The Maturation of the Acoustic Change Complex in Response to Iterated Ripple Noise in 'Normal'-Hearing Infants, Toddlers, and Adults.

BACKGROUND: Infants and toddlers are still being evaluated for their hearing sensitivity but not their auditory-processing skills. Iterated rippled noise (IRN) stimuli require the auditory system to utilize the temporal periodicity and autocorrelate the iterations to perceive pitch. PURPOSE: This study investigated the acoustic change complex (ACC) elicited by IRN in "normal"-hearing infants, toddlers, and adults to determine the maturation of cortical processing of IRN stimuli. DESIGN: Cortical responses to filtered white noise (onset) concatenated with IRN stimuli (d = 10 milliseconds, gain = 0.7 dB: 4-32 iterations) were recorded in quiet, alert participants. STUDY SAMPLE: Participants included 25 infants (2.5-15 months), 27 toddlers (22-59 months), and 8 adults (19-25 years) with "normal" hearing sensitivity. DATA COLLECTION AND ANALYSIS: Cortical auditory-evoked responses were recorded for each participant, including the onset response to the noise and an ACC to the transition from noise to IRN. Group differences were assessed using repeated-measures analyses of variance. RESULTS: Most infants had a replicable onset (P) response, while only about half had a measurable ACC (PACC) response to the high-saliency IRN condition. Most toddlers had onset responses and showed a P-NACC response to the IRN16 and IRN32 conditions. Most of the toddler group had responses present to the onset and showed a P-NACC response to all IRN conditions. Toddlers and adults showed similar P-NACC amplitudes; however, adults showed an increase in N1ACC amplitude with increase in IRN iterations (i.e., increased salience). CONCLUSION: While cortical responses to the percept of sound as determined by the onset response (P) to a stimulus are present in most infants, ACC responses to IRN stimuli are not mature in infancy. Most toddlers as young as 22 months, however, exhibited ACC responses to the IRN stimuli even when the pitch saliency was low (e.g., IRN4). The findings of the current study have implications for future research when investigating maturational effects on ACC and the optimal choice of stimuli.

Hippocampal dysfunction in the pathophysiology of schizophrenia: a selective review and hypothesis for early detection and intervention.

Scientists have long sought to characterize the pathophysiologic basis of schizophrenia and develop biomarkers that could identify the illness. Extensive postmortem and in vivo neuroimaging research has described the early involvement of the hippocampus in the pathophysiology of schizophrenia. In this context, we have developed a hypothesis that describes the evolution of schizophrenia-from the premorbid through the prodromal stages to syndromal psychosis-and posits dysregulation of glutamate neurotransmission beginning in the CA1 region of the hippocampus as inducing attenuated psychotic symptoms and initiating the transition to syndromal psychosis. As the illness progresses, this pathological process expands to other regions of the hippocampal circuit and projection fields in other anatomic areas including the frontal cortex, and induces an atrophic process in which hippocampal neuropil is reduced and interneurons are lost. This paper will describe the studies of our group and other investigators supporting this pathophysiological hypothesis, as well as its implications for early detection and therapeutic intervention.

Tau and amyloid-related pathologies in the entorhinal cortex have divergent effects in the hippocampal circuit.

The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co-occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability. Most importantly, mice co-expressing hAPP and hTau show that hTau has a dominant effect, dampening the excitatory effects of hAPP. Additionally, compensatory synaptic downscaling, in response to increased excitability in EC was observed in subicular neurons of hAPP mice. Based on simulations, we propose that EC interneuron pruning can account for both EC hyperexcitability and subicular synaptic downscaling found in mice expressing hAPP.

Memory after silent stroke: hippocampus and infarcts both matter.

OBJECTIVE: Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear. METHODS: We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability. RESULTS: Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume. CONCLUSIONS: Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.

Subclinical cerebrovascular disease in mild cognitive impairment.

BACKGROUND: Cerebrovascular disease (CVD) may contribute to mild cognitive impairment (MCI). We sought to determine the relation of white matter hyperintensity (WMH) volume and infarcts in brain MRI to MCI in a community-based sample. METHODS: A total of 679 elderly persons without dementia underwent brain MRI. WMH and infarcts were quantified using research methods. WMH was adjusted for total cranial volume. The Petersen criteria were used to define MCI. MCI was further subclassified into amnestic and non-amnestic. We used logistic regression to relate WMH and infarcts to prevalent MCI. RESULTS: WMH were associated with amnestic MCI (odds ratio [OR] = 1.9; 95% confidence interval [CI] 1.1, 3.4) but not non-amnestic MCI (OR = 1.2; 95% CI 0.4, 1.6) after adjusting for age, gender, ethnic group, education, and APOE-epsilon4. Infarcts were more strongly associated with non-amnestic MCI (OR = 2.7; 95% CI 1.5, 4.8) than amnestic MCI (OR = 1.4; 95% CI 0.9, 2.3). In secondary analyses using continuous cognitive scores as outcomes, WMH, but not infarcts, were related to memory, while infarcts were more strongly related with non-amnestic domains. CONCLUSION: White matter hyperintensity (WMH) is more strongly related to amnestic mild cognitive impairment (MCI). Infarcts are more strongly related to non-amnestic MCI. The nature of WMH in amnestic MCI requires further study.

Spatio-temporal analysis of molecular delivery through the blood-brain barrier using focused ultrasound.

The deposition of gadolinium through ultrasound-induced blood-brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 degrees C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison; 25-50 microl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5-1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2-4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 microm, scan time: 45-180 min) with gadolinium (Omniscan; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.

A novel phosphorylcholine-coated contact lens for extended wear use.

The preparation and characterisation of a new phosphorylcholine (PC)-coated silicone hydrogel contact lens for use in extended wear is described. The Michael-type addition of amines to acrylates forms the basis of the synthesis of a novel silicone-based macromer with hydrophilic functionality. It is demonstrated that this macromer can be combined with other silicone-based monomers, hydrophilic monomers and crosslinker to produce a contact lenses formulation. Examples of lenses with water contents of 33% and 46% are illustrated and their properties compared to other commercially available lenses. Materials with comparatively low modulus (<0.3 MPa) and adequate tear strength (>2-4MPa) with excellent elongation to break (>200%) can be obtained using this technology. In addition to the mechanical aspects. both the oxygen and solute permeabilities of the material can be controlled by the hydrophilic: hydrophobic monomer balance in the formulation. to obtain materials with attributes suitable for extended wear use. The PC coating is achieved by means of an in-mould coating (IMC) technique that produces a uniform and stable surface as determined by staining and XPS. The coating imparts both improved lens wettability (advancing contact angle of approximately 50 with virtually no hysteresis) and lower protein adsorption relative to the uncoated lens.

Memory performance in healthy elderly without Alzheimer's disease: effects of time and apolipoprotein-E.

Transgenic mice expressing human APOE-epsilon4 develop an age-dependent decline in memory without pathological features of Alzheimer's disease (AD). This implicates APOE in the maintenance of memory during normal senescence, but parallel human studies are limited because longitudinal investigations of memory usually do not exclude patients with AD or "questionable" AD (QD). The current study examined the effect of APOE on cognitive function over time in elderly without dementia. We hypothesized that, compared to other APOE alleles memory decline even in healthy elderly would be greater among those with an APOE-epsilon4. The results of neuropsychological tests, grouped into domains of memory, language and visuospatial/cognitive function by factor analysis, were examined at three intervals over a seven-year period in 563 healthy elderly without AD or QD using generalized estimating equations. Memory performance declined over time, while scores on the visuospatial/cognitive and language factors did not change. Increased age was associated with lower scores, and higher education with higher scores on all factors at each interval. No APOE allele was associated with performance on a specific cognitive factor at any interval, but the presence of an APOE-epsilon4 allele was associated with a more rapid decline in the memory factor over the follow-up period. The effect was most pronounced among individuals with less than 10 years of formal education. There was no similar time-dependent relationship between APOE-epsilon4 and the language or visuospatial/cognitive factors. Transgenic mice and elderly humans without AD or QD expressing APOE-epsilon4 show a decline in memory performance over time. These observations provide evidence for an APOE-specific effect on memory during senescence.

Age-related memory decline: current concepts and future directions.

The effect of age on memory and the brain has been the focus of many studies. Results have identified critical questions that need to be addressed to further our understanding of age-related memory decline: Is cognitive decline diffuse or selective? Where does memory decline localize to anatomically? Does decline represent an abnormal state? What are the causes of memory decline? What level of analysis is needed to investigate age-related cortical changes? These questions are reviewed herein, and attempts at early answers are discussed.

Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation.

Circuits within the hippocampal formation are active during memory processing. Here we used functional magnetic resonance imaging (fMRI) to examine multiple sites across the long axis of the hippocampal formation while subjects performed different phases of an associative memory task, learning to associate faces with names. Viewing faces and hearing names in isolation resulted in separate hippocampal activation patterns. Pairing faces with names resulted a spatially redistributed activation pattern, rather than a simple summation of the activation patterns resulting from viewing faces and hearing names in isolation. Recalling names when cued with faces reactivated a pattern similar to that found during paired training. Finally, the activation patterns representing faces and names were found to be experience dependent, emerging with repeated exposure. Interpreted in the context of hippocampal anatomy and physiology, these findings reveal hippocampal circuit mechanisms that underlie memory encoding and retrieval.

Evaluating the function of hippocampal subregions with high-resolution MRI in Alzheimer's disease and aging.

Memory ability declines in older age groups. There is a growing list of physiological processes that target the hippocampal formation in an age-related fashion, and some might underlie the hippocampal component of memory decline. The hippocampal formation is comprised of separate subregions, and physiological processes differentially target these subregions. The ability to evaluate the functional integrity of individual subregions-performing subregional analysis-is a major clinical goal since it can aid in the diagnosis of memory decline, as well as in elucidating mechanisms of disease and testing potential interventions. Because of its superior spatial resolution, magnetic resonance imaging (MRI) is best suited to accomplish this goal. Despite limited success, most functional MRI (fMRI) protocols have difficulty in performing complete subregional analysis of the hippocampal formation. Here we address sources of difficulty by (1) generating T2* -weighted maps of the hippocampal formation with sub-millimeter resolution; and (2) by adapting an approach used by animal investigators to identify the hippocampal subregions using anatomical landmarks. The protocol is tested in patients with Alzheimer's disease and in healthy controls, in an effort to determine whether it can detect neuronal dysfunction. Results showed diminished signal in the hippocampal formation of patients with Alzheimer's disease (AD) compared to controls, and multivariate analysis showed that this difference was most prominent in the entorhinal cortex. The protocol can be used to perform subregional analysis of the hippocampal formation. Testing the protocol in other clinical populations is needed to demonstrate its efficacy in evaluating the neuronal integrity of all hippocampal subregions.

Endogenous estrogen levels and Alzheimer's disease among postmenopausal women.

BACKGROUND: Although several studies have suggested that hormone replacement therapy lowers the risk of AD among postmenopausal women, few studies have evaluated the relationship of endogenous estrogen levels and AD. The current study investigated whether serum estrone and estradiol levels were related to the presence of AD among postmenopausal women not currently taking hormone replacement therapy. METHODS: Using a case-control design, we examined an ethnically diverse sample of postmenopausal women who met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for AD (n = 50) and nondemented controls (n = 93). All women were participants in a study of aging and dementia and were seen consecutively between August 1997 and October 1998. RESULTS: Patients with AD had lower estradiol (F[1,141] = 8.3, p = 0.005) levels than did normal controls. Patients also had lower estrone levels; however, this comparison did not quite meet significance criteria (F[1,141] = 3.6, p = 0.06). Compared to estradiol levels >20 pg/mL, women with AD were four to six times more likely to have levels <20 pg/mL after adjusting for age, years of education, presence of an APOE-epsilon4 allele, ethnicity, and body mass index. There were no significant differences in frequency of AD among women within different quartiles of estrone after adjusting for potential confounds. CONCLUSIONS: The results of this preliminary case-control study suggest that estradiol levels may decline significantly in women in whom AD develops.

Imaging physiologic dysfunction of individual hippocampal subregions in humans and genetically modified mice.

We have developed a variant of functional magnetic resonance imaging (fMRI) designed to be sensitive to static neuronal function. This method is based on resting instead of dynamic changes in oxygen-dependent signal and therefore allows for a spatial resolution that can detect signal from different hippocampal subregions in human subjects as well as in mice. We found that hippocampal signal was significantly diminished in elderly subjects with memory decline compared to age-matched controls, and different subjects showed dysfunction in different subregions. Among healthy elders, signal intensity from the subiculum was correlated selectively with memory performance. This method does not require an activation task; it can be used in anesthetized normal and in genetically modified and cognitively impaired mice. In mice the signal was found to be sufficiently sensitive to detect functional changes in the absence of underlying anatomical changes.

Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease.

Mutations in the amyloid precursor protein and presenilin 1 and 2 genes result in elevated plasma levels of the amyloid beta-peptide species terminating at amino acid residue 42 (A beta1-42). In a longitudinal study of unrelated elderly individuals, those who subsequently developed Alzheimer's disease had higher plasma levels of A beta1-42 at entry than did those who remained free of dementia. The results indicate that elevated plasma levels of the released A beta peptide A beta1-42 may be detected several years before the onset of symptoms, supporting that extracellular A beta1-42 plays an important role in the pathogenesis of late-onset Alzheimer's disease.

Selective decline in memory function among healthy elderly.

OBJECTIVE: To use longitudinally acquired data to establish whether aging is associated with memory decline. BACKGROUND: Memory loss is one of the most frequent complaints among the elderly. Nevertheless, age-related memory decline remains controversial in large part because it has been established with cross-sectional studies. METHODS: A total of 212 community-based healthy people were followed prospectively and evaluated annually with a neuropsychological battery testing memory and other cognitive domains. To control for the learning effect-the improvement in test performance associated with repeated exposure-longitudinal performance was compared between two age groups. RESULTS: The older age group displayed a relative decline in memory performance with time. In contrast to memory, a relative age-related decline was not observed in tests of language, visuospatial ability, and abstract reasoning. Furthermore, within the memory domain, age-related decline was restricted to a specific aspect of memory, manifesting only in a measure sensitive to the acquisition and early retrieval of new information, and not in a measure of memory retention. This profile of age-related cognitive decline anatomically localizes to the hippocampal formation. CONCLUSION: This study establishes age-related memory decline using longitudinal data, and shows that this decline does not occur diffusely across multiple cognitive domains. Both early AD as well as non-AD processes likely contribute to age-related memory decline, and continued follow-up may reveal distinguishing features between these two.

Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease.

The hippocampal formation is composed of separate anatomical regions interconnected to form a circuit, and investigating abnormal hippocampal function is most revealing at the level of these regions. Until recently, regional analysis of the hippocampal formation could be performed only in animals or in human postmortem tissue. Here, we report a method using functional magnetic resonance imaging that evaluates the hippocampal regions in vivo, and we use this method to study elderly with normal memory, with isolated memory decline, and with probable Alzheimer's disease (AD). Although age-related memory decline occurs commonly, the cause of this decline remains unknown, with disagreement as to whether this decline represents one or more etiologies. Analysis revealed two distinct patterns of regional dysfunction among elderly with isolated memory decline--one pattern similar to that found in elders with AD, involving all hippocampal regions, and a second pattern with dysfunction restricted to only one hippocampal region, the subiculum. These results offer direct evidence of hippocampal dysfunction associated with memory decline in the elderly, and implicate both predementia AD and non-AD processes as possible underlying causes.

Effect of literacy on neuropsychological test performance in nondemented, education-matched elders.

The current investigation compared neuropsychological test performance among nondemented literate and illiterate elders. The sample included participants in an epidemiological study of normal aging and dementia in the Northern Manhattan community. All participants were diagnosed as nondemented by a neurologist, and did not have history of Parkinson's disease, stroke, or head injury. Literacy level was determined by self-report. MANOVAs revealed a significant overall effect for literacy status (literate vs. illiterate) on neuropsychological test performance when groups were matched on years of education. The overall effect of literacy status remained significant after restricting the analyses to elders with no formal education, and after controlling for the effects of language of test administration. Specifically, illiterates obtained lower scores on measures of naming, comprehension, verbal abstraction, orientation, and figure matching and recognition. However tests of verbal list delayed recall, nonverbal abstraction, and category fluency were unaffected by literacy status, suggesting that these measures can be used to accurately detect cognitive decline among illiterate elders in this sample. Differences in organization of visuospatial information, lack of previous exposure to stimuli, and difficulties with interpretation of the logical functions of language are possible factors that contribute to our findings.

Cognitive test performance among nondemented elderly African Americans and whites.

We examined the neuropsychological test performance of a randomly selected community sample of English-speaking non-Hispanic African American and white elders in northern Manhattan. All participants were diagnosed as nondemented by a neurologist, whose assessment was made independent of neuropsychological test scores. African American elders obtained significantly lower scores on measures of verbal and nonverbal learning and memory, abstract reasoning, language, and visuospatial skill than whites. After using a stratified random sampling technique to match groups on years of education, many of the discrepancies became nonsignificant; however, significant ethnic group differences on measures of figure memory, verbal abstraction, category fluency, and visuospatial skill remained. Discrepancies in test performance of education-matched African Americans and whites could not be accounted for by occupational attainment or history of medical conditions such as hypertension and diabetes. These findings emphasize the importance of using culturally appropriate norms when evaluating ethnically diverse elderly for dementia.

Sexual abuse history and number of sex partners among female adolescents.

A survey completed 1996 of 10,868 adolescent females from one Midwestern state indicates that 10% had experienced sexual abuse by an adult or by someone older than themselves-9% in the past and 1% in an ongoing situation. Past and current victims of sexual abuse had had more sexual partners during the past year (2.3 and 1.2, respectively) than their peers who had never been sexually abused (0.5). Regardless of sexual abuse history, teenagers whose activities were closely monitored by their parents, who received high levels of parental support and whose parents disapproved of teenagers having sex had fewer sexual partners than other adolescents. Respondents who had experienced physical abuse in addition to sexual abuse were at further increased risk of having had multiple sexual partners. Overall, sexually abused adolescents with a supportive family had fewer recent partners than those from a less supportive family environment; family context had less influence on number of partners among respondents with no history of sexual abuse.