Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults (original) (raw)
The Aging Hippocampus: Cognitive, Biochemical and Structural Findings
Cerebral Cortex, 2003
Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collectively, our results suggest that hippocampus undergoes structural and biochemical changes with normal aging and that these changes may represent an important component of age-related deterioration in hippocampusdependent cognition.
Memory training alters hippocampal neurochemistry in healthy elderly
NeuroReport, 2003
Accumulating epidemiological evidence supports the notion of brain reserve, but there has been no investigation of neurobiological change associated with brief mental activation training in humans. Healthy older individuals were therefore investigated with magnetic resonance spectroscopy (MRS) in di¡erent brain regions before and after 5 weeks of focused memory training. Recall of a test-word list of 4 23 items was achieved accompanied by eleva-tion of creatine and choline signals in the hippocampus. Those at risk for neural dysfunction, as indicated by lower neurometabolites at baseline, demonstrated the largest MRS increases after training. Biochemical changes related to cellular energy and cell-membrane turnover were found to increase after structured memory exercises and were limited to the medial temporal lobe. NeuroReport
The aging hippocampus: cognitive, biochemical and structural findings. Cereb Cortex 2003
2013
Aging is often accompanied by learning and memory problems, many of which resemble deficits associated with hippocampal damage. Studies of aging in nonhuman animals have demonstrated hippocampus-related memory decline, and point to a possible locus for impairments associated with normal and pathological aging in humans. Two well-characterized hippocampus-dependent tasks in nonhuman animal literature are the Morris water task (MWT) and the transverse patterning discrimination task (TPDT). We employed the virtual MWT and the TPDT to assess hippocampus-dependent cognition in humans. Magnetic resonance imaging and proton magnetic resonance spectroscopy were employed to measure hippocampal volume and neurochemistry respectively. Age-related deficits were observed in performance on both hippocampus-dependent tasks. This pattern of impairment was accompanied by decreased hippocampal NAA/Cre ratios and volume, both of which imply neuronal loss and/or decrease in neuronal density. Collective...
Linking Hippocampal Structure and Function to Memory Performance in an Aging Population
Archives of Neurology, 2009
Background: Hippocampal atrophy and reductions in basal cerebral blood volume (CBV), a hemodynamic correlate of brain function, occur with cognitive impairment in Alzheimer disease, but whether these are early or late changes remains unclear. Magnetic resonance imaging is used to assess structure and function in the hippocampal formation. Objective: To estimate differences in the associations of hippocampal and entorhinal cortex volumes and CBV with memory function in the early and late stages of cognitive impairment by relating these measures to memory function in persons with and without dementia who underwent detailed brain imaging and neuropsychological assessment. Design: Multivariate regression analyses were used to relate entorhinal cortex volume, entorhinal cortex CBV, hippocampal volume, and hippocampal CBV to measurements of memory performance. The same measures were related to language function as a reference cognitive domain. Setting: Community-based cohort. Participants: Two hundred thirty-one elderly Medicare recipients (aged Ն65 years) residing in northern Manhattan, New York. Main Outcome Measures: Values for entorhinal cortex volume, hippocampal volume, entorhinal cortex CBV, and hippocampal CBV and their relation to memory performance. Results: No association was noted between entorhinal cortex volume or hippocampal CBV and memory. Decreased hippocampal volume was strongly associated with worse performance in total recall, and lower entorhinal cortex CBV was associated with lower performance in delayed recall. Excluding persons with Alzheimer disease, the association of entorhinal cortex CBV with memory measures was stronger, whereas the association between hippocampal volume and total recall became nonsignificant. Conclusions: In the early stages of Alzheimer disease or in persons without dementia with worse memory ability, functional and metabolic hippocampal hypofunction contributes to memory impairment, whereas in the later stages, functional and structural changes play a role.
Frontiers in Aging Neuroscience
We aimed to longitudinally assess the relationship between changing brain energy metabolism (glucose and acetoacetate) and cognition during healthy aging. Participants aged 71 ± 5 year underwent cognitive evaluation and quantitative positron emission tomography (PET) and magnetic resonance imaging (MRI) scans at baseline (N = 25) and two (N = 25) and four (N = 16) years later. During the follow-up, the rate constant for brain extraction of glucose (K glc) declined by 6%-12% mainly in the temporo-parietal lobes and cingulate gyri (p ≤ 0.05), whereas brain acetoacetate extraction (Kacac) and utilization remained unchanged in all brain regions (p ≥ 0.06). Over the 4 years, cognitive results remained within the normal age range but an age-related decline was observed in processing speed. K glc in the caudate was directly related to performance on several cognitive tests (r = +0.41 to +0.43, all p ≤ 0.04). Peripheral insulin resistance assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) was significantly inversely related to K glc in the thalamus (r = −0.44, p = 0.04) and in the caudate (r = −0.43, p = 0.05), and also inversely related to executive function, attention and processing speed (r = −0.45 to −0.53, all p ≤ 0.03). We confirm in a longitudinal setting that the age-related decline in K glc is directly associated with declining performance on some tests of cognition but does not significantly affect Kacac.
Age-related changes in metabolic profiles of rat hippocampus and cortices
European Journal of Neuroscience, 2010
The time course of metabolic changes was investigated in the hippocampus and the parietal, rhinal and frontal cortices of rats from 4 to 30 months old. Samples were analysed by the solid-state high-resolution magic angle spinning nuclear magnetic resonance method. Quantification was performed with the quest procedure of jmrui software. Eighteen metabolites were identified and separated in the spectrum. Six of them were not age sensitive, in particular alanine, glutamine and lactate. In contrast, choline, glycerophosphocholine, myo-inositol, N-acetylaspartate, scyllo-inositol (s-Ins) and taurine (Tau) were notably altered over aging. Interestingly, each age group showed a specific metabolic profile. The concentration of metabolites such as Tau was altered in middle-aged rats only, whereas the sIns level decreased in old rats only. Most metabolites showed progressive alteration during the process of aging, which was initiated during the middle-aged period (18 months). Taken together, these results suggest that cell membrane integrity is perturbed with age. Each brain region investigated had distinctive qualitative and ⁄ or quantitative metabolic age-related features. These age-related changes would affect network connectivities and then cognitive functions.
Relationship between Hippocampal Structure and Memory Function in Elderly Humans
Journal of Cognitive Neuroscience, 2006
& With progressing age, the ability to recollect personal events declines, whereas familiarity-based memory remains relatively intact. It has been hypothesized that age-related hippocampal atrophy may contribute to this pattern because of its critical role for recollection in younger humans and after acute injury. Here, we show that hippocampal volume loss in healthy older persons correlates with gray matter loss (estimated with voxelbased morphometry) of the entire limbic system and shows no correlation with an electrophysiological (event-related po-tential [ERP]) index of recollection. Instead, it covaries with more substantial and less specific electrophysiological changes of stimulus processing. Age-related changes in another complementary structural measure, hippocampal diffusion, on the other hand, seemed to be more regionally selective and showed the expected correlation with the ERP index of recollection. Thus, hippocampal atrophy in older persons accompanies limbic atrophy, and its functional impact on memory is more fundamental than merely affecting recollection. & D
Midlife memory improvement predicts preservation of hippocampal volume in old age
Neurobiology of Aging, 2012
This study examines whether midlife change in episodic memory predicts hippocampal volume in old age. From the Seattle Longitudinal Study we retrospectively identified 84 healthy, cognitively normal individuals, age 52 to 87, whose episodic memory had reliably declined (n ϭ 33), improved (n ϭ 28) or remained stable (n ϭ 23) over a 14-year period in midlife (age 43-63). Midlife memory improvement was associated with 13% larger hippocampal volume (p Ͻ 0.01) in old age (age 66 -87), compared with old age individuals whose midlife episodic memory had either declined or remained stable during midlife. Midlife memory change did not predict total hippocampal volume for those currently in late middle age (age 52-65). The pattern of findings was not modified by gender, apolipoprotein 4 status, education or current memory performance. Change in midlife memory scores over 14 years, but not any single assessment, predicted hippocampal volumes in old age, emphasizing the importance of longitudinal data in examining brain-cognition relationships. These findings suggest that improvement in memory in midlife is associated with sparing of hippocampal volume in later life.
Clinical and Cognitive Correlates of Structural Hippocampal Change in "At-Risk" Older Adults
Journal of Geriatric Psychiatry and Neurology, 2013
With estimates of dementia expected to rise over the coming decades, there is interest in understanding the factors associated with promoting neuroprotection and limiting neurodegeneration. In this study, we examined the change in the volume of the hippocampus over a 2-month period in 34 older people ''at risk'' of cognitive decline (mean age ¼ 66.8 years, 38% male). Factors that were examined included cognitive reserve, neuropsychological functioning, depression as well as a lifestyle (cognitive training) intervention. The results showed that over a 2-month period, increases in hippocampal size were associated with having higher premorbid intellect, greater occupational attainment, superior memory, and higher levels of functioning. Conversely, depression and disability were associated with decreases in hippocampal volume. Cognitive training was not associated with changes in hippocampal volume. These findings suggest that factors associated with cognitive reserve, cognition and depression may play an integral pathophysiological role in determining hippocampal volumes in ''at-risk'' older adults.
Neurobiology of Aging, 1999
Magnetic resonance imaging (MRI) studies have produced controversial results concerning the correlation of hippocampal volume loss with increasing age. The goals in this study were: 1) to test whether levels of N-acetyl aspartate (NAA, a neuron marker) change in the hippocampus during normal aging and 2) to determine the relationship between hippocampal NAA and volume changes. Proton magnetic resonance spectroscopic imaging ( 1 H MRSI) and MRI were used to measure hippocampal metabolites and volumes in 24 healthy adults from 36 to 85 years of age. NAA/Cho decreased by 24% (r ϭ 0.53, p ϭ 0.01) and NAA/Cr by 26% (r ϭ 0.61, p Ͻ 0.005) over the age range studied, whereas Cho/Cr remained stable, implying diminished NAA levels. Hippocampal volume shrank by 20% (r ϭ 0.64, p Ͻ 0.05). In summary, aging effects must be considered in 1 H MRSI brain studies. Furthermore, because NAA is considered a marker of neurons, these results provide stronger support for neuron loss in the aging hippocampus than volume measurements by MRI alone.
Hippocampal volumes are important predictors for memory function in elderly women
BMC Medical Imaging, 2009
Background: Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOEgene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46-77 years).
The neurobiology of memory changes in normal aging
Experimental Gerontology, 2003
Cognitive alterations occur over the lifespan of every species studied and have been quantified carefully in humans, other primates and rodents. Correspondingly, changes in hippocampal function have been associated with a number of observed memory impairments across species. It appears that humans, alone, show Alzheimer's disease-like cognitive and neural pathology spontaneously. Thus, a comparison of normal age-related changes in cognition in other animals can help disambiguate the boundary between normal and pathological states of aging in humans. Another important contribution made from studying aging in non-human species is the ability to examine, in more detail, the basic neural mechanisms that may be responsible for brain aging in these species. So far, most of the functional neurobiological studies have been conducted in the aged rat. We propose that the link between rodent and human work can be made much stronger by combining neurophysiological and behavioral investigation of normal aging in the non-human primate. q
Aging Cell, 2015
The hippocampus is critical for cognition and memory formation and is vulnerable to age-related atrophy and loss of function. These phenotypes are attenuated by caloric restriction (CR), a dietary intervention that delays aging. Here, we show significant regional effects in hippocampal energy metabolism that are responsive to age and CR, implicating metabolic pathways in neuronal protection. In situ mitochondrial cytochrome c oxidase activity was region specific and lower in aged mice, and the impact of age was region specific. Multiphoton laser scanning microscopy revealed region-and age-specific differences in nicotinamide adenine dinucleotide (NAD)-derived metabolic cofactors. Age-related changes in metabolic parameters were temporally separated, with early and late events in the metabolic response to age. There was a significant regional impact of age to lower levels of PGC-1a, a master mitochondrial regulator. Rather than reversing the impact of age, CR induced a distinct metabolic state with decreased cytochrome c oxidase activity and increased levels of NAD(P)H. Levels of hippocampal PGC-1a were lower with CR, as were levels of GSK3b, a key regulator of PGC-1a turnover and activity. Regional distribution and colocalization of PGC-1a and GSK3b in mouse hippocampus was similar in monkeys. Furthermore, the impact of CR to lower levels of both PGC-1a and GSK3b was also conserved. The studies presented here establish the hippocampus as a highly varied metabolic environment, reveal cell-type and regional specificity in the metabolic response to age and delayed aging by CR, and suggest that PGC-1a and GSK3b play a role in implementing the neuroprotective program induced by CR.
Hippocampal formation size predicts declining memory performance in normal aging
Neurology, 1996
Hippocampal formation (HF) atrophy, although common in normal aging, has unknown clinical consequences.We used MRI to derive HF size measurements at baseline on 44 cognitively normal older adults entering a longitudinal study of memory function (mean age = 68.4 years, mean follow-up = 3.8 years). Only one subject became demented at follow-up. Multiple regression analyses controlling for age, gender, education, and diffuse cerebral atrophy revealed that HF size significantly predicted longitudinal change on memory tests previously found sensitive to decline in normal aging. These results indicate HF atrophy may be a risk factor for accelerated memory dysfunction in normal aging.NEUROLOGY 1996;47: 810-813
Scientific Reports
The heterogeneous specialisation of hippocampal subfields across memory functions has been widely shown in animal models. Yet, few in vivo studies in humans have explored correspondence between hippocampal subfield anatomy and memory performance in ageing. Here, we used a well-validated automated MR segmentation protocol to measure hippocampal subfield volumes in 436 non-demented adults aged 50+. We explored relationships between hippocampal subfield volume and verbal episodic memory, as indexed by word list recall at immediate presentation and following delay. In separate multilevel models for each task, we tested linearity and non-linearity of associations between recall performance and subfield volume. Fully-adjusted models revealed that immediate and delayed recall were both associated with cubic fits with respect to volume of subfields CA1, CA2/3, CA4, molecular layer, and granule cell layer of dentate gyrus; moreover, these effects were partly dissociable from quadratic age trends, observed for subiculum, molecular layer, hippocampal tail, and CA1. Furthermore, analyses of semantic fluency data revealed little evidence of robust associations with hippocampal subfield volumes. Our results show that specific hippocampal subfields manifest associations with memory encoding and retrieval performance in non-demented older adults; these effects are partly dissociable from age-related atrophy, and from retrieval of well-consolidated semantic categories. Hippocampus is among the most important brain structures involved in memory 1-3 , and is a critical site of pathogenesis in dementing illnesses such as Alzheimer's Disease 4-7. Decades of ex vivo human studies and in vivo animal studies have revealed anatomical and functional heterogeneity of the hippocampal subfields 8-12. Yet, until recently, very few in vivo studies in humans had shown dissociable relationships between performance in different memory domains and hippocampal subfield anatomy or function 13-15. The role of the hippocampal subfields with respect to select domains of memory thus remains under explored. Recent work has shown that errors during real-world spatial navigation are negatively associated with hippocampal tail volume in mild cognitive impairment (MCI), but with Cornu Ammonis (CA) 3 volume in healthy controls 16. Yet, despite this, there remains a limited understanding of the role of hippocampal subfields in other memory domains relied on in daily life, such as verbal episodic memory (e.g., recalling a grocery list) or semantic memory (e.g., retrieving familiar nouns) [but see 17 ]. Verbal episodic and semantic memory have been shown to dissociate to hippocampal versus anterior temporal regions respectively 18-22. However, much of our understanding of these dissociations is based on small and heterogeneous patient cohorts 19-21. Little is known about these relationships in the context of healthy ageing; less still is known about the effects of age with respect to relationships between hippocampal subfields and specific memory domains, despite evidence of age-related variation in subfield anatomy 23-25 .
European Journal of Radiology, 2012
To study age-related metabolic changes in N-acetylaspartate (NAA), total creatine (tCr), choline (Cho) and myo-inositol (Ins). Proton magnetic resonance spectroscopy (1H-MRS) was performed in the posterior cingulate cortex (PCC) and the left hippocampus (HC) of 90 healthy subjects (42 women and 48 men aged 18-76 years, mean±SD, 48.4±16.8 years). Both metabolite ratios and absolute metabolite concentrations were evaluated. Analysis of covariance (ANCOVA) and linear regression were used for statistical analysis. Metabolite ratios Ins/tCr and Ins/H2O were found significantly increased with age in the PCC (P<0.05 and P≤0.001, respectively), and in the HC (P<0.01 for both). An increased tCr/H2O was only observed in the PCC (P<0.01). Following absolute quantification based on the internal water signal, significantly increased concentrations of Ins and tCr in the PCC confirmed the relative findings (P<0.01 for both). Age-related increases of tCr and Ins are found in the PCC, whereas this holds only true for Ins in the HC, indicating possible gliosis in the ageing brain. No age-dependent NAA decreases were observed in the PCC nor the HC. The 1H-MRS results in these specific brain regions can be important to differentiate normal ageing from age-related pathologies such as mild cognitive impairment (MCI) and Alzheimer's disease.
Behavioral Neuroscience, 2003
Magnetic resonance imaging-derived entorhinal and hippocampal volumes were measured in 14 nondemented, community-dwelling older adults. Participants were selected so that memory scores from 2 years prior to scanning varied widely but were not deficient relative to age-appropriate norms. A median split of these memory scores defined high-memory and low-memory groups. Verbal memory scores at the time of imaging were lower, and entorhinal and hippocampal volumes were smaller, in the low-memory group than in the high-memory group. Left entorhinal cortex volume showed the strongest correlation (r ϭ .79) with immediate recall of word lists. Left hippocampal volume showed the strongest correlation (r ϭ .57) with delayed paragraph recall. These results suggest that entorhinal and hippocampal volumes are related to individual differences in dissociable kinds of memory performance among healthy older adults.
Hippocampal atrophy in the healthy is initially linear and independent of age
Neurobiology of Aging, 2006
Patients with minimal cognitive impairment (MCI) or Alzheimer's disease (AD) have smaller hippocampal volumes (HV) and increased rates of HV loss (rHVL). A 6-year study was conducted to assess rHVL in healthy aging subjects (HC) in which four MRI scans, each 2 years apart, were obtained on 26 HC with a mean age of 58.8 years when entering the study. rHVLs were linear and significantly differed among subjects, even those sharing an identical apoliporotein E genotype, ranging from .027 to .191 cc/year (S.D. = .022 cc/year), and were not affected by age or sex. rHVL, but not HV, at time of subject entry, was found to predict performance on the delayed recall measure of the Selective Reminder Task obtained 6 years after subject entry into study. Although the molecular events underlying rHVL are unclear, the significance of rHVL in subjects in their sixth and seventh decades of life for predicting age-related cognitive trajectories and whether changes in rHVLs foreshadow the development of MCI are the subject of ongoing study.