Validations of apomorphine-induced BOLD activation correlations in hemiparkinsonian rhesus macaques.

Identification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements. Animals with unilateral treatments with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), that expressed stable, long-term hemiparkinsonism were challenged with the dopaminergic receptor agonist, apomorphine, and structure-specific phMRI blood oxygen level-dependent (BOLD) activation responses were measured. Behavioral, histopathological, and neurochemical measurements were obtained and correlated with phMRI activation of structures of the cortico-basal ganglia system. Greater phMRI activations in the basal ganglia and cortex were associated with slower movement speed, decreased daytime activity, or more pronounced parkinsonian features. Animals showed decreased stimulus-evoked dopamine release in the putamen and substantia nigra pars compacta and lower basal glutamate levels in the motor cortex on the MPTP-lesioned hemisphere compared to the contralateral hemisphere. The altered neurochemistry was significantly correlated with phMRI signals in the motor cortex and putamen. Finally, greater phMRI activations in the caudate nucleus correlated with fewer tyrosine hydroxylase-positive (TH+) nigral cells and decreased TH+ fiber density in the putamen. These results reveal the correlation of phMRI signals with the severity of the motor deficits and pathophysiological changes in the cortico-basal ganglia circuit.

Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques.

BACKGROUND: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. NEW METHOD: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125I-labeled DNSP-11 dose. RESULTS: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. COMPARISON WITH EXISTING METHODS: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. CONCLUSIONS: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system.

A synthetic five amino acid propeptide increases dopamine neuron differentiation and neurochemical function.

A major consequence of Parkinson's disease (PD) involves the loss of dopaminergic neurons in the substantia nigra (SN) and a subsequent loss of dopamine (DA) in the striatum. We have shown that glial cell line-derived neurotrophic factor (GDNF) shows robust restorative and protective effects for DA neurons in rats, non-human primates and possibly in humans. Despite GDNF's therapeutic potential, its clinical value has been questioned due to its limited diffusion to target areas from its large size and chemical structure. Several comparatively smaller peptides are thought to be generated from the prosequence. A five amino-acid peptide, dopamine neuron stimulating peptide-5 (DNSP-5), has been proposed to demonstrate biological activity relevant to neurodegenerative disease. We tested the in vitro effects of DNSP-5 in primary dopaminergic neurons dissected from the ventral mesencephalon of E14 Sprague Dawley rat fetuses. Cells were treated with several doses (0.03, 0.1, 1.0, 10.0 ng/mL) of GDNF, DNSP-5, or an equivalent volume of citrate buffer (vehicle). Morphological features of tyrosine hydroxylase positive neurons were quantified for each dose. DNSP-5 significantly increased (p < 0.001) all differentiation parameters compared to citrate vehicle (at one or more dose). For in vivo studies, a unilateral DNSP-5 treatment (30 µg) was administered directly to the SN. Microdialysis in the ipsilateral striatum was performed 28 days after treatment to determine extracellular levels of DA and its primary metabolites (3,4-dihydroxyphenylacetic acid and homovanillic acid). A single treatment significantly increased (~66%) extracellular DA levels compared to vehicle, while DA metabolites were unchanged. Finally, the protective effects of DNSP-5 against staurosporine-induced cytotoxicity were investigated in a neuronal cell line showing substantial protection by DNSP-5. Altogether, these studies strongly indicate biological activity of DNSP-5 and suggest that DNSP-5 has neurotrophic-like properties that may be relevant to the treatment of neurodegenerative diseases like PD.

Intraputamenal infusion of exogenous neurturin protein restores motor and dopaminergic function in the globus pallidus of MPTP-lesioned rhesus monkeys.

The neurorestorative effects of exogenous neurturin (NTN) delivered directly into the putamen via multiport catheters were studied in 10 MPTP-lesioned rhesus monkeys expressing stable parkinsonism. The parkinsonian animals were blindly assigned to receive coded solutions containing either vehicle (n = 5) or NTN (n = 5, 30 microg/day). Both solutions were coinfused with heparin using convection-enhanced delivery for 3 months. The NTN recipients showed a significant and sustained behavioral improvement in their parkinsonian features during the treatment period, an effect not seen in the vehicle-treated animals. At study termination, locomotor activity levels were increased by 50% in the NTN versus vehicle recipients. Also, DOPAC levels were significantly increased by 150% ipsilateral (right) to NTN infusion in the globus pallidus, while HVA levels were elevated bilaterally in the NTN-treated animals by 10% on the left and 67% on the right hemisphere. No significant changes in DA function were seen in the putamen. Volumetric analysis of putamenal NTN labeling showed between-subject variation, with tissue distribution ranging from 214 to 744 mm3, approximately equivalent to 27-93% of area coverage. Our results support the concept that intraparenchymal delivery of NTN protein may be effective for the treatment of PD. More studies are needed to determine strategies that would enhance tissue distribution of exogenous NTN protein, which could contribute to optimize its trophic effects in the parkinsonian brain.

MRI volumetric and intensity analysis of the cerebellum in Parkinson's disease patients infused with glial-derived neurotrophic factor (GDNF).

BACKGROUND: A recent human therapeutic trial using intraputaminal infusion of glial cell-derived neurotrophic factor (GDNF) in Parkinson's disease (PD) was abruptly terminated, partly due to safety concerns raised by the finding of cerebellar lesions in monkeys given high-dose GDNF. METHODS: Magnetic resonance images from nine PD patients participating in this trial were analyzed to determine whether subtle volumetric or intensity changes could be detected in the cerebellum or elsewhere following GDNF treatment for over 1 year. Subtraction images were compared to a reference standard deviation map constructed by using identically-processed paired scans from 25 normal adults. In a separate voxel-based group morphometric (VBM) analysis of the same patient images, grey matter intensity was compared between pre and post-GDNF infusion scans using a repeated measures ANOVA with family-wise error threshold of P = 0.10. Two expert readers independently reviewed serial FLAIR images from all patients. RESULTS: (1) There were no significant cerebellar differences in any of the nine individual PD patients (difference image analysis), (2) there were no significant morphometric differences between pre- and post-GDNF scans (VBM), and (3) there were no signal abnormalities in the cerebellum detected on the FLAIR images in PD patients (clinical scan review). CONCLUSIONS: In concert with lack of evidence of cerebellar dysfunction on clinical examination, we find no imaging evidence of cerebellar injury in human subjects undergoing chronic intracerebral GDNF infusion.

Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits.

Increasing evidence suggests that abnormal iron handling may be involved in the pathogenesis of Parkinson's disease. The present study investigates the role of iron and the iron-storage protein ferritin in inflammation-induced degeneration of dopaminergic neurons of the substantia nigra pars compacta. Injection of lipopolysaccharide into the globus pallidus of young and middle-aged rats substantially decreased tyrosine hydroxylase immunostaining in substantia nigra pars compacta four weeks after injection. Loss of tyrosine hydroxylase expression was accompanied by increased iron and ferritin levels in glial cells of the substantia nigra pars reticulata. Despite greater increases in nigral iron levels, ferritin induction was less pronounced in older rats, suggesting the regulation of ferritin was compromised with age. Automated movement tracking analyses showed that young rats recovered from LPS-induced locomotor deficits within four weeks, yet older rats failed to improve on measures of speed and total distance moved. Intrapallidal lipopolysaccharide injection also increased expression of alpha-synuclein and ubiquitin in tyrosine hydroxylase-positive neurons of the substantia nigra pars compacta. These results suggest that pallidal inflammation significantly increases stress on dopamine-containing neurons in the substantia nigra pars compacta. Alterations in nigral iron levels and protein handing may increase the vulnerability of nigral neurons to degenerative processes.

Memories that last in old age: motor skill learning and memory preservation.

Using an automated test panel, age-associated declines in learning, remembering and performing a novel visuomotor task were assessed in 497 normal adults ranging from 18 to 95 years old. As predicted, task performance times slowed with increasing age in the cross-sectional portion of the study. However in the subsequent longitudinal study, while motor learning was significantly slower in adults over 62 years old, motor memory was pristinely preserved in normal adults from 18 to 95 years old. When tested 2 years after the first training session and without intervening rehearsal, mean performance times were retained and continued to improve by 10% in young adults and 13% in aged adults, reflecting long lasting preservation of motor memories. While the maximum lifetime of an unpracticed, novel motor memory in humans is not known, the present study suggests that new motor memories can be retained for at least 2 years without rehearsal in normal aged adults. This age-resistant component of motor memory stands in contrast to the well-known decrements in other motor and cognitive processes with human aging.

Pharmacological MRI mapping of age-associated changes in basal ganglia circuitry of awake rhesus monkeys.

While the pathophysiological changes induced by the loss of dopamine innervation in the basal ganglia by Parkinson's disease (PD) are well studied, little is known about functional changes in the neural circuitry of this area during normal aging. Here we report the first survey of age-associated changes in the basal ganglia of behaviorally characterized, awake rhesus monkeys, using pharmacological MRI to map responses to dopaminergic stimulation. Apomorphine, a mixed D(1)/D(2) dopamine receptor agonist, evoked little change in the substantia nigra (SN) of aged animals while significantly reducing activation in young adult monkeys. Compared to young animals, both apomorphine and d-amphetamine (which increases synaptic dopamine levels) significantly increased activation of the aged rhesus globus pallidus externa (GPe). In addition, the aged animals showed decreased activity in the putamen in response to d-amphetamine administration. Although the responses in the SN and putamen of the aged monkeys differed from those in animal models of PD, the apomorphine-evoked activation of their GPe corresponded with apomorphine-induced increases in neuronal activity seen in Parkinson's patients and animal models. Given the major role of the GPe in regulating motor behavior, the altered responses in the aged GPe may contribute significantly to the motor slowing and movement dysfunctions characterizing advanced age.

Neuroprotective effects of GDNF against 6-OHDA in young and aged rats.

In young adult rats, glial cell line-derived neurotrophic factor (GDNF) can completely protect against 6-hydroxydopamine-induced loss of nigral dopamine neurons when administered 6 h prior to the 6-hydroxydopamine. The present study was undertaken to determine if GDNF would provide similar protective effects in aged rats. Male, Fischer 344 x Brown Norway hybrid rats of 3, 18 and 24 months of age were given an intranigral injection of GDNF or vehicle followed 6 h later with an intranigral injection of 6-hydroxydopamine. Nigral dopamine neuron cell survival, and striatal and nigral dopamine and DOPAC levels, were evaluated 2 weeks after the lesions. In vehicle treated animals cell survival on the lesioned side ranged from 15 to 27%. GDNF promoted significant cell survival in the nigra of all three age groups; however, the percent survival was lowest in the 24-month-old animals (85% at 3 months, 75% at 18 months, 56% at 24 months). Similarly, dopamine levels in the striatum and substantia nigra on the lesioned side remained significantly greater in the GDNF treated animals compared to the vehicle treated animals. As with the cell survival experiment, the protective effects of GDNF on dopamine levels were less in the 24-month-old animals. GDNF pretreatment also protected against 6-hydroxydopamine-induced reductions in striatal DOPAC levels in all age groups. Overall, these results indicate that GDNF can protect nigrostriatal dopamine neurons against the effects of 6-hydroxydopamine in aged as well as young adult rats. However, the extent of protection is less in the aged (24-month-old) animals.

Cumulative and single-dose design to assess the bronchodilator effects of beta2-agonists in individuals with asthma.

With the development of different chlorofluorocarbon (CFC)-free metered dose aerosol and dry powder devices, it is necessary to study and validate the methods used for assessing and comparing their efficacy. This study evaluated the cumulative dose design by determining the bronchodilator response to salbutamol given according to either a high or a low cumulative dose regimen. Adults with asthma (n = 24) were studied in a placebo-controlled, randomized, double-blind, cross-over design. On separate days, cumulative doses of salbutamol (50+50+100+200 or 100+100+ 200+400 or 400+0+0+0 or 0+0+0+0 microg) were given via Turbuhaler with 30 min between doses. The two cumulative dose regimens produced almost identical bronchodilator responses at each time point. The relative dose-potency between the 800- and 400- microg cumulative dose regimens was 0.7 with a 95% confidence interval of 0.5-1.0, excluding the true value of 2. The 400-microg cumulative dose regimen resulted in a higher FEV1 at 115 min than the 400-microg single-dose regimen. There was no difference in the bronchodilator response to the single dose of 50, 100, or 400 microg of salbutamol after either 5 or 25 min. Thus, care should be exercised when using either a cumulative or single-dose design for comparing different beta2-agonists, or different inhalation devices, with respect to their relative dose-potency. In addition, this study provides further evidence that for short-acting beta2-agonists such as salbutamol, lower doses than those normally recommended may be used, and that repeated self-administration of low doses over a period of 60 min may give a better bronchodilator response than a single administration of a high dose.

Chronic Intracerebral Delivery of Trophic Factors via a Programmable Pump as a Treatment for Parkinsonism.

The most common treatment for Parkinson's disease (PD) aims at pharmacologically augmenting striatal dopamine (DA) using the DA precursor levodopa. Such treatment provides symptomatic relief, but does not slow or halt continued degeneration of nigral dopaminergic neurons. Considerable effort has been devoted to the search for neurotrophic factors with survival-promoting activities on dopaminergic neurons that could potentially be of therapeutic value in the treatment of PD. One such candidate is glial cell line-derived neurotrophic factor (GDNF).

Motor slowing and parkinsonian signs in aging rhesus monkeys mirror human aging.

Motor slowing is a universal feature of human aging, and parkinsonian signs are commonly expressed in human senescence. In the present study, age-associated declines in motor functions in 31 female rhesus monkeys were quantified by activity monitors and an automated test panel, and the incidence of parkinsonian signs was scored using a movement dysfunction assessment scale. Activity levels in middle-aged monkeys (12-17 years old) were less than half that of young animals (5-8 years old) and were further depressed in aged monkeys (21-27 years old). Movement dysfunction scores increased significantly with increasing age. Two or more parkinsonian signs were exhibited by 20% of the middle-aged monkeys and 36% of the aged monkeys. Slowing performance times on fine-motor hand tasks correlated significantly with increasing age. Motor learning was seen in all age groups, but improved faster in the young monkeys. The data suggest that aging rhesus monkeys provide an appropriate model to analyze the biological processes leading to motor slowing and the expression of parkinsonian signs in human senescence.

Dopaminergic therapy improves upper limb motor performance in aged rhesus monkeys.

The potential of dopaminergic treatments to improve upper limb motor movements was tested in 7 aged rhesus monkeys using L-3,4-dihydroxyphenylalanine (L-dopa) or the selective dopamine uptake inhibitor 1-2(bis[4-fluorophenyl] methoxy]ethyl)-4-(3-phenylpropyl) piperazine hydrochloride (GBR-12909). Six young monkeys were studied for comparison. L-Dopa or GBR-12909 improved upper limb motor performance by up to 40% in the aged animals. At this point their performance was comparable to that of young adults. Dopaminergic therapy could be useful in elderly humans experiencing declines in upper limb motor functions.

Functional MRI of apomorphine activation of the basal ganglia in awake rhesus monkeys.

Functional magnetic resonance imaging (fMRI) was used to analyze blood oxygen level-dependent (BOLD) responses in the nigrostriatal system (caudate nucleus, putamen and substantia nigra) of awake rhesus monkeys to systemic apomorphine administration. The study (1) measured BOLD responses as an index of neuronal activity in the three structures following injections of the mixed D1/D2 agonist, and (2) assessed the effects of isoflurane anesthesia on the fMRI responses. Compared to control saline injections, 0.1 mg/kg apomorphine significantly activated the caudate nucleus (P < or = 0.005), putamen (P < or = 0.001) and substantia nigra (P < or = 0.005). The responses were consistent with activation of GABAergic neurons in these three structures seen in other animal models. Isoflurane gas measurably blunted the response to apomorphine, so that a significant apomorphine activation was only seen in the substantia nigra of anesthetized animals. Even there, the mean MR signal change was reduced from 9.8% in awake monkeys to 2.3% in anesthetized animals. The data support the hypothesis that fMRI can be used to study the effects of drugs that alter basal ganglia activity in awake rhesus monkeys.

Participation of prostate apoptosis response-4 in degeneration of dopaminergic neurons in models of Parkinson's disease.

Dysfunction and death of midbrain dopaminergic neurons underlies the clinical features of Parkinson's disease (PD). Increasing evidence suggests roles for oxidative stress and a form of cell death called apoptosis in the pathogenesis of PD. We recently identified a 38-kd protein called prostate apoptosis response-4 (Par-4), which is rapidly induced in cultured neurons after exposure to apoptotic insults, and appears to play a necessary role in the cell death process. We now report that Par-4 levels increase dramatically in midbrain dopaminergic neurons of monkeys and mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The increase in Par-4 levels occurs in both neuronal cell bodies in the substantia nigra and their axon terminals in the striatum, and precedes loss of tyrosine hydroxylase immunoreactivity and cell death. In the monkey model, Par-4 levels were also increased in several brain regions (red nucleus, lateral geniculate nucleus, and cerebral cortex) in which functional alterations have previously been documented in PD patients and MPTP-treated monkeys. Exposure of cultured human dopaminergic neural cells to the complex I inhibitor rotenone, or to Fe2+, resulted in Par-4 induction, mitochondrial dysfunction, and subsequent apoptosis. Blockade of Par-4 induction by antisense treatment prevented rotenone- and Fe2+-induced mitochondrial dysfunction and apoptosis demonstrating a critical role for Par-4 in the cell death process. The data suggest that Par-4 may be involved in the neurodegenerative process in PD.

Critical decline in fine motor hand movements in human aging.

BACKGROUND: Slowing of motor movements in human aging is a well-known occurrence, but its biologic basis is poorly understood. Reliable quantitation may refine observations of this phenomenon to better aid research on this entity. METHODS: A panel equipped with timing sensors under computer control was used to measure upper extremity movement times in two groups of healthy individuals: adults younger than 60 years of age (n = 56; range, 18-58 years) and adults older than 60 years of age (n = 38; range, 61-94 years). RESULTS: Fine motor performance was better in the dominant hand (p = 0.0007) regardless of age. Adult and aged groups differed on two basic timing measures, which reflect coarse motor and fine motor performance (p < 0.0001). There were no gender differences on either measure. There was a strong effect of task difficulty with age on coarse motor (p < 0.01) and fine motor (p < 0.0001) measures. The fine motor measure of hand performance in healthy individuals correlated in a nonlinear fashion with age for more difficult tasks (r2 = 0.63) but showed a simple linear relation for less-demanding tasks (r2 = 0.5). CONCLUSION: This technique sensitively detects age-related motor performance decline in humans. There may be a critical period in late midlife when fine motor performance decline either begins or abruptly worsens.

An automated movement assessment panel for upper limb motor functions in rhesus monkeys and humans.

As part of our studies of age-associated changes in motor functions, we have designed an automated movement assessment panel (MAP) to evaluate upper limb and hand movements. Here we describe two versions of the MAP, one for human testing and one for nonhuman primates, and methods for conducting parallel tests in rhesus monkeys and human volunteers. The results are reported from a battery of tests on young adult rhesus monkeys (n = 10, 5-8 years old), young adult human subjects (n = 10, 18-22 years old) and ten aged human subjects (n = 10, 66-68 years old) to demonstrate the capability of the MAP in quantifying arm and hand movement times. The performance times on the two simplest tasks tested were consistent from trial to trial, demonstrating that a stable behavioral baseline could be established for evaluating changes in motor functions over time and assessing treatments for improving motor functions. Motor learning was seen in the more complex movement tasks tested, indicating their usefulness in analyzing this behavior. Finally, age-associated changes in performance times were robustly delineated by the four tasks evaluated in the human subjects.

Functional MRI of basal ganglia responsiveness to levodopa in parkinsonian rhesus monkeys.

Functional MRI (fMRI) was used to study striatal sensitivity to levodopa in hemiparkinsonian rhesus monkeys. Responses consistent with increased neuronal activity were seen in areas whose normal dopaminergic input from the substantia nigra pars compacta had been ablated by MPTP. Sites of increased activity following levodopa included the lateral putamen, the ventral region of the caudate head, septal areas, and midlateral amygdala in the MPTP-lesioned hemisphere. Increased activity was also observed in the same areas in the nonlesioned hemisphere, but was less pronounced in spatial extent and magnitude, suggesting either subclinical contralateral damage and/or functional adaptations in the contralateral dopamine systems. The increases in neuronal activity following levodopa treatment were temporally correlated with increases in striatal dopamine levels. Chronic levodopa treatment reduced behavioral responsiveness to levodopa and abolished the fMRI response. These results suggest that fMRI can detect changes in dopamine receptor-mediated neuronal sensitivity to dopaminergic agents.

Principal component analysis of the dynamic response measured by fMRI: a generalized linear systems framework.

Principal component analysis (PCA) is one of several structure-seeking multivariate statistical techniques, exploratory as well as inferential, that have been proposed recently for the characterization and detection of activation in both PET and fMRI time series data. In particular, PCA is data driven and does not assume that the neural or hemodynamic response reaches some steady state, nor does it involve correlation with any pre-defined or exogenous experimental design template. In this paper, we present a generalized linear systems framework for PCA based on the singular value decomposition (SVD) model for representation of spatio-temporal fMRI data sets. Statistical inference procedures for PCA, including point and interval estimation will be introduced without the constraint of explicit hypotheses about specific task-dependent effects. The principal eigenvectors capture both the spatial and temporal aspects of fMRI data in a progressive fashion; they are inherently matched to unique and uncorrelated features and are ranked in order of the amount of variance explained. PCA also acts as a variation reduction technique, relegating most of the random noise to the trailing components while collecting systematic structure into the leading ones. Features summarizing variability may not directly be those that are the most useful. Further analysis is facilitated through linear subspace methods involving PC rotation and strategies of projection pursuit utilizing a reduced, lower-dimensional natural basis representation that retains most of the information. These properties will be illustrated in the setting of dynamic time-series response data from fMRI experiments involving pharmacological stimulation of the dopaminergic nigro-striatal system in primates.

Age-associated changes in rhesus CNS composition identified by MRI.

Multispectral automated segmentation of MR images of the brains of 10 young (5-8 years), 10 middle-aged (12-17 years), and 11 old (21-27 years) female rhesus monkeys revealed age-associated changes in brain volume and composition. Total brain parenchymal volume (expressed as fraction of intracranial volume-%ICV) decreased at a linear rate of 0.3+/-0.04% ICV/year. Up to age approximately 15 years, this loss was almost entirely due to gray matter loss, with a compensatory increase in cerebrospinal fluid (CSF), and possibly some white matter. Brain tissue composition, expressed as the gray matter/white matter volume ratio confirmed that gray matter loss exceeded white matter loss, but the rate of decline in the gray/white ratio began to slow after approximately 15 years. Comparison of these age-associated changes in rhesus brain with those in humans suggest that the brain aging in rhesus is a good model of human brain aging, but occurs approximately 3-fold faster.