoms (M = 20.92, SD = 4.9). Findings are consistent with and contribute to previous neuropsychological and clinicoanatomical research suggesting increased frontal dysfunction in AD with psychotic symptoms and lend additional empirical support to subtyping AD based on the presence of psychotic symptoms. Furthermore, findings provide preliminary evidence indicating which specific type of neurobehavioral abnormalities are related to the presence of distressing psychotic symptoms.     

额叶变异型阿尔茨海默病的临床和影像学特征一例

目的额叶变异型阿尔茨海默病(AD)是一种以精神行为等症状为主要表型的少见特殊类型AD,本文报道1例额叶变异型AD的临床特点、影像学特征,以增加临床医生对该病的认识。方法报道1例额叶变异型AD患者的临床资料,分析其临床表现、辅助检查及影像学资料。结果本例患者以妄想和行为异常等为主要和最早临床表现,发病2年后才出现记忆力减退、言语表达困难、计算不能等症状,头颅MRI提示双侧额颞叶萎缩,以左侧为著。头颅SPECT显示:双侧额叶、颞叶和顶叶葡萄糖摄取普遍减低。PIB-PET(淀粉样蛋白PET):大脑皮质PIB显著滞留,考虑为PIB阳性显像。结论额叶变异型AD与行为变异型额颞叶痴呆临床表现类似,淀粉样蛋白PET检查可有效区分两者。     

Cortico-basal degeneration

Cortico-basal degeneration (CBD) or cortico-basal ganglionic degeneration is a condition characterised by selective cortical atrophy of parietal and in a lesser extent, frontal lobe associated with dysfunction of the basal ganglia. The clinical symptoms of CBD, predominantly extrapyramidal signs (bradykinesia and rigidity) and apraxia, affect often only one body side in the onset phase, with the left one being more frequent. Neuropathological studies reveal neuronal loss, gliosis, and achromasia chiefly in frontal and parietal cortex, as well as in basal ganglia and substantia nigra. Functional investigations, such as SPECT, disclose similar distribution of abnormalities (hypometabolism). The aetiology and causative treatment of CBD are unknown. The authors highlight the diagnostic difficulties in CBD including a necessity of a prolonged patient's observation in order to ascertain the differential diagnosis of other neurodegenerative disorders, in particular progressive supranuclear palsy, Alzheimer's disease and Parkinson's disease.     

Default mode network activity in schizophrenia studied at resting state using probabilistic ICA

Alterations in brain function in schizophrenia and other neuropsychiatric disorders are evident not only during specific cognitive challenges, but also from functional MRI data obtained during a resting state. Here we apply probabilistic independent component analysis (pICA) to resting state fMRI series in 25 schizophrenia patients and 25 matched healthy controls. We use an automated algorithm to extract the ICA component representing the default mode network (DMN) as defined by a DMN-specific set of 14 brain regions, resulting in z-scores for each voxel of the (whole-brain) statistical map. While goodness of fit was found to be similar between the groups, the region of interest (ROI) as well as voxel-wise analysis of the DMN showed significant differences between groups. Healthy controls revealed stronger effects of pICA-derived connectivity measures in right and left dorsolateral prefrontal cortices, bilateral medial frontal cortex, left precuneus and left posterior lateral parietal cortex, while stronger effects in schizophrenia patients were found in the right amygdala, left orbitofrontal cortex, right anterior cingulate and bilateral inferior temporal cortices. In patients, we also found an inverse correlation of negative symptoms with right anterior prefrontal cortex activity at rest and negative symptoms. These findings suggest that aberrant default mode network connectivity contributes to regional functional pathology in schizophrenia and bears significance for core symptoms.     

The regional cerebral blood flow changes in major depressive disorder with and without psychotic features

Depressive patients with psychotic features demonstrate distinct biological abnormalities in the hypothalamic-pituitary-adrenal axis (HPA), dopaminergic activity, electroencephalogram sleep profiles and measures of serotonergic function when compared to nonpsychotic depressive patients. However, very few functional neuroimaging studies were specifically designed for studying the effects of psychotic features on neuroimaging findings in depressed patients. The objective of the present study was to compare brain Single Photon Emission Tomography (SPECT) images in a group of unmedicated depressive patients with and without psychotic features. Twenty-eight patients who fully met DSM-IV criteria for major depressive disorder (MDD, 12 had psychotic features) were included in the study. They were compared with 16 control subjects matched for age, gender and education. Both psychotic and nonpsychotic depressed patients showed significantly lower regional cerebral blood flow (rCBF) values in the left and right superior frontal cortex, and left anterior cingulate cortex compared to those of controls. In comparison with depressive patients without psychotic features (DwoPF), depressive patients with psychotic features (DwPF) showed significantly lower rCBF perfusion ratios in left parietal cortex, left cerebellum but had higher rCBF perfusion ratio in the left inferior frontal cortex and caudate nucleus. The present study showed that DwPF have a different rCBF pattern compared to patients without psychotic features. Abnormalities involving inferior frontal cortex, striatum and cerebellum may play an important role in the generation of psychotic symptoms in depression.     

Selective delayed response deficits in Parkinson's and Alzheimer's disease

Experimental paradigms adopted from animal models were used to contrast the functional anatomy of frontal systems involved in Alzheimer's disease and the dementia of Parkinson's disease. Patients with Parkinson's disease with dementia were compared with patients with Alzheimer's disease, and nondemented patients with Parkinson's disease, and normal controls. The tasks administered, delayed alternation and delayed response (DR), are sensitive to frontal system damage. Different aspects of each task are mediated by separate frontosubcortical neuronal networks. Patients with Parkinson's disease with dementia were significantly impaired only on DR, whereas patients with Alzheimer's disease were impaired on DR and delayed alternation, even though both groups were equated for severity of dementia. Although dysfunction in the frontal lobes, and/or their subcortical connections, is implicated in both Parkinson's and Alzheimer's disease, dorsolateral frontal systems appear primarily impaired in Parkinson's disease, whereas dorsolateral frontal impairment combined with other regions, possibly orbitofrontal, are prominent in Alzheimer's disease.     

Increased brain activation during working memory in cognitively intact adults with the APOE epsilon4 allele

OBJECTIVE: Altered patterns of brain activity during cognitive tasks have been demonstrated using functional magnetic resonance imaging (fMRI) in mild cognitive impairment and Alzheimer's disease. However, there have been few studies of adults at genetic risk for Alzheimer's disease prior to the onset of symptoms. The purpose of this study was to determine whether brain activation patterns associated with working memory differ as a function of apolipoprotein E (APOE) genotype in cognitively intact adults. METHOD: Participants were cognitively intact, healthy adults who completed genotyping, comprehensive neuropsychological testing, and structural and functional neuroimaging. Twenty-two participants had the APOE epsilon3/epsilon3 genotype, and 13 participants had the APOE epsilon3/epsilon4 genotype. The study employed an auditory verbal N-back task to probe working memory-related brain activity. RESULTS: The epsilon3/epsilon3 and epsilon3/epsilon4 groups did not differ in demographic characteristics, cognitive ability, mood, or in-scanner task performance. The epsilon3/epsilon4 group showed greater activity during working memory in the medial frontal and parietal regions bilaterally and in the right dorsolateral prefrontal cortex. There were no regions in which the epsilon3/epsilon3 group showed greater activation than the epsilon3/epsilon4 group. CONCLUSIONS: These results indicate that differences in brain activity are evident in cognitively intact individuals who are at risk for late-onset Alzheimer's disease by virtue of their APOE allele status. As neuroprotective interventions become available, early detection will increase in importance. The combination of genetic and functional neuroimaging strategies may prove useful for monitoring individuals at risk for Alzheimer's disease before the onset of cognitive symptoms.     

Findings of proton magnetic resonance spectometry in the dorsolateral prefrontal cortex in adolescents with first episodes of psychosis

Knowledge of the neurobiology of early onset psychosis is limited. We used proton magnetic resonance spectroscopy to investigate the possible existence of dorsolateral prefrontal brain biochemical abnormalities in adolescents with psychosis and to determine possible differential effects related to specific psychotic diagnoses. We measured the ratios of N-acetyl-aspartate (NAA), choline (Cho), and creatine (Cr) to water in two groups of adolescents with a first episode of psychosis (schizophrenia n=8; non-schizophrenia n=15) and in 32 healthy controls matched for age, gender, and years of education. Proton magnetic resonance spectroscopy at 1.5 T was used to study two 6.75-cc voxels placed in the left and right dorsolateral prefrontal region. The schizophrenia patients presented statistically significant reductions in NAA/water levels in the left dorsolateral prefrontal voxel as compared with non-schizophrenia patients and healthy controls. No significant differences were detected between groups for NAA/water in the right dorsolateral prefrontal voxel or for Cho/water and Cr/water levels in any hemisphere. A reduction of the NAA/water level in the left dorsolateral prefrontal region may be selectively present at the onset of psychosis during adolescence in patients who later progress to schizophrenia, but not in those who later progress to other psychotic disorders.     

Orbital and dorsolateral frontal perfusion defect associated with behavioral response to cholinesterase inhibitor therapy in Alzheimer's disease

The authors retrospectively explored the behavioral and functional imaging profile of Alzheimer's disease (AD) patients who respond to cholinesterase inhibitor therapy by using the Neuropsychiatric Inventory (NPI) and baseline [99mTc]HMPAO SPECT. Thirty AD patients were divided into three groups (Responders, Nonresponders, and Unchanged) based on their behavioral response to donepezil. Responders had significantly (P < or = 0.01) more pretreatment irritability, disinhibition (P < or = 0.05), and euphoria (P = 0.05) than Nonresponders and significantly lower lateral orbital frontal (P < 0.00001) and dorsolateral frontal (P < or = 0.0005) perfusion bilaterally. A pretreatment orbitofrontal syndrome may predict behavioral response to cholinesterase inhibitor therapy in AD.     

Functional ability in executive variant Alzheimer's disease and typical Alzheimer's disease

A frontal, or executive, variant of Alzheimer's disease (EAD) has been described in the literature in which frontal dysfunction accompanies temporal and parietal changes in the early stages of the illness. However, no study has empirically investigated associated aspects, such as neuropsychiatric symptoms, instrumental activities of daily living, or caregiver burden in this EAD subgroup. We compared the performance of two subgroups of mild Alzheimer's disease patients (e.g., EAD and typical Alzheimer's disease; TAD) on neuropsychological and associated measures. Results revealed that the EAD group, selected based on poor executive scores, did not significantly differ from the TAD group on nonexecutive neuropsychological tests of intelligence, language, verbal and nonverbal memory, or visual-spatial abilities. However, the EAD group evidenced more severe neuropsychiatric symptoms, impaired activities of daily living, and greater caregiver distress than the TAD group. Thus, the EAD subgroup is characterized by executive dysfunction, neuropsychiatric symptoms, and functional disability in excess of that seen in TAD. Whether our EAD subgroup represents an actual frontal variant of Alzheimer's disease awaits replication in a larger sample including neuroimaging and pathological confirmation, as well as longitudinal assessment of cognition and neuropsychiatric symptoms.     

Specificity of changes in cerebral blood flow in patients with frontal lobe dementia.

Eight patients with a clinical diagnosis of probable Alzheimer's disease, eight patients with the clinical diagnosis of frontal lobe dementia, and eight controls were examined with single photon emission tomography (SPECT) using 99Tc-HMPAO. Patients with Alzheimer's disease and those with frontal lobe dementia met DSM-III-R criteria for mild dementia and were in the early stages of the illness. Compared with patients with Alzheimer's disease, the group with frontal lobe dementia had significantly lower blood flow in the frontal lobes (dorsolateral and orbital), the anterior temporal cortex, and the basal ganglia. Within the frontal lobe dementia group, blood flow was significantly lower in the orbital than in the dorsal frontal cortex, and in the anterior temporal than in the dorsal temporal cortex. The present study shows the specificity of changes in regional cerebral blood flow in the diagnosis of different types of dementia, and supports the importance of orbitofrontal, anterior temporal, and basal ganglia dysfunction in the production of the psychiatric syndrome of frontal lobe dementia.     

A single photon emission computerized tomography (SPECT) study of regional cerebral blood flow in bipolar disorder

Data on functional imaging of bipolar disorder (BD) utilizing single photon emission computerized tomography (SPECT) is limited. This study assessed regional cerebral blood flow (rCBF), using ^99mTc-ECD SPECT, among patients with BD, with mania (N=10) or depression (N=10), compared with 10 patients with unipolar depression and 10 normal controls. Regions of interest were analysed using a semi-automatic brain quantification programme. Compared to controls, patients with mania had significantly reduced perfusion mainly in the left frontal area, also in the left anterior cingulate and parietal cortices; those with bipolar depression had significantly lowered rCBF principally in the anterior temporal regions bilaterally, as well as the left parietal area. Patients with unipolar depression had significantly lowered perfusion than controls in most of the regions examined, chiefly in the anterior temporal and frontal cortices bilaterally; they also had lowered perfusion in the right anterior temporal and frontal areas, as well as the right middle temporal area and the right thalamus, compared to patients with mania. Increased severity of psychotic symptoms was associated with reduced rCBF in patients. These results indicate that altered blood flow in the frontal-subcortical systems characterises patients with BD, as well as those with unipolar depression.     

Frontal lobe N-acetylaspartate correlates with psychopathology in schizophrenia: a proton magnetic resonance spectroscopy study

INTRODUCTION: Clinical, neuropsychological and functional neuroimaging studies in schizophrenia suggest impaired frontal lobe function, especially of the dorsolateral prefrontal region (DLPFR). This dysfunction has in particular been associated with negative or "deficit" symptoms. Despite these findings, morphological studies have failed to show consistent structural abnormalities in the frontal lobe. This may be because existing techniques are not sensitive enough to detect structural abnormalities or that dysfunction in the frontal lobe is caused by lesions elsewhere. We used volume-localised proton magnetic resonance spectroscopy (1H-MRS) to measure N-acetylaspartate (NAA), a neuronal marker, to evaluate the neuronal integrity of the dorsolateral prefrontal region in schizophrenic patients with persistent negative symptoms and in healthy comparison subjects. METHOD: Twenty-five patients who fulfilled DSM-IV criteria for schizophrenia and met the criteria for the Deficit syndrome were compared to 26 healthy controls matched for age and gender. Bilateral proton MR spectra were collected from a 2-cm(3) volume in the dorsolateral prefrontal region and the absolute concentrations of N-acetylaspartate, choline (Cho) and creatine+phosphocreatine (Cr+PCr) were measured. RESULTS: There was a significant negative correlation between severity of symptoms and NAA concentration in the schizophrenic patients. This was more marked for positive symptoms and for general psychopathology than for negative symptoms. There was also a significant correlation between NAA concentration and social functioning within the schizophrenic group. There were no significant differences between the two groups for the three metabolites. CONCLUSIONS: The negative association between severity of symptoms and NAA in schizophrenic patients and an association of NAA with social functioning suggest that NAA may be an indicator of disease severity. The lack of significant mean difference in NAA between the two groups suggests that there is no marked neuronal loss in the dorsolateral prefrontal region in schizophrenia.     

Cortical activation during memory-guided saccades

Using functional magnetic resonance imaging, we compared responses during visually guided saccades with those evoked during memory-guided saccades, in which participants executed saccades to remembered locations. Eye movements were recorded in the magnetic resonance tomograph. Significantly stronger activation during memory-guided saccades was observed in the posterior portion of the right inferior frontal gyrus, in the left inferior frontal eye field, in the posterior parietal cortex, as well as in the right posterior superior temporal gyrus. The posterior part of the dorsal anterior cingulum and a small voxel cluster in the dorsolateral prefrontal area, anterior to the left inferior frontal eye field, were only active in the memory-guided condition.     

Single photon emission computed tomography using 99mTc-HM-PAO in the routine evaluation of Alzheimer's disease

Regional cerebral blood flow was studied in 7 patients with clinically suspected Alzheimer's disease and 10 normal controls by single photon computed emission tomography (SPECT) using HM-PAO. All patients with Alzheimer's disease and no controls had parietal lobe hypoperfusion which was usually bilateral. In patients with more severe dementia hypoperfusion extended into the frontal lobes. Parietal lobe hypoperfusion corresponds to parietal lobe degeneration which is the one of the first neocortical regions to show the typical degenerative changes of Alzheimer's disease. SPECT with HM-PAO is a non-invasive investigation available in most nuclear medicine departments and complements existing tests in the routine evaluation of patients presenting with dementia.     

Regional cerebral blood flow deficits in mild Alzheimer's disease using high resolution single photon emission computerized tomography

In spite of its wide availability, single photon emission computerized tomography (SPECT) scanning is uncommonly used in the assessment of Alzheimer's disease (AD) and related dementias. In light of recent advances in scanning protocols and image analysis, SPECT needs to be re-examined as a tool in the diagnosis of dementia. A total of 18 subjects with early AD and 10 healthy elderly control subjects were examined with high resolution SPECT during the performance of a simple word discrimination task. SPECT images were coregistered with individual magnetic resonance imaging scans, allowing delineation of predetermined neuroanatomical Regions of Interest (ROI). There was a gradation of regional cerebral blood flow (rCBF) values in both groups, with the lowest values being in the hippocampus and the highest in the striatum, thalamus and cerebellum. Compared to healthy controls, AD subjects demonstrated lower relative rCBF in parietal and prefrontal cortices. Analysis of individual ROI demonstrated bilateral reduction of rCBF in prefrontal poles, posterior temporal and anterior parietal cortex, and unilateral reduction of rCBF in left dorsolateral prefrontal cortex, right posterior parietal cortex and the left cingulate body. There were no significant differences for hippocampal, occipital or basal ganglia rCBF. Discriminant function analysis indicated that rCBF in the prefrontal polar regions achieved the best classification of cases. SPECT has utility in the diagnostic assessment of AD if standardized and semiquantitative techniques are used.