Absence of cognitive impairment or decline in preclinical Alzheimer's disease

OBJECTIVE: To determine whether clinically nondemented elderly individuals with pathologically confirmed preclinical AD are characterized by cognitive decline as measured by psychometric tests before death. METHODS: Psychometric performance was examined retrospectively in 14 individuals who were nondemented at time of death and grouped in accordance with their neuropathologic findings: 1) Healthy brain (n = 9) was characterized by the absence of senile plaques or by only patchy neocortical deposits of plaques; 2) preclinical AD (n = 5) was characterized by neuritic and diffuse plaques distributed throughout the neocortex. All individuals showed neurofibrillary pathologic change in medial temporal lobe structures. For comparison, we also evaluated 10 individuals who died in the earliest symptomatic stage of dementia of the Alzheimer type (DAT). All individuals had been assessed by clinical and psychometric measures during life. The psychometric measures yielded a standardized factor score that represented global cognitive performance. RESULTS: At the last assessment before death, individuals with very mild DAT were impaired on the factor score and on individual psychometric measures with respect to the nondemented individuals. Those nondemented individuals with preclinical AD did not differ in performance from those with healthy brains. For individuals with at least three psychometric assessments during life, there was no decline in performance for either those with healthy brains (n = 5) or preclinical AD (n = 3), although decline was evident for very mild DAT individuals (n = 5). CONCLUSIONS: Pathologically confirmed preclinical AD is not associated with cognitive impairment or decline, even on measures shown to be sensitive to very mild DAT.     

Alzheimer's disease can be accurately diagnosed in very mildly impaired individuals

BACKGROUND: The growing propensity to diagnose AD in individuals with very mild cognitive impairment increases the danger of false-positive diagnostic errors. Unfortunately, there is little systematically acquired information about the accuracy of the AD diagnosis in very mildly impaired patients. OBJECTIVE: To determine the accuracy of the diagnosis of AD in very mildly impaired patients and to identify objective measures that effectively distinguish these patients from elderly normal controls (NC). METHODS: Consecutive patients with Mini-Mental State Examination scores of > or = 24 who received a clinical diagnosis of AD were evaluated annually for at least 3 years. The initial diagnosis was verified or refuted by autopsy or by information obtained in subsequent evaluations. Initial neuropsychological test scores of verified AD patients were compared with those of NC subjects to identify effective diagnostic measures. RESULTS: The diagnosis of AD was confirmed in 98 of 110 (89%) very mildly impaired patients (33/36 by autopsy, 65/74 by disease progression). The diagnosis was inaccurate in 12 patients (11%): Seven were subsequently diagnosed with other neurologic disorders, and five were ultimately found to be normal. Neuropsychological measures of delayed recall, verbal fluency, and global cognitive status (i.e., Mattis Dementia Rating Scale) provided excellent sensitivity (> or = 96%) and specificity (> or = 93%) for differentiating between very mildly impaired AD patients and NC subjects. CONCLUSIONS: When comprehensive assessment procedures are employed, AD can be diagnosed with reasonably high accuracy in very mildly impaired individuals. However, the dementia evaluation should be repeated after approximately 1 year to ensure the accuracy of the initial diagnosis.     

Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease

Controversy exists regarding the apolipoprotein E (ApoE) epsilon4 allele association with vascular dementia (VaD), ranging from increased epsilon4 frequency, similar to that found for Alzheimer's disease (AD), to no association between the epsilon4 allele and VaD. To clarify further the relationship between ApoE alleles polymorphism and cerebrovascular disease (CVD) in demented and cognitively impaired patients, we examined the ApoE phenotypes in a sample of 280 patients: 155 with AD, 21 with VaD, 32 with mixed dementia (MD), 45 with mild cognitive impairment (MCI) but without CVD, and 27 in which vascular disease was the most probable cause of cognitive decline [vascular mild cognitive impairment (VMCI)]. Our results show that the frequency of the ApoE epsilon4 allele in patients over 70 years old with clinically diagnosed VaD and VMCI does not differ significantly from that of controls. In contrast, ApoE epsilon4 allele-bearing individuals had greater risk of having late-onset AD (OR = 8.8; 95% CI 3.7-21.0), or non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0).     

Visual attention impairments in Alzheimer's disease

BACKGROUND: Impaired attention can hinder information processing at multiple levels and may explain aspects of functional decline in aging and dementia. Impairments of attention in early AD may contribute to performance reductions in other cognitive domains, including memory and executive functions.Method:- The authors analyzed the scores on a battery of tests of attention and cognitive abilities in 64 older individuals: 42 with mild AD and 22 control subjects without dementia. The authors tested the hypotheses that patients with AD would have impairments of visual attention, and that these impairments would correlate with dysfunction in other key cognitive domains. RESULTS: Patients with AD performed significantly worse than control subjects on measures of sustained attention, divided attention, selective attention, and visual processing speed. The differences were not due to differences in age, education, or basic visual function. Strong relationships were identified between reduced attention skills and overall cognitive impairment. CONCLUSIONS: Deterioration of attention abilities occurs in early stages of AD, and likely contributes to functional decline in these patients. More routine assessment of visual attention deficits could give a more accurate measure of functionally useful perception in patients with AD who show normal visual acuity and visual fields, perhaps providing useful clues to diagnosis and staging.     

Motor dysfunction in mildly demented AD individuals without extrapyramidal signs.

BACKGROUND: Although not as prominent as cognitive decline, motor dysfunction occurs in AD, particularly in the later stages of the disease. OBJECTIVE: To determine whether early-stage AD is also characterized by motor impairment. METHODS: We examined very mildly (Clinical Dementia Rating [CDR] 0.5) and mildly (CDR 1) demented AD individuals in comparison with healthy elderly control individuals (CDR 0) on a variety of nonmotor cognitive and psychomotor measures and on four motor measures (gait velocity, finger tapping, reaction time, movement time). To minimize the possibility of extrapyramidal dysfunction contaminating the groups, only individuals who were clinically free of extrapyramidal signs were included in the study. RESULTS: Mildly demented AD individuals were slowed on all motor measures except for finger tapping. No evidence of motor dysfunction was found in the very mildly demented AD group. As expected, both AD groups were impaired on the nonmotor cognitive and psychomotor tests. CONCLUSIONS: These results indicate that AD alone, in the absence of clinically confirmed extrapyramidal dysfunction, is associated with motor slowing in a stage-dependent manner. It remains to be determined whether this motor slowing represents a general characteristic of mild AD or indicates other neuropathology such as PD or the Lewy body variant of AD.     

Alzheimer's disease neuroimaging initiative and mild cognitive impairment]

Alzheimer's disease (AD) generally begins with mild memory problems in an insidious manner and progresses to develop multiple cognitive as well as functional impairment within a few years. Currently, the diagnosis of AD requires multiple cognitive deficits including memory disturbance and exclusion of other dementing disorders. However, normal elderly people quite commonly complain of increasing forgetfulness with age. Mild cognitive impairment (MCI) is generally regarded as an intermediate state between normal aging and dementia. In other words, MCI refers to persons that are not normal nor clinically diagnosed dementia. (Winblad et al. J. Intern. Med. 2004). When daily functioning is impaired as a result of cognitive decline, dementia is the appropriate diagnostic label. Alzheimer's Disease Neuroimaging Initiative (ADNI) aims at; 1) Major goal is collection of data and to establish a brain imaging and biomarker database; 2) Determine the optimum methods for acquiring and processing images for clinical trials: 3) Develop "standards" for imaging, biomarkers; 4) "Validate" imaging and biomarker data by correlating with behavioral data to facilitate new AD therapies by disease modifiers. Japan-ADNI will be started as a part of world wide ADNI. Currently, gamma-secretase modifiers and Abeta aggregation inhibitors as well as amyloid vaccination are under clinical trials.     

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.     

Pathologic and nicotinic receptor binding differences between mild cognitive impairment, Alzheimer disease, and normal aging

BACKGROUND: Neurochemical and pathologic studies show that mild cognitive impairment (MCI) is frequently a transitional state between normal aging and Alzheimer disease (AD). Neuropathologic sample sizes have been limited because relatively few individuals with MCI die before dementia develops. Decreased neocortical nicotinic receptor binding is characteristic of AD but has not been investigated in subjects with MCI. OBJECTIVE: To assess nicotinic receptor binding and pathologic differences in control subjects with no dementia (ND) and in subjects with clinically and pathologically described MCI or Alzheimer disease. DESIGN: This was a clinicopathologic analysis. Subjects with ND had no demonstrable cognitive or functional impairment. Subjects with MCI met Petersen clinical criteria for single- or multiple-domain amnestic MCI and died before the disorder progressed to AD. Subjects with AD met National Institute for Neurological Diseases and Stroke/Alzheimer's Disease and Related Disorders Association clinical criteria for AD. All subjects underwent a complete diagnostic and semiquantitative neuropathologic examination. Data were examined after both clinical and histopathologic classification of subjects. SETTING: Sun Health Research Institute Brain Donation Program, and Arizona Alzheimer Disease Center. PARTICIPANTS: Twenty-one control subjects with ND, 8 subjects with MCI, and 70 subjects with AD, prospectively followed up to autopsy. MAIN OUTCOME MEASURES: Nicotinic acetylcholine receptor binding value, total tangle density, total plaque density, and Braak stage. RESULTS: At the last examination before death, subjects with AD were significantly younger, less educated, and more cognitively and globally impaired compared with subjects with ND. When categorized by clinical diagnosis, MCI was always intermediate between ND and AD. On the whole, MCI was pathologically intermediate between ND and AD for senile plaque density, neurofibrillary tangle density, and Braak stage, but some subjects with MCI lacked neuritic plaques entirely. Binding for nicotinic acetylcholine receptors did not differ between the ND and MCI groups, but it was significantly less in the AD group. CONCLUSIONS: Most MCI may be considered a transitional state between ND and AD clinically and neuropathologically, but in some MCI cases there is lack of neuritic plaques, and, therefore, it cannot be considered early AD. Nicotinic receptor binding seems to be lost during the transition from MCI to AD.     

Volumetric MRI measurements can differentiate Alzheimer's disease,mild cognitive impairment,and normal aging

BACKGROUND: Volumetric magnetic resonance imaging (MRI) has been extensively studied in the last decade as a method to help with the clinical diagnosis of Alzheimer's disease (AD). In recent years, researchers have also started investigating if that technique would be useful to identify individuals with mild cognitive impairment (MCI), differentiating them from AD patients and from normal elderly controls. This research project was planned to assess the accuracy of volumetric MRI to differentiate those groups of individuals. METHOD: The investigation involved 39 patients with diagnosis of mild to moderate dementia in AD, according to the criteria of the NINCDS-ADRDA, DSM-III-R, and ICD-10; 21 subjects with complaints of cognitive decline without other psychiatric disorders (MCI); and 20 normal elderly controls. All the subjects were submitted to a standard protocol, including volumetric MRI evaluations. RESULTS: The results indicated that all regions of interest measured (amygdala, hippocampus, and parahippocampal gyrus) were significantly different (p < .005) in AD patients compared to MCI subjects and controls. The left volumetric measures (amygdala, hippocampus, and parahippocampal gyrus) were also significantly different between the MCI subjects and controls (p < .05). The discriminant function analysis correctly classified 88.14% of the AD patients and controls, 81.67% of AD patients and MCI subjects, and 80.49% of the MCI subjects and controls. CONCLUSIONS: The results suggest that measures of medial temporal lobe regions are useful to identify mild to moderate AD patients and MCI subjects, separating them from normal elderly individuals.     

Alzheimer disease: are we intervening too late?

The affirmative position is argued in response to the question of whether intervention in the disease course of Alzheimer disease (AD) occurs too late. AD is not a singular, homogeneous disease, but rather a final common pathway or end-point that can be arrived at through multiple routes. As part of the affirmative argument, there is a delineation of two long-term trajectories leading to AD: (1) normal elderly progression to AD, and (2) depressed elderly progression to AD. In documenting normal elderly devolution into AD, two “normal” elderly pre-AD or prodromal stages are discussed: age-associated memory impairment (AAMI) and mild cognitive impairment (MCI). Data are provided evidencing significantly high conversion rates from these pre-AD stages to actual AD. Using the same paradigmatic approach that is used in documenting normal elderly decline into AAMI and MCI with eventual conversion to AD; there is explication of depressed elderly conversion to AD. The long-term, multiphasic disease progression of major depression without dementia to depressive dementia to final conversion to AD is brought into focus as another example of why intervention must occur prior to actual conversion to AD. Depression is defined as a cognitive syndrome and risk factor for AD requiring aggressive targeted intervention. AD does not just come suddenly out of nowhere. First intervention must occur during the pre-AD phases in an attempt to prevent, delay, and interrupt long-term neurodegenerative processes involved in both normal elderly and depressed elderly conversion to AD. A primary strategy proposed is to delay onset of AD. Population statistics indicate that if AD is delayed by a modest 1 year, there would be 9.5 million fewer cases by 2050, resulting in significant reduction in burden of disease. Data show early intervention with cognitive stimulation (mental exercise), physical exercise, aggressive treatment of AD risk factors and excess disability, psychotherapy, and other nonpharmacological interventions in combination with each other and/or with medications can result in delay of onset of AD. First intervention at time of diagnosis of AD is too late, when by definition, final conversion to AD has already occurred. When we have knowledge to successfully intervene earlier, why would we not want to do so.     

Rates of cognitive decline in Alzheimer's disease and dementia with Lewy bodies

Increased interest in types of dementia has developed as more cases are identified in aging populations. Here we compare the rates of cognitive decline over time in three groups with dementia from the University of Western Ontario Dementia Study: Alzheimer's disease (AD), dementia with Lewy bodies and a group with both AD and Lewy bodies. All diagnoses were verified by autopsy using standard diagnostic methods. Cognitive impairment was measured with the Extended Scale for Dementia (ESD). Members of each group with dementia were age and sex matched with individuals without dementia as controls. The 15 cases of AD, 7 cases with Lewy bodies and 8 cases with both conditions were all free of significant vascular disease. Linear regression was used to determine the rate of changes in ESD scores over time in months. All three control groups showed no change in cognitive status over time. As expected, all groups with dementia showed progressive cognitive impairment. Analysis of the slope parameter showed that all groups deteriorated at the same rate of approximately 2 ESD points per month. Quadratic models fit better than simple linear models in all groups. Results suggest that the final rate of cognitive decline in dementia may not necessarily reflect the underlying cause.     

Mortality in elderly Canadians with and without dementia: a 5-year follow-up.

OBJECTIVES: Based on the national Canadian Study of Health and Aging (CSHA), to compare 5-year overall mortality and causes of death in elderly with and without dementia. To determine how frequently dementia was mentioned on the death certificate. METHODS: For people who underwent a clinical examination in 1991 (n = 2,923), overall and cause-specific mortality rate ratios were calculated by dementia status (AD; vascular dementia; other dementias/other cognitive impairment; and normal cognition), age group (65 to 74, 75 to 84, 85+ years), and sex, using the Canadian general population as the reference. Similar rate ratios were calculated for people in the community who screened negative for cognitive impairment and who did not undergo a clinical examination (n = 7,340). Among elderly diagnosed as having AD or vascular dementia through the CSHA and who later died, it was determined how frequently dementia was recorded on the death certificate. RESULTS: The subgroup without cognitive dysfunction had a survival rate similar to that of the overall Canadian population except in the oldest age group, where the survival rate was better than that of the general population, which includes people with dementia. People in the three groups with cognitive impairment had a poorer survival in all age/sex groups than those without cognitive impairment and the general Canadian population. The most common causes of death in all groups were from vascular diseases. People with vascular dementia had the highest relative mortality rates for heart and cerebrovascular disease. Most of the AD groups also had high relative vascular system mortality rates. Among patients clinically diagnosed with AD, only 14.3% had any dementing illness recorded as the underlying cause of death; 41.8% had any dementing illness recorded anywhere on the death certificate. For vascular dementia, the corresponding numbers were 5.8% and 23.3%. CONCLUSION: Elderly with dementia have clearly increased mortality rates relative to elderly without cognitive impairment in all age/sex categories. People with vascular dementia have a particularly poor prognosis. Studies of AD and vascular dementia using death certificate data will grossly underestimate the proportions of elderly with these diseases.     

Alzheimer’s disease neuropathology may not predict functional impairment in HIV: a report of two individuals

With aging of HIV populations, there is concern that Alzheimer’s disease (AD) may become prevalent and difficult to distinguish from HIV-associated neurocognitive disorders. To date, there are no reports documenting histologically verified Alzheimer’s neuropathology in individuals with HIV and dementia. Herein, we report two antiretroviral-treated, virally suppressed, HIV-infected individuals autopsied by the Manhattan HIV Brain Bank. Subject A presented to study at 52 years, already dependent in instrumental activities of daily living (ADLs), with severe cognitive impairment inclusive of learning and memory dysfunction. Her history was significant for educational disability and head trauma. She had rapid cognitive decline and, by death at age 59 years, was bed-bound, incontinent, and non-communicative. At autopsy, she exhibited severe AD neuropathologic change (NIA-AA score A3B3C3) and age-related tau astrogliopathy (ARTAG). She was homozygous for APOE ε3/ε3. No HIV DNA was detected in frontal lobe by nested polymerase chain reaction. Subject B was a community dwelling 81-year-old woman who experienced sudden death by pulmonary embolus. Prior to death, she was fully functional, living independently, and managing all ADLs. At autopsy, she displayed moderate amyloid and severe tau AD neuropathologic changes (A2B3C2), ARTAG, and cerebral congophilic angiopathy. She was an APOE ε3/ε4 heterozygote, and HIV DNA, but not RNA, was detected in frontal lobe, despite 20 years of therapy-induced viral suppression. We conclude that in the setting of HIV, AD neuropathology may occur with or without symptomatic cognitive dysfunction; as with seronegative individuals, there are likely to be complex factors in the generation of clinically relevant impairments.     

Natural history of mild cognitive impairment in older persons

BACKGROUND: Cognitive abilities of older persons range from normal, to mild cognitive impairment, to dementia. Few large longitudinal studies have compared the natural history of mild cognitive impairment with similar persons without cognitive impairment. METHODS: Participants were older Catholic clergy without dementia, 211 with mild cognitive impairment and 587 without cognitive impairment, who underwent annual clinical evaluation for AD and an assessment of different cognitive abilities. Cognitive performance tests were summarized to yield a composite measure of global cognitive function and separate summary measures of episodic memory, semantic memory, working memory, perceptual speed, and visuospatial ability. The authors compared the risk of death, risk of incident AD, and rates of change in global cognition and different cognitive domains among persons with mild cognitive impairment to those without cognitive impairment. All models controlled for age, sex, and education. RESULTS: On average, persons with mild cognitive impairment had significantly lower scores at baseline in all cognitive domains. Over an average of 4.5 years of follow-up, 30% of persons with mild cognitive impairment died, a rate 1.7 times higher than those without cognitive impairment (95% CI, 1.2 to 2.5). In addition, 64 (34%) persons with mild cognitive impairment developed AD, a rate 3.1 times higher than those without cognitive impairment (95% CI, 2.1 to 4.5). Finally, persons with mild cognitive impairment declined significantly faster on measures of episodic memory, semantic memory, and perceptual speed, but not on measures of working memory or visuospatial ability, as compared with persons without cognitive impairment. CONCLUSIONS: Mild cognitive impairment is associated with an increased risk of death and incident AD, and a greater rate of decline in selected cognitive abilities.     

Alzheimer's disease pathology does not mediate the association between depressive symptoms and subsequent cognitive decline

BackgroundDepressive symptoms in nondemented individuals appear to hasten the progression from mild cognitive impairment to clinical Alzheimer's disease (AD) and double the risk of incident AD. However, the mechanism(s) by which depression might affect this risk has not been well established. The purpose of this analysis was to test the hypothesis that AD pathology mediates depression's apparent effect on the risk of dementia conversion using longitudinally collected psychometric testing and autopsy data from the Honolulu–Asia Aging Study.MethodsLatent factor variables representing AD, cortical Lewy body (CLB), and ischemic neuropathology were tested as potential mediators of the association between the Center for Epidemiological Studies depression scale (CES-D) score and the 10-year prospective rate of cognitive decline, adjusted for baseline cognition, age, education, total number of medications, and brain weight at autopsy.ResultsCES-D scores, neurofibrillary tangle counts, CLB counts, and ischemic lesions each made significant independent contributions to cognitive decline. However, CES-D scores were not significantly associated with any pathological variable; thus the pathological variables were not mediators of the effect of CES-D scores on cognitive decline.ConclusionsSubsyndromal depressive symptoms are significantly associated with subsequent cognitive decline. Although the effect is relatively modest, it is stronger than that of amyloid-related neuropathologies and independent of that of neurofibrillary tangles, cortical Lewy bodies, and ischemic lesions. Our results argue against the role of AD-related neuropathology as a mediator of depression's effect on cognitive decline, but cannot rule out a significant mediation effect in a subset of cases, perhaps with more severe baseline depressive symptoms.     

Volumetric MRI predicts rate of cognitive decline related to AD and cerebrovascular disease

OBJECTIVE: To examine volumetric MRI correlates of longitudinal cognitive decline in normal aging, AD, and subcortical cerebrovascular brain injury (SCVBI). BACKGROUND: Previous cross-sectional studies examining the relationship between cognitive impairment and dementia have shown that hippocampal and cortical gray matter atrophy are the most important predictors of cognitive impairment, even in cases with SCVBI. The authors hypothesized that hippocampal and cortical gray matter volume also would best predict rate of cognitive decline in cases with and without SCVBI. METHODS: Subjects were recruited for a multicenter study of contributions to dementia of AD and SCVBI. The sample (n = 120) included cognitively normal, cognitively impaired, and demented cases with and without lacunes identified by MRI. Cases with cortical strokes were excluded. Average length of follow-up was 3.0 years. Measures of hippocampal volume, volume of cortical gray matter, presence of subcortical lacunes, and volume of white matter hyperintensity were derived from MRI. Random effects modeling of longitudinal data was used to assess effects of baseline MRI variables on longitudinal change in a measure of global cognitive ability. RESULTS: Cortical gray matter atrophy predicted cognitive decline regardless of whether lacunes were present. Hippocampal atrophy predicted decline only in those without lacunes. Neither lacunes nor white matter hyperintensity independently predicted decline. CONCLUSIONS: Results suggest that cortical atrophy is an index of disease severity in both AD and subcortical cerebrovascular brain injury and consequently predicts faster progression. Hippocampal volume may index disease severity and predict progression in AD. The absence of this effect in cases with lacunes suggests that this group is etiologically heterogeneous and is not composed simply of cases of AD with incidental stroke.     

Fluctuations in attention: PD dementia vs DLB with parkinsonism

BACKGROUND: Marked impairments in and fluctuation of attention are characteristic of dementia with Lewy bodies (DLB). The comparative impairment of these cognitive domains in PD and PD dementia (PD dementia) has not been studied, and is important to the conceptual understanding of parkinsonian dementias. METHOD: Detailed evaluations of attention and fluctuating attention (Cognitive Drug Research computerized battery) were undertaken in 278 subjects (50 DLB, 48 PD dementia, 50 PD, 80 AD, 50 elderly controls) from the Newcastle dementia register and the Stavanger PD register (controls, PD, and PD dementia patients were recruited from both centers). DLB, AD, PD, and PD dementia were diagnosed using operationalized criteria. RESULTS: Impairments in reaction time, vigilance, and fluctuating attention were comparable in patients with DLB and PD dementia, but were less substantially impaired in patients with DLB without parkinsonism. Patients with PD had significantly greater impairment of cognitive reaction time than elderly controls, and comparable impairments of cognitive reaction time to patients with AD. Patients with PD, however, did not exhibit fluctuation of attention. CONCLUSION: The profile of attentional impairments and fluctuating attention is similar in PD dementia and DLB with parkinsonism. The current findings do not support the current arbitrary distinctions between these patient groups. Importantly, patients with PD do not experience fluctuating attention.     

Current concepts in mild cognitive impairment.

The field of aging and dementia is focusing on the characterization of the earliest stages of cognitive impairment. Recent research has identified a transitional state between the cognitive changes of normal aging and Alzheimer's disease (AD), known as mild cognitive impairment (MCI). Mild cognitive impairment refers to the clinical condition between normal aging and AD in which persons experience memory loss to a greater extent than one would expect for age, yet they do not meet currently accepted criteria for clinically probable AD. When these persons are observed longitudinally, they progress to clinically probable AD at a considerably accelerated rate compared with healthy age-matched individuals. Consequently, this condition has been recognized as suitable for possible therapeutic intervention, and several multicenter international treatment trials are under way. Because this is a topic of intense interest, a group of experts on aging and MCI from around the world in the fields of neurology, psychiatry, geriatrics, neuropsychology, neuroimaging, neuropathology, clinical trials, and ethics was convened to summarize the current state of the field of MCI. Participants reviewed the world scientific literature on aging and MCI and summarized the various topics with respect to available evidence on MCI. Diagnostic criteria and clinical outcomes of these subjects are available in the literature. Mild cognitive impairment is believed to be a high-risk condition for the development of clinically probable AD. Heterogeneity in the use of the term was recognized, and subclassifications were suggested. While no treatments are recommended for MCI currently, clinical trials regarding potential therapies are under way. Recommendations concerning ethical issues in the diagnosis and the management of subjects with MCI were made.     

Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function

OBJECTIVE: To test the hypothesis that the association of amyloid load with clinical Alzheimer disease (AD) and cognitive impairment is mediated through neurofibrillary tangles. DESIGN: Longitudinal clinicopathologic cohort study. PARTICIPANTS AND SETTING: Forty-four individuals with clinically diagnosed AD and 53 without dementia who participated in the Religious Orders Study underwent a uniform structured clinical evaluation for AD and cognitive testing about 8 months prior to death, and brain autopsy at death. METHODS: The percent area occupied by amyloid-beta and the density of neurofibrillary tangles were quantified from 6 brain regions and averaged to yield summary measures of amyloid load and neurofibrillary tangles. Multivariate regression analyses were used to simultaneously examine the effects of amyloid load and neurofibrillary tangles on clinically diagnosed AD and level of cognition. MAIN OUTCOME MEASURES: Clinically diagnosed AD and level of global cognitive function proximate to death. RESULTS: In separate logistic regression analyses, each 1% increase in amyloid load was associated with about a 50% increase in the odds of clinical AD (P =.002), and each neurofibrillary tangle was associated with a greater than 20% increase in the odds of clinical AD (P<.001). When a term for tangles was added to the regression model with amyloid, the association of amyloid load with clinical disease was reduced by more than 60% and was no longer significant, whereas the association of tangles with clinical disease was essentially unchanged. Similar results were found in analyses of global cognitive function. CONCLUSION: These findings are consistent with a sequence of pathologic events whereby the effect of amyloid deposition on clinical disease is mediated by neurofibrillary tangles.