Non-demented Elderly Subjects Research Articles

Regional Cerebral Blood Flow in [123]I-IMP Single-photon Emission Computed Tomography and the Wechsler Memory Scale-revised in Nondemented Elderly Subjects with Subjective Cognitive Impairment.

Objective Regional cerebral blood flow (rCBF) imaging with single-photon emission computed tomography (SPECT) is useful in the early diagnosis of dementia. We aimed to investigate the association between the rCBF and various domains related to the memory function in elderly subjects with subjective cognitive impairment (SCI). Methods Thirty-two subjects with SCI were included in the present study. Patients with dementia and mild cognitive impairment (MCI) were excluded based on the presence of logical memory impairment. N-isopropyl-p-[123I]-iodoamphetamine SPECT was performed and Wechsler Memory Scale-Revised (WMS-R) was administered to all subjects (mean age, 68.4 years; average Mini-Mental State Examination score, 27.6). The SPECT results were analyzed using the easy Z-score imaging system and the voxel-based stereotactic extraction estimation method. Correlation analyses were performed to investigate the correlation between the mean positive Z-scores in the decrease of the rCBF and the WMS-R indices. Results The SPECT study indicated marked hypoperfusion in some areas, including the bilateral temporal areas, the caudate, and the thalamus, in these subjects in comparison to the normal database. The decrease in the rCBF that was observed in several regions, including the left precuneus and left inferior frontal gyrus (LIFG), showed a significant negative correlation with several indices of the memory function, particularly visual memory. Conclusion The regional hypoperfusion observed in the study using the voxel-based stereotactic extraction estimation method suggest that the regional cerebral dysfunction is associated with the memory function of patients with SCI, even though the subjects in the present study were cognitively intact. The correlation analysis with the WMS-R suggested the contribution of the LIFG to the memory function and indicated the significance of visual memory dysfunction in the neuropsychological assessment to determine the stage of SCI.

Comparison of Metal Levels between Postmortem Brain and Ventricular Fluid in Alzheimer's Disease and Nondemented Elderly Controls.

An essential metal hypothesis for neurodegenerative disease suggests an alteration in metal homeostasis contributing to the onset and progression of disease. Similar associations have been proposed for nonessential metals. To examine the relationship between metal levels in brain tissue and ventricular fluid (VF), postmortem samples of frontal cortex (FC) and VF from Alzheimer's disease (AD) cases and nondemented elderly subjects were analyzed for arsenic (As), cadmium (Cd), chromium (Cr), cobalt (Co), copper (Cu), iron (Fe), lead (Pb), manganese (Mn), mercury (Hg), nickel (Ni), tin (Sn), vanadium (V), and zinc (Zn) using inductively coupled plasma sector field mass spectrometry. All metals, with exception of equivalent Pb levels, were lower in the VF, compared to FC. Within-subject comparisons demonstrated that VF levels were not representative of levels within brain tissue. The essential metals Cu, Fe, and Zn were found highest in both compartments. Cd, Hg, and V levels in the VF were below the limit of quantification. In AD cases, FC levels of Fe were higher and As and Cd were lower than levels in controls, while levels of As in the VF were higher. Parameter estimates for FC metal levels indicated an association of Braak stage and higher Fe levels and an association of Braak stage and lower As, Mn, and Zn levels. The data showed no evidence of an accumulation of nonessential metals within the AD brain and, with the exception of As, showed no significant shift in the ratio of FC to VF levels to indicate differential clearance.

The effects of an APOE promoter polymorphism on human cortical morphology during nondemented aging.

Apolipoprotein E (APOE) is the best-known susceptibility gene for AD. It has been well demonstrated that the ε4 allele of the APOE gene can affect brain structure/function in nondemented individuals; however, other polymorphisms in the APOE gene have been largely overlooked when assessing the effects of APOE on the neural system. Rs405509 is a newly recognized AD-related polymorphism located in the APOE promoter region that can regulate the transcriptional activity of the APOE gene. To date, it remains unknown whether and how this APOE promoter polymorphism affects the human brain in aging. Here, for the first time, we investigate the effects of the rs405509 genotype (T/T vs G-allele) on human cortical morphology using a large cohort of nondemented elderly subjects (120 subjects in total; aged 52- 81 years). High-resolution structural MRI was performed; cortical thickness and surface area were analyzed separately. Intriguingly, nondemented carriers of the rs405509 T/T genotype showed an accelerated age-related reduction of thickness in the left parahippocampal gyrus compared with the G-allele carriers. Furthermore, the cortical thickness covariance between the left parahippocampal gyrus and left medial cortex, including the left medial superior frontal gyrus, supplementary motor area, and paracentral lobule, was modulated by the interaction of the rs405509 genotype and age. These novel findings suggest an important role for the APOE promoter polymorphism in the human brain and also provide valuable insights into how the rs405509 genotype shapes the neural system to modulate the risk of developing AD.

Cortical localization of microbleeds in cerebral amyloid angiopathy: an ultra high-field 7T MRI study.

The extent of cortical involvement of cerebral amyloid angiopathy (CAA)-related microbleeds (CMBs) remains unclear. We examined five consecutive patients with probable CAA and three non-demented elderly subjects with ultra-high field 7T MRI, to identify the precise location of CAA-related CMBs. In five CAA patients, 169 of a total of 170 lobar CMBs were located in cortical areas on 7T MRI, while a precise cortical versus juxtacortical localization was unable to be determined for 50/76 CMBs observed by conventional MRI. 7T MRI demonstrates that nearly all lobar CMBs are located in cortex in CAA.

TAU PET IMAGING IN ANIMAL MODELS AND HUMANS

Accumulation of tau aggregates has been implicated in Alzheimer's disease (AD) and a subset of non-AD dementias. Pathogenetic signaling cascade of AD is supposedly triggered by deposition of amyloid-β peptide (Aβ), while initiation of tau pathologies may not be necessarily secondary to Aβ abnormalities. Prion-like intracranial transmission of tau fibrillogenesis in these tauopathies and modulation of this spreading by other pathogenic molecules such as Aβ and TDP-43 have also been of paramount interest. These issues could be examined by visualization of tau inclusions in tauopathy patients and animal models. We developed an imaging agent, PBB3, applicable to in vivo detection of tau aggregates in patients with AD and diverse other tauopathies and tau transgenic mice. Binding of PBB3 along with various tau-binding fluorescent compounds to tau inclusions in sliced human and mouse brains was comparatively assessed. Preclinical characterization of PBB3 was performed in tau transgenic mice using imaging optics and PET. Clinical PET studies were conducted with [11 C]PBB3 and Aβ ligand, [11 C]PIB. Tested tau ligands differentially reacted with tau inclusions in AD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), argyrophilic grain disease, familial FTLD-tau and two tau transgenic mouse lines (PS19 and rTg4510), presumably due to structural diversities of tau fibril strains. Two-photon laser microscopic and microPET imaging enabled kinetic assessments of PBB3 in mouse models. Clinical PET assays demonstrated [11 C]PBB3-positive tau aggregates in the hippocampal formation of a subpopulation of [11 C]PIB-negative non-demented elderly subjects. Tau deposits spread to extensive brain areas in transition from normal aging to severe AD, supporting the utility of [11 C]PBB3-PET for objectively determining severity of AD from a preclinical stage. Increases of [11 C]PBB3 signals in patients with PSP, CBD and other FTLDs were also consistent with local atrophies and reported postmortem distribution of tau lesions in these illnesses, and were intimately associated with their characteristic symptoms. [11 C]PBB3-PET would serve for clarification of mechanisms by which tau accumulates and spreads and for differential diagnosis and pathological staging of tauopathies. Differential use of PBB3 and other tau ligands would help translational research and drug development targeting specific tau strains.

Both Targeted Mass Spectrometry and Flow Sorting Analysis Methods Detected the Decreased Serum Apolipoprotein E Level in Alzheimer's Disease Patients

Apolipoprotein E (ApoE) polymorphism has been appreciated as a valuable predictor of Alzheimer disease (AD), and the associated ε4 allele has been recognized as an indicator of susceptibility to this disease. However, serum ApoE levels have been a controversial issue in AD, due to the great variability regarding the different target detection methods, ethnicity, and the geographic variations of cohorts. The aim of this study was to validate serum ApoE levels in relation to AD, particularly using two distinct detection methods, liquid chromatography-selected reaction monitoring (SRM) mass spectrometry and microsphere-based fluorescence-activated cell sorting (FACS) analysis, to overcome experimental variations. Also, comparison of serum ApoE levels was performed between the level of protein detection by FACS and peptide level by SRM in both control and AD patients. Results from the two detection methods were cross-confirmed and validated. Both methods produced fairly consistent results, showing a significant decrease of serum ApoE levels in AD patients relative to those of a control cohort (43 control versus 45 AD, p < 0.0001). Significant correlation has been revealed between results from FACS and SRM (p < 0.0001) even though lower serum ApoE concentration values were measured in protein by FACS analysis than in peptide-level detections by SRM. Correlation study suggested that a decrease of the serum ApoE level in AD is related to the mini-mental state exam score in both results from different experimental methods, but it failed to show consistent correlation with age, gender, or clinical dementia rating.

Basal forebrain atrophy and cortical amyloid deposition in nondemented elderly subjects

BackgroundBoth neurodegeneration of the cholinergic basal forebrain (BF) and deposition of β-amyloid are early events in the course of Alzheimer's disease (AD). Associations between increased amyloid pathology and cholinergic atrophy have been described in autopsy studies. MethodsWe used structural MRI and AV45-PET amyloid imaging data of 225 cognitively normal or mildly impaired elderly subjects from the Alzheimer's Disease Neuroimaging Initiative to assess in vivo associations between BF atrophy and cortical amyloid deposition. Associations were examined using region-of-interest (ROI) and voxel-based approaches with reference to cytoarchitectonic mappings of the cholinergic BF nuclei. ResultsROI- and voxel-based approaches yielded complementary evidence for an association between BF volume and cortical amyloid deposition in presymptomatic and predementia stages of AD, irrespective of age, gender, and APOE genotype. ConclusionsThe observed correlations between BF atrophy and cortical amyloid load likely reflect associations between cholinergic degeneration and amyloid pathology as reported in neuropathologic examination studies.

Incomplete Penetrance of the C9ORF72 Hexanucleotide Repeat Expansions: Frequency in a Cohort of Geriatric Non-Demented Subjects

We genotyped for the C9ORF72 hexanucleotide repeat expansion a population of 156 non-demented elderly subjects, recruited in a geriatric unit as control group for association studies in patients with Alzheimer's disease (AD), and found two carriers (1.2%). The first was referred for subjective memory complaints, at age 81. He was followed up until age 84 and did not develop dementia. The second was an 80-year old volunteer (spouse and caregiver of a patient with AD), non-demented at time of recruitment. We have not had information on her condition since that time. These results suggest that the penetrance of the mutation is definitely incomplete.

Prevalence of hippocampal morphologic variants between healthy elderly subjects and patients with Alzheimer′s disease

Background:Alzheimer's disease (AD) is a neurodegenerative disease with atrophic changes in the temporal lobe. Enlargement of cerebrospinal fluid (CSF) spaces, hippocampal sulcus (HS) enlargement, or an increase in the number or size of hippocampal cavities (HCs) could be associated with medial temporal lobe atrophy (MTA). In this study, we assessed the relation of these CSF spaces with AD.Materials and Methods:A total 36 demented patients with diagnosis of Alzheimer (Mini-Mental State Examination (MMSE) ≤25) and 36 non-demented elderly individuals were referred for basic magnetic resonance imaging (MRI) before initiating anti-dementia therapy in the demented group. Two observers assessed the maximal HS width, as well as the occurrence, number, and size of HCs, and the visual rating score of MTA on magnified coronal high-resolution T1-weighted MR images.Results:The findings of our study indicate that the presence of hippocampal cavity (HC) (especially in the left side) and medial temporal lobe atrophy in demented patients was significantly higher in comparison with non-demented elderly subjects (P ≤ 0.05). There was a significant relationship between MTA and HS width (P = 0.003, r = 0.00323), and it also had a trend to be significant with size of HCs (P = 0.08, r = 0.00314). A correlation between MTA and number of HCs was not detected.Conclusion:HS width is associated with MTA in patients with AD. It may serve as a measure to evaluate MTA for identifying individuals at particularly high risk for Alzheimer progression, and could be employed for selecting subjects for clinical trials or for treatment decisions.

Sleep problems associated with behavioral and psychological symptoms as well as cognitive functions in Alzheimer's disease.

Background and PurposeIt has been shown that sleep problems in Alzheimer's disease (AD) are associated with cognitive impairment and behavioral problems. In fact, most of studies have founded that daytime sleepiness is significantly correlated with cognitive decline in AD. However, a few studies have also shown that nighttime sleep problems are associated with cognitive function and behavioral symptoms in AD. Accordingly, the aim of this study was to evaluate the effects of nighttime sleep on cognition and behavioral and psychological symptoms of dementia (BPSD) in AD.MethodsThe study population comprised 117 subjects: 63 AD patients and 54 age- and sex-matched non-demented elderly subjects. Detailed cognitive functions and behavioral symptoms were measured using the Seoul Neuropsychological Screening Battery (SNSB) and the Korean version of the Neuropsychiatric Inventory (NPI-K). Sleep characteristics were evaluated using the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K). The correlations between PSQI-K and SNSB scores and between PSQI-K and NPI-K scores were analyzed.ResultsIn AD patients, sleep latency was found to be negatively correlated with praxis (p=0.041), Rey-Osterrieth Complex Figure Test (RCFT) immediate recall (p=0.041), and RCFT recognition (p=0.008) after controlling for age and education, while sleep duration and sleep efficiency were positively correlated with praxis (p=0.034 and p=0.025, respectively). Although no significant correlation was found between PSQI-K and NPI-K scores, sleep disturbance and total PSQI-K scores were found to be significantly associated with apathy/indifference in AD.ConclusionsSleep problems such as prolonged sleep duration, sleep latency, and poor sleep efficiency in AD patients were correlated with cognitive dysfunction, and especially frontal executive and visuospatial functions, and BPSD. These findings suggest that treatment of nighttime sleep problems might improve cognition and behavioral symptoms in AD patients.

Markers of cholesterol transport are associated with amyloid deposition in the brain

Cholesterol is implicated in the development of late-onset Alzheimer's disease (AD). We sought to determine the associations between beta amyloid (Aβ) plaque deposition in vivo using Pittsburgh compound B (PiB) and several indices of cholesterol homeostasis (i.e., total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein E (ApoE), clusterin, oxysterol metabolites of cholesterol, and previously reported genes associated with late-onset AD) in 175 nondemented elderly subjects. High Aβ deposition was associated significantly with a lower Mini-Mental State Examination score (<27 points, p = 0.04), high systolic blood pressure (p = 0.04), carrying the apolipoprotein E epsilon 4 allele (p < 0.01), and lower plasma ApoE levels (p = 0.02), and variation in the ABCA7 (p = 0.02) and EPHA1 genes (p = 0.02). Cholesterol measures were not related to Aβ deposition in this cohort of nondemented elderly adults. However, plasma and genetic factors relating to cholesterol transport were associated with Aβ deposition in the brain. A better understanding of cholesterol transport mechanisms may lead to the design of potential targets for the prevention of Aβ deposition in the brain.

Systemic inflammation and brain white matter in non-demented elderly human subjects: A diffusion tensor magnetic resonance imaging investigation

Systemic inflammation and brain white matter in non-demented elderly human subjects: A diffusion tensor magnetic resonance imaging investigation

In vivo assessment of amyloid‐β deposition in nondemented very elderly subjects

This study examined amyloid-β (Aβ) deposition in 190 nondemented subjects aged ≥82 years to determine the proportion of Aβ-positive scans and associations with cognition, apolipoprotein E (APOE) status, brain volume, and Ginkgo biloba (Gb) treatment. Subjects who agreed to participate had a brain magnetic resonance imaging and positron emission tomography scan with (11) C-labeled Pittsburgh compound B (PiB) following completion of a Gb treatment clinical trial. The youngest subject in this imaging study was 82 years, and the mean age of the subjects was 85.5 years at the time of the scans; 152 (80%) were cognitively normal, and 38 (20%) were diagnosed with mild cognitive impairment (MCI) at the time of the PiB study. A high proportion of the cognitively normal subjects (51%) and MCI subjects (68%) were PiB-positive. The APOE*4 allele was more prevalent in PiB-positive than in PiB-negative subjects (30% vs 6%). Measures of memory, language, and attentional functions were worse in PiB-positive than in PiB-negative subjects, when both normal and MCI cases were analyzed together; however, no significant associations were observed within either normal or MCI subject groups alone. There was no relationship between Gb treatment and Aβ deposition as determined by PiB. The data revealed a 55% prevalence of PiB positivity in nondemented subjects age >80 years and 85% PiB positivity in the APOE*4 nondemented elderly subjects. The findings also showed that long-term exposure to Gb did not affect the prevalence of cerebral Aβ deposition.

Amyloid Deposition and Hippocampal Volume as Predictors of Incident Dementia in Non-Demented Very Elderly Subjects (IN3-2.004)

Amyloid Deposition and Hippocampal Volume as Predictors of Incident Dementia in Non-Demented Very Elderly Subjects (IN3-2.004)

Amyloid Deposition and Hippocampal Volume as Predictors of Incident Dementia in Non-Demented Very Elderly Subjects (S04.005)

Amyloid Deposition and Hippocampal Volume as Predictors of Incident Dementia in Non-Demented Very Elderly Subjects (S04.005)

English

Introduction Genetic polymorphisms modulate the function of human apolipoprotein E and disease susceptibility. Inheriting the apolipoprotein E4 allele is linked to higher peripheral cholesterol levels and increased risk for atherosclerosis. This gene allele is also a major genetic risk factor for Alzheimer’s disease, but it is unclear how harbouring the apolipoprotein E4 allele causes earlier disease manifestation. This is because little is known about the function of human apolipoprotein E in the brain. While intranasal insulin can improve cognition, this has little effect on apolipoprotein E4 non-demented elderly subjects. These subjects are also found to have lower cerebral glucose metabolic rate.

Diabetes, impaired fasting glucose, and cognitive decline in a population of elderly community residents

Diabetes and impaired fasting glucose, as well as cognitive impairment, are common in the elderly. Although several cross-sectional studies have demonstrated the influence of diabetes on cognitive impairment, only a few longitudinal studies have assessed the relationship between diabetes, impaired fasting glucose and cognitive decline in non-demented elderly community dwellers, by means of extensive neuropsychological batteries. The present study assesses the relationship between baseline diabetes, impaired fasting glucose (IFG) and 2- year evolution of memory, attention and executive performance in a sample of non-demented elderly subjects. Population-based cohort study [(PROgnostic indicator OF cardiovascular and cerebrovascular events (PROOF)]. One hundred and sixty-three community dwellers aged 65 years without dementia at recruitment. Memory, attention and executive performance. A significant association was observed between baseline diabetes mellitus and a higher 2-year decline in the Trial Making Test B and Stroop test exploring attention and executive function. This effect remained significant after adjusting for age, gender, education, anxiety and depressive symptoms, as well as other cardiovascular risk factors (F=2.41; p=0.007). Instead, no relationship was observed between IFG and cognitive decline. Our study showed that, in a sample of elderly non-demented community dwellers, diabetes mellitus (but not IFG) is associated with a higher decline in selective attention and executive functioning. These results emphasize the importance of detecting and man- aging diabetes and impaired fasting glucose, in order to prevent cognitive impairment and dementia.

P3‐136: Over‐diagnosis of dementia in younger patients: A nationwide register‐based study

test the effectiveness of cognitive stimulation in non-demented elderly subjects in relation to APOE genotype. Methods: Invece.Ab is a longitudinal multidimensional population study on brain aging (NCT01345110; http:// clinicaltrials.gov) in 1321 subjects living in Abbiategrasso (Milan, Italy) and born between 1935 and 1939. Within this population, 77 non-demented cognitively healthy subjects with familiarity for sporadic dementia (NDFAM) and 54 subjects with mild cognitive impairment (MCI) were enrolled to test the effectiveness of cognitive stimulation. They were separately randomly assigned to a “treatment” (ten sessions of light physical activity and exercises for cognitive functions) and a “control” (two sanitary education lessons) group. MMSE, MOCA test and CORSI test were administered before and after the interventions by a blind trained psychologist. A blood sample was taken for APOE genotyping by Real-Time Allelic Discrimination assay.Results:NDFAMandMCI benefited from both cognitive stimulation and sanitary education. NDFAM registered a better improvement of performance in the neuropsychological tests after cognitive stimulation than MCI subjects and only for NDFAM, the improvement after the intervention was significantly different between the treatment and the control group. Furthermore subjects carrying at least an APOE34 allele, a risk factor for dementia, were less likely to benefit from the cognitive stimulation protocol adopted. Conclusions: The participation to cognitive stimulation sessions or to sanitary education lessons improved cognitive performance in non-demented subjects with and without mild cognitive impairment. Anyway, only cognitively healthy subjects got a higher benefit from participating to the cognitive stimulation sessions rather than to sanitary education lessons. Furthermore, the extent of the benefit arisen from cognitive stimulation was related to the presence of the risk factor APOE34.

Corpus Callosum Tissue Loss and Development of Motor and Global Cognitive Impairment: The LADIS Study

Objective: To examine the impact of corpus callosum (CC) tissue loss on the development of global cognitive and motor impairment in the elderly. Methods: This study was based on the Leukoaraiosis and Disability (LADIS) study. Assessment of cognitive and motor functions and magnetic resonance imaging (MRI) were done at baseline and at a 3-year follow-up in nondemented elderly subjects. Results: 328 of 639 LADIS subjects had MRIs at baseline and at the 3-year follow-up, which allowed for assessment of CC. Logistic regression revealed differential tissue loss rates in posterior CC in subjects converting to dementia, compared to nonconverters (p < 0.05). Anterior and posterior CC tissue loss was significantly correlated with self-perceived memory impairment in nonconverters (p < 0.05). CC tissue loss was also significantly associated with impaired single leg stance time (p < 0.01). Conclusion: The present longitudinal study on CC supports the role of callosal tissue loss in the development of global cognitive as well as motor impairment.

Vascular risk factors, apolipoprotein E, and hippocampal decline on magnetic resonance imaging over a 10‐year follow‐up

Decline of hippocampal volume on magnetic resonance imaging (MRI) may be considered as a surrogate biomarker of accumulating Alzheimer disease (AD) pathology. Previously, we showed in the prospective population-based Rotterdam Scan Study that a higher rate of decline of hippocampal volume on MRI precedes clinical AD or memory decline. We studied potential risk factors for decline of hippocampal volume. At baseline (1995-1996), 518 nondemented elderly subjects were included, and the cohort was re-examined in 1999 and in 2006. At each examination, hippocampal volume was determined using an automated segmentation procedure. In all, 301 persons had at least two three-dimensional MRI scans to assess decline in hippocampal volume. Persons carrying the apolipoprotein E (APOE) ɛ4 allele had lower hippocampal volumes than persons with the ɛ3/ɛ3 genotype, but the rate of decline was not influenced by APOE genotype. In persons who did not use antihypertensive treatment, both a high (>90 mm Hg) and a low (<70 mm Hg) diastolic blood pressure were associated with a faster decline in hippocampal volume. Also, white matter lesions on baseline MRI were associated with a higher rate of decline in hippocampal volume. In a nondemented elderly population, persons with the APOE ɛ4 allele have a smaller hippocampal volume but not a higher rate of decline. Rate of decline of hippocampal volume was influenced by white matter lesions and diastolic blood pressure, supporting their hypothesized role in the pathogenesis of AD.