Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia.... more Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia. A prominent feature of Alzheimer's disease (AD) is a progressive decline in language. We investigated if subtle anomalies in EEG activity of MCI patients during a word comprehension task could provide insight into the likelihood of conversion to AD. We studied 25 amnestic MCI patients, a subset of whom developed AD within 3-years, and 11 elderly controls. In the task, auditory category descriptions (e.g., 'a type of wood') were followed by a single visual target word either semantically congruent (i.e., oak) or incongruent with the preceding category. We found that the MCI convertors group (i.e. patients that would go on to convert to AD in 3-years) had a diminished early posterior-parietal theta (3-5 Hz) activity induced by first presentation of the target word (i.e., access to lexico-syntactic properties of the word), compared to MCI non-convertors and controls. Moreover, ...
Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syn... more Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory “oddball” task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection....
Cognitive event-related brain potential (ERP) studies of decision-making and attention, language,... more Cognitive event-related brain potential (ERP) studies of decision-making and attention, language, and memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are reviewed. Circumscribed lesions of the medial temporal lobe (MTL), as may be the case in individuals with amnestic MCI, generally produce altered plasticity of the late positive P600 component, with relative sparing of earlier sensory ERP components. However, as the neuropathology of AD extends to neocortical association areas, abnormalities of the P300 and N400 (and perhaps even P50) become more common. Critically, ERP studies of individuals at risk for AD may reveal neurophysiological changes prior to clinical deficits, which could advance the early detection and diagnosis of "presymptomatic AD".
ObjectiveTo investigate the nature of cognitive impairments and underlying brain mechanisms in ol... more ObjectiveTo investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X‐associated tremor/ataxia syndrome (FXTAS).MethodsExtensive neuropsychological testing and cognitive event‐related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years).ResultsBoth premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2017
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry... more Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the APOE ɛ4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10(-6)). Our findings highlight...
Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder caused by FMR1 ... more Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder caused by FMR1 gene premutations, typically associated with frontal-subcortical type cognitive impairments. High prevalence (~50%) of superimposed Alzheimer׳s pathology has been reported in FMR1 premutation carriers, and standardized neuropsychological tests have not yielded any robust discriminators between FXTAS and Alzheimer׳s disease (AD) dementia. The similarities/differences in memory processes between FXTAS and early AD remain underexplored. 32-channel event-related potentials (ERPs) were obtained from a semantic judgment task in which semantically congruous (50%) and incongruous pairs repeat pseudorandomly. The N400 and late positive component (LPC) of 25 FXTAS patients (M(age)=71.2, MMSE=26.6) were compared to a matched group of 25 patients with MCI or early AD (1 mild AD dementia, 24 amnestic MCI, of whom 18 later converted to AD; M(age)=73.4, MMSE=26.4), and 25 healthy elderly. Both patient ...
Journal of the International Neuropsychological Society, 2000
Individuals given a series of words to memorize normally show better immediate recall for items f... more Individuals given a series of words to memorize normally show better immediate recall for items from the beginning and end of the list than for midlist items. This phenomenon, known as the serial position effect, is thought to reflect the concurrent contributions of secondary and primary memory, respectively, to recall performance. The present study compared the serial position effects produced on Trial 1 of the California Verbal Learning Test (CVLT) in mildly demented (N = 25; M MMSE = 20.0) and very mildly demented (N = 25; M MMSE = 25.5) patients with Alzheimer's disease (AD), and age- and education-matched normal control (NC) participants (N = 50). In addition, the serial position effects of the very mildly demented AD patients were compared to those of patients with a transient, circumscribed amnesia arising from a prescribed series of electroconvulsive therapy (ECT) treatments for the relief of depressive illness (N = 11). While the NC group exhibited the typical serial po...
Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia.... more Only a subset of mild cognitive impairment (MCI) patients progress to develop a form of dementia. A prominent feature of Alzheimer's disease (AD) is a progressive decline in language. We investigated if subtle anomalies in EEG activity of MCI patients during a word comprehension task could provide insight into the likelihood of conversion to AD. We studied 25 amnestic MCI patients, a subset of whom developed AD within 3-years, and 11 elderly controls. In the task, auditory category descriptions (e.g., 'a type of wood') were followed by a single visual target word either semantically congruent (i.e., oak) or incongruent with the preceding category. We found that the MCI convertors group (i.e. patients that would go on to convert to AD in 3-years) had a diminished early posterior-parietal theta (3-5 Hz) activity induced by first presentation of the target word (i.e., access to lexico-syntactic properties of the word), compared to MCI non-convertors and controls. Moreover, ...
Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syn... more Progressive cognitive deficits are common in patients with fragile X-associated tremor/ataxia syndrome (FXTAS), with no targeted treatment yet established. In this substudy of the first randomized controlled trial for FXTAS, we examined the effects of NMDA antagonist memantine on attention and working memory. Data were analyzed for patients (24 in each arm) who completed both the primary memantine trial and two EEG recordings (at baseline and follow-up) using an auditory “oddball” task. Results demonstrated significantly improved attention/working memory performance after one year only for the memantine group. The event-related potential P2 amplitude elicited by non-targets was significantly enhanced in the treated group, indicating memantine-associated improvement in attentional processes at the stimulus identification/discrimination level. P2 amplitude increase was positively correlated with improvement on the behavioral measure of attention/working memory during target detection....
Cognitive event-related brain potential (ERP) studies of decision-making and attention, language,... more Cognitive event-related brain potential (ERP) studies of decision-making and attention, language, and memory impairments in Alzheimer's disease (AD) and mild cognitive impairment (MCI) are reviewed. Circumscribed lesions of the medial temporal lobe (MTL), as may be the case in individuals with amnestic MCI, generally produce altered plasticity of the late positive P600 component, with relative sparing of earlier sensory ERP components. However, as the neuropathology of AD extends to neocortical association areas, abnormalities of the P300 and N400 (and perhaps even P50) become more common. Critically, ERP studies of individuals at risk for AD may reveal neurophysiological changes prior to clinical deficits, which could advance the early detection and diagnosis of "presymptomatic AD".
ObjectiveTo investigate the nature of cognitive impairments and underlying brain mechanisms in ol... more ObjectiveTo investigate the nature of cognitive impairments and underlying brain mechanisms in older female fragile X premutation carriers with and without fragile X‐associated tremor/ataxia syndrome (FXTAS).MethodsExtensive neuropsychological testing and cognitive event‐related brain potentials (ERPs; particularly, the auditory P300) were examined in 84 female participants: 33 fragile X premutation carriers with FXTAS (mean age = 62.8 years), 25 premutation carriers without FXTAS (mean age = 55.4 years), and 26 normal healthy controls (mean age = 59.3 years).ResultsBoth premutation groups exhibited executive dysfunction on the Behavioral Dyscontrol Scale, with subtle impairments in inhibition and performance monitoring in female carriers without FXTAS, and more substantial deficits in FXTAS women. However, the female carrier group without FXTAS showed more pronounced deficiencies in working memory. Abnormal ERPs were recorded over the frontal lobes, where FXTAS patients showed both...
Alzheimer's & dementia : the journal of the Alzheimer's Association, Jan 6, 2017
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry... more Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the APOE ɛ4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10(-6)). Our findings highlight...
Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder caused by FMR1 ... more Fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder caused by FMR1 gene premutations, typically associated with frontal-subcortical type cognitive impairments. High prevalence (~50%) of superimposed Alzheimer׳s pathology has been reported in FMR1 premutation carriers, and standardized neuropsychological tests have not yielded any robust discriminators between FXTAS and Alzheimer׳s disease (AD) dementia. The similarities/differences in memory processes between FXTAS and early AD remain underexplored. 32-channel event-related potentials (ERPs) were obtained from a semantic judgment task in which semantically congruous (50%) and incongruous pairs repeat pseudorandomly. The N400 and late positive component (LPC) of 25 FXTAS patients (M(age)=71.2, MMSE=26.6) were compared to a matched group of 25 patients with MCI or early AD (1 mild AD dementia, 24 amnestic MCI, of whom 18 later converted to AD; M(age)=73.4, MMSE=26.4), and 25 healthy elderly. Both patient ...
Journal of the International Neuropsychological Society, 2000
Individuals given a series of words to memorize normally show better immediate recall for items f... more Individuals given a series of words to memorize normally show better immediate recall for items from the beginning and end of the list than for midlist items. This phenomenon, known as the serial position effect, is thought to reflect the concurrent contributions of secondary and primary memory, respectively, to recall performance. The present study compared the serial position effects produced on Trial 1 of the California Verbal Learning Test (CVLT) in mildly demented (N = 25; M MMSE = 20.0) and very mildly demented (N = 25; M MMSE = 25.5) patients with Alzheimer's disease (AD), and age- and education-matched normal control (NC) participants (N = 50). In addition, the serial position effects of the very mildly demented AD patients were compared to those of patients with a transient, circumscribed amnesia arising from a prescribed series of electroconvulsive therapy (ECT) treatments for the relief of depressive illness (N = 11). While the NC group exhibited the typical serial po...
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