Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer's disease

The present study examined the cortical functional representation of neuropsychological domains in Alzheimer's disease (AD) using positron emission tomography (PET) and the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Thirty patients with clinical probable AD and 10 elderly healthy controls underwent (18)FDG brain PET imaging during a resting state. Correlations between metabolic values and cognitive measures were determined using a region of interest analysis with NEUROSTAT (University of Michigan, USA) and a voxel-based analysis with SPM96 (Wellcome Department, London, UK). Specific correlations were seen between measures of episodic memory, verbal fluency and naming and left hemispheric temporal and prefrontal metabolism. Drawing was correlated with metabolism in left prefrontal and left inferior parietal regions. The presented data support the use of metabolic-cognitive correlations to demonstrate the neuronal substrates of cognitive impairment in AD. Subtests of the CERAD battery give a good representation of left, but not of right hemisphere function in AD.     

Distribution of cerebral atrophy assessed by magnetic resonance imaging reflects patterns of neuropsychological deficits in Alzheimer's dementia

Neuropsychological deficits were investigated with respect to regional distribution of cerebral atrophy as assessed by volumetric magnetic resonance imaging (MRI) in 50 patients with Alzheimer's dementia (AD; NINCDS-ADRDA criteria) and 20 healthy volunteers. When compared between groups, test performance of all investigated neuropsychological domains including declarative memory, language, praxia, psychomotor speed, as well as attention and concentration was significantly impaired. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex correlated with declarative memory performance, whereas volumes of the left temporo-parietal regions correlated with performance in naming and praxia. Furthermore, left frontal lobe atrophy was associated with verbal fluency. Our data confirm the central role that medial temporal atrophy plays for declarative memory deficits in AD and indicate that additional changes in the parietal, temporal and frontal lobes are responsible for further neuropsychological deficits characteristic of this disorder.     

The differentiation of semantic dementia and frontal lobe dementia (temporal and frontal variants of frontotemporal dementia) from early Alzheimer's disease: a comparative neuropsychological study

The authors compared age-matched groups of patients with the frontal and temporal lobe variants of frontotemporal dementia (FTD; dementia of frontal type [DFT] and semantic dementia), early Alzheimer's disease (AD), and normal controls (n = 9 per group) on a comprehensive neuropsychological battery. A distinct profile emerged for each group: Those with AD showed a severe deficit in episodic memory with more subtle, but significant, impairments in semantic memory and visuospatial skills; patients with semantic dementia showed the previously documented picture of isolated, but profound, semantic memory breakdown with anomia and surface dyslexia but were indistinguishable from the AD group on a test of story recall; and the DFT group were the least impaired and showed mild deficits in episodic memory and verbal fluency but normal semantic memory. The frontal and temporal presentations of FTD are clearly separable from each other and from early AD.     

The pattern of function-related regional cerebral blood flow investigated by single photon emission tomography with 99mTc-HMPAO in patients with presenile Alzheimer's disease and Korsakoff's psychosis

Single photon emission tomography (SPET) with the lipophilic blood flow marker 99mTc-hexamethyl propyleneamine oxime (99mTc-HMPAO) has been used to determine regional uptake of radiolabel into brain regions of patients with presenile Alzheimer's disease and Korsakoff's psychosis, and age-matched controls. Using occipital cortical uptake as reference area, the pattern of relative regional cerebral blood flow (rCBF) was determined in other cortical areas and basal ganglia. In Alzheimer's disease, reduction in rCBF occurred most strikingly in posterior temporal and parietal areas. By contrast, in Korsakoff's psychosis, posterior temporal rCBF was maintained, although there was a trend to reduced tracer uptake in other cortical areas. These impairments of flow were correlated with impairments of neuropsychological function. In Alzheimer's disease, left posterior temporal and left parietal regions in particular showed rCBF to be strongly correlated with most aspects of cognitive function. In Korsakoff's psychosis, however, impaired flow in frontal regions was correlated with impaired performance on tests of memory and orientation. The findings in Alzheimer's disease show quantitative parallels with those from studies using Positron Emission Tomography (PET), and extend our understanding of the relationship between cognition and regional brain function in dementia. The findings in Korsakoff's psychosis offer the first direct evidence linking frontal lobe dysfunction with the cognitive impairment seen in the disorder.     

Psychometric properties and factor structure of an expanded CERAD neuropsychological battery in an elderly VA sample.

Recent research by Strauss and Fritsch [Strauss, M.E., & Fritsch, T. (2004). Factor structure of the CERAD neurophysiological battery. Journal of the International Neuropsychological Society, 10, 559-565] suggested additions to the original Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery. In the present study, the data from a clinical series of military veteran patients referred for neuropsychological evaluation of suspected dementia using an Expanded CERAD battery was explored. Logistic regression analysis and exploratory factor analysis with quantitative methods for determining the number of factors strongly supported the addition of the Indiana University Token Test. A one-factor model best accounted for the demented subjects data and a two-factor model emerged when the total sample (demented and non-demented subjects) data were factor analyzed. The benefit of using computational methods for determining the number of underlying factors was discussed.     

糖尿病视网膜病变患者自发活动性异常的脑区与MoCA的相关性研究

目的 基于静息态功能磁共振局部一致性技术探讨糖尿病视网膜病变患者局部脑区一致性的改变及与认知关系.方法 选择27例糖尿病视网膜病变(DR)及与之年龄、性别、受教育年限相匹配的单纯糖尿病(N-DR)患者27例,均进行实验室检查、蒙特利尔量表(MoCA)检测及头颅磁共振扫描.利用多元回归分析及Pearson回归分析观察临床变量与活动性异常活动脑区ReHo值之间的关系.结果 相对于N-DR,DR患者在左小脑后叶、右额叶/额中回/内侧回、右枕叶/楔叶/距状回、左颞叶/上/中回、右边缘叶/后扣带回、左顶叶/中央后回ReHo值降低;在左额叶/眶部额上回、左顶叶/楔前叶ReHo值增强.而且MoCA量表评分与颞叶及楔前叶异常活动的脑区存在相关性.降低的枕叶距状回及颞叶中回与糖化血红蛋白呈负相关,增强的眶额叶与糖化血红蛋白呈正相关.结论 糖尿病视网膜病变患者存在多个脑区活动性异常的表现,且这些局部异常活动的脑区与认知功能及糖化血红蛋白存在相关.     

The neural basis of naming impairments in Alzheimer's disease revealed through positron emission tomography.

The naming impairments in Alzheimer's disease (AD) have been attributed to a variety of cognitive processing deficits, including impairments in semantic memory, visual perception, and lexical access. To further understand the underlying biological basis of the naming failures in AD, the present investigation examined the relationship of various classes of naming errors to regional brain measures of cerebral glucose metabolism as measured with 18 F-Fluoro-2-deoxyglucose (FDG) and positron emission tomography (PET). Errors committed on a visual naming test were categorized according to a cognitive processing schema and then examined in relationship to metabolism within specific brain regions. The results revealed an association of semantic errors with glucose metabolism in the frontal and temporal regions. Language access errors, such as circumlocutions, and word blocking nonresponses were associated with decreased metabolism in areas within the left hemisphere. Visuoperceptive errors were related to right inferior parietal metabolic function. The findings suggest that specific brain areas mediate the perceptual, semantic, and lexical processing demands of visual naming and that visual naming problems in dementia are related to dysfunction in specific neural circuits.     

Cerebral metabolic patterns at early stages of frontotemporal dementia and semantic dementia. A PET study

OBJECTIVE: To determine the patterns of cerebral glucose metabolism in frontotemporal dementia (FTD) and semantic dementia (SD). METHODS: 25 patients with mild FTD and 9 patients with mild SD as well as 15 healthy age-matched control subjects underwent 18F-FDG- positron emission tomography. Patient scans were compared with control scans using SPM-99. RESULTS: As compared with healthy control subjects patients with FTD showed an extensive symmetrical hypometabolism of the frontal lobes (height threshold P <0.01) which spared the motor cortex. Patients with SD showed a hypometabolism in the whole left temporal lobe and in the right temporal pole. CONCLUSIONS: In the clinical syndromes of FTD and SD two distinct patterns of cerebral metabolism were identified. FTD was associated with frontal hypometabolism, whereas in SD cerebral glucose metabolism was exclusively reduced in the temporal lobes. Our findings are consistent with the notion that FTD and SD begin as strictly lobar neuronal degenerations and that a spread of pathological changes is not seen until more advanced stages.     

Correlations of regional cerebral metabolism with memory performance and executive function in patients with herpes encephalitis or frontal lobe lesions

Cerebral [18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) data from patients suffering amnesia following herpes encephalitis (n=7) or frontal lobe pathology (n=14) were compared with data from age-matched nonamnesic subjects (n=10). All subjects received structural MRI, resting 18FDG-PET scans, and neuropsychological evaluation. PET data were analyzed using complementary statistical parametric mapping and region-of-interest methods. Differential patterns of hypometabolism were found in patients relative to healthy controls. Factor analysis of the neuropsychological data revealed that memory performance was associated with retrosplenial and medial temporal metabolism, and executive function was associated with dorsolateral frontal metabolism. The association between memory performance and retrosplenial metabolism remained statistically significant after accounting for measures of cerebral atrophy using MRI. The significance of the retrosplenium as a major relay station between the thalamus and the medial temporal and frontal lobes--sensitive to changes in either--is discussed in the light of the findings.     

Behavioural and neuropsychological correlates of frontal lobe features in dementia

BACKGROUND: In order to characterize frontal lobe features and their behavioural and cognitive correlates across diagnostic categories, we performed a cross-sectional analysis of behavioural and neuropsychological data from a large, prospective Belgian study on behavioural and psychological signs and symptoms of dementia (BPSD). METHOD: Patients with probable Alzheimer's disease (AD) (n=170), frontotemporal dementia (FTD) (n=28), mixed dementia (MXD) (n=29) and dementia with Lewy bodies (DLB) (n=21) were included and underwent neuropsychological and behavioural assessment by means of a battery of tests and scales. Frontal lobe symptoms were quantified by means of the Middelheim Frontality Score (MFS). RESULTS: In AD (and to a lesser extent in MXD), MFS total scores were negatively correlated with scores on MMSE (Spearman: r=-0.36, p<0.001) and a Verbal Fluency Task (r=-0.38, p<0.001) and were associated with increased severity and frequency of psychosis (r=0.24, p<0.01), activity disturbances (r=0.44, p<0.001) and aggressiveness (r=0.43, p<0.001). In DLB, MFS total scores were negatively correlated with MMSE scores (r=-0.50, p=0.020). No associations were found in FTD patients. CONCLUSIONS: A cross-sectional analysis of frontal lobe features, behavioural characteristics and neuropsychological data demonstrated that, in AD (and to a lesser extent in MXD) patients, frontal lobe symptoms were associated with more pronounced cognitive deficits (of frontal origin), with increased severity and frequency of agitated and aggressive behaviour, and with increased severity of psychosis and depressive symptoms. Given the small sample sizes of the DLB and FTD patient groups, negative findings in these patient groups should be interpreted cautiously.     

Measurements of cerebral blood flow and metabolism in patients with Alzheimer's disease

Positron emission tomography (PET) was used to measure cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and cerebral metabolic rate of glucose (CMRglc) in patients with Alzheimer's disease. In the patients, values for CBF, CMRO2, and CMRglc have been shown to drop by 30-50% in comparison to age-matched normal controls. In the early stage (stage I), reductions in CBF and CMRO2 are prominent in the temporal and the temporoparietal cortices. In stage II, reduction in the parietal cortex also become quite prominent, and in the late stage (stage III) reduction begins prominently in the frontal cortex as well. These PET findings in Alzheimer's disease differ from those in vascular dementia, Pick's disease, and Huntington's disease. In the interrelationship among CBF, CMRO2 and higher brain function, CBF and CMRO2 decrease especially in the left frontal, the left temporal and the left parietal cortices in patients with marked language disability. On the contrary, CBF and CMRO2 decrease in the right temporal and the right parietal cortices in patients with marked apraxia and visuospatial deficits. Cerebral blood flow and metabolism are closely related to the functioning of nerve cells. Therefore we can isolate the region responsible for higher brain dysfunction and similarly evaluate the effects of treatment using cerebral blood flow and metabolism measurements.     

Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition

Observational studies suggest that estrogen replacement therapy (ERT) may protect against age-related memory decline and lower the risk of Alzheimer's disease (AD). This study aimed to characterize the neural substrates of those effects by comparing 2-year longitudinal changes in regional cerebral blood flow (rCBF) in 12 ERT users and 16 nonusers. Positron emission tomography (PET) measurements of rCBF were obtained under three conditions: rest, and verbal and figural recognition memory tasks. Groups showed different patterns of change in rCBF over time in a number of brain areas. These group differences, for the most part, reflected regions of increased rCBF over time in users compared to nonusers. The greatest differences between ERT users and nonusers were in the hippocampus, parahippocampal gyrus, and temporal lobe, regions that form a memory circuit and that are sensitive to preclinical AD. Across a battery of standardized neuropsychological tests of memory, users obtained higher scores than did nonusers of comparable intellect. Group differences in longitudinal change in rCBF patterns may reflect one way through which hormones modulate brain activity and contribute to enhanced memory performance among ERT users.     

Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons

Epidemiological studies suggest that elevated blood pressure (BP) in midlife is associated with increased risk of Alzheimer's disease (AD) in late life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid-beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late middle-aged to older adult apolipoprotein E (APOE) ε4 homozygotes, heterozygotes and noncarriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal, and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB distribution volume ratios and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower glucose metabolism in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late midlife may be associated with increased risk of presymptomatic AD.     

Hippocampal metabolic abnormalities in mild cognitive impairment and Alzheimer's disease

Mild cognitive impairment (MCI) defines a group of otherwise healthy elderly subjects with a markedly elevated risk of developing Alzheimer's disease (AD). In the search for biomarkers of MCI, we assessed whether MCI shares neurochemical abnormalities with AD in areas affected early in the course of the disease. As a secondary study aim, we tested to what extent neurochemical findings reflect neuropsychological deficits. Proton spectroscopy was performed in 19 MCI patients, 18 AD patients and 22 age and gender matched controls (CON) within the parietal gray and white matter (PWM and PGM) and the hippocampus (HIP). The cognitive test battery used included measures compiled by the Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The N-acetyl-aspartate to creatine ratio (NAA/Cr) was significantly reduced in the HIP of MCI and AD compared with CON (p < 0.05). Only AD patients showed parietal abnormalities, namely significantly elevated myoinositol (mI/Cr and mI/NAA) in PGM, reduced NAA/Cr and elevated mI/NAA in PWM. MCI subjects were significantly impaired in categorical verbal fluency (VF) (p < 0.001) and delayed verbal recall (DVR) (p < 0.001). VF was positively correlated with hippocampal NAA/Cr (p < 0.05) and parietal mI/NAA (p < 0.05). In summary, this study demonstrates shared neurobiological hippocampal abnormalities in MCI and AD, whereas parietal lobe neurochemical profiles and functions were normal in MCI. Thus, biological evidence is provided that MCI represents a precursor stage of AD. Moreover, multivoxel 1H MRS may enable an objective staging of the neurodegenerative process underlying the age-dependent cognitive deficits eventually leading to dementia.     

Anatomical and functional alterations in semantic dementia: a voxel-based MRI and PET study

Rare studies have used magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) to assess atrophy, and only two positron emission tomography (PET) studies used SPM to examine functional changes in semantic dementia (SD). Our aim was to highlight both morphological and functional abnormalities in a same group of 10 SD patients, in the entire brain, using a “state of the art” methodology (optimized VBM procedure, PET data corrected for partial volume effects and voxel-based analyses). We also used an extensive neuropsychological battery. We showed that main alterations concerned the left temporal lobe, in accordance with the striking impairment of semantic memory in SD patients, as well as the hippocampal region, which may partly explain their moderate episodic memory deficits. Hypometabolism was more extensive than grey matter loss in both temporal lobes, and specifically concerned the orbitofrontal areas, consistent with the moderate impairment of executive functions and behavioural changes. While PET is more sensitive than MRI, there is striking concordance between morphological and functional abnormalities, which contrasts with the discordance observed in Alzheimer's disease and might be a typical feature of SD.     

Distinguishing between neurodegenerative disease and disease-free aging: correlating neuropsychological evaluations and neuropathological studies in centenarians

OBJECTIVE: In an examination of disease-free aging and neurodegenerative disease in 100-year-olds, the New England Centenarian Study compared data from neuropsychological evaluations with postmortem brain studies of fourteen 100-year-olds to ascertain if the presence or absence of Alzheimer disease changes correlated with measured cognitive abilities. METHODS: Fourteen of 74 centenarians who underwent annual extensive neuropsychological evaluation proceeded to postmortem neuropathological examination. CERAD criteria, emphasizing neuritic amyloid plaques and Braak and Braak staging of neurofibrillary tangles were used to assess the 14 brains. RESULTS: Neuropsychological and neuropathological findings correlated well for four subjects with no dementia on testing (CDR = 0) and for six subjects with CDR scores in the dementia range (CDR = 1-5). In the latter group, Alzheimer's disease was diagnosed in four brains; Pick's disease was an etiological factor in the fifth and hippocampal sclerosis in the sixth. Correlation was low for four subjects: two subjects with no dementia on neuropsychological testing met CERAD neuropathological criteria for possible AD; two subjects with dementia on testing did not meet CERAD criteria for definite Alzheimer's disease and had otherwise minimal changes to correlate with the cognitive findings. CONCLUSIONS: Lack of correlation between level of cognitive functioning and brain pathology in two subjects with no dementia raised the question of whether a functional reserve delayed the functional expression of pathological changes. For two subjects with dementia on testing, there appeared to be no sufficient pathological explanation for the extent of the cognitive changes; depression and such factors as environment, sensory impairment, and medical illness may all have played a role. There may also have been neuropathologic changes not detected by current methods.     

无痴呆综合症的艾滋病患者局部脑血流的变化

目的:观察无痴呆综合症的艾滋病(AIDS)患者局部脑血流(rCBF)的变化。方法:对4例无痴呆综合症的男性AIDS患者(IV期)进行了^99mTc-双半胱乙脂(ECD)脑血流灌注断层显像, 并定量测定rCBF。16例性别、年龄匹配的健康者作正常对照。结果:4例无痴呆综合症的AIDS患者双侧额、顶、颞叶、基底节和丘脑、以及直回和桥脑rCBF明显低于正常对照组(P＜0.01)。结论:无痴呆综合症的AIDS患者存在脑皮层和皮层下rCBF减少。     

Brain atrophy associated with baseline and longitudinal measures of cognition

The overall goal was to identify patterns of brain atrophy associated with cognitive impairment and future cognitive decline in non-demented elders. Seventy-one participants were studied with structural MRI and neuropsychological testing at baseline and 1-year follow-up. Deformation-based morphometry was used to examine the relationship between regional baseline brain tissue volume with baseline and longitudinal measures of delayed verbal memory, semantic memory, and executive function. Smaller right hippocampal and entorhinal cortex (ERC) volumes at baseline were associated with worse delayed verbal memory performance at baseline while smaller left ERC volume was associated with greater longitudinal decline. Smaller left superior temporal cortex at baseline was associated with worse semantic memory at baseline, while smaller left temporal white and gray matter volumes were associated with greater semantic memory decline. Increased CSF and smaller frontal lobe volumes were associated with impaired executive function at baseline and greater longitudinal executive decline. These findings suggest that baseline volumes of prefrontal and temporal regions may underlie continuing cognitive decline due to aging, pathology, or both in non-demented elderly individuals.     

Metabolic correlates of clinical heterogeneity in questionable Alzheimer's disease

Thirty-four subjects with questionable Alzheimer's disease (QAD) were included in a 3-year prospective study and underwent neuropsychological testing and measurement of brain metabolism using FDG-PET at entry. Seventeen patients (50%) did not convert to AD during the follow-up period. Compared to elderly controls of similar age, the cerebral activity of non-converters was reduced in the dorsolateral prefrontal cortex. Moreover, the variability of metabolism in the posterior cingulate cortex was related to their visuospatial memory performance, while disparity in parietal activity was related to their verbal memory performance. These results demonstrate the cerebral metabolic heterogeneity of patients with QAD. Initial functional images of converters showed that activity was already impaired in the posterior cingulate, lateral temporal cortex, anterior cingulate and orbitofrontal cortex. This metabolic pattern is consistent with a pre-dementia stage of AD, and highlights the fact that significant frontal metabolic involvement may be associated with impaired activity in posterior associative cortices in very early AD.     

The relationship between auditory ERP and neuropsychological assessments in schizophrenia.

To clarify the cognitive significance of event-related potential (ERP) abnormalities in schizophrenia, we examined the relationships of amplitudes and latencies of ERP components with performance on neuropsychological tests in schizophrenic patients. Twenty patients underwent the Trail Making B Test (TM-B), which is sensitive to frontal lobe dysfunction, and the logical memory, verbal paired-association, and visual reproduction subtests of the Wechsler Memory Scale (WMS), which are sensitive to temporal lobe dysfunctions, and ERP recordings during performance of an oddball auditory discrimination task. Pearson product-moment correlations indicated that an increased P200 amplitude was correlated with poor performance on the TM-B, whereas a decreased P300 amplitude was correlated with poor performance on the verbal paired-association subtest of the WMS. These findings suggest that a P200 abnormality represents the frontal lobe dysfunction, and a P300 abnormality represents the left temporal lobe dysfunction in schizophrenia.