Although differences among people are frequently assumed to increase with age, cross-sectional comparisons of measures of brain structure and measures of cognitive functioning often reveal similar magnitudes of between-person variability across most of adulthood. The phenomenon of nearly constant variability despite systematically lower means with increased age suggests that individual differences in rates of aging may be relatively small, particularly compared to the individual differences apparent at any age. The current study examined between-person variability in cross-sectional means and in short-term longitudinal changes in five cognitive abilities at different ages in adulthood. The variability in both level and change in cognitive performance was found to be similar among healthy adults from 25 to 75 years of age in all five cognitive abilities. Furthermore, the correlations between scores at the first and second occasions were very high, and nearly the same magnitude at all ages. The results indicate that between-person differences in short-term cognitive changes are not inevitably greater among healthy older adults than among young adults.
We have previously reported that a modified Stone T-maze (STM), using escape from water as motivation, was effective in evaluating learning and memory ability in young C57/BL6 mice. Here we report on the effectiveness and sensitivity of the STM in the assessment of age-related learning and memory deficits in mice using either escape from foot shock or water as the motivational manipulations. C57BL/6Nia mice 7-, 12-, 20- and 24-mo old received 15 massed trials in the escape from foot shock motivated STM while C57BL/6Nia mice 5-, 12-, and 25-mo old were tested in the escape from water STM. Analysis of errors, the main performance variable, revealed similar results in both versions of the task with younger mice making fewer errors. Notably mice of all ages in the water-motivated version moved quickly through the maze, while all ages of mice in the shock-motivated version tended to wait for shock to be initiated to move forward. Overall, both versions of the STM appear to be sensitive to age-related changes in learning and memory and provide an alternative to other testing paradigms such as the Morris water waze which are susceptible to performance confounds which can lead to uninterpretable results.
Aging; mice; learning; memory; maze
Alzheimer’s disease (AD) has been well characterized by the presence of reactive microglia, often associated with Aβ-plaque deposition. The oligomeric form of Aβ peptide (Aβo) has neurotoxic effects in the presence of microglia and is suggested to potentiate proinflammatory changes in microglia in AD. Primary murine microglia cultures stimulated with Aβo displayed increased protein phospho-tyrosine and secreted TNF-α levels which were attenuated by the Src/Abl inhibitor, dasatinib. Intracerebroventricular infusions of Aβo into C57BL6/J mice stimulated increased microgliosis and protein phospho-tyrosine levels that were also attenuated by dasatinib administration. The rodent findings were validated in human AD brains versus age-matched controls demonstrating reactive microglial association with Aβo deposits and increased microglial protein phospho-tyrosine and phospho-Src levels. These data suggest a role for Aβo in microglial activation through a tyrosine kinase-dependant pathway both in rodent models and human disease. Use of a selective non-receptor tyrosine kinase inhibitor such as dasatinib to attenuate microglial-dependent proinflammatory changes may prove to be an important step towards developing anti-inflammatory treatments for AD.
amyloid beta oligomer; tyrosine kinase; microglia activation
Numerous studies have identified age differences in brain structure and function that correlate with declines in motor performance. While these investigations have typically focused on activity in isolated regions of the brain, resting state functional connectivity MRI and diffusion tensor imaging allow for more integrative assessments of spatially disparate neural networks. The novel contribution of the current study is to combine both resting state functional connectivity and diffusion tensor imaging to examine motor cortico-cortical circuits in young and older adults. We find that relatively greater functional connectivity between the primary motor cortices was strongly associated with decreased structural connectivity and poorer motor performance solely in older adults. We suggest that greater functional connectivity in older adults may be reflective of a release from the normally predominantly inhibitory interhemispheric communication associated with the primary motor cortices.
We hypothesize that normal aging implies neuronal durability, reflected by age-independent concentrations of their marker - the amino acid derivative N-acetylaspartate (NAA). To test this we obtained the whole-brain and whole-head NAA concentration (WBNAA and WHNAA), with proton MR spectroscopy; and the fractional brain parenchyma volume (fBPV) – a metric of atrophy, by segmenting the MRI from 42 (18 male) healthy young (31.9±5.8 years-old) and 100 (64 male, 72.6±7.3 years-old) cognitively-normal elderly. The 12.8±1.9 mM WBNAA of the young was not significantly different from the 13.1±3.1 mM in the elderly (p>0.05). In contrast, both fBPV (87.3±4.7% versus 74.8±4.8%) and WHNAA (11.1±1.7 mM versus 9.8±2.4 mM) were significantly higher in the young (~14%, p<.0001 for both). The similarity in mean WBNAA between two cohorts 4 decades of normal aging apart suggests that neuronal integrity is maintained across the lifespan. Clinically, WBNAA could be used as a marker for normal (hence, also abnormal) brain aging. In contrast, WHNAA and fBPV seem age-related suggesting that brain atrophy may occur without compromising the remaining tissue.
Aging; Brain volumetry; Elderly; Healthy human brain; MRI; N-acetylaspartate (NAA); Proton MR Spectroscopy; Whole-brain
Relations among antecedant biomarkers of AD were evaluated using causal modeling; although correlation cannot be equated to causation, causation does require correlation. Individuals aged 43 to 89 years (N = 220) enrolled as cognitively normal controls in longitudinal studies had clinical and psychometric assessment, structural magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) biomarkers, and brain amyloid imaging via positron emission tomography with Pittsburgh Compound B (PIB) obtained within 1 year. CSF levels of Aβ42 and tau were minimally correlated, indicating they represent independent processes. Aβ42, tau, and their interaction explained 60% of the variance in PIB. Effects of APOE genotype and age on PIB were indirect, operating through CSF markers. Only spurious relations via their common relation with age were found between the biomarkers and regional brain volumes or cognition. Hence, at least two independent hypothesized processes, one reflected by CSF Aβ42 and one by CSF tau, contribute to the development of fibrillar amyloid plaques preclinically. The lack of correlation between these two processes and brain volume in the regions most often affected in AD suggests the operation of a third process related to brain atrophy.
preclinical Alzheimer disease; amyloid-β; tau; PIB; amyloid plaque; APOE; brain volumetry; memory; biomarkers; cerebrospinal fluid
Like humans, rhesus monkeys show cognitive decline and this review considers what structural age-related changes underlie this decline. Some structural measures do not alter significantly with age. These include brain weight, overall cortical thickness; numbers of cortical neurons; and numbers of astrocytes and microglial cells. Other structural measures change with age, but the change does not correlate with cognitive decline. These changes include nerve fiber loss from some fiber tracts, degeneration and regeneration of myelin sheaths, and increase in the frequency of oligodendrocytes. Among the structural measures that increase in frequency with age and also correlate with cognitive decline are the increased frequency of degenerating myelin sheaths and a loss of nerve fibers from some fiber tracts; and the loss of synapses and dendritic spines from upper layers of prefrontal cortex. Consequently, the existing data suggest that cognitive decline correlates with changes in myelinated nerve fibers and with disconnections between and within cortical areas, as reflected by the age-related loss of synapses and of dendritic spines from some cortical areas.
Macaca mulatta; normal aging; cerebral cortex; synapses; myelinated nerve fibers; neuroglia
Glucocorticoids (GC)--corticosterone (CORT) in rodents and cortisol in primates--are stress-induced hormones secreted by adrenal glands that interact with the hypothalamic pituitary axis. High levels of cortisol in humans are observed in neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), as well as in diabetes, post-traumatic stress syndrome, and major depression. Experimental models of diabetes in rats and mice have demonstrated that reduction of CORT reduces learning and memory deficits and attenuates loss of neuronal viability and plasticity. In contrast to the negative associations of elevated GC levels, CORT is moderately elevated in dietary restriction (DR) paradigms which are associated with many healthy anti-aging effects including neuroprotection. We demonstrate here in rats that ablating CORT by adrenalectomy (ADX) with replenishment to relatively low levels (30% below that of controls) prior to the onset of a DR regimen (ADX-DR) followed by central administration of the neurotoxin, kainic acid (KA), significantly attenuates learning deficits in a 14-unit T-maze task. The performance of the ADX-DR KA group did not differ from a control group (CON) that did not receive KA and was fed ad libitum (AL). By contrast, the sham-operated DR (SHAM-DR KA) group, SHAM-AL KA group, and ADX-AL KA group demonstrated poorer learning behavior in this task compared to the CON group. Stereological analysis revealed equivalent DR-induced neuroprotection in the SH-DR KA and ADX-DR KA groups, as measured by cell loss in the CA2/CA3 region of the hippocampus, while substantial cell loss was observed in SH-AL and ADX-AL rats. A separate set of experiments was conducted with similar dietary and surgical treatment conditions but without KA administration to examine markers of neurotrophic activity, brain-derived neurotrophic factor (BDNF), transcriptions factors (pCREB), and chaperone proteins (HSP-70). Under these conditions, we noted elevations in both BDNF and pCREB in ADX DR rats compared to the other groups; whereas, HSP-70, was equivalently elevated in ADX-DR and SH-DR groups and was higher than observed in both SH-AL and ADX-AL groups. These results support findings that DR protects hippocampal neurons against KA-induced cellular insult. However, this neuroprotective effect was further enhanced in rats with a lower-than control level of CORT resulting from ADX and maintained by exogenous CORT supplementation. Our results then suggest that DR-induced physiological elevation of GC may have negative functional consequences to DR-induced beneficial effects. These negative effects, however, can be compensated by other DR-produced cellular and molecular protective mechanisms.
Little is known about gene-environment interactions in Parkinson disease (PD). We examined potential interactions of smoking and caffeine intake with ten GWAS SNPs at or near the SNCA, MAPT, LRRK2 and HLA loci among 584 PD patients and 1,571 controls. The main effects of these SNPs and environmental exposures were consistent with previous reports. Family history of PD was associated with PD risk (OR=2.71, 95% CI: 1.97–3.74), which was little affected by further adjustment for these SNPs and environmental exposures. Overall, we did not find significant interactions of either smoking or caffeine intake with these SNPs. However, with a combined smoking and caffeine intake exposure, we found a significant interaction with rs2896905 at SLC2A13, near LRRK2 (p uncorrected= 0.0008). Each A allele was associated with a 35% higher PD risk among never smokers with low caffeine intake, but with a 32% lower risk among smokers with high caffeine intake. This study provides preliminary evidence of a potential gene-environment interaction for PD, which should be investigated in future studies.
Parkinson disease (PD); gene-environment interactions; genome-wide association study
Flexible instrumental learning is required to harness the appropriate behaviors to obtain rewards and to avoid punishments. The precise contribution of dopaminergic midbrain regions (substantia nigra/ventral tegmental area [SN/VTA]) to this form of behavioral adaptation remains unclear. Normal aging is associated with a variable loss of dopamine neurons in the SN/VTA. We therefore tested the relationship between flexible instrumental learning and midbrain structural integrity. We compared task performance on a probabilistic monetary go/no-go task, involving trial and error learning of: “go to win,” “no-go to win,” “go to avoid losing,” and “no-go to avoid losing” in 42 healthy older adults to previous behavioral data from 47 younger adults. Quantitative structural magnetization transfer images were obtained to index regional structural integrity. On average, both some younger and some older participants demonstrated a behavioral asymmetry whereby they were better at learning to act for reward (“go to win” > “no-go to win”), but better at learning not to act to avoid punishment (“no-go to avoid losing” > “go to avoid losing”). Older, but not younger, participants with greater structural integrity of the SN/VTA and the adjacent subthalamic nucleus could overcome this asymmetry. We show that interindividual variability among healthy older adults of the structural integrity within the SN/VTA and subthalamic nucleus relates to effective acquisition of competing instrumental responses.
Aging; Instrumental learning; Magnetization transfer; Novelty seeking; Substantia nigra
The amplitudes of many circadian rhythms, at the behavioral, physiological, cellular, and biochemical levels, decrease with advanced age. Previous studies suggest that the amplitude of the central circadian pacemaker is decreased in old animals. Recently, it has been reported that expression of several circadian clock genes, including Clock, is lower in the master circadian pacemaker of old rodents. To test the hypothesis that decreased activity of a circadian clock gene renders animals more susceptible to the effects of aging, we analyzed the circadian rhythm of locomotor activity in young and old wild-type and heterozygous Clock mutant mice. We found that the effects of age and the Clock mutation were additive. These results indicate that age-related changes in circadian rhythmicity occur equally in wild-type and heterozygous Clock mutants, suggesting that the Clock mutation does not render mice more susceptible to the effects of age on the circadian pacemaker.
Aging; Circadian rhythm; Clock; Clock mutation
To characterize the white matter structural changes at the tract level and tract group level, comprehensive analysis with four metrics derived from DTI, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD), was conducted. Tract groups, namely limbic, commissural, association and projection tracts, include white matter tracts of similar functions. DTI data were acquired from 61 subjects (26 AD, 11 subjects with amnestic mild cognitive impairment or aMCI, 24 age-matched controls). An atlas-based approach was used to survey 30 major cerebral white matter tracts with the measurements of FA, MD, AxD and RD. Regional cortical atrophy and cognitive functions of AD patients were also measured to correlate with the structural changes of white matter. Synchronized structural changes of cingulum bundle and fornix, both of which are part of limbic tract group, were revealed. Widespread yet distinctive structural changes were found in limbic, commissural, association and projection tract groups between control and AD subjects. Specifically, FA, MD and RD of limbic tracts, FA, MD, AxD and RD of commissural tracts, MD, AxD and RD of association tracts and MD and AxD of projection tracts are significantly different between AD patients and control subjects. In contrast, the comparison between aMCI and control subjects shows disruption only in the limbic and commissural tract groups of aMCI subjects. MD values of all tract groups of AD patients are significantly correlated to cognitive functions. Difference between AD and control and that between MCI and control indicates a progression pattern of white matter disruption from limbic and commissural tract group to other tract groups. High correlation between FA, MD and RD measurements from limbic tracts and cortical atrophy suggests the disruption of the limbic tract group is caused by the neuronal damage.
Alzheimer’s disease; atlas; DTI; white matter tract; tract group; biomarker
The decline in cognitive function that accompanies normal aging has a negative impact on the quality of life of the elderly and their families. Studies in humans and rodents show that spatial navigation and other hippocampus-dependent functions are particularly vulnerable to the deleterious effects of aging. However, reduced motor activity and alterations in the stress response that accompany normal aging can hinder the ability to study certain cognitive behaviors in aged animals. In an attempt to circumvent these potential confounds, we used a hippocampus-dependent object-place recognition task to show that long-term spatial memory is impaired in aged mice. Aged animals performed similarly to young adult mice on an object recognition task that does not rely on hippocampal function.
Spatial memory; aging; mice; object recognition; hippocampus
Iron is essential for triggering oligodendrocytes to myelinate, however, in gray matter (GM) iron increases with age and is associated with age-related degenerative brain diseases. Women have lower iron levels than men, both in the periphery and in the brain, particularly in white matter (WM), possibly due to iron loss through menstruation. We tested the hypothesis that hysterectomy could increase WM iron levels.
We assessed three WM and five GM regions in 39 post-menopausal women, of whom 15 had premenopausal hysterectomy, utilizing a validated magnetic resonance imaging technique called FDRI that quantifies ferritin iron. A group of 54 matched male subjects was included for comparison.
Amongst women, hysterectomy was associated with significantly higher frontal lobe WM iron. Men had higher iron levels than women without hysterectomy in three brain regions but did not differ from women with hysterectomy in any region.
The results suggest that menstruation-associated blood loss is a source of gender differences in brain iron. It is possible that brain iron can be influenced by peripheral iron levels and may thus be a modifiable risk factor for age-related degenerative diseases.
hysterectomy; iron; metal; dementia; risk; gender; myelin; oligodendrocytes; white matter; gray matter; treatment; prevention
Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA-R) receptor and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth Hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline. An in vitro CA1 hippocampal slice preparation was used to compare hippocampal excitatory transmission and plasticity in old animals treated for 6–8 months with either saline or GH. Our findings indicate that GH treatment restores NMDA-R dependent basal synaptic transmission in old rats to young adult levels and enhances both AMPA-R-dependent basal synaptic transmission and long-term potentiation. These alterations in synaptic function occurred in the absence of changes in presynaptic function, as measured by paired-pulse ratios, the total protein levels of AMPA-R and NMDA-R subunits or in plasma or hippocampal levels of insulin-like growth factor-I. These data suggest a direct role for GH in altering age-related changes in excitatory transmission and provide a possible cellular mechanism through which GH changes the course of cognitive decline.
Long-term potentiation; paired-pulse ratios; input-output curves; AMPA receptor; NMDA receptor
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the 11C–Pittsburgh Compound-B (PiB) retention and regional hypometabolism on PET and regional cortical atrophy on MRI are complementary in characterizing patients with DLB and differentiating them from AD. We studied age, gender and education matched patients with a clinical diagnosis of DLB (n=21), AD (n=21), and cognitively normal subjects (n=42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic=0.98).Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that MRI and PiB PET contribute to characterizing the distinct pathological mechanisms in patients with AD compared to DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
Stroke and Alzheimer’s disease (AD) are major age-related neurodegenerative diseases that may worsen the prognosis of each other. Our study was designed to delineate the prostaglandin E2 EP1 receptor role in AD and in the setting of cerebral ischemia. Genetic deletion of the prostaglandin EP1 receptor significantly attenuated the more severe neuronal damage (38.5 ± 10.6%) and memory loss induced by ischemic insult that observed in AD transgenic mice (percentage of viable hippocampal CA1 neurons: 11.2 ± 2.9%) when compared to wildtype mice (45.1 ± 9.1%). In addition, we found that the amyloid plaques were reduced in EP1 deleted AD mice. Aβ-induced toxicity (18.0 ± 7.1%) and Ca2+ response (91.8 ± 12.9%) were also reduced in EP1−/− neurons compared to control neurons in in vitro. Hence, EP1 might mediate most of the toxicity associated with COX-2 and contribute substantially to the cell death pathways in AD and stroke. Exploring potential therapeutic agent targeting EP1 receptor could potentially benefit treatments for stroke and AD patients.
Beta-amyloid; Cyclooxygenase; Neuroinflammation; Prostaglandin E2; Stroke
We report a cross-sectional study of olfactory impairment with age based on both odorant-stimulated responses of human olfactory sensory neurons (OSNs) and tests of olfactory threshold sensitivity. A total of 621 OSNs from 440 subjects in two age groups of younger ( 45 years) and older (≥60 years) subjects were investigated using fluorescence intensity ratio fura-2 imaging. OSNs were tested for responses to two odorant mixtures, as well as to subsets of and individual odors in those mixtures. Whereas cells from younger donors were highly selective in the odorants to which they responded, cells from older donors were more likely to respond to multiple odor stimuli, despite a loss in these subjects’ absolute olfactory sensitivity, suggesting a loss of specificity. This degradation in peripheral cellular specificity may impact odor discrimination and olfactory adaptation in the elderly. It is also possible that chronic adaptation as a result of reduced specificity contributes to observed declines in absolute sensitivity.
Olfactory sensory neurons; odor thresholds; age-related odor impairment; intracellular calcium; olfactory epithelium
This study investigated the hypothesis that vascular risk factors are amyloidogenic. Participants were 43 persons, most with normal cognition or mild cognitive impairment. Vascular risk was quantified using the Framingham Coronary Risk Profile score (FCRP). Cerebral amyloid was measured by 11C-PIB PET and quantified with a Global PIB index, which is the average of distribution volume ratios in selected cortical regions of interest. In a bivariate model FCRP accounted for 16% of the variance in PIB index (p < .008) and the positive association remained significant controlling for age and sex. The effect of FCRP was independent of APOE genotype, which was also associated as expected with PIB. Carotid intima-media thickness was not associated with PIB index. Effects of individual FCRP component risk factors, cholesterol and glycemic status on PIB index were all non-significant, suggesting an aggregate effect of risk factors. Although this is a correlational observation it may represent a causal relationship as there are multiple, plausible, amyloidogenic mechanisms of vascular risk factors.
vascular risk factors; coronary risk factors; cerebral amyloid; Mild Cognitive Impairment; Normal Aging; Alzheimer’s disease
This proteomic study investigates the widely observed clinical phenomenon, that after comparable brain injuries, geriatric patients fare worse and recover less cognitive and neurologic function than younger victims. Utilizing a rat traumatic brain injury model, sham surgery or a neocortical contusion was induced in 3 age groups. Geriatric (21 months) rats performed worse on behavioral measures than young adults (12–16 weeks) and juveniles (5– 6 weeks). Motor coordination and certain cognitive deficits showed age-dependence both before and after injury. Brain proteins were analyzed using silver-stained two-dimensional electrophoresis gels. Spot volume changes (>2-fold change, p<0.01) were identified between age and injury groups using computer-assisted densitometry. Sequences were determined by mass spectrometry of tryptic peptides. The 19 spots identified represented 13 different genes that fell into 4 general age- and injury-dependent expression patterns. Fifteen isoforms changed differentially with respect to both age and injury (p<0.05). Further investigations into the nature and function of these isoforms may yield insights into the vulnerability of older patients and resilience of younger patients in recovery after brain injuries.
Age; Geriatric brain injury; Adult brain injury; Pediatric brain injury; Proteomics
Alzheimer’s disease is confirmed at autopsy according to the accumulation of brain neuritic plaques and neurofibrillary tangles in the brain. Neuritic plaques contain Aβ and lower levels of Aβ correspond to an increase in ADAM10 α-secretase activity. ADAM10 α-secretase activity produces a soluble APP alpha (sAPPα) product and negates the pathological production of Aβ. In this investigation it was hypothesized that genetic variation with the ADAM10 promoter is associated with ADAM10 expression levels as well as CSF sAPPα levels. Results from this investigation suggest that the ADAM10 rs514049–rs653765 C-A promoter haplotype is associated with; 1) higher CSF sAPPα levels in cognitively normal controls compared to AD, 2) higher post mortem brain hippocampus, but not cerebellum, ADAM10 protein levels in low plaque score subjects compared to high plaque score subjects and 3) higher promoter activity for promoter only reporter constructs compared to promoter – 3′UTR constructs in the human neuroblastoma SHSY5Y cell line, but not in HepG2 or U118 cell lines. Taken together, these findings suggest that ADAM10 expression is modulated according to a promoter haplotype that is influenced in a brain region and cell type specific manner.
ADAM10; haplotype; sAPPα; Alzheimer’s Disease; reporter assay; neuritic plaques; brain; hippocampus; cerebrospinal fluid
We recently reported that mutations in the VCP gene are a cause of 1–2% of familial amyotrophic lateral sclerosis (ALS) cases, but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of VCP in 701 sporadic ALS cases. Three pathogenic variants (p.Arg159Cys, p.Asn387Thr, and p.R662C) were found in three US cases, each of whom presented with progressive upper and lower motor neuron signs consistent with definite ALS by El Escorial diagnostic criteria. Our data indicate that VCP mutations may underlie apparently sporadic ALS, but account for less than 1% of this form of disease.
Amyotrophic lateral sclerosis; valosin-containing protein; mutations; sporadic disease
The proteolytic processing of amyloid precursor protein (APP) to generate the neurotoxic Aβ peptide is central to the pathogenesis of Alzheimer disease (AD). The endocytic system mediates the processing of APP by controlling its access to secretases that cleave APP. A key mediator of APP localization is SorL1 – a membrane protein that has been genetically linked to AD. The retromer complex is a conserved protein complex required for endosome-to-Golgi retrieval of a number of physiologically important membrane proteins including SorL1. Based on the prior suggestion that endocytosis and retromer sorting pathways might be involved, we hypothesized that variants in other genes in this pathway might also modulate AD risk. Genetic association of AD with 451 polymorphisms in 15 genes encoding retromer or retromer-associated proteins was tested in a Caucasian sample of 8,309 AD cases and 7,366 cognitively normal elders using individual SNP and gene-based tests. We obtained significant evidence of association with KIAA1033 (Paris p = 0.025), SNX1 (Paris p =0.035), SNX3 (p = 0.0057) and RAB7A (Paris p = 0.018). Ten KIAA1033 SNPs were also significantly associated with AD in a group of African Americans (513 AD cases, 504 controls). Findings with four significant SNX3 SNPs in the discovery sample were replicated in a community-based sample of Israeli-Arabs (124 AD cases, 142 controls). We show that Snx3 and Rab7A proteins interact with the cargo-selective retromer complex through independent mechanisms to regulate the membrane association of retromer and thereby are key mediators of retromer function. These data implicate additional AD risk genes in the retromer pathway and formally demonstrate a direct link between the activity of the retromer complex and the pathogenesis of AD.
Older adults (OA) show more diffuse brain activity than young adults (YA) during the performance of cognitive, motor, and perceptual tasks. It is unclear whether this over-activation reflects compensation or dedifferentiation. Typically, these investigations have not evaluated the organization of the resting brain, which can help to determine whether more diffuse representations reflect physiological or task- dependent effects. In the present study we used transcranial magnetic stimulation (TMS) to determine whether there are differences in motor cortex organization of both brain hemispheres in YA and OA. We measured resting motor threshold, motor evoked potential (MEP) latency and amplitude, and extent of first dorsal interosseous representations, in addition to a computerized measure of reaction time. There was no significant age difference in motor threshold, but we did find that OA had larger contralateral MEP amplitudes and a longer contralateral MEP latency. Furthermore, the spatial extent of motor representations in OA was larger. We found that larger dominant hemisphere motor representations in OA were associated with higher reaction times, suggesting dedifferentiation rather than compensation effects.
aging; transcranial magnetic stimulation; motor cortex
Tauopathies are characterized by progressive neurodegeneration caused by intracellular accumulation of hyperphosphorylated tau protein aggregates in the brain. The present study was designed to test whether a grape seed polyphenolic extract (GSPE) previously shown to inhibit tau protein aggregation in vitro could benefit tau-mediated neuropathology and behavior deficits in JNPL3 transgenic mice expressing a human tau protein containing the P301L mutation. Nine months old JNPL3 mice were treated with GSPE delivered through their drinking water for six months. We found that GSPE treatment significantly reduced the number of motor neurons immunoreactive for hyperphosphorylated and conformationally-modified tau in the ventral horns of the spinal cord identified using AT100, PHF-1, AT8 and Alz50 tau antibodies. This coincided with a drastically reduced level of hyperphosphorylated and sarcosyl-insoluble tau in spinal cord fractions. Furthermore, the reduction of tau pathology was accompanied by an improvement in the motor function assessed by a wire hang test. Collectively, our results suggest that GSPE can interfere with tau-mediated neurodegenerative mechanisms and ameliorate neurodegenerative phenotype in an animal model of tauopathy. Our studies support further evaluation of GSPE for preventing and/or treating of tauopathies in humans.