Normal Elderly Individuals Research Articles

Baseline neuropsychiatric symptoms and the risk of incident mild cognitive impairment: A population-based study

Objective: The authors conducted a prospective cohort study to estimate the risk of incident mild cognitive impairment in cognitively normal elderly (aged $70 years) individuals with or without neuropsychiatric symptoms at baseline. The research was conducted in the setting of the populationbased Mayo Clinic Study of Aging. Method: Ac lassification of normal cognitive aging, mild cognitive impairment, and dementia was adjudicated by an expert consensus panelbased onpublished criteria. Hazard ratios and 95% confidence intervals were computed usingCoxproportionalhazardsmodel,withage as a time scale. Baseline Neuropsychiatric Inventory Questionnaire data were available for 1,587 cognitively normal persons who underwent at least one follow-up visit. Results: The cohort was followedto incident mild cognitive impairment (N=365) or censoring variables (N=179) for a median of 5 years. Agitation (hazard ratio=3.06, 95% CI=1.89– 4.93),apathy(hazard ratio=2.26,95%CI=1.49– 3.41), anxiety (hazard ratio=1.87, 95% CI=1.28–2.73), irritability (hazard ratio=1.84, 95% CI=1.31–2.58), and depression (hazard ratio=1.63, 95% CI=1.23–2.16), observed initially, increased risk for later mild cognitive impairment. Delusion and hallucination did not. A secondary analysis, limited in significance by the small number of study participants, showed that euphoria, disinhibition, and nighttime behaviors were significant predictors of nonamnestic mild cognitive impairment but not amnestic mild cognitive impairment. By contrast, depression predicted amnestic mild cognitive impairment (hazard ratio=1.74, 95% CI=1.22–2.47) but notnonamnesticmildcognitiveimpairment. Conclusions: An increased incidence of mild cognitive impairment was observed in community-dwelling elderly adults who had nonpsychotic psychiatric symptoms at baseline. These baseline psychiatric symptoms were of similar or greater magnitude as biomarkers (genetic and structural MRI) in increasing the risk of incident mild cognitive impairment. (Am J Psychiatry 2014; 171:572–581)

Outcomes of Mild Cognitive Impairment by Definition

Mild cognitive impairment (MCI) has been defined in several ways. To determine the 1-year outcomes of MCI by different definitions at the population level. Inception cohort with 1-year follow-up. Participants were classified as having MCI using the following definitions operationalized for this study: amnestic MCI by Mayo criteria, expanded MCI by International Working Group criteria, Clinical Dementia Rating (CDR) = 0.5, and a purely cognitive classification into amnestic and nonamnestic MCI. General community. Stratified random population-based sample of 1982 individuals 65 years and older. For each MCI definition, there were 3 possible outcomes: worsening (progression to dementia [CDR ≥ 1] or severe cognitive impairment), improvement (reversion to CDR = 0 or normal cognition), and stability (unchanged CDR or cognitive status). Regardless of MCI definition, over 1 year, a small proportion of participants progressed to CDR > 1 (range, 0%-3%) or severe cognitive impairment (0%-20%) at rates higher than their cognitively normal peers. Somewhat larger proportions of participants improved or reverted to normal (6%-53%). Most participants remained stable (29%-92%). Where definitions focused on memory impairment and on multiple cognitive domains, higher proportions progressed and lower proportions reverted on the CDR. As ascertained by several operational definitions, MCI is a heterogeneous entity at the population level but progresses to dementia at rates higher than in normal elderly individuals. Proportions of participants progressing to dementia are lower and proportions reverting to normal are higher than in clinical populations. Memory impairments and impairments in multiple domains lead to greater progression and lesser improvement. Research criteria may benefit from validation at the community level before incorporation into clinical practice.

Cognitive Impairment in Mild General Paresis of the Insane: AD-Like Pattern

Background/Aims: We investigated the clinical and cognitive features of patients with mild general paresis of the insane (GPI) in comparison to Alzheimer’s disease (AD) patients, mild frontotemporal dementia (FTD) patients and normal elderly individuals. Methods: Twelve patients with mild GPI, 24 patients with mild AD, 11 patients with mild FTD and 36 healthy subjects participated in the current study. A comprehensive neuropsychological battery was used to assess memory, language, attention, executive function, visuospatial ability, etc. In addition, cranial MRI were also obtained from the 3 patient groups. Results: Mild GPI showed a similar pattern of cognitive impairments in memory, language and executive function to mild AD, but a mixed pattern of dissimilarities to mild FTD. Mild GPI patients had more complaints and positive signs in the nervous system than mild AD patients, and cranial MRI results showed that mild GPI patients usually had atrophy of the medial temporal lobe. Conclusion: There is an overall decline in cognitive functions of mild GPI patients, which is comparable to that in AD patients, suggesting that there is a wide range of structural changes in the brains of mild GPI patients as well. However, further studies are needed to verify whether these structural changes are similar to those in AD.

White matter lesions in Parkinson disease

Pure vascular parkinsonism without evidence of nigral Lewy body pathology may occur as a distinct clinicopathological entity, but a much more frequent occurrence is the comorbid presence of age-associated white matter lesions (WMLs) in idiopathic Parkinson disease (PD). WMLs are associated with motor and cognitive symptoms in otherwise normal elderly individuals. Comorbid WMLs are, therefore, expected to contribute to clinical symptoms in PD. Studies of WMLs in PD differ with regard to methods of assessment of WML burden and the patient populations selected for analysis, but converging evidence suggests that postural stability and gait motor functions are predominantly affected. WMLs are described to contribute to dementia in Alzheimer disease, and emerging but inconclusive evidence indicates similar effects in PD. In this article, we review the literature addressing the occurrence and impact of WMLs in PD, and suggest that WMLs may exacerbate or contribute to some motor and cognitive deficits associated with PD. We review existing and emerging methods for studying white matter pathology in vivo, and propose future research directions.

CERAD-neuropsychological battery in screening mild Alzheimer’s disease

The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery (nb) is used as an evaluation tool for dementia. In Finland, CERAD-nb was introduced in 1999 and has been proposed to be used in primary health care. However, some of its parts need reassessment and focusing. The goal of this study was to examine the sensitivity and specificity of the subtests and their cut-off points most appropriate for identifying mild Alzheimer's disease (AD). The study population consisted of 171 patients with mild AD and 315 cognitively normal elderly. Both groups underwent CERAD-nb investigation as a part of a wider examination procedure. The most efficient subtests to discriminate patients with mild AD from the normal elderly were Wordlist delayed recall and savings, Wordlist learning and Wordlist recognition and a new variable of Total recall. Optimal cut-off points for each subtest are suggested. The sensitivities of the verbal memory subtests varied between 0.75 and 0.94, the specificities between 0.80 and 0.93 and the areas under the receiver operating characteristics curve between 0.89 and 0.96. The CERAD-nb is capable of differentiating cases with mild AD from normal elderly individuals particularly with its verbal memory subtests. New cut-off scores for CERAD's subtests validated in the study further enhance the differentiating power, and with these clarifications, CERAD-nb is considered appropriate to be used as a screening tool for AD even in primary health care.

一般高齢者を対象とした誰でもできる運動器の機能向上体験プログラムの効果に関する研究

一般高齢者を対象とした誰でもできる運動器の機能向上体験プログラムの効果に関する研究

The Executive Control of Face Memory

Patients with frontal lobe damage and cognitively normal elderly individuals demonstrate increased susceptibility to false facial recognition. In this paper we review neuropsychological evidence consistent with the notion that the common functional impairment underlying face memory distortions in both subject populations is a context recollection/source monitoring deficit, coupled with excessive reliance on relatively preserved facial familiarity signals in recognition decisions. In particular, we suggest that due to the breakdown of strategic memory retrieval, monitoring, and decision operations, individuals with frontal lobe impairment caused by focal damage or age-related functional decline do not have a reliable mechanism for attributing the experience of familiarity to the correct context or source. Memory illusions are mostly apparent under conditions of uncertainty when the face cue does not directly elicit relevant identity-specific contextual information, leaving the source of familiarity unspecified or ambiguous. Based on these findings, we propose that remembering faces is a constructive process that requires dynamic interactions between temporal lobe memory systems that operate in an automatic or bottom-up fashion and frontal executive systems that provide strategic top-down control of recollection. Executive memory control functions implemented by prefrontal cortex play a critical role in suppressing false facial recognition and related source memory misattributions.

The executive control of face memory.

Patients with frontal lobe damage and cognitively normal elderly individuals demonstrate increased susceptibility to false facial recognition. In this paper we review neuropsychological evidence consistent with the notion that the common functional impairment underlying face memory distortions in both subject populations is a context recollection/source monitoring deficit, coupled with excessive reliance on relatively preserved facial familiarity signals in recognition decisions. In particular, we suggest that due to the breakdown of strategic memory retrieval, monitoring, and decision operations, individuals with frontal lobe impairment caused by focal damage or age-related functional decline do not have a reliable mechanism for attributing the experience of familiarity to the correct context or source. Memory illusions are mostly apparent under conditions of uncertainty when the face cue does not directly elicit relevant identity-specific contextual information, leaving the source of familiarity unspecified or ambiguous. Based on these findings, we propose that remembering faces is a constructive process that requires dynamic interactions between temporal lobe memory systems that operate in an automatic or bottom-up fashion and frontal executive systems that provide strategic top-down control of recollection. Executive memory control functions implemented by prefrontal cortex play a critical role in suppressing false facial recognition and related source memory misattributions.

Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study

Extract of Ginkgo biloba (EGb), a dietary supplement used for a number of conditions including dementia, has been suggested to increase cerebral bloodflow (CBF). The purpose of this study was to determine if changes in CBF could be detected by dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI)in elderly human subjects taking EGb. DSC-MRI was performed in nine healthy men(mean age 61±10 years) before and after 4 weeks of 60 mg EGb taken twice daily. One subject underwent six consecutive scans to evaluate intrasubject reproducibility. CBF values were computed before and after EGb, and analyzed at three different levels of spatial resolution, using voxel-based statistical parametric mapping (SPM), and regions of interest in different lobes, and all regions combined. Normalized intrasubject CBF (nCBF) measurements had a standard deviation of 7% and 4% in gray and white matter (WM) regions, respectively. SPM using an uncorrected, voxel-level threshold of P≤0.001 showed a small CBF increase in the left parietal-occipital region.CBF in individual lobar regions did not show any significant change post-EGb, but all regions combined showed a significant increase of non-normalized CBF after EGb (15% in white and 13% in gray matter, respectively, P≤0.0001). nCBF measured by DSC-MRI has good intrasubject reproducibility. In this small cohort of normal elderly individuals, a mild increase in CBF is found in the left parietal-occipital WM after EGb, as well as a small but statistically significant increase in global CBF.

Targeting Tau Protein in Alzheimerʼs Disease

Alzheimer's disease (AD) is characterized histopathologically by numerous neurons with neurofibrillary tangles and neuritic (senile) amyloid-beta (Abeta) plaques, and clinically by progressive dementia. Although Abeta is the primary trigger of AD according to the amyloid cascade hypothesis, neurofibrillary degeneration of abnormally hyperphosphorylated tau is apparently required for the clinical expression of this disease. Furthermore, while approximately 30% of normal aged individuals have as much compact plaque burden in the neocortex as is seen in typical cases of AD, in several tauopathies, such as cortical basal degeneration and Pick's disease, neurofibrillary degeneration of abnormally hyperphosphorylated tau in the absence of Abeta plaques is associated with dementia. To date, all AD clinical trials based on Abeta as a therapeutic target have failed. In addition to the clinical pathological correlation of neurofibrillary degeneration with dementia in AD and related tauopathies, increasing evidence from in vitro and in vivo studies in experimental animal models provides a compelling case for this lesion as a promising therapeutic target. A number of rational approaches to inhibiting neurofibrillary degeneration include inhibition of one or more tau protein kinases, such as glycogen synthase kinase-3beta and cyclin-dependent protein kinase 5, activation of the major tau phosphatase protein phosphatase-2A, elevation of beta-N-acetylglucosamine modification of tau through inhibition of beta-N-acetylglucosaminidase or increase in brain glucose uptake, and promotion of the clearance of the abnormally hyperphosphorylated tau by autophagy or the ubiquitin proteasome system.

Comparing Cerebral White Matter Lesion Burdens between Parkinson's Disease with and without Dementia.

Cerebral white matter lesions (CWMLs) have been suggested to be associated with an increased risk of dementia, disability, and death. CWMLs are more common in individuals with Alzheimer’s disease (AD) than in normal elderly individuals of comparable age. Only a few studies have been done to determine whether CWMLs may influence cognitive decline in Parkinson’s disease (PD). Fully developed PD with concurrent AD was reported to likely cause impaired cognition in spite of accumulating evidence suggesting that PD with dementia (PDD) is more closely associated with Lewy body (LB) pathology. Currently, contradictory data on the neuropathology of dementia in PD require further prospective clinicopathological studies in larger cohorts to elucidate the impact of AD and α-synuclein (SCNA) pathologies on the cognitive status in these disorders. Previous reports did not suggest CWMLs to be associated with an increased risk of PDD. After adjusting for age at death, age at onset of PD, and duration of PD, our recent study investigating CWMLs in PDD via autopsy has shown a positive correlation between the burden of CWMLs and PDD. The frequent co-existence of both LB and AD lesions suggests that both pathologies independently or synergistically contribute to both movement disorders and cognitive impairment. The individual and cumulative burden of CWMLs, LB lesions, and AD lesions may synergistically contribute to cognitive decline in LB disorders such as PDD.

Joint Modeling for Cognitive Trajectory and Risk of Dementia in the Presence of Death

Dementia is characterized by accelerated cognitive decline before and after diagnosis as compared to normal aging. It has been known that cognitive impairment occurs long before the diagnosis of dementia. For individuals who develop dementia, it is important to determine the time when the rate of cognitive decline begins to accelerate and the subsequent gap time to dementia diagnosis. For normal aging individuals, it is also useful to understand the trajectory of cognitive function until their death. A Bayesian change-point model is proposed to fit the trajectory of cognitive function for individuals who develop dementia. In real life, people in older ages are subject to two competing risks, e.g., dementia and dementia-free death. Because the majority of people do not develop dementia, a mixture model is used for survival data with competing risks, which consists of dementia onset time after the change point of cognitive function decline for demented individuals and death time for nondemented individuals. The cognitive trajectories and the survival process are modeled jointly and the parameters are estimated using the Markov chain Monte Carlo method. Using data from the Honolulu Asia Aging Study, we show the trajectories of cognitive function and the effect of education, apolipoprotein E 4 genotype, and hypertension on cognitive decline and the risk of dementia.

Advances in Vascular Cognitive Impairment

Advances in Vascular Cognitive Impairment

Brain Atrophy in Healthy Aging Is Related to CSF Levels of Aβ1-42

Reduced levels of beta-amyloid(1-42) (Abeta1-42) and increased levels of tau proteins in the cerebrospinal fluid (CSF) are found in Alzheimer's disease (AD), likely reflecting Abeta deposition in plaques and neuronal and axonal damage. It is not known whether these biomarkers are associated with brain atrophy also in healthy aging. We tested the relationship between CSF levels of Abeta1-42 and tau (total tau and tau phosphorylated at threonine 181) proteins and 1-year brain atrophy in 71 cognitively normal elderly individuals. Results showed that under a certain threshold value, levels of Abeta1-42 correlated highly with 1-year change in a wide range of brain areas. The strongest relationships were not found in the regions most vulnerable early in AD. Above the threshold level, Abeta1-42 was not related to brain changes, but significant volume reductions as well as ventricular expansion were still seen. It is concluded that Abeta1-42 correlates with brain atrophy and ventricular expansion in a subgroup of cognitively normal elderly individuals but that reductions independent of CSF levels of Abeta1-42 is common. Further research and follow-up examinations over several years are needed to test whether degenerative pathology will eventually develop in the group of cognitively normal elderly individuals with low levels of Abeta1-42.

Intrathecal enzyme replacement therapy to treat spinal cord compression in mucopolysaccharidosis: Overview and rationale

Spinal cord compression has been described in mucopolysaccharidosis I, II, IV, VI, and VII. The spinal cord compression in the mucopolysaccharidoses is believed to originate from narrowing of the vertebral canal due to bony abnormalities, and thickening of the meninges and spinal ligaments due to glycosaminoglycan infiltration [12]. The current standard of care involves surgical decompression. However, the surgery is extensive, MPS patients are high-risk surgical and anesthesia candidates, and the problem may recur after surgery. Neurosurgical treatment of spinal cord compression involves a multi-level decompressive laminectomy and opening of the thickened dura [12]. Many patients also require a suboccipital craniectomy. Some patients require instrumentation and fusion because they have ligamentous or spinal instability. Overall, the surgical repair can be more extensive than that required for spondylotic degeneration and myelopathy in normal elderly individuals.

Frontal Dysfunction Underlies Depression in Mild Cognitive Impairment: A FDG-PET Study

ObjectiveDepression is a very common symptom in people with mild cognitive impairment (MCI), a preclinical stage of Alzheimer's disease (AD), and in those with clinically evident AD. Moreover, MCI individuals with depression show a higher conversion rate to clinical AD than those without depression. This study aimed to elucidate the functional neuroanatomical substrate of depression in MCI.MethodsThirty-six patients were recruited from a University Hospital-based cohort; 18 of these subjects had MCI with depression (MCI_D); the remaining 18 subjects were age- and gender-matched, and had MCI with no depression (MCI_ND). For comparison, 16 cognitively normal (CN) elderly individuals were also included. All subjects underwent Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scanning and regional cerebral glucose metabolism was compared among the three groups by a voxel-based method. The relationship between severity of depression, as measured by Hamilton Rating Scale for Depression (HRSD) scores, and glucose metabolism was also investigated.ResultsMCI_D showed lower glucose metabolism in the right superior frontal gyrus than MCI_ND. There was a significant negative correlation between HRSD score and glucose metabolism at the same frontal region for overall MCI subjects. When compared with CN, both MCI_D and MCI_ND showed decreased glucose metabolism in the precuneus, while MCI_D had, in addition, reduced metabolism in other diffuse brain regions.ConclusionGiven previous observations on depression in AD, our results suggest that functional disruption of the frontal region, known to be associated with primary or other secondary depression, underlies depression in preclinical AD as well as clinically evident AD.

DNA Methylation Impacts on Cognitive Decline in a Cohort of Elderly Men

ISEE-0568 Background and Objective: Environmental exposures have been associated with both epigenetic mechanisms and decrements in cognitive function. Epigenetic phenomena regulate the normal function of cells, including neurons, while epigenetic dysregulation has been identified in cognitive function disorders. The role of DNA methylation on changes in cognitive function over time has not been investigated. The objective of the current study was to evaluate whether DNA methylation in repetitive elements widely represented across the human genome is associated with changes in cognitive function in normal aging individuals. Methods: A longitudinal cohort study was conducted in the context of the Normative Aging Study (Boston, USA) among 646 community-dwelling elderly men who underwent a battery of cognitive tests and who also had DNA methylation measurements. We used mixed effects models to assess the association between repeated measurements of scores on a battery of cognitive tests over time and DNA methylation in Alu and LINE-1 (long interspersed nucleotide element-1) repetitive elements. Cognitive testing was performed from 1993 through 2007 and a total of 1,659 observations were included in the final analysis. Results: The mean age of participants at baseline visit was 67.7 (SD = 7) years and the mean number of years of education was 14.4 (SD = 2.7). In multivariable models, a statistically significant greater decrease on a working memory test score (digit span backward test) over time with increasing LINE-1 DNA methylation (b = −0.019, P = 0.0397) was found. A decline in performance over time was observed on the majority of the tests as DNA methylation increased but the associations did not reach statistical significance. Conclusion: Higher levels of DNA methylation in LINE-1 repetitive elements may adversely affect cognitive function, particularly in the working memory domain.

Lack of strategy holding: A new pattern of learning deficit in cortical dementias

The aim of this study was to demonstrate, by means of systematic research and qualitative data analysis, the presence, among a group of patients with fronto-temporal lobar degeneration of a subgroup that, at variance with the standard pattern, is able to devise and implement learning strategies, but appear impaired at carrying them on from a trial to the next. In order to provide evidence of the existence of a group of patients showing this type of learning disability, that we refer to as lack of strategy holding, we performed a stepwise hierarchical cluster analysis of a set of variables whose scores were selected from the subject's performance at the Test de Aprendizaje Verbal España-Complutense. Results substantiate the segregation of three groups of subjects characterized by the following patterns of performance: normal elderly individuals, who show a quite preserved ability to discover a semantic strategy along the learning trials and to carry it from a trial to the next, patients presenting with a deficit in implementing semantic learning strategies and possibly use of serial and/or phonological strategies to perform the task, and to patients who, although able to generate and implement appropriate learning strategies, appear unable to carry them over the learning trials. The presence of this new pattern raises a few questions that seem worth trying to address.

Metacognitive monitoring abilities and amyloid deposition imaging in normal elderly individuals

Metacognitive monitoring abilities and amyloid deposition imaging in normal elderly individuals

No Association Between Telomere Length and Blood Cell Counts in Elderly Individuals

Telomeres play a crucial role in maintaining the physical integrity of chromosomes. Telomere length (TL) is severely reduced in individuals with dyskeratosis congenita and a number of other bone marrow failure syndromes. The TL of healthy individuals is highly variable, but shortens with age. It is presently unclear if variations in TL observed in normal aging individuals affect significantly their hematopoietic reserve. Method We studied the correlation between leukocyte age-adjusted TL (aTL) and blood cell parameters (total leukocytes, neutrophils, monocytes, eosinophils, lymphocytes, hemoglobin, and platelets) in a large cohort (n=717) of women aged 38-100 years. Result We did not find any significant correlation between aTL and blood counts. Our data suggest that the aTL of aging individuals is not significantly predictive of their hematopoietic reserve, which implies that TL measurement may not be clinically useful in the selection of hematopoietic stem cell transplantation donors.