Visual association pathology in preclinical Alzheimer disease

The transition from normal aging to mild cognitive impairment to Alzheimer disease (AD) is often indistinct. Imaging studies suggest early changes in posterior brain regions, including posterior temporoparietal and occipital cortex, but pathologic studies show initial changes in the medial temporal lobe with progressive neocortical involvement as cognition deteriorates. We evaluated the regional distribution of AD pathology in 41 elderly brain donors from the Framingham Heart Study who were cognitively intact, mildly impaired, or demented on the basis of probable AD. We found that 52% of the cognitively intact subjects, and all subjects with mild cognitive impairment or dementia, had dense neurofibrillary tangles (NFTs), neuropil threads, and tau-immunoreactive neurites surrounding neuritic plaques (NPs) in visual association cortex Brodmann area 19. All cognitively intact subjects with area 19 NFTs also had dense core NP and beta amyloid (Abeta) angiopathy in area 19. Area 19 pathology was occasionally present in the absence of substantial pathology in the hippocampus or entorhinal cortex and was not correlated with medial temporal lobe pathology. Dense AD pathology in area 19 is present in some cognitively intact subjects with preclinical AD. The unique metabolic, connectional, and vascular features of this region may confer enhanced vulnerability to neurodegeneration.     

Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment

To determine whether the medial temporal lobe is atrophic in subjects with mild cognitive impairment, and whether atrophy of this structure is a better predictor of dementia than memory dysfunction. Forty-five noninstitutionalized subjects aged 65–85 years were randomly selected from a population based study to obtain a sample with Alzheimer’s disease (AD; n = 7), and a clinically nondemented sample (n = 38). Twenty of the latter subjects displayed some cognitive impairment and fulfilled CAMDEX criteria for “minimal dementia.” Coronal T1-weighted magnetic resonance imaging was used to visualize the medial temporal lobe. The volume of the parahippocampal gyrus and hippocampus was measured, and medial temporal lobe atrophy was assessed qualitatively. The memory subscore from the CAMCOG was used as a measure of memory functioning. The follow-up period was 3 years. Nine subjects who were diagnosed as being minimally demented at baseline met the criteria for AD during follow-up. At baseline the volume of the parahippocampal gyrus of these subjects was smaller than that of the other subjects with minimal dementia. The memory score was the best predictor of clinical outcome. All medial temporal lobe measures increased the accuracy of prediction compared with only the memory score, by reducing the number of false-negative classifications of dementia. Severe medial temporal lobe atrophy is present even in some subjects with mild cognitive impairment and is an indicator of subsequent AD. The absence of medial temporal lobe atrophy, however, does not exclude the development of dementia. In the majority of subjects memory impairment was a better predictor of dementia than atrophy of the medial temporal lobe. The combination of the two increased predictive accuracy. Nondemented subjects with severe atrophy of the medial temporal lobe could be enrolled in drug trials aimed at slowing the progression of AD. Received: 18 June 1998 Received in revised form: 28 September 1998Accepted: 4 November 1998     

Self-consciousness and Alzheimer''s disease

OBJECTIVES: To propose a neuropsychological study of the various aspects of self-consciousness (SC) in Alzheimer's disease. METHODS: Forty-five patients with probable mild or moderate AD were included in the study. Severity of their dementia was assessed by the Mini Mental State (MMS). Fourteen questions were prepared to evaluate SC. RESULTS: No significant correlations were found between SC score and educational level, age, and duration of disease. A significant correlation was found between SC score and the severity of dementia, whereas frontal disturbances were just short of the significance threshold. The various aspects of SC were not impaired to the same degree. The most disturbed ones were awareness of cognitive deficiencies, moral judgements and prospective memory. The least disturbed aspects were awareness of identity and of mental representation of the body. Items relating to anosognosia and moral judgements were significantly correlated with the MMS score, whereas affective state, body representation disorders, prospective memory, and capacities for introspection were not related to the severity of the dementia. Consciousness of identity was sound, regardless of MMS score. CONCLUSIONS: AD clearly induces an heterogeneous impairment of SC. SC requires a convergence of many neural networks. In AD, neuronal alterations involve many cortical areas and information sent to the associative frontal cortex from memory, language and visuospatial areas is lacking or disturbed. Thus, the sequential order of successive stimuli cannot be maintained by the heteromodal associative cortex (dorsal convexity of the prefrontal cortex), and the supramodal associative cortex (located rostrally in the frontal lobes) is unable to provide reliable monitoring and assessment of simultaneous neural cognitive networks carrying insufficient and inadequate input. The core deficiency in AD patients might be impaired SC equated with the disability to maintain sequential and simultaneous "attention to life". The Self-Consciousness Questionnaire, a clinical scale providing multidimensional measurement, indicates that different aspects of consciousness are not correlated with overall cognitive deficiency as determined by the MMSE.     

Detailed assessment of activities of daily living in moderate to severe Alzheimer's disease.

Patients with Alzheimer's Disease (AD) who have reached a stage of moderate to severe dementia are capable of completing a restricted range of cognitive tests and performing a limited range of activities of daily living (ADL). As part of an initiative to develop instruments to evaluate AD, we analyzed data describing the performance of a large number of ADL and scores on cognitive and global assessment measures in a cohort of patients with AD with moderate to severe cognitive impairment, defined as a Mini-Mental State Examination score ranging from 0-15 (out of 30). From the large pool of ADL, 19 met criteria of applicability, reliability, good scaling, concordant validity, and sensitivity to detect change in performance over 6-12 months. A total score derived from these 19 ADL ratings, comprising a scale termed the Alzheimer Disease Cooperative Study ADL-sev, correlated strongly with measures of cognition and of global dementia severity. Patients with moderate to severe AD showed a decline on the ADL-sev and cognitive measures over 6 and 12 months, consistent with the progression of AD. Detailed evaluation of ADL may provide a useful index to evaluate patients with moderate to severe AD and may complement cognitive assessment, especially for characterizing change in interventional or therapeutic studies.     

Relationship between blood flow kinetics and severity of Alzheimer's disease: assessment of severity using a questionnaire-type examination, Alzheimer's disease assessment scale, cognitive sub-scale (ADAS(cog)).

We assessed hemokinetics associated with changes in Alzheimer's disease (AD) severity in 90 AD patients by researching the relationship between AD Assessment Scale, cognitive sub-scale (ADAS(cog)) scores and regional cerebral blood flow (rCBF). In the present study, we employed the questionnaire-type ADAS(cog) examination to accurately assess the severity of AD. Between five groups classified on the basis of ADAS(cog) score, significant differences were observed in parietal, lateral temporal and superior frontal rCBF. In addition, in parietal and lateral temporal regions, significant correlations were also observed between ADAS(cog) score and rCBF. In superior frontal rCBF, significant differences were noted only between group 5 (> or =40 ADAS(cog) points) and each of the other groups; there was no significant correlation between rCBF and ADAS(cog) score. Thus, we propose the following mechanism for blood flow kinetics associated with changed severity: In an early stage of AD, blood flow in the medial temporal cortex is impaired, and gradually involves the temporoparietal regions. While the medial temporal impairment of blood flow reaches a plateau, temporoparietal blood flow continues to be impaired well into a severe stage, at which point blood flow impairment in the frontal region is initiated.     

Impairment of decision-making cognition in a case of frontotemporal lobar degeneration (FTLD) presenting with pathologic gambling and hoarding as the initial symptoms.

OBJECTIVE: The aim of this study was to use the Iowa Gambling Task (IGT) to examine decision-making cognition in a patient with mild frontal variant of frontotemporal dementia (fv-FTD). BACKGROUND: Although fv-FTD may present with bizarre and dramatic behavioral changes, traditional executive tasks are sometimes preserved in patients with mild fv-FTD. Some evidence suggests that tasks assessing decision-making cognition, such as the IGT, may be sensitive to detect cognitive dysfunction in patients with mild fv-FTD. Here, we report a patient with fv-FTD who presented with bizarre behavior including hoarding, pathologic gambling, and abnormal sexual behavior. METHODS: A 54-year-old man who had been diagnosed as having fv-FTD was examined using a behavioral assessment, a wide range of neuropsychologic tasks, and the IGT. Brain magnetic resonance imaging and brain 99mTc-ethylcysteinate dimer single-photon emission computed tomography examinations were also performed. RESULTS: Although the patient's cognitive abilities were almost fully preserved for a number of traditional neuropsychologic tasks (memory, executive function), the IGT suggested that his decision-making cognition was impaired. The 99mTc-ethylcysteinate dimer single-photon emission computed tomography examination revealed hypometabolism in bilateral medial frontal and orbitofrontal regions of the cerebral cortex, and also in the cingulate gyri. CONCLUSIONS: Our findings suggest that the IGT may be a sensitive tool for assessing patients with mild fv-FTD before the development of severe dementia. We speculate that the deficit in decision-making cognition observed in the present case was associated with hypometabolism in the neural networks of the frontal lobe and involving both the bilateral medial frontal and orbitofrontal regions of the cerebral cortex.     

Limbic hypometabolism in Alzheimer's disease and mild cognitive impairment

The neural basis of the amnesia characterizing early Alzheimer's disease (AD) remains uncertain. Postmortem pathological studies have suggested early involvement of the mesial temporal lobe, whereas in vivo metabolic studies have shown hypometabolism of the posterior cingulate cortex. Using a technique that combined the anatomic precision of magnetic resonance imaging with positron emission tomography, we found severe reductions of metabolism throughout a network of limbic structures (the hippocampal complex, medial thalamus, mamillary bodies, and posterior cingulate) in patients with mild AD. We then studied a cohort with mild cognitive impairment in whom amnesia was the only cognitive abnormality and found comparable hypometabolism through the same network. The AD and mild cognitive impairment groups were differentiated, however, by changes outside this network, the former showing significant hypometabolism in amygdala and temporoparietal and frontal association cortex, whereas the latter did not. The amnesia of very early AD reflects severe but localized limbic dysfunction.     

Cognitive and functional neuroimaging correlate for anosognosia in mild cognitive impairment and Alzheimer's disease

OBJECTIVES: To investigate the correlation between anosognosia and behavioural symptoms, performance on executive tests, and frontal cortex regional cerebral blood flow (rCBF) in patients with 'amnestic mild cognitive impairment' (MCI) and mild Alzheimer's disease (AD). METHODS: From a prospective Memory Clinic cohort including consecutively referred patients, age 60 years or above, and with MMSE score 20 or above, 36 patients with AD and 30 with MCI were included in this study. Anosognosia was assessed using a categorical scale and discrepancy scores between patients' and relatives' reports on a 20-item Memory Questionnaire (MQ). Behavioural symptoms were assessed with Frontal Behavioural Inventory (FBI). Executive functions were examined with a range of neuropsychological tests. Tc99m-HMPAO SPECT was obtained in an unselected sample of 55 of the 66 patients, and rCBF was analysed in six cortical frontal regions. RESULTS: Insight was equally impaired in the two patient groups. A significant correlation was found between impaired awareness and dementia severity (MMSE). Discrepancy-scores on the MQ were significantly correlated to scores on FBI and to rCBF in the right inferior frontal gyrus, but not to executive tests. The groups classified by the categorical ratings 'full', 'shallow' and 'no' awareness were not characterized by differences in behavioural symptoms, executive performance or frontal rCBF. CONCLUSIONS: Impaired awareness is associated with behavioural symptoms and may reflect functional impairment in the right inferior frontal cortex.     

Anosognosia and neuropsychiatric symptoms and disorders in mild Alzheimer disease and mild cognitive impairment

Anosognosia is a multidimensional phenomenon that negatively affects course of illness. This study aimed to explore the association between anosognosia and neuropsychiatric phenomena in mild Alzheimer's disease (AD) and in mild cognitive impairment (MCI). The Anosognosia Questionnaire for Dementia to assess anosognosia, and the Neuropsychiatric Inventory to assess neuropsychiatric symptoms were administered to 209 patients (103 mild AD, 52 amnestic-MCI, and 54 amnestic multidomain-MCI). Categorical diagnoses of apathy, depression, and psychosis were made using specific criteria for dementia. With regard to continuous scores, in mild AD, we found positive correlation between symptoms of anosognosia and apathy, agitation and aberrant motor behaviors, while in MCI, we did not find significant association. At a categorical level, the diagnosis of anosognosia in mild AD was associated with the diagnosis of apathy. In mild AD, the frequent co-occurrence of frontally mediated behavioral disorders and anosognosia, particularly apathy, supports the hypothesis of a shared neuropsychogenic process due to the disruption of frontal brain networks.     

皮质下缺血性血管病的神经心理特征

目的 探讨皮质下缺血性血管病（subcortical ischemic vascular disease,SIVD）的认知和情感特征。方法 对符合SIVD标准的缺血性卒中患者进行详细的临床访谈和神经心理、神经精神检查。结果 50例患者平均年龄（70±8）岁,男性占78%,轻度SIVD 20例（40%）,中重度30例（60%）。33例诊断为血管性认知功能障碍（vascular cognitive impairment,VCI）,其中24例（72.7%）为血管性认知损害非痴呆（vascular cognitive impairment no dementia,V-CIND）。在VCI患者中,11例（33.3%）为单一认知域损害,22例（66.7%）为多认知域受损,执行和记忆功能是损害最突出的认知域。本组患者没有语言和空间能力的单独受累。VCI患者39.3%伴抑郁,而非VCI者仅11.8%伴抑郁,差异有统计学意义（P =0.043）。妄想、幻觉、过度兴奋和夜间不寻常活动仅见于VaD患者。中重度SIVD中患VCI比例显著高于轻度者（P =0.002）,伴抑郁的比例亦有增高的趋势（P =0.059）。结论 认知障碍在SIVD中常见,但多为V-CIND,以执行功能和记忆损害最为突出,易伴抑郁,提示额叶皮质皮质下环路损伤可能是两者共同损害的主要机制。     

Anosognosia: patients' distress and self-awareness of deficits in Alzheimer's disease

We aimed to study how patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) suffer from awareness of their deficits. Self-awareness was assessed using the Anosognosia Questionnaire for Dementia in 12 pairs of MCI outpatients and caregivers, 23 with mild AD, and 18 with moderate AD. The discrepancy between patient's and caregiver's evaluation (anosognosia) became greater as AD progressed. The predictors of patients' distress, shown by multiple linear regression analyses, were awareness of decline in intellectual or social functioning; self-awareness of deficits in remembering appointments in MCI; in remembering appointments, writing, mental calculation, and understanding the newspaper in mild AD; and in mental calculation and doing clerical work in moderate AD. Caregivers assumed the predictors of patients' distress differently: awareness of deterioration of memory in MCI and mild AD, and basic activities of daily living in moderate AD. Understanding patients' disability from patients' perspective is required for successful care.     

Neural correlates of impaired performance on the clock drawing test in Alzheimer's disease

To identify the neural correlates for impaired performance on the clock drawing test (CDT) in patients with Alzheimer's disease (AD), we examined the relationship between the CDT performances and the regional cerebral blood flow (rCBF) in 100 AD patients. The patients were equally divided into a mildly impaired CDT group, a severely impaired CDT group, and two normal CDT groups, with age and dementia severity matched. Between-group comparisons revealed that rCBF reduction in the posterolateral region of the left temporal lobe was consistently associated with mild to severe impairment of the CDT in AD. Correlation analysis also showed that the rCBF in the left posterolateral temporal cortex was linearly correlated with CDT performance. The CDT scores in AD were significantly improved for the copy condition relative to the drawing-to-command condition. These findings suggest that CDT performance has a close relationship with the left posterior temporal function, and that semantic memory deficit may at least partly contribute to impaired CDT performance in AD.     

Automated Neuropsychological Test Battery (CANTAB) in mild cognitive impairment and in Alzheimer's disease

Neuropsychological deficits, such as poor episodic memory, are consistent features of mild cognitive impairment and also that of early stage of dementia. The aim of the present study was to detect cognitive dysfunction among patients with Alzheimer's disease or with mild cognitive impairment (MCI), which refers to a transitional state between the cognition of normal aeging and mild dementia regarded as a high-risk condition for the development of clinically probable Alzheimer's disease (AD). Computerized tests of memory, attention and executive functions were studied in groups of AD subjects (n=15) and MCI subjects (n=25). On all measures, the performance of the AD group was significantly weaker compared to healthy individuals or to the MCI group. The performance of both the AD and MCI patients in the Paired Associate Learning test was significantly impaired, which may suggest that MCI patients are already in the early stages of the disease.     

Differential expression of synaptic proteins in the frontal and temporal cortex of elderly subjects with mild cognitive impairment

Alterations in synaptic protein stoichiometry may contribute to neocortical synaptic dysfunction in Alzheimer disease (AD). Whether perturbations in synaptic protein expression occur during the earliest stages of cognitive decline remain unclear. We examined protein levels of synaptophysin (SYP), synaptotagmin (SYT), and drebrin (DRB) in 5 neocortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual) of people clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Normalized SYP levels were decreased approximately 35% in the superior temporal and inferior parietal cortex in severe AD compared with NCI. SYT levels were unchanged across clinical diagnosis in the cortical regions. Levels of DRB, a dendritic spine plasticity marker, were reduced approximately 40% to 60% in all cortical regions in AD compared with NCI. DRB protein was also reduced approximately 35% in the superior temporal cortex of MCI subjects, and DRB and SYP levels in the superior temporal cortex correlated with Mini-Mental State Examination and Braak scores. In contrast, DRB levels in the superior frontal cortex increased approximately 30% in MCI subjects. The differential changes in DRB expression in the frontal and temporal cortex in MCI suggest a disparity of dendritic plasticity within these regions that may contribute to the early impairment of temporal cortical functions subserving memory and language compared with the relative preservation of frontal cortical executive function during the initial stages of cognitive decline.     

The earliest stage of cognitive impairment in transition from normal aging to Alzheimer disease is marked by prominent RNA oxidation in vulnerable neurons

Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approachto identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinicaldementia rating score and postmortem brain pathologic diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that, although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD.     

Single photon emission computed tomography in Alzheimer's disease. Abnormal iofetamine I 123 uptake reflects dementia severity

To determine whether abnormalities in regional cerebral functional activity estimated by iofetamine hydrochloride I 123 and single photon emission computed tomography can be detected in mild or moderate as well as severe cases of Alzheimer's disease (AD), we performed iofetamine I 123-single photon emission computed tomography in 37 patients with probable AD (nine patients with mild, 18 patients with moderate, and ten patients with severe dementia) and nine age-matched control subjects. Iofetamine I 123 uptake was measured in right and left frontal, temporal, parietal, and occipital cortices. Mean (right and left) iofetamine I 123 activity was lowest in the parietal region of patients with AD and was significantly reduced in the other three regions compared with control subjects. Only in the parietal region was lower relative iofetamine I 123 activity associated with an impaired level of patient function and with cognitive deficit.     

Impact of Alzheimer's pathology on cognitive trajectories in nondemented elderly

OBJECTIVE: Some individuals who are asymptomatic for dementia while alive have substantial Alzheimer's disease (AD) neuropathology at autopsy. We investigated whether cognitive trajectories differ between clinically normal elderly individuals with and without AD neuropathology and how they compare with trajectories of clinically impaired individuals before dementia diagnosis. METHODS: Eighty-one elderly participants in the Baltimore Longitudinal Study of Aging (BLSA) were followed prospectively with neurological and neuropsychological assessments before autopsy evaluation at death. Trajectories of cognitive change were estimated for a number of domains using cognitive data before a clinical diagnosis of dementia. RESULTS: Clinically normal elderly individuals with and without AD-type neuropathology have similar cognitive trajectories across different cognitive domains. In contrast, individuals with mild cognitive impairment/AD show steeper rates of longitudinal decline in several aspects of cognition compared with clinically normal elderly individuals regardless of whether the latter have AD neuropathology. Moreover, the cognitive differences between impaired and unimpaired groups can be detected years before a diagnosis of dementia. INTERPRETATION: Clinically normal individuals with and without AD neuropathology do not differ in rates of cognitive decline across a number of cognitive domains. Understanding the factors that protect some individuals with AD pathology from cognitive impairment may contribute to the maintenance of cognitive health in the elderly.     

Relation of anosognosia to frontal lobe dysfunction in Alzheimer''s disease.

A self-rating scale of memory functions was administered to 24 non-depressed patients with probable Alzheimer's disease, divided into two groups according to the overall severity of dementia (mild, mini-mental state (MMS) > 21; moderate, MMS between 10 and 20). These groups did not significantly differ in their self-rating of memory functions. The same questionnaire was submitted to a member of each patient's family, who had to rate the patient's memory. An "anosognosia score" was defined as the difference between patient's and family's ratings. This score was highly variable, and covered, in the two groups, the full range between complete awareness of deficits and total anosognosia. Correlations between the anosognosia score and several neuropsychological data were searched for. No significant correlation was found with either the Wechsler memory scale, the MMS, or linguistic abilities and gestures. In contrast, this score was highly correlated with the "frontal score", defined as the sum of scores on the Wisconsin card sorting test (WCST), verbal fluency, Luria's graphic series, and "frontal behaviours" (prehension, utilisation, imitation behaviours, inertia, indifference). Among these tests of executive functions, the highest correlation with the anosognosia score was obtained on the WCST. This suggests that anosognosia in Alzheimer's disease is not related to the degree of cognitive deterioration but results, at least in part, from frontal dysfunction.     

Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease

Degeneration of cholinergic nucleus basalis (NB) cortical projection neurons is associated with cognitive decline in late-stage Alzheimer's disease (AD). NB neuron survival is dependent on coexpression of the nerve growth factor (NGF) receptors p75(NTR) and TrkA, which bind NGF in cortical projection sites. We have shown previously a significant reduction of NB perikarya expressing p75(NTR) and TrkA protein during the early stages of AD. Whether there is a concomitant reduction in cortical levels of these receptors during the progression of AD is unknown. p75(NTR) and TrkA protein was evaluated by quantitative immunoblotting in five cortical regions (anterior cingulate, superior frontal, superior temporal, inferior parietal, and visual cortex) of individuals clinically diagnosed with no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD, or severe AD. Cortical p75(NTR) levels were stable across the diagnostic groups. In contrast, TrkA levels were reduced approximately 50% in mild/moderate and severe AD compared with NCI and MCI in all regions except visual cortex. Mini-Mental Status Examination scores correlated with TrkA levels in anterior cingulate, superior frontal, and superior temporal cortex. The selective reduction of cortical TrkA levels relative to p75(NTR) may have important consequences for cholinergic NB function during the transition from MCI to AD.