The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment

Subjects in the preclinical stages of Alzheimer's disease (AD) typically record neuropsychological performance between that of healthy older individuals and demented patients. More specifically, deficits on measures of verbal episodic memory are commonly reported in these patients, while other cognitive functions (e.g. language, praxis and executive function) seem to be spared. A similar neuropsychological profile is observed in elderly subjects with mild cognitive impairment (MCI), a disorder that is attracting increasing research interest. Evidence from lesion and functional imaging studies, as well as volumetric imaging in probable AD and MCI patients, suggests that the cognitive deficits observed in these disorders may be related to medial temporal lobe dysfunction. An issue currently under investigation is whether MCI represents the preclinical stages of AD or a distinct and static cognitive aetiology. In an attempt to address this issue, present investigations are adopting a convergent approach to the detection of preclinical AD, where multiple risk factors are considered when making a diagnosis.     

The investigation of Alzheimer''s disease with single photon emission tomography.

Twenty patients satisfying standard clinical criteria for Alzheimer's disease (AD) and six age-matched normal controls were studied using 99mTc hexamethyl-propyleneamine oxime and single photon emission tomography. The AD patients had lower regional cerebral blood flow (rCBF) in the temporal and posterior parietal lobes compared to controls. AD patients with apraxia and aphasia had lower rCBF in the lateral temporal and posterior parietal lobes than AD patients without these features. Within the AD group, correlations were found between neuropsychological tests and rCBF: praxis correlated with posterior parietal activity, memory with left temporal lobe activity and language with activity throughout the left hemisphere.     

Neuropsychological correlates of cerebral atrophy in Alzheimer's dementia

This study aims to systematically analyze the relationship between neuropsychological deficits and regional cerebral atrophic changes in Alzheimer's dementia (AD). As an extension of previous studies we not only investigated substructures of the medial temporal lobe but also included other relevant cerebral regions such as frontal, temporal, and parietal lobes. This approach was based on the assumption that morphological correlates of global and specific cognitive dysfunction might reflect to a certain degree the neuronal basis of the respective function. Accordingly, the functional role assigned to a certain cerebral structure or region can be further elucidated which might lead to a better understanding of the clinical and neuropsychological heterogeneity of AD. Fifty patients with AD (NINCDS-ADRDA criteria) and 20 healthy elderly control subjects were included. All patients and controls were examined on a standardized neuropsychological test battery. In addition, magnetic resonance imaging (MRI) of the brain was performed. Volumes of the whole brain, CSF-spaces, amygdala-hippocampus complex, frontal lobes, temporal lobes, and parietal lobes were measured using a standardized protocol. AD-patients were characterized by neuropsychological deficits with respect to memory, language, praxia, cognitive speed as well as attention and concentration. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex were correlated with declarative memory performance in the non-verbal visual domain. Furthermore, an association between left temporo-parietal regions and aspects of semantic memory, as well as verbal recall and left frontal regions could be established. The validity of our results is supported by recent findings from neuropathological and functional neuroimaging studies. In conclusion, our data indicate that MRI-based volumetry can be successfully used to detect morphological correlates of neuropsychological heterogeneity in AD and that this methodological approach allows to fruitfully study the neuronal basis of cognitive functions.     

轻度认知功能障碍患者正电子发射计算机体层摄影术和神经心理学测定的初步研究

目的　探讨轻度认知功能障碍患者脑葡萄糖代谢与神经心理学特点及其相互关系。方法　采用正电子发射体层摄影术 (PET)、简易智能状态测定 (MMSE)、韦克斯勒记忆量表测定 (WMS)和总体衰退量表 (GDS)测定 10例轻度认知功能障碍 (MCI)患者和 10名健康志愿者 (HC)。结果 (1)MCI组MMSE[(2 4.6± 2 2 )分 ]、WMS[(6 9.4± 10 .4)分 ]分值低于HC组 [分别为 (2 8.9± 1.1)分和 (93.1± 9.0 )分 ;P〈0 .0 1];(2 )MCI组左侧眶回、右侧颞叶中回和右侧壳核的局部脑葡萄糖代谢率 (rCMRglc)较HC组低 (P〈0 .0 5～ 0 .0 1) ;(3)将年龄、受教育年限、MMSE、WMS与不同脑区用18F标记的脱氧葡萄糖放射性比值进行相关分析显示 ,与年龄呈负相关 (P〈0 .0 5或P〈0 .0 1)的脑区有 :眶回、左侧额上回、左侧额下回、颞叶中回、颞叶下回、左侧顶叶、左侧中央前回、右侧中央后回、左颞叶内侧皮质、左侧海马回、左侧海马旁回、右侧前扣带回、后扣带回、左侧杏仁核等。与文化程度呈正相关 (P〈0 .0 5或P〈0 .0 1)的脑区有 :左侧颞叶下回、中央前回、左侧中央后回等 ;而右侧壳核则呈负相关。与MMSE呈正相关 (P〈0 .0 5或P〈0 .0 1)的脑区有 :额下回、左侧颞叶上回、颞叶中回、颞叶下回、左侧顶叶、左侧中央前回、中央后回、颞叶内侧皮     

CERAD test performances in amnestic mild cognitive impairment and Alzheimer's disease

OBJECTIVES: The aim of the study was to examine the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test performances cross-sectionally in patients suffering from amnestic mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Moreover, we wanted to determine the sensitivity to amnestic MCI and mild AD, as well as the specificity of different CERAD subtests in our study groups. MATERIAL AND METHODS: Fifteen healthy elderly individuals, 15 amnestic MCI patients and 15 probable AD patients suffering from mild dementia were tested with the CERAD neurocognitive dementia screening test. RESULTS: Significant differences were found in all CERAD tests except Constructional praxis (copy) and Clock drawing between the controls and the AD group. The MCI group was differentiated from the controls only in the Wordlist learning test. In the language tests the sensitivity to MCI and AD was quite low and the specificity very high. In the savings scores the sensitivity to AD was high, but the specificity rather low. The Wordlist recognition test screened no false positives using the current cut-off score and the sensitivity to AD was 0.6, but only one MCI patient was detected using the current cut-off score. Raising the cut-off score also raised the sensitivity to MCI without dramatic loss of specificity. Cut-off scores for the Wordlist learning test and Wordlist delayed recall, which have been found to differentiate normal aging from dementia, are lacking in the Finnish CERAD. The current data indicates that the Wordlist learning test might be relatively sensitive to MCI. CONCLUSIONS: The results indicate that the Finnish CERAD test battery with its current cut-off scores has low sensitivity to MCI, and using it as a sole cognitive screening instrument for MCI and preclinical dementia might result in false negatives.     

Quantitative analysis of brain perfusion SPECT in Alzheimer's disease using a fully automated regional cerebral blood flow quantification software, 3DSRT

PURPOSE: The clinical symptoms of Alzheimer's disease (AD) show great diversity depending on the clinical stage. We investigated the correlation of regional cerebral blood flow (rCBF) changes and the clinical severity of AD patients. METHODS: Thirty-nine AD patients and 16 normal subjects participated in this study. AD patients were divided into three subgroups by clinical severity. Quantitative brain perfusion SPECT analyses were performed using a rCBF quantification software, 3DSRT. RESULTS: In mild AD, significant decreases of rCBF were detected in the bilateral parietal, angular gyrus, pericallosal, thalamus, right temporal and left hippocampal regions. Moderate AD patients showed significantly lower blood flow than those with mild AD only to the right hippocampus. Analysis of the severe AD group revealed a nearly diffuse decrease of rCBF throughout the cerebral cortex except for part of the frontal lobe compared with moderate patients. CONCLUSIONS: These results were consistent with previous findings demonstrated by qualitative analysis of CBF. The decreased thalamic blood flow was noteworthy as this finding has rarely been reported. In consideration of the structure and function of the Papez circuit, which connects the medial temporal lobe and thalamus, a remote metabolic effect might be the cause of lower rCBF in the thalamus.     

A voxel based morphometry study on mild cognitive impairment

BACKGROUND: Mild cognitive impairment (MCI) is the most widely used concept in classifying cognitive impairment in the elderly who do not fulfil the criteria for dementia. MCI is considered to confer an increased risk of progressing to dementia and most often Alzheimer's disease (AD). Various approaches such as imaging of the brain have been applied to predict the conversion of MCI to dementia. A number of volumetric magnetic resonance imaging (MRI) studies have detected atrophy of the medial temporal lobe in subjects with MCI, but for the other cerebral regions the results have been inconsistent. OBJECTIVE: To study the pattern of brain atrophy in MCI. METHODS: Thirty two controls and 51 individuals with MCI deriving from population based cohorts were studied by MRI using voxel based morphometry. The threshold of t maps was set at p < 0.001. RESULTS: Individuals with MCI had significant unilateral atrophy in the medial temporal lobe on the right side. Less extensive atrophy was found elsewhere-for example, in the temporal lobe, left superior parietal lobule, left anterior cingulate gyrus, and bilaterally in the thalami. CONCLUSIONS: The MRI findings in MCI resemble those seen in early AD.     

Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study

BACKGROUND: Mild cognitive impairment (MCI) is a recently described transitional clinical state between normal aging and AD. Assuming that amnestic MCI patients had pathologic changes corresponding to an early phase and probable AD patients to a later phase of the disease progression, the authors could approximate the temporal course of proton MR spectroscopic (1H MRS) alterations in AD with a cross-sectional sampling scheme. METHODS: The authors compared 1H MRS findings in the superior temporal lobe, posterior cingulate gyri, and medial occipital lobe in 21 patients with MCI, 21 patients with probable AD, and 63 elderly controls. These areas are known to be involved at different neurofibrillary pathologic stages of AD. RESULTS: The N-acetylaspartate (NAA)/creatine (Cr) ratios were significantly lower in AD patients compared to both MCI and normal control subjects in the left superior temporal and the posterior cingulate volumes of interest (VOI) and there were no between-group differences in the medial occipital VOI. Myoinositol (MI)/Cr ratios measured from the posterior cingulate VOI were significantly higher in both MCI and AD patients than controls. The choline (Cho)/Cr ratios measured from the posterior cingulate VOI were higher in AD patients compared to both MCI and control subjects. CONCLUSION: These findings suggest that the initial 1H MRS change in the pathologic progression of AD is an increase in MI/Cr. A decrease in NAA/Cr and an increase in Cho/Cr develop later in the disease course.     

Correlations between Z‐scores of VSRAD and regional cerebral blood flow of SPECT in patients with Alzheimer's disease and mild cognitive impairment

Aims: The purpose of the present study was to investigate whether there were correlations between atrophy of the entorhinal cortex and individual regional cerebral blood flow (rCBF) in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (MCI) to better clarify the relationships between morphological and functional changes in AD. Methods: Twenty‐six patients including sixteen AD and 10 amnestic MCI patients were enrolled. Z scores of voxel‐based specific regional analysis system for AD (VSRAD) were determined to assess the degree of atrophy of the entorhinal cortex. Single‐photon emission computed tomography (SPECT) and 3‐D stereotaxic region of interest template (3DSRT) were used to quantify absolute rCBF. Results: The Z scores of the entorhinal cortex were found to have significant negative correlations with the absolute rCBF in the bilateral hippocampus, thalamus and temporal regions. A negative correlation between Z scores and rCBF of the cerebellum region, especially on the right side, was also noted. Conclusions: Atrophy of the entorhinal cortex had an obvious functional relationship with rCBF changes in the hippocampus, thalamus, temporal lobe and cerebellum in AD and MCI patients, which was attributed to their close anatomical and physiological connections.     

The functional neuroanatomy of verbal memory in Alzheimer’s disease: [18F]-Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) correlates of recency and recognition memory

Introduction: The objective of this study was to distinguish the functional neuroanatomy of verbal learning and recognition in Alzheimer’s disease (AD) using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Word Learning task. Method: In 81 Veterans diagnosed with dementia due to AD, we conducted a cluster-based correlation analysis to assess the relationships between recency and recognition memory scores from the CERAD Word Learning Task and cortical metabolic activity measured using [¹⁸F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Results: AD patients (Mini-Mental State Examination, MMSE mean = 20.2) performed significantly better on the recall of recency items during learning trials than of primacy and middle items. Recency memory was associated with cerebral metabolism in the left middle and inferior temporal gyri and left fusiform gyrus (p < .05 at the corrected cluster level). In contrast, recognition memory was correlated with metabolic activity in two clusters: (a) a large cluster that included the left hippocampus, parahippocampal gyrus, entorhinal cortex, anterior temporal lobe, and inferior and middle temporal gyri; (b) the bilateral orbitofrontal cortices (OFC). Conclusions: The present study further informs our understanding of the disparate functional neuroanatomy of recency memory and recognition memory in AD. We anticipated that the recency effect would be relatively preserved and associated with temporoparietal brain regions implicated in short-term verbal memory, while recognition memory would be associated with the medial temporal lobe and possibly the OFC. Consistent with our a priori hypotheses, list learning in our AD sample was characterized by a reduced primacy effect and a relatively spared recency effect; however, recency memory was associated with cerebral metabolism in inferior and lateral temporal regions associated with the semantic memory network, rather than regions associated with short-term verbal memory. The correlates of recognition memory included the medial temporal lobe and OFC, replicating prior studies.     

Similar 1H magnetic resonance spectroscopic metabolic pattern in the medial temporal lobes of patients with mild cognitive impairment and Alzheimer disease

Structures of the medial temporal lobes are recognized to play a central role in memory processing and to be the primary sites of deterioration in Alzheimer disease (AD). Mild cognitive impairment (MCI) represents potentially an intermediate state between normal aging and AD. Proton magnetic resonance spectroscopy (MRS) was used to examine brain metabolic changes in patients with AD and MCI in the medial temporal lobes (MTLs), parietotemporal cortices (PTCs) and prefrontal cortices (PFCs). Fourteen patients with MCI, 14 patients with mild AD and 14 age- and sex-matched control subjects were studied. Patients with AD and MCI demonstrated significant reductions of NAA/H(2)O and Cho/H(2)O in the left MTL relative to control subjects. Patients with AD showed mI/H(2)O increases relative to patients with MCI and control subjects in all six regions investigated, and a statistically significant mI/H(2)O increase was measured in the right PTC. Patients with AD and MCI demonstrated the same metabolic pattern in the left MTL, suggesting a similar pathological process underlying memory impairment. Increased mI signal appears to be a neurochemical abnormality associated mostly with AD and the dementia process. Some interhemispheric metabolite asymmetries were increased in AD patients.     

Episodic and semantic memory in mild cognitive impairment

Little is known about episodic and semantic memory in the early predementia stage of Alzheimer's disease (AD), which is referred to as mild cognitive impairment (MCI). To explore person knowledge, item recognition and spatial associative memory, we designed the Face Place Test (FPT). A total of 75 subjects participated: 22 patients with early AD, 24 with MCI and 29 matched controls. As predicted, AD patients showed significant deficits in person naming, item recognition and recall of spatial location (placing). Surprisingly, subjects with MCI were also impaired on all components. There was no significant difference between AD and MCI except on the placing component. Analysis of the relationship between semantic (naming) and episodic (recognition and placing) components of the FPT revealed a significant association between the two episodic tasks, but not between episodic and semantic performance. Patients with MCI show deficits of episodic and semantic memory. The extent of impairment suggests dysfunction beyond the medial temporal lobe. The FPT might form the basis of a sensitive early indicator of AD.     

Risk classification in mild cognitive impairment patients for developing Alzheimer's disease

The objective of this study was to develop new risk classifications for conversion to Alzheimer's disease (AD) by comparing the relative reliability of classifiers in patients with mild cognitive impairment (MCI). The 397 MCI subjects and all baseline data, including characteristics, neuropsychological tests, cerebrospinal fluid biomarkers and MRI findings in Alzheimer's Disease Neuroimaging Initiative (ADNI), were used for analysis by Cox proportional hazard regression, bootstrap sampling, and c-index. Multivariate Cox regression analysis revealed the following factors to be associated with increased risk of conversion from MCI to AD during the 53-month follow-up period: AVLT 30-minute delayed recall, AVLT trial 1, Boston naming, logical delayed recall, trail-making B, CDR-sob, ADAS13, the cortical thickness of the right inferior temporal lobe (st91ta), and the left hippocampus volume. The combinations of ADAS13 at a cutoff point of 15.67 with CDR-sob at 1.5 or with the cortical thickness of the right inferior temporal lobe at 2.56 mm3 produced high conversion rates of 92.7% (82.4%-100.0%) and 88.8% (77.3%-100.0%), respectively, at 48 months. The discriminative ability based on c-index for the proposed combination was 0.68. The sample size was estimated as 504 in the group with a combination of ADAS13 and CDR-sob whose conversion rate is highest. The combination of ADAS13 with CDR-sob at an optimal cutoff point has a high reliability in classifying the MCI patients into high- and low-risk conversion to AD and will be benefit for patients' assessment and potentially facilitate the clinical development of novel therapeutics.     

A critical evaluation of the lateralizing significance of material-specific memory deficits in patients with mesial temporal lobe epilepsy with hippocampal sclerosis

To critically assess the value of material-specific memory deficits in lateralizing temporal lobe dysfunction preoperatively, we compared the neuropsychological data of 50 consecutive patients with unilateral mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS; right: 31, left: 19) with those of 50 age- and education-matched healthy control subjects. On case-control comparison, both the subcohorts with left and right MTLE-HS performed poorly on intelligence tests, in addition to individual memory tests. However, comparison of the verbal and visual memory functions between subcohorts with right and left MTLE-HS revealed that learning trials and delayed word list recall were the only tests that hypothesized left temporal lobe dysfunction. We conclude that material-specific memory deficits are largely test driven, but there is a lateralizing role for task-specific deficits in left MTLE-HS. Although neuropsychological data help to define baseline neuropsychological impairment, caution should be exercised in interpreting the lateralizing value of material-specific memory deficits prior to surgery.     

A visual [18F]FDG-PET rating scale for the differential diagnosis of frontotemporal lobar degeneration

This study presents a visual rating scale for the assessment of cerebral [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) scans to characterize typical findings in dementias associated with frontotemporal lobar degeneration (FTLD) and to differentiate individual patients with FTLD compared to Alzheimer’s disease (AD) and mild cognitive impairment (MCI). A total of 43 cerebral PET scans from patients with FTLD (n = 16, mean age 58.4 years), AD (n = 16, 59.9 years) and MCI (n = 11, 57.9 years) were analysed. Every PET data set was visually rated for seven brain regions on each hemisphere (frontal lobe, temporal lobe, parietal lobe, occipital lobe, basal ganglia, thalamus and cerebellum). The extent of the impairment in metabolism was classified as absent, mild, medium or strong. Using this four-stage visual rating scale, characteristic profiles of metabolic impairment in FTLD, AD, MCI and the FTLD-subgroup FTD (n = 9) could be demonstrated. Patients with FTLD showed a significantly lower metabolism in the left frontal lobe and in the left basal ganglia when compared to AD and to MCI. Complementary analyses using statistical parametric mapping (SPM2) supported the findings of the visual analysis. In detecting FTLD with visual rating, sensitivity/specificity was 81/94% compared to AD and 81/64% compared to MCI. Patients with FTD were correctly attributed to a diagnosis of FTLD with a sensitivity of 89%. This visual rating scale may facilitate the differential diagnosis of FTLD in clinical routine.     

阿尔茨海默病脑白质葡萄糖代谢异常分析

目的探讨阿尔茨海默病(AD)脑白质葡萄糖代谢异常的意义。方法纳入33例符合美国精神障碍诊断与统计手册-第四版(DSM-IV)AD诊断标准的患者和健康对照20名,进行脑正电子发射断层成像(PET)检查。应用SPM软件对PET图像进行分析。结果①与健康对照相比,AD患者有广泛的白质葡萄糖代谢减低,减低较为明显的区域有右侧额叶皮质下白质、左侧额叶上中回皮质下白质(P<0.001);另外,AD患者左侧额叶内侧回皮质下白质、左侧枕叶楔回皮质下白质葡萄糖代谢增强(P<0.001);②与不伴有精神行为症状(BPS)的AD患者(16例)相比,伴有BPS的AD患者(17例)在左右枕叶中回、右侧枕叶楔回、右侧顶下小叶、左侧颞叶梭形回、左侧额叶内侧回等脑区的皮质下白质葡萄糖代谢增强(P<0.001);而左右额叶中央旁回、右侧额叶上回和中回、左侧颞叶上回等脑区的皮质下白质葡萄糖代谢减低(P<0.001)。结论AD有广泛的白质脑葡萄糖代谢异常,有无BPS的AD白质代谢异常不同。     

Left anterior temporal lobe sustains naming in Alzheimer's dementia and mild cognitive impairment

Cognitive decline in degenerative dementia is paralleled by progressive brain atrophy, with the localization of atrophy reflecting specific cognitive impairment. Confrontation naming deficits are frequently observed in dementia across etiologies. In this study we aimed to identify the brain regions underlying this deficit. In patients with clinically diagnosed dementia or mild cognitive impairment (MCI) we investigated the relationship between gray matter volume (GMV) and performance on a standardized confrontation naming test. 268 patients with one of three probable etiologies were included: Alzheimer's Dementia (AD), AD with signs of cerebrovascular pathology, and frontotemporal dementia. Applying voxel-based morphometry using a diffeomorphic registration algorithm we contrasted GMV of patients performing within the normal range with those of patients with pathological performance. Further, differential effects of gray matter atrophy on impaired performance in AD versus MCI of AD type were investigated. Results revealed significantly reduced GMV in the left anterior temporal lobe (ATL) in pathological performers compared to normal performers. The subgroup analysis confined to MCI of AD type and AD patients confirmed this relationship. While left ATL atrophy is known to be implicated in naming deficits in semantic dementia, our data confirm the same in AD and MCI of AD type.     

Cognitive event-related potentials: biomarkers of synaptic dysfunction across the stages of Alzheimer's disease

Cognitive event-related brain potential (ERP) studies of decision-making and attention, language, and memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are reviewed. Circumscribed lesions of the medial temporal lobe (MTL), as may be the case in individuals with amnestic MCI, generally produce altered plasticity of the late positive P600 component, with relative sparing of earlier sensory ERP components. However, as the neuropathology of AD extends to neocortical association areas, abnormalities of the P300 and N400 (and perhaps even P50) become more common. Critically, ERP studies of individuals at risk for AD may reveal neurophysiological changes prior to clinical deficits, which could advance the early detection and diagnosis of "presymptomatic AD".     

Altered topological patterns of brain networks in mild cognitive impairment and Alzheimer's disease: a resting-state fMRI study

Recent studies have shown that cognitive and memory decline in patients with Alzheimer's disease (AD) is coupled with losses of small-world attributes. However, few studies have investigated the characteristics of the whole brain networks in individuals with mild cognitive impairment (MCI). In this functional magnetic resonance imaging (fMRI) study, we investigated the topological properties of the whole brain networks in 18 AD patients, 16 MCI patients, and 18 age-matched healthy subjects. Among the three groups, AD patients showed the longest characteristic path lengths and the largest clustering coefficients, while the small-world measures of MCI networks exhibited intermediate values. The finding was not surprising, given that MCI is considered to be the prodromal stage of AD. Compared with normal controls, MCI patients showed decreased nodal centrality mainly in the medial temporal lobe as well as increased nodal centrality in the occipital regions. In addition, we detected increased nodal centrality in the medial temporal lobe and frontal gyrus, and decreased nodal centrality mainly in the amygdala in MCI patients compared with AD patients. The results suggested a widespread rewiring in AD and MCI patients. These findings concerning AD and MCI may be an integrated reflection of reorganization of the brain networks accompanied with the cognitive decline that may lead to AD.