Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.

Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.

Alpha-2 macroglobulin is genetically associated with Alzheimer disease.

Alpha-2-macroglobulin (alpha-2M; encoded by the gene A2M) is a serum pan-protease inhibitor that has been implicated in Alzheimer disease (AD) based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits. Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for AD (Mantel-Haenzel odds ratio=3.56, P=0.001). The sibship disequilibrium test (SDT) also revealed a significant association between A2M and AD (P=0.00009). These values were comparable to those obtained for the APOE-epsilon4 allele in the same sample, but in contrast to APOE-epsilon4, A2M-2 did not affect age of onset. The observed association of A2M with AD did not appear to account for the previously published linkage of AD to chromosome 12, which we were unable to confirm in this sample. A2M, LRP1 (encoding the alpha-2M receptor) and the genes for two other LRP ligands, APOE and APP (encoding the amyloid beta-protein precursor), have now all been genetically linked to AD, suggesting that these proteins may participate in a common neuropathogenic pathway leading to AD.

Single photon emission computed tomography perfusion differences in mild cognitive impairment.

OBJECTIVE: To relate cerebral perfusion abnormalities to subsequent changes in clinical status among patients with mild cognitive impairment (MCI). METHODS: Perfusion single photon emission computed tomography (SPECT) images were acquired in 105 elderly patients without dementia with MCI, using 99mTc-HMPAO. Clinical outcome after a 5-year follow-up period was heterogeneous. RESULTS: Baseline SPECT data differed in those patients with MCI who were later diagnosed with Alzheimer's disease (the converter group) from those patients with MCI who experienced clinically evident decline but did not progress to a diagnosis of Alzheimer's disease within the follow-up period (the decliner group), from patients with MCI who had no clinical evidence of progression (the stable group), and from a group of 19 normal subjects (the control group). The most consistent decreases in relative perfusion in converters compared with the normal, stable and decliner groups were observed in the caudal anterior cingulate, and in the posterior cingulate. In addition, converters showed increased relative perfusion in the rostral anterior cingulate in comparison to the stable and decliner groups. A group of patients with Alzheimer's disease were also included for purposes of comparison. The group of patients with Alzheimer's disease at baseline differed from each of the other groups, with temporoparietal regions showing the most significant reductions in perfusion. CONCLUSIONS: These results suggest that clinical heterogeneity in MCI is reflected in SPECT perfusion differences, and that the pattern of perfusion abnormalities evolves with increasing clinical severity.

Knowledge of and attitudes about Alzheimer disease genetics: report of a pilot survey and two focus groups.

OBJECTIVES: In preparation for the development of an educational intervention on Alzheimer disease (AD) genetics, we undertook a pilot survey of knowledge in this area and attitudes toward genetic testing for AD among individuals with a family history of AD. METHODS: For the pilot study, we administered a 30-min questionnaire to 57 unaffected individuals from a genetic linkage study. For the focus groups, we interviewed two groups of subjects, ages 44-70 years, with a family history of AD, one of 10 Caucasians and the other of 6 African-Americans. RESULTS: The pilot study showed that there was limited knowledge of genetics overall and AD genetics in particular, considerable concern about personal risk, and little knowledge of or interest in genetic testing for the disease. The focus groups reinforced and fleshed out these impressions and highlighted the importance of caregiving experience in the attitudes toward personal risk for AD. CONCLUSIONS: These results underscore the value of genetics education for this and other complex diseases and suggest specific foci for educational interventions.

Entorhinal Cortex: Antemortem Cortical Thickness and Postmortem Neurofibrillary Tangles and Amyloid Pathology.

BACKGROUND AND PURPOSE: The entorhinal cortex, a critical gateway between the neocortex and hippocampus, is one of the earliest regions affected by Alzheimer disease-associated neurofibrillary tangle pathology. Although our prior work has automatically delineated an MR imaging-based measure of the entorhinal cortex, whether antemortem entorhinal cortex thickness is associated with postmortem tangle burden within the entorhinal cortex is still unknown. Our objective was to evaluate the relationship between antemortem MRI measures of entorhinal cortex thickness and postmortem neuropathological measures. MATERIALS AND METHODS: We evaluated 50 participants from the Rush Memory and Aging Project with antemortem structural T1-weighted MR imaging and postmortem neuropathologic assessments. Here, we focused on thickness within the entorhinal cortex as anatomically defined by our previously developed MR imaging parcellation system (Desikan-Killiany Atlas in FreeSurfer). Using linear regression, we evaluated the association between entorhinal cortex thickness and tangles and amyloid-ß load within the entorhinal cortex and medial temporal and neocortical regions. RESULTS: We found a significant relationship between antemortem entorhinal cortex thickness and entorhinal cortex (P = .006) and medial temporal lobe tangles (P = .002); we found no relationship between entorhinal cortex thickness and entorhinal cortex (P = .09) and medial temporal lobe amyloid-ß (P = .09). We also found a significant association between entorhinal cortex thickness and cortical tangles (P = .003) and amyloid-ß (P = .01). We found no relationship between parahippocampal gyrus thickness and entorhinal cortex (P = .31) and medial temporal lobe tangles (P = .051). CONCLUSIONS: Our findings indicate that entorhinal cortex-associated in vivo cortical thinning may represent a marker of postmortem medial temporal and neocortical Alzheimer disease pathology.

'Alzheimer's Progression Score': Development of a Biomarker Summary Outcome for AD Prevention Trials.

BACKGROUND: Alzheimer's disease (AD) prevention research requires methods for measurement of disease progression not yet revealed by symptoms. Preferably, such measurement should encompass multiple disease markers. OBJECTIVES: Evaluate an item response theory (IRT) model-based latent variable Alzheimer Progression Score (APS) that uses multi-modal disease markers to estimate pre-clinical disease progression. DESIGN: Estimate APS scores in the BIOCARD observational study, and in the parallel PREVENT-AD Cohort and its sister INTREPAD placebo-controlled prevention trial. Use BIOCARD data to evaluate whether baseline and early APS trajectory predict later progression to MCI/dementia. Similarly, use longitudinal PREVENT-AD data to assess test measurement invariance over time. Further, assess portability of the PREVENT-AD IRT model to baseline INTREPAD data, and explore model changes when CSF markers are added or withdrawn. SETTING: BIOCARD was established in 1995 and participants were followed up to 20 years in Baltimore, USA. The PREVENT-AD and INTREPAD trial cohorts were established between 2011-2015 in Montreal, Canada, using nearly identical entry criteria to enroll high-risk cognitively normal persons aged 60+ then followed for several years. PARTICIPANTS: 349 cognitively normal, primarily middle-aged participants in BIOCARD, 125 high-risk participants aged 60+ in PREVENT-AD, and 217 similar subjects in INTREPAD. 106 INTREPAD participants donated up to four serial CSF samples. MEASUREMENTS: Global cognitive assessment and multiple structural, functional, and diffusion MRI metrics, sensori-neural tests, and CSF concentrations of tau, Aß42 and their ratio. RESULTS: Both baseline values and early slope of APS scores in BIOCARD predicted later progression to MCI or AD. Presence of CSF variables strongly improved such prediction. A similarly derived APS in PREVENT-AD showed measurement invariance over time and portability to the parallel INTREPAD sample. CONCLUSIONS: An IRT-based APS can summarize multimodal information to provide a longitudinal measure of pre-clinical AD progression, and holds promise as an outcome for AD prevention trials.

Neurobiological bases of age-related cognitive decline in the rhesus monkey.

The rhesus monkey offers a useful model of normal human aging because when monkeys are tested on a battery of behavioral tasks that can also be used to evaluate cognition in humans, it is found that the monkeys undergo an age-related decline in several domains of cognitive function as do humans. In monkeys these changes begin at about 20 years of age. To determine what gives rise to this cognitive decline, we have examined several parameters in the brains of monkeys. Some parameters do not change with age. Examples of this are the numbers of neurons in the neocortex and hippocampal formation, and the numbers of synapses in the hippocampal formation. Changes in other parameters can be positively correlated with chronological age; examples of this are numbers of neuritic plaques, a decrease in the numbers of neurons in the striatally projecting pars compacta of the substantia nigra, and a decrease in the thickness of layer I in primary visual cortex. But the most interesting changes are those that correlate either with cognitive decline alone, or with both cognitive decline and chronological age. Among these are a breakdown in the integrity of myelin around axons, an overall reduction in the volume of white matter in the cerebral hemispheres, thinning of layer I in area 46 of prefrontal cortex, and decreases in the cell density in cortically projecting brain stem nuclei. To date then, our studies suggest that the cognitive declines evident in the rhesus monkey may be a consequence of changes in layer I and in the integrity of myelinated axons, rather than an age-related loss of cortical neurons or synapses, as has long been assumed.

Increase in urinary cortisol excretion and memory declines: MacArthur studies of successful aging.

Cortisol production is increased during stress, and the actions of cortisol on receptors in the brain and other body organs are involved in allostasis, the process of adaptation to stress, as well as in allostatic load, the wear and tear associated with excessive exposure to cortisol. Using data from a community-based longitudinal study of older men and women, aged 70-79 yr, we tested the hypothesis that exposure to increasing levels of cortisol is associated with declines in memory performance. Associations between 12-h urinary free cortisol excretion and performance on tests of memory (delayed verbal recall and spatial recognition), abstraction, and spatial ability were examined. Among the women, greater cortisol excretion was associated with poorer baseline memory performance, independent of socio-demographic, health status, health behavior, and psychosocial characteristics. Moreover, women who exhibited increases in cortisol excretion over a 2.5-yr follow-up period were more likely to show declines in memory performance. By contrast, women who experienced declines in cortisol exhibited improvements in memory performance. No significant associations were found among the men. The results for the women suggest that decrements in memory performance associated with increases in cortisol may not represent irreversible effects, as declines in cortisol were associated with improvements in memory.

Cognitive deficits in patients with chronic fatigue syndrome.

Twenty-nine subjects with chronic fatigue syndrome (CFS) and 25 healthy control subjects were administered a lengthy neuropsychological battery that included standard neuropsychological tests and a computerized set of tasks that spanned the same areas of ability. The primary significant differences between patients and controls were found on tests of learning and memory. These differences remained when the degree of psychiatric symptomatology in the subjects was covaried. Patients on and off psychoactive medications did not differ in their performance on these tasks. These results suggest that at least a subset of CFS patients may experience significant impairments in learning and memory.

Special behavioral paradigms in animals to study age-related changes in memory.

Animal models are important to understand age-related changes in humans. However, the models do not always agree about the effects of aging on memory, and some of the results with animals are different from those with humans. Points of similarity and difference are discussed, indicating some directions for future research.

Perfusion abnormalities in prodromal AD.

Cerebral perfusion abnormalities in patients with established Alzheimer's disease (AD) are most commonly seen in the temporoparietal cortex. As the disease progresses, this perfusion pattern is increasingly prevalent. Recently, investigators have begun to examine the patterns of perfusion among individuals at risk for AD. To date, such studies have been conducted either in individuals who have a progressive memory difficulty but do not yet meet clinical criteria for AD, or in individuals with a genetic risk factor or family history of AD, either with or without a memory problem. These latter studies suggest that a set of brain regions show decreased perfusion during the prodromal phase of AD, and that a brain network or networks with multiple nodes is affected early in the course of AD. These perfusion abnormalities may also shed light on how AD progresses during the prodromal phase of disease and may ultimately lead to improved diagnosis or methods of monitoring response to treatment.

Effects of age upon interhemispheric EEG coherence in normal adults.

Age-related differences in quantified electrophysiological measures of interhemispheric EEG coherence were studied in 371 subjects (171 males and 200 females), ages 20-80, all of whom were judged to be optimally healthy. Principal components analysis (PCA) was performed on interhemispheric coherence of Laplacian referenced data from eight homologous left-right electrode pairs, from 0.5 to 32 Hz. Regression procedures, using signals from artifact monitoring channels, were used to minimize effects of eye movement and muscle artifact. Forty-six factors described 80% of the total variance, with electrode location the primary source of communality in factor formation. Within 350 right-handed subjects, results indicated a broad trend for decreased interhemispheric coherence with advancing age. Using canonical correlation, the coherence-based factors also successfully predicted spectral variables, previously found to maximally illustrate age-related EEG desynchronization. We speculate that age-related reduction of interhemispheric coherence may in part explain age-related EEG desynchrony and stems from age-related reduction of cortical connectivity. Gender differences of interhemispheric coherence were also evident. Females demonstrated higher interhemispheric coherence than males. Within a smaller subpopulation of 63 subjects (21 left and 42 right handed), there was a gender-by-handedness interaction, with higher interhemispheric coherence in right-handed females than right-handed males and the reverse in left-handed male and female subjects.

The pattern of age-related differences in electrophysiological activity of healthy males and females.

Age-related differences in quantified electrophysiological measures were examined in 202 subjects (109 females; 93 males) ages 30-80 all of whom were judged to be optimally healthy on a wide variety of criteria. The study utilized both absolute and relative measures from EEG spectral analysis as well as additional measures from long latency-evoked potentials. The same findings were noted for the 109 newly studied females as were reported for 63 previously studied male subjects. Results indicate that there is a broad trend for decreased EEG slow and increased fast activity with age, however, some of the measures change linearly and others are best represented by nonlinear functions. There is no decade where activities remain stable. Overall the pattern of change for males and females is similar, however, gender differences in both the EEG and EP data were present. The females had higher magnitudes for almost all absolute spectral and fast relative spectral measures. However, females demonstrated lower absolute alpha amplitude, lower relative slow activity, and lower late-latency EP data. Moreover, the absolute slow activity measure showed a gender X age interaction, indicating that the females had a different change in pattern of activity with increasing age than the males. Thus, gender-related findings were complex and could not be expressed as simple differences in overall amplitude. Age-related change is not a simple linear process but differs for differing EEG spectral bands, relative, and absolute spectral measures and for males and females. The overall findings contradict the common wisdom that EEG and alpha slow with age and that age related EEG change is on a continuum with findings in Alzheimer's disease where increased slowing predominates.

Temporal gradients in the retrograde amnesia of patients with alcoholic Korsakoff's disease.

Eleven alcoholic patients with Korsakoff's disease and 15 control subjects were given three tests of retrograde amnesia. The first consisted of photographs of famous faces from the past, the second was a recall test of famous people and events, and the third was a multiple-choice questionnaire. To determine whether previously reported temporal gradients (ie, preservation of remote events) were related to item difficulty, half of the questions dealt with events of transient fame while half concerned subjects that continued to receive public attention for many years. The findings indicate that alcoholic patients with Korsakoff's disease have a marked retrograde amnesia that is characterized by a steep temporal gradient, and that this gradient is not an artifact due to the difficulty of the questions or the method of testing.

Patterns of remote memory in amnesic and demented patients.

Patients with Huntington's disease (HD) were compared on three tests of remote memory with patients with alcoholic Korsakoff's syndrome (KS) and with control subjects. Though both patient groups were severely impaired in overall performance with respect to the normal control subjects on all three tests, striking differences were evident in the degree of loss for each decade interval. The patients with HD had as much difficulty identifying faces and events from the 1930s and 1940s as faces and events from the 1960s and 1970s. Thus, the pattern of their remote memory loss was "flat", that is, equal for all periods sampled. The retrograde amnesia of the patients with KS was characterized by a steep temporal gradient in which facts pertaining to the distant past were more accurately retrieved than facts concerning events that occurred just prior to the onset of their illness. Taken in conjunction with other recent studies of retrograde amnesia, these results suggest that neurologic patients exhibit at least three different patterns of remote memory loss.

Perception of affect in patients with dementia of the Alzheimer type.

The ability to perceive affect was examined in 19 patients with Alzheimer's disease and in 19 control subjects. Nine tasks were given. All participants were asked to recognize facial emotion, to provide verbal labels of facial emotion, and to identify emotion portrayed in drawings or in verbal descriptions of emotional situations. The results indicate that there are significant differences between patients with Alzheimer's disease and control subjects on all of the tasks. However, when test scores were adjusted for the cognitive abilities of the subjects, few of the tests continue to differentiate the groups. These results suggest that the deficits of patients with Alzheimer's disease on perception of affect tasks are likely to be the result of their cognitive defects and not the result of a primary impairment in the perception of emotion.

Electrophysiologic comparisons between two groups of patients with Alzheimer's disease.

Two groups of patients with Alzheimer's disease were compared using brain electrical activity mapping. The patients were selected on the basis of their cognitive history. The initial symptom of disease of the patients in group 1 was a significant and profound memory deficit, whereas the patients in group 2 initially presented with a gradually progressive spatial impairment. Fourteen topographic features distinguished the groups. Eleven of the 14 features pertained to electrical activity differences in parietal regions, and 9 were bilateral. These features were highly correlated with cognitive measures that are also useful in distinguishing the groups.

Differential patterns of memory loss among patients with Alzheimer's disease, Huntington's disease, and alcoholic Korsakoff's syndrome.

Patients with Huntington's disease (HD), alcoholic Korsakoff's syndrome (KS), and Alzheimer's disease (AD) were compared with normal control subjects on a task designed to assess recognition memory for different classes of stimuli: spatial, verbal, color, pattern, and facial. In addition, recall of verbal stimuli was assessed at two delay intervals. On recognition testing, AD and KS patients were impaired on each of the five stimulus conditions. However, HD patients, though impaired on four of the recognition conditions, were unimpaired when verbal stimuli were used. On recall testing, the AD, HD, and KS groups were equally impaired at the shorter delay (15 s). However, at the longer delay (two minutes), the KS and HD patients, though still impaired relative to the normal control group, performed significantly better than the AD group.

Age-related differences in computed tomographic scan measurements.

Seventy-nine healthy men ranging in age from 31 to 87 years underwent a computed tomographic (CT) scan and were administered a neuropsychologic test battery. Midventricular, high ventricular, and supraventricular CT slices were analyzed for each individual. Computerized techniques calculated the percent of fluid volume and the mean CT density for each slice. The mean CT density of a standard tissue sample was also evaluated. The results suggest that fluid volume at the level of the ventricles is fairly stable until individuals are in their 60s, when a dramatic increase occurs. The percent of fluid volume above the level of the ventricles appears to increase slightly the ventricles appears to increase slightly in the 50s and then level off. Whole slice mean CT density numbers decreased in a linear fashion with increasing age, but the mean CT density of a standard tissue sample did not. A discriminant function derived from the CT measures was significantly correlated with a discriminant function derived from the neuropsychologic test battery. Findings based on subjects whose health status has been less carefully screened may differ from those in the present study.

Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Pick's Disease.

An international group of clinical and basic scientists participated in the Frontotemporal Dementia and Pick's Disease Criteria Conference at the National Institutes of Health in Bethesda, Md, on July 7, 2000, to reassess clinical and neuropathological criteria for the diagnosis of frontotemporal dementia (FTD). Previous criteria for FTD have primarily been designed for research purposes. The goal of this meeting was to propose guidelines that would enable clinicians (particularly neurologists, psychiatrists, and neuropsychologists) to recognize patients with FTD and, if appropriate, to expedite their referral to a diagnostic center. In addition, recommendations for the neuropathological criteria of FTD were reviewed, relative to classical neuropathology and modern molecular biology.