Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until ... more Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60 year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.
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....
Objective: We describe 3 carriers of the FMR1 premutation with the Fragile X-associated Tremor At... more Objective: We describe 3 carriers of the FMR1 premutation with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) whose tremor was significantly improved by bilateral Deep Brain Stimulation (DBS) to Ventral Intermediate nucleus (Vim) of the thalamus. Background: FXTAS is a recently described neurodegenerative disorder caused by CGG expansions of the FMR1 gene within the premutation range (55 to 200 CGG repeats). Individuals with FXTAS typically develop an intention tremor followed by gait ataxia within two years. Vim DBS has been shown to effectively treat tremor in a variety of disorders, including Parkinson's disease and essential tremor. Design/Methods/Results: Three men ages 62, 59 and 70 with FXTAS were treated surgically with bilateral Vim DBS. All patients experienced a significantly beneficial effect on tremor. Ataxia improved in case 1 and temporarily in case 2, but worsened in case 3. All patients experienced mild worsening of dysarthria, although the patients and their families unanimously felt there was a worthwhile benefit overall. Conclusions: These cases provided first hand evidence that bilateral Vim DBS effectively manages tremor in selected patients with FXTAS. DBS may prove to be a viable therapeutic option for treating tremor and/or ataxia with or without other medical therapeutics in patients with FXTAS.
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".
Background-Parkinsonian features have been used as a minor diagnostic criterion for fragile X-ass... more Background-Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures. Methods-Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). Results-The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor. Interpretation-Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and
Objective: We sought cognitive event-related potential (ERP) biomarkers of disease progression an... more Objective: We sought cognitive event-related potential (ERP) biomarkers of disease progression and subsequent conversion to dementia in mild cognitive impairment (MCI). Background: Two ERP components, the P600 and N400, are sensitive to abnormal episodic/ declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a widespread failure of synaptic plasticity. Methods: Patients with amnestic MCI (n ϭ 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-toAD converters (within 3 years) vs nonconverters, using split-plot analyses of variance. Results: A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F ϭ 9.9, p ϭ 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood. Conclusions: Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.
Journal of Neurology, Neurosurgery & Psychiatry, 2002
Background: It has been reported that patients with amnesia have a reduced effect of word repetit... more Background: It has been reported that patients with amnesia have a reduced effect of word repetition upon the late positive component of the event related potential (ERP), which peaks at around 600 ms after word onset. Objective: To study a word repetition ERP paradigm in subjects with mild cognitive impairment. Subjects: 14 patients with mild cognitive impairment (mean mini-mental state examination score = 27); 14 normal elderly controls. Methods: Auditory category statements were each followed by a single visual target word (50% "congruous" category exemplars, 50% "incongruous") while ERPs were recorded. N400 (an ERP component elicited by semantically "incongruous" words) and LPC amplitude data were submitted to analysis of variance. Results: The latency of the N400 was slower in mild cognitive impairment. In normal controls, the ERPs to "congruous" targets showed a late positive component to new words, which was greatly diminished with repetition. This repetition effect in normal subjects started before 300 ms at right frontal sites, and peaked at ∼600 ms post-stimulus over posterior sites. In contrast, the group with mild cognitive impairment had a reduced repetition effect (p < 0.02), which started around 500 ms, with a more central distribution. Further comparisons within the cognitive impairment group showed no appreciable congruous word repetition effect among seven individuals who subsequently converted to probable Alzheimer's disease. The congruous word repetition effect in the group with mild cognitive impairment was almost entirely accounted for by the non-converters. The amplitude of the congruous late positive component word repetition effect was significantly correlated (0.38 < r < 0.73) with several verbal memory measures. Conclusions: The congruous word repetition ERP effect appears sensitive to the memory impairment in mild cognitive impairment and could have value in predicting incipient Alzheimer's disease.
We sought cognitive event-related potential (ERP) biomarkers of "Preclinical Alzheimer's disease"... more We sought cognitive event-related potential (ERP) biomarkers of "Preclinical Alzheimer's disease" (Pre-AD) using an incidental verbal learning paradigm with high sensitivity to prodromal AD. Seven elderly persons, with normal cognition at the time of ERP recordings, but who showed subsequent cognitive decline or AD pathology at autopsy (n=5, mean Braak stage=2.8), were compared to 12 "robust" normal elderly (RNE) who remained cognitively normal (M follow-up =9.0 years). EEG was recorded during a word repetition paradigm (semantically congruous (50%) and incongruous target words repeat ~10-140 seconds later). The RNE P600 congruous word repetition ERP effects (New minus Old congruous words) were significantly larger than in Pre-AD (mean amplitudes = 3.28 vs. 0.10 µV, p= 0.04). High group discrimination (84%) was achieved (by a P600 amplitude cutoff of ~1.5 µV). Abnormal P600 word repetition effects in cognitively normal elderly persons may be an important sign of synaptic dysfunction and Preclinical AD.
Objective-We hypothesized that an ERP word repetition paradigm, which reliably elicits and modula... more Objective-We hypothesized that an ERP word repetition paradigm, which reliably elicits and modulates the P600 and N400 components, would be particularly sensitive to the memory deficits and altered synaptic plasticity in mild Alzheimer's disease (AD). The P600 (a late positive component, or 'LPC'), and the N400, are sensitive indices of memory encoding and semantic processing, respectively. Methods-We studied 11 patients with mild AD (mean MMSE = 22.9) and 11 elderly (mean age = 77.1) normal controls (NC) on a paradigm in which semantically 'congruous' category statement/ exemplar pairs (50%) and 'incongruous' category statement/non-exemplar pairs (50%) repeat at 10-140 s intervals. A minimum of 19 channels ERP data were recorded and submitted to split-plot ANOVAs. Results-Normal ERP data showed: (1) a significant word repetition effect for congruous words, with a widespread late positivity between ~300 and 800 ms post-stimulus (P600) that is larger for New than Old words; (2) a significant N400 repetition effect for incongruous words, with a right posterior negativity that is reduced for Old relative to New words. By contrast, neither of these word repetition effects was reliably present in the mild AD group. Good group discrimination was achieved by requiring that both these repetition effects were ≥ the 10th percentile, with 100% sensitivity and 82% specificity. Conclusions-We found significant abnormalities of the N400 and P600 in mild AD, with both potentials showing markedly reduced sensitivity to word repetition. Significance-The absence of normal N400 and LPC/P600 word repetition effects suggests impaired functioning of their neural generators, several of which are located in medial temporal lobe predilection sites (e.g. anterior fusiform, parahippocampal gyrus, hippocampus) for AD/tau pathology.
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...
Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), ... more Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.
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 ...
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorde... more The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation-both female and male-demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.
This study examined trajectories of cognitive change in psychometrically matched measures of epis... more This study examined trajectories of cognitive change in psychometrically matched measures of episodic memory, semantic memory, and executive function in an ethnically, demographically, and cognitively diverse sample of older persons. Individual rates of change showed considerable heterogeneity in each domain. Baseline clinical diagnosis predicted differential change in semantic memory and executive function (dementia > mild cognitive impairment (MCI) > normal), but average decline in verbal episodic memory was similar across all three diagnostic groups. There was substantial overlap of distributions of cognitive change across baseline diagnostic groups for all three measures. Cognitive change was strongly related to change in clinical diagnosis. Rapid and similar change was present for all three cognitive measures in demented cases and in normals and cases with MCI who progressed clinically. In cognitively normal cases, verbal episodic memory change was greater than change in the other two domains. Global status, measured by the Clinical Dementia Rating scale, predicted change in semantic memory and executive function, while ApoE genotype predicted change in verbal episodic memory, and age had no effect on rates of change in any domain independent of global status and ApoE. Results show important limitations in using cross sectional diagnosis to predict prognosis, and suggest that research to identify robust predictors of cognitive change across the full spectrum from normal to dementia is needed for better early identification of diseases causing progressive decline. Keywords Cognitive change; diagnosis; dementia; mild cognitive impairment; normal cognition; aging Trajectories of change in cognitive function in later adult life are heterogeneous. There are robust individual differences in cognitive functioning throughout adulthood and this heterogeneity is compounded by different courses of cognitive change that emerge as people age. Longitudinal studies of older individuals reveal widely different rates of cognitive decline, as well as stable function and even modest improvement in many cases (
Background-Trajectories of cognitive decline among elderly individuals are heterogeneous, and mar... more Background-Trajectories of cognitive decline among elderly individuals are heterogeneous, and markers that have high reliability for predicting cognitive trajectories across a broad spectrum of the elderly population have yet to be identified. Method-This study examined the utility of a variety of MRI-based brain measures, obtained at baseline, as predictors of subsequent declines in domain-specific measures of cognitive function in a cohort of 307 community-dwelling elderly individuals with varying degrees of cognitive impairment who were diverse across a number of relevant demographic variables and were evaluated yearly. Psychometrically matched measures of cognition were used to assess episodic memory, semantic memory, and executive function. Relationships between baseline MRI measures, including the volumes of the brain, hippocampus, and white matter hyperintensities (WMH), and cognitive trajectories were assessed in mixed effects regression models that modeled MRI effects on cognitive performance at baseline and rate of change as well as inter-individual variability in cognitive baseline and rate of change. Results-Greater baseline brain volume predicted slower subsequent rate of decline in episodic memory and smaller WMH volume predicted slower subsequent rate of decline in executive function and semantic memory. Baseline hippocampal volume, while strongly related to baseline cognitive function, was not predictive of subsequent change in any of the cognitive domains.
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...
Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until ... more Women with fragile X mental retardation (FMR1) gene premutations (55-200 CGG repeats) were until recently believed to be unaffected. It is now known that up to 8% of older female FMR1 premutation carriers develop fragile X-associated tremor/ataxia syndrome (FXTAS). Female carriers may also develop primary ovarian insufficiency, thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. We present a 60 year-old woman with FMR1 premutation who had depression, anxiety, and conversion disorder with seizures. The FMR1 premutation with its associated mRNA toxicity is postulated as an underlying neurobiological mechanism of conversion symptoms, through functional and structural neural dysconnectivity.
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....
Objective: We describe 3 carriers of the FMR1 premutation with the Fragile X-associated Tremor At... more Objective: We describe 3 carriers of the FMR1 premutation with the Fragile X-associated Tremor Ataxia Syndrome (FXTAS) whose tremor was significantly improved by bilateral Deep Brain Stimulation (DBS) to Ventral Intermediate nucleus (Vim) of the thalamus. Background: FXTAS is a recently described neurodegenerative disorder caused by CGG expansions of the FMR1 gene within the premutation range (55 to 200 CGG repeats). Individuals with FXTAS typically develop an intention tremor followed by gait ataxia within two years. Vim DBS has been shown to effectively treat tremor in a variety of disorders, including Parkinson's disease and essential tremor. Design/Methods/Results: Three men ages 62, 59 and 70 with FXTAS were treated surgically with bilateral Vim DBS. All patients experienced a significantly beneficial effect on tremor. Ataxia improved in case 1 and temporarily in case 2, but worsened in case 3. All patients experienced mild worsening of dysarthria, although the patients and their families unanimously felt there was a worthwhile benefit overall. Conclusions: These cases provided first hand evidence that bilateral Vim DBS effectively manages tremor in selected patients with FXTAS. DBS may prove to be a viable therapeutic option for treating tremor and/or ataxia with or without other medical therapeutics in patients with FXTAS.
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".
Background-Parkinsonian features have been used as a minor diagnostic criterion for fragile X-ass... more Background-Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures. Methods-Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). Results-The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor. Interpretation-Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and
Objective: We sought cognitive event-related potential (ERP) biomarkers of disease progression an... more Objective: We sought cognitive event-related potential (ERP) biomarkers of disease progression and subsequent conversion to dementia in mild cognitive impairment (MCI). Background: Two ERP components, the P600 and N400, are sensitive to abnormal episodic/ declarative memory and semantic processing. When congruous category-exemplars are repeated, smaller P600s (relative to initial presentation) are normally elicited. Repetitions of semantically incongruous words yield smaller N400 amplitude. In mild Alzheimer disease (AD), abnormalities of both the N400 and P600 repetition effects are present, suggesting a widespread failure of synaptic plasticity. Methods: Patients with amnestic MCI (n ϭ 32) were longitudinally studied annually with an ERP paradigm in which semantically congruous (50%) and incongruous target words are repeated 10 to 140 seconds after initial presentation. ERP data were analyzed to contrast MCI-toAD converters (within 3 years) vs nonconverters, using split-plot analyses of variance. Results: A statistically significant P600 congruous word repetition effect was found only in the nonconverter group (F ϭ 9.9, p ϭ 0.005 vs MCI converters). This effect correlated with verbal memory measures. Repetition of incongruous words produced a significant N400 amplitude attenuation (across right-hemisphere sites) in nonconverters, but not in converters. Patients with MCI with abnormal/reduced N400 or P600 word repetition effects had an 87 to 88% likelihood of dementia within 3 years while those with normal/spared N400 and P600 repetition effects had only an 11 to 27% likelihood. Conclusions: Abnormalities of the P600 or N400 in mild cognitive impairment are associated with an increased risk of subsequent conversion to Alzheimer disease (AD). These event-related potential components may offer useful biomarkers for the detection and staging of very early AD.
Journal of Neurology, Neurosurgery & Psychiatry, 2002
Background: It has been reported that patients with amnesia have a reduced effect of word repetit... more Background: It has been reported that patients with amnesia have a reduced effect of word repetition upon the late positive component of the event related potential (ERP), which peaks at around 600 ms after word onset. Objective: To study a word repetition ERP paradigm in subjects with mild cognitive impairment. Subjects: 14 patients with mild cognitive impairment (mean mini-mental state examination score = 27); 14 normal elderly controls. Methods: Auditory category statements were each followed by a single visual target word (50% "congruous" category exemplars, 50% "incongruous") while ERPs were recorded. N400 (an ERP component elicited by semantically "incongruous" words) and LPC amplitude data were submitted to analysis of variance. Results: The latency of the N400 was slower in mild cognitive impairment. In normal controls, the ERPs to "congruous" targets showed a late positive component to new words, which was greatly diminished with repetition. This repetition effect in normal subjects started before 300 ms at right frontal sites, and peaked at ∼600 ms post-stimulus over posterior sites. In contrast, the group with mild cognitive impairment had a reduced repetition effect (p < 0.02), which started around 500 ms, with a more central distribution. Further comparisons within the cognitive impairment group showed no appreciable congruous word repetition effect among seven individuals who subsequently converted to probable Alzheimer's disease. The congruous word repetition effect in the group with mild cognitive impairment was almost entirely accounted for by the non-converters. The amplitude of the congruous late positive component word repetition effect was significantly correlated (0.38 < r < 0.73) with several verbal memory measures. Conclusions: The congruous word repetition ERP effect appears sensitive to the memory impairment in mild cognitive impairment and could have value in predicting incipient Alzheimer's disease.
We sought cognitive event-related potential (ERP) biomarkers of "Preclinical Alzheimer's disease"... more We sought cognitive event-related potential (ERP) biomarkers of "Preclinical Alzheimer's disease" (Pre-AD) using an incidental verbal learning paradigm with high sensitivity to prodromal AD. Seven elderly persons, with normal cognition at the time of ERP recordings, but who showed subsequent cognitive decline or AD pathology at autopsy (n=5, mean Braak stage=2.8), were compared to 12 "robust" normal elderly (RNE) who remained cognitively normal (M follow-up =9.0 years). EEG was recorded during a word repetition paradigm (semantically congruous (50%) and incongruous target words repeat ~10-140 seconds later). The RNE P600 congruous word repetition ERP effects (New minus Old congruous words) were significantly larger than in Pre-AD (mean amplitudes = 3.28 vs. 0.10 µV, p= 0.04). High group discrimination (84%) was achieved (by a P600 amplitude cutoff of ~1.5 µV). Abnormal P600 word repetition effects in cognitively normal elderly persons may be an important sign of synaptic dysfunction and Preclinical AD.
Objective-We hypothesized that an ERP word repetition paradigm, which reliably elicits and modula... more Objective-We hypothesized that an ERP word repetition paradigm, which reliably elicits and modulates the P600 and N400 components, would be particularly sensitive to the memory deficits and altered synaptic plasticity in mild Alzheimer's disease (AD). The P600 (a late positive component, or 'LPC'), and the N400, are sensitive indices of memory encoding and semantic processing, respectively. Methods-We studied 11 patients with mild AD (mean MMSE = 22.9) and 11 elderly (mean age = 77.1) normal controls (NC) on a paradigm in which semantically 'congruous' category statement/ exemplar pairs (50%) and 'incongruous' category statement/non-exemplar pairs (50%) repeat at 10-140 s intervals. A minimum of 19 channels ERP data were recorded and submitted to split-plot ANOVAs. Results-Normal ERP data showed: (1) a significant word repetition effect for congruous words, with a widespread late positivity between ~300 and 800 ms post-stimulus (P600) that is larger for New than Old words; (2) a significant N400 repetition effect for incongruous words, with a right posterior negativity that is reduced for Old relative to New words. By contrast, neither of these word repetition effects was reliably present in the mild AD group. Good group discrimination was achieved by requiring that both these repetition effects were ≥ the 10th percentile, with 100% sensitivity and 82% specificity. Conclusions-We found significant abnormalities of the N400 and P600 in mild AD, with both potentials showing markedly reduced sensitivity to word repetition. Significance-The absence of normal N400 and LPC/P600 word repetition effects suggests impaired functioning of their neural generators, several of which are located in medial temporal lobe predilection sites (e.g. anterior fusiform, parahippocampal gyrus, hippocampus) for AD/tau pathology.
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...
Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), ... more Older FMR1 premutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder manifesting cognitive deficits that often subsequently progress to dementia. To date, there is no specific treatment available for FXTAS. Studies have demonstrated the premutation-associated overactivation of glutamatergic receptors in neurons. Memantine, a NMDA receptor antagonist approved for treatment of Alzheimer's disease, thus was tested in the first placebo-controlled, double-blind, randomized clinical trial in FXTAS. Prior event-related brain potential (ERP) studies in FXTAS found reduced N400 repetition effect, a glutamate-related electrophysiological marker of semantic priming, and verbal memory processes. This substudy of the randomized clinical trial of memantine in FXTAS sought to use the N400 repetition effect to evaluate effects of chronic memantine treatment on verbal memory. Subsequent recall and recognition memory tests for the experimental stimuli were administered to characterize verbal memory. Data from 41 patients who completed the 1-year memantine trial (21 on memantine) and also completed longitudinal ERP studies were analyzed. Results showed treatment-associated benefits on both cued-recall memory and N400 repetition effect amplitude. Importantly, improvement in cued recall was positively correlated with amplitude increase of the N400 repetition effect. The placebo group, in contrast, displayed a significant reduction of the N400 repetition effect after 1 year. These results suggest that memantine treatment may have beneficial effects on verbal memory in FXTAS. Additional studies of memantine, perhaps in combination with other therapeutic agents, appear warranted, as symptomatic treatments and neuroprotective treatments are both needed for this recently recognized neurodegenerative disorder.
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 ...
The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorde... more The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation-both female and male-demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.
This study examined trajectories of cognitive change in psychometrically matched measures of epis... more This study examined trajectories of cognitive change in psychometrically matched measures of episodic memory, semantic memory, and executive function in an ethnically, demographically, and cognitively diverse sample of older persons. Individual rates of change showed considerable heterogeneity in each domain. Baseline clinical diagnosis predicted differential change in semantic memory and executive function (dementia > mild cognitive impairment (MCI) > normal), but average decline in verbal episodic memory was similar across all three diagnostic groups. There was substantial overlap of distributions of cognitive change across baseline diagnostic groups for all three measures. Cognitive change was strongly related to change in clinical diagnosis. Rapid and similar change was present for all three cognitive measures in demented cases and in normals and cases with MCI who progressed clinically. In cognitively normal cases, verbal episodic memory change was greater than change in the other two domains. Global status, measured by the Clinical Dementia Rating scale, predicted change in semantic memory and executive function, while ApoE genotype predicted change in verbal episodic memory, and age had no effect on rates of change in any domain independent of global status and ApoE. Results show important limitations in using cross sectional diagnosis to predict prognosis, and suggest that research to identify robust predictors of cognitive change across the full spectrum from normal to dementia is needed for better early identification of diseases causing progressive decline. Keywords Cognitive change; diagnosis; dementia; mild cognitive impairment; normal cognition; aging Trajectories of change in cognitive function in later adult life are heterogeneous. There are robust individual differences in cognitive functioning throughout adulthood and this heterogeneity is compounded by different courses of cognitive change that emerge as people age. Longitudinal studies of older individuals reveal widely different rates of cognitive decline, as well as stable function and even modest improvement in many cases (
Background-Trajectories of cognitive decline among elderly individuals are heterogeneous, and mar... more Background-Trajectories of cognitive decline among elderly individuals are heterogeneous, and markers that have high reliability for predicting cognitive trajectories across a broad spectrum of the elderly population have yet to be identified. Method-This study examined the utility of a variety of MRI-based brain measures, obtained at baseline, as predictors of subsequent declines in domain-specific measures of cognitive function in a cohort of 307 community-dwelling elderly individuals with varying degrees of cognitive impairment who were diverse across a number of relevant demographic variables and were evaluated yearly. Psychometrically matched measures of cognition were used to assess episodic memory, semantic memory, and executive function. Relationships between baseline MRI measures, including the volumes of the brain, hippocampus, and white matter hyperintensities (WMH), and cognitive trajectories were assessed in mixed effects regression models that modeled MRI effects on cognitive performance at baseline and rate of change as well as inter-individual variability in cognitive baseline and rate of change. Results-Greater baseline brain volume predicted slower subsequent rate of decline in episodic memory and smaller WMH volume predicted slower subsequent rate of decline in executive function and semantic memory. Baseline hippocampal volume, while strongly related to baseline cognitive function, was not predictive of subsequent change in any of the cognitive domains.
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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Papers by John Olichney