The authors examine the differences in outcome between black and white patients receiving ECT as a part of the CORE multi-site study.
A total of 624 patients were enrolled in an NIMH-funded, randomized controlled ECT trial comparing the efficacy of continuation ECT versus continuation pharmacotherapy between 1997 and 2004. This analysis focuses on the 32 black and 483 white patients who participated in phase I of the study. The authors compared baseline demographic and clinical variables, and acute outcomes of these two groups.
Compared to whites, far fewer blacks participated in the study. Those who did were less likely to have failed adequate medication trials and were more likely to have psychotic features. Their initial HAMD24 scores were higher than whites, and they showed a greater reduction in these HAMD24 scores by the end of the treatment period. While sample size limited the statistical significance of the findings, black patients also showed a higher rate of remission after an acute phase of ECT.
This study found that black and white patients with major depressive disorder had comparable outcomes. We also found that fewer black patients received ECT than whites, a difference that has been reported in other samples.
Electroconvulsive therapy; ECT; race; depression; CORE; outcome
Maintaining and improving quality of life has become a major focus in geriatric medicine, but the oldest old have received limited attention in clinical investigations. We aimed to investigate the relationship between self-perceived and caregiver-perceived quality of life (QOL), cognitive functioning, and depressive symptoms in the oldest old.
This IRB-approved prospective study recruited community dwellers aged 90–99 years old. Collected data included neurological evaluation, DSM III-R criteria for dementia, Mini-Mental State Examination (MMSE), Dementia Rating Scale (DRS), Geriatric Depression Scale (GDS), Record of Independent Living (ROIL), and QOL assessment using the Linear Analogue Self Assessment (LASA).
Data on 144 subjects (56 cognitively normal (normal), 13 mild cognitive impairment (MCI), 41 dementia (DEM), 34 dementia with stroke and parkinsonism (DEMSP)) over a three-year period were analyzed. Mean ages ranged from 93 to 94 years, and the majority were female with at least high school education. Overall functional ability was higher in groups without dementia (p < 0.0001). All subjects reported high overall QOL (range 6.76–8.3 out of 10), regardless of cognitive functioning. However, caregivers perceived the subjects’ overall QOL to be lower with increasing severity of cognitive impairment (p < 0.0001). Lower GDS scores correlate with higher self-perceived overall QOL (ρ = −0.38, p < 0.0001).
In our community sample of the oldest old, there was a fairly high level of overall QOL, whether or not cognitive impairment exists. Individuals perceive their QOL better than caregivers do, and the difference in subjects’ and caregivers’ perception is more pronounced for the groups with dementia. QOL is more strongly correlated with depressive symptoms than with dementia severity.
geriatric; well being; cognition; depression; dementia; stroke; parkinsonism; MCI
To examine alternative models of defining and characterizing successful aging.
A retrospective cohort study
Olmsted County, MN.
560 community-dwelling non-demented adults, aged 65 years and older.
Three models were developed. Each model examined subtests in four cognitive domains: memory, attention/executive function, language, and visual-spatial skills. A composite domain score was generated for each of the four domains. In Model 1, a global z-score was further generated from the four cognitive domains, and subjects with mean global z-score in the top 10% were classified as “successful agers” whereas those in the remaining 90% were classified as “typical agers”. In Model 2, subjects with all 4 domain scores above the 50th percentile were classified as “successful agers.” In Model 3, a primary neuropsychological variable was selected from each domain, and subjects whose score remained above minus 1 SD compared to norms for young adults were labeled successful agers. Validation tests were conducted to determine the ability of each model to predict survival and conversion to mild cognitive impairment (MCI).
Model 1 showed 65% lower mortality in successful agers compared to typical agers, and also a 25% lower conversion rate to MCI.
Model 1 was most strongly associated with longevity and cognitive decline; as such, it can be useful in investigating various predictors of successful aging, including plasma level, APOE genotype, and neuroimaging measurements.
successful aging; optimal aging; longevity; cognitive decline
The clinical features of dementia with Lewy bodies (DLB) during wakefulness are well known. Other than REM sleep behavior disorder (RBD), only limited data exists on other sleep disturbances and disorders in DLB. We sought to characterize the polysomnographic (PSG) findings in a series of DLB patients with sleep-related complaints.
Retrospective study of patients with DLB who underwent clinical PSG at Mayo Clinic Rochester or Mayo Clinic Jacksonville over an almost 11 year span for evaluation of dream enactment behavior, excessive nocturnal movements, sleep apnea, hypersomnolence, or insomnia. The following variables were analyzed: respiratory disturbance index (RDI) in disordered breathing events/hour, periodic limb movement arousal index (PLMAI), arousals for no apparent reason (AFNAR), total arousal index (TAI), presence of REM sleep without atonia (RSWA), and percent sleep efficiency (SE).
Data on 78 patients (71M, 7F) were analyzed. The mean age was 71 ± 8 years. Seventy-five (96%) patients had histories of recurrent dream enactment during sleep with 83% showing confirmation of RSWA +/- dream enactment during PSG. Mean RDI = 11.9 ± 5.8, PLMAI = 5.9 ± 8.5, AFNARI = 10.7 ± 12.0, and TAI = 26.6 ± 17.4. SE was <80% in 72% of the sample, <70% in 49%, and <60% in 24%. In patients who did not show evidence of significant disordered breathing (23 with RDI<5), 62% of arousals were AFNARs. In those patients who had significant disordered breathing (55 with RDI ≥ 5), 36% of arousals were AFNARs. Six patients underwent evaluations with PSG plus MSLT. Two patients had mean initial sleep latencies less than five minutes, and both had RDI<5. No patient had any sleep onset rapid eye movement periods. Nineteen patients have undergone neuropathologic examination, and 18 have had limbic- or neocortical-predominant Lewy body pathology. One had progressive supranuclear palsy, but no REM sleep was recorded in prior PSG.
In patients with DLB and sleep-related complaints, several sleep disturbances in addition to RBD are frequently present. In this sample, about three quarters had a significant number of arousals not accounted for by a movement or breathing disturbance, and the primary sleep disorders do not appear to entirely account for the poor sleep efficiency in DLB, especially in those without a significant breathing disorder. Further studies are warranted to better understand the relationship between disturbed sleep, arousal and DLB; such characterization may provide insights into potential avenues of treatment of symptoms which could impact quality of life.
Sleep disorders; REM sleep behavior disorder; dementia with Lewy bodies; synucleinopathy
Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia after Alzheimer's disease (AD). Our objective was to determine whether the 11C–Pittsburgh Compound-B (PiB) retention and regional hypometabolism on PET and regional cortical atrophy on MRI are complementary in characterizing patients with DLB and differentiating them from AD. We studied age, gender and education matched patients with a clinical diagnosis of DLB (n=21), AD (n=21), and cognitively normal subjects (n=42). Hippocampal atrophy, global cortical PiB retention and occipital lobe metabolism in combination distinguished DLB from AD better than any of the measurements alone (area under the receiver operating characteristic=0.98).Five of the DLB and AD patients who underwent autopsy were distinguished through multimodality imaging. These data demonstrate that MRI and PiB PET contribute to characterizing the distinct pathological mechanisms in patients with AD compared to DLB. Occipital and posterior parietotemporal lobe hypometabolism is a distinguishing feature of DLB and this regional hypometabolic pattern is independent of the amyloid pathology.
Dementia with Lewy bodies; MRI; PET; FDG; PiB; Alzheimer's disease
To determine the association between the focal atrophy measures on antemortem MRI and postmortem neuropathologic classification of dementia with Lewy bodies (DLB) using the Third Report of the DLB Consortium criteria.
We retrospectively identified 56 subjects who underwent antemortem MRI and had Lewy body (LB) pathology at autopsy. Subjects were pathologically classified as high (n = 25), intermediate (n = 22), and low likelihood DLB (n = 9) according to the Third Report of the DLB Consortium criteria. We included 2 additional pathologic comparison groups without LBs: one with low likelihood Alzheimer disease (AD) (control; n = 27) and one with high likelihood AD (n = 33). The associations between MRI-based volumetric measurements and the pathologic classification of DLB were tested with analysis of covariance by adjusting for age, sex, and MRI-to-death interval.
Antemortem hippocampal and amygdalar volumes increased from low to intermediate to high likelihood DLB (p < 0.001, trend test). Smaller hippocampal and amygdalar volumes were associated with higher Braak neurofibrillary tangle stage (p < 0.001). Antemortem dorsal mesopontine gray matter (GM) atrophy was found in those with high likelihood DLB compared with normal control subjects (p = 0.004) and those with AD (p = 0.01). Dorsal mesopontine GM volume decreased from low to intermediate to high likelihood DLB (p = 0.01, trend test).
Antemortem hippocampal and amygdalar volumes increase and dorsal mesopontine GM volumes decrease in patients with low to high likelihood DLB according to the Third Report of the DLB Consortium criteria. Patients with high likelihood DLB typically have normal hippocampal volumes but have atrophy in the dorsal mesopontine GM nuclei.
Acetylcholinesterase inhibitors are commonly used to treat patients with dementia with Lewy bodies. Hippocampal atrophy on magnetic resonance imaging and amyloid-β load on positron emission tomography are associated with the Alzheimer’s disease-related pathology in patients with dementia with Lewy bodies. To date, few studies have investigated imaging markers that predict treatment response in patients with dementia with Lewy bodies. Our objective was to determine whether imaging markers of Alzheimer’s disease-related pathology such as hippocampal volume, brain amyloid-β load on 11C Pittsburgh compound B positron emission tomography predict treatment response to acetylcholinesterase inhibitors in patients with dementia with Lewy bodies. We performed a retrospective analysis on consecutive treatment-naive patients with dementia with Lewy bodies (n = 54) from the Mayo Clinic Alzheimer’s Disease Research Centre who subsequently received acetylcholinesterase inhibitors and underwent magnetic resonance imaging with hippocampal volumetry. Baseline and follow-up assessments were obtained with the Mattis Dementia Rating Scale. Subjects were divided into three groups (reliable improvement, stable or reliable decline) using Dementia Rating Scale reliable change indices determined previously. Associations between hippocampal volumes and treatment response were tested with analysis of covariance adjusting for baseline Dementia Rating Scale, age, gender, magnetic resonance field strength and Dementia Rating Scale interval. Seven subjects underwent 11C Pittsburgh compound B imaging within 12 weeks of magnetic resonance imaging. Global cortical 11C Pittsburgh compound B retention (scaled to cerebellar retention) was calculated in these patients. Using a conservative psychometric method of assessing treatment response, there were 12 patients with reliable decline, 29 stable cases and 13 patients with reliable improvement. The improvers had significantly larger hippocampi than those that declined (P = 0.02) and the stable (P = 0.04) group. An exploratory analysis demonstrated larger grey matter volumes in the temporal and parietal lobes in improvers compared with those who declined (P < 0.05). The two patients who had a positive 11C Pittsburgh compound B positron emission tomography scan declined and those who had a negative 11C Pittsburgh compound B positron emission tomography scan improved or were stable after treatment. Patients with dementia with Lewy bodies who do not have the imaging features of coexistent Alzheimer’s disease-related pathology are more likely to cognitively improve with acetylcholinesterase inhibitor treatment.
dementia with Lewy bodies; acetylcholinesterase inhibitors; MRI; PiB; PET; amyloid
Although electroconvulsive therapy (ECT) has been shown to be extremely effective for the acute treatment of major depression, it has never been systematically assessed as a strategy for relapse prevention.
To evaluate the comparative efficacy of continuation ECT (C-ECT) and the combination of lithium carbonate plus nortriptyline hydrochloride (C-Pharm) in the prevention of depressive relapse.
Multisite, randomized, parallel design, 6-month trial performed from 1997 to 2004.
Five academic medical centers and their outpatient psychiatry clinics.
Two hundred one patients with Structured Clinical Interview for DSM-IV–diagnosed unipolar depression who had remitted with a course of bilateral ECT.
Random assignment to 2 treatment groups receiving either C-ECT (10 treatments) or C-Pharm for 6 months.
Main Outcome Measure
Relapse of depression, compared between the C-ECT and C-Pharm groups.
In the C-ECT group, 37.1% experienced disease relapse, 46.1% continued to have disease remission at the study end, and 16.8% dropped out of the study. In the C-Pharm group, 31.6% experienced disease relapse, 46.3% continued to have disease remission, and 22.1% dropped out of the study. Both Kaplan-Meier and Cox proportional hazards regression analyses indicated no statistically significant differences in overall survival curves and time to relapse for the groups. Mean±SD time to relapse for the C-ECT group was 9.1±7.0 weeks compared with 6.7±4.6 weeks for the C-Pharm group (P=.13). Both groups had relapse proportions significantly lower than a historical placebo control from a similarly designed study.
Both C-ECT and C-Pharm were shown to be superior to a historical placebo control, but both had limited efficacy, with more than half of patients either experiencing disease relapse or dropping out of the study. Even more effective strategies for relapse prevention in mood disorders are urgently needed.
This study assessed the incidence, severity, and course of expressed suicidal intent in depressed patients who were treated with ECT. The data are from the first phase of an ongoing, collaborative multicenter study, the overall aim of which was to compare continuation ECT with pharmacotherapy in the prevention of relapse after a successful course of ECT.
Suicidal intent, as expressed by patients during an interview, was scored at baseline and before each ECT session with item 3 on the 24-item Hamilton Depression Rating Scale in 444 patients with unipolar depression.
One hundred thirty-one patients (29.5%) reported suicidal thoughts and acts (score of 3 or 4) at baseline. Scores decreased to 0 after 1 week (three ECT sessions) in 38.2% of the patients, after 2 weeks (six ECT sessions) in 61.1%, and in 80.9% at the end of the course of treatment.
Expressed suicidal intent in depressed patients was rapidly relieved with ECT. Evidence-based treatment algorithms for major depressive mood disorders should include dichotomization according to suicide risk, as assessed by interview. For patients at risk, ECT should be considered earlier than at its conventional “last resort” position.
Remogliflozin etabonate (RE) is the prodrug of remogliflozin, a selective inhibitor of the renal sodium-dependent glucose transporter 2 (SGLT2), which could increase urine glucose excretion (UGE) and lower plasma glucose in humans.
This double-blind, randomized, placebo-controlled, single-dose, dose-escalation, crossover study is the first human trial designed to evaluate safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of RE. All subjects received single oral doses of either RE or placebo separated by approximately 2 week intervals. In Part A, 10 healthy subjects participated in 5 dosing periods where they received RE (20 mg, 50 mg, 150 mg, 500 mg, or 1000 mg) or placebo (4:1 active to placebo ratio per treatment period). In Part B, 6 subjects with type 2 diabetes mellitus (T2DM) participated in 3 dose periods where they received RE (50 mg and 500 mg) or placebo (2:1 active to placebo per treatment period). The study protocol was registered with the NIH clinical trials data base with identifier NCT01571661.
RE was generally well-tolerated; there were no serious adverse events. In both populations, RE was rapidly absorbed and converted to remogliflozin (time to maximum plasma concentration [Cmax;Tmax] approximately 1 h). Generally, exposure to remogliflozin was proportional to the administered dose. RE was rapidly eliminated (mean T½ of ~25 min; mean plasma T½ for remogliflozin was 120 min) and was independent of dose. All subjects showed dose-dependent increases in 24-hour UGE, which plateaued at approximately 200 to 250 mmol glucose with RE doses ≥150 mg. In T2DM subjects, increased plasma glucose following OGTT was attenuated by RE in a drug-dependent fashion, but there were no clear trends in plasma insulin. There were no apparent effects of treatment on plasma or urine electrolytes.
The results support progression of RE as a potential treatment for T2DM.
Remogliflozin etabonate; Sodium-dependent glucose transporter 2 inhibitor; Pharmacokinetics; Pharmacodynamics; Type 2 diabetes mellitus
The association between antemortem [11C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with LB (DLB). 76-year-old man presenting with a clinical diagnosis of DLB had undergone PiB–positron emission tomography (PET), 18F FDG-PET and MRI 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ density and PiB retention in the 17 corresponding ROIs (r=0.899; p<0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques; whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r=0.13; p=0.66); nor between NFT density and PiB retention (r=−0.36; p=0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.
Dementia with Lewy bodies; amyloid imaging; PET; pathology; amyloid
Serial assessments are commonplace in neuropsychological practice and used to document cognitive trajectory for many clinical conditions. However, true change scores may be distorted by measurement error, repeated exposure to the assessment instrument, or person variables. The present study provides reliable change indices (RCI) for the Boston Naming Test, derived from a sample of 844 cognitively normal adults aged 56 years and older. All participants were retested between 9 and 24 months after their baseline exam. Results showed that a 4-point decline during a 9–15 month retest period or a 6-point decline during a 16–24 month retest period represents reliable change. These cutoff values were further characterized as a function of a person’s age and family history of dementia. These findings may help clinicians and researchers to characterize with greater precision the temporal changes in confrontation naming ability.
BNT; RCI; Aging; Dementia; Serial; Assessment
To investigate whether demographic (age and education) adjustments for the Mini-Mental State Examination (MMSE) attenuate mean score discrepancies between African American and Caucasian adults, and to determine whether demographically-adjusted MMSE scores improve the diagnostic classification accuracy of dementia in African American adults when compared to unadjusted MMSE scores.
Community-dwelling adults participating in the Mayo Clinic Alzheimer’s Disease Patient Registry (ADPR) and Alzheimer’s Disease Research Center (ADRC).
Three thousand two hundred fifty-four adults (2819 Caucasian, 435 African American) aged 60 and older.
MMSE at study entry.
African American adults obtained significantly lower unadjusted MMSE scores (23.0 ± 7.4) compared to Caucasian adults (25.3 ± 5.4). This discrepancy persisted despite adjustment of MMSE scores for age and years of education using established regression weights or newly-derived weights. However, controlling for dementia severity at baseline and adjusting MMSE scores for age and quality of education attenuated this discrepancy. Among African American adults, an age- and education-adjusted MMSE cut score of 23/24 provided optimal dementia classification accuracy, but this represented only a modest improvement over an unadjusted MMSE cut score of 22/23. The posterior probability of dementia in African American adults is presented for various unadjusted MMSE cut scores and prevalence rates of dementia.
Age, dementia severity at study entry, and quality of educational experience are important explanatory factors to understand the existing discrepancies in MMSE performance between Caucasian and African American adults. Our findings support the use of unadjusted MMSE scores when screening African American elders for dementia, with an unadjusted MMSE cut score of 22/23 yielding optimal classification accuracy.
MMSE; African American; ethnicity; dementia; cognition
REM sleep behavior disorder (RBD) is associated with neurodegenerative disease and particularly with the synucleinopathies. Convenience samples involving subjects with idiopathic RBD have suggested an increased risk of incident mild cognitive impairment (MCI), dementia (usually dementia with Lewy bodies) or Parkinson’s disease (PD). There is no data on such risk in a population-based sample.
Cognitively normal subjects aged 70–89 in a population-based study of aging who screened positive for probable RBD using the Mayo Sleep Questionnaire were followed at 15 month intervals. In a Cox Proportional Hazards Model, we measured the risk of developing MCI, dementia, PD among the exposed (pRBD+) and unexposed (pRBD−) cohorts.
Forty-four subjects with pRBD+ at enrollment (median duration of pRBD features was 7.5 years), and 607 pRBD− subjects, were followed prospectively for a median of 3.8 years. Fourteen of the pRBD+ subjects developed MCI and one developed PD (15/44=34% developed MCI / PD); none developed dementia. After adjustment for age, sex, education, and medical comorbidity, pRBD+ subjects were at increased risk of MCI / PD [Hazard Ratio (HR) 2.2, 95% Confidence Interval (95%CI) 1.3 – 3.9; p=0.005]. Inclusion of subjects who withdrew from the study produced similar results, as did exclusion of subjects with medication-associated RBD. Duration of pRBD symptoms did not predict the development of MCI / PD (HR 1.05 per 10 years, 95%CI 0.84 – 1.3; p=0.68).
In this population-based cohort study, we observed that pRBD confers a 2.2-fold increased risk of developing MCI / PD over four years.
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism; synuclein
We examined the utility of cognitive evaluation to predict instrumental activities of daily living (IADLs) and decisional ability in Mild Cognitive Impairment (MCI).
Sixty-seven individuals with single domain amnestic MCI were administered the Dementia Rating Scale-2 as well as the Everyday Cognition (ECog) form to assess functional ability.
DRS-2 Total Scores and Initiation/Perseveration and Memory subscales were found to be predictive of IADLs, with Total Scores accounting for 19% of the variance in IADL performance on average. Additionally, DRS-2 Initiation/Perseveration and Total Score were predictive of ability to understand information, and DRS-2 Conceptualization helped predict ability to communicate with others, both key variables in decision making ability.
These findings suggest that performance on the DRS-2, and specific subscales related to executive function and memory, is significantly related to IADLs in individuals with MCI. These cognitive measures are also associated in decision making related abilities in MCI.
Mild Cognitive Impairment; Cognitive Ability; Activities of Daily Living; Decision Making Ability
To evaluate the use of a semiautomated computerized system for measuring speech and language characteristics in patients with frontotemporal lobar degeneration (FTLD).
FTLD is a heterogeneous disorder comprising at least 3 variants. Computerized assessment of spontaneous verbal descriptions by patients with FTLD offers a detailed and reproducible view of the underlying cognitive deficits.
Audiorecorded speech samples of 38 patients from 3 participating medical centers were elicited using the Cookie Theft stimulus. Each patient underwent a battery of neuropsychologic tests. The audio was analyzed by the computerized system to measure 15 speech and language variables. Analysis of variance was used to identify characteristics with significant differences in means between FTLD variants. Factor analysis was used to examine the implicit relations between subsets of the variables.
Semiautomated measurements of pause-to-word ratio and pronoun-to-noun ratio were able to discriminate between some of the FTLD variants. Principal component analysis of all 14 variables suggested 4 subjectively defined components (length, hesitancy, empty content, grammaticality) corresponding to the phenomenology of FTLD variants.
Semiautomated language and speech analysis is a promising novel approach to neuropsychologic assessment that offers a valuable contribution to the toolbox of researchers in dementia and other neurodegenerative disorders.
spontaneous speech; language; prosody; frontotemporal lobar degeneration; automated speech analysis
To validate a questionnaire focused on REM sleep behavior disorder (RBD) among participants in an aging and dementia cohort.
RBD is a parasomnia that can develop in otherwise neurologically-normal adults as well as in those with a neurodegenerative disease. Confirmation of RBD requires polysomnography (PSG). A simple screening measure for RBD would be desirable for clinical and research purposes.
We had previously developed the Mayo Sleep Questionnaire (MSQ), a 16 item measure, to screen for the presence of RBD and other sleep disorders. We assessed the validity of the MSQ by comparing the responses of patients’ bed partners with the findings on PSG. All subjects recruited in the Mayo Alzheimer’s Disease Research Center at Mayo Clinic Rochester and Mayo Clinic Jacksonville from 1/00 to 7/08 who had also undergone a PSG were the focus of this analysis.
The study sample was comprised of 176 subjects [150 male; median age 71 years (range 39–90)], with the following clinical diagnoses: normal (n=8), mild cognitive impairment (n=44), Alzheimer’s disease (n=23), dementia with Lewy bodies (n=74), as well as other dementia and/or parkinsonian syndromes (n=27). The core question on recurrent dream enactment behavior yielded a sensitivity (SN) of 98% and specificity (SP) of 74% for the diagnosis of RBD. The profile of responses on four additional subquestions on RBD and one on obstructive sleep apnea improved specificity.
These data suggest that among aged subjects with cognitive impairment and/or parkinsonism, the MSQ has adequate SN and SP for the diagnosis of RBD. The utility of this scale in other patient populations will require further study.
sleep disorders; parasomnias; dementia; Alzheimer’s disease; dementia with Lewy bodies; parkinsonism
Few studies have reported neuropsychiatric symptoms (NPS) in Primary Progressive Aphasia (PPA), a neurodegenerative disorder that primarily affects the left hemisphere. Depression is associated with left-sided stroke, but it remains unclear if depression and other NPS are also associated with PPA. The authors compared the frequency of NPS in 55 cases of PPA with 110 cognitively normal persons matched for age, sex and education. Depression, apathy, agitation, anxiety, appetite change, and irritability are associated with PPA. Hallucinations, delusion and night time behavior were not associated with PPA.
Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2–18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed-effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline.
frontotemporal dementia; behaviour; functional decline; brain volumes; mixed effects models
DNA methyltransferase 1 (DNMT1) is crucial for maintenance of methylation, gene regulation and chromatin stability1-3. DNA mismatch repair, cell cycle regulation in post-mitotic neurons4,5 and neurogenesis6 are influenced by DNA methylation. Here we show mutations in DNMT1 cause both central and peripheral neurodegeneration in one form of hereditary sensory and autonomic neuropathy (HSAN1) with dementia and hearing loss7,8. Exome sequencing led to the identification of DNMT1 mutation c.A1484G (p.Tyr495Cys) in two American and one Japanese kindreds and a triple nucleotide change c.1470TCC-1472ATA (p.Asp490Glu-Pro491Tyr) in one European kindred. All mutations are within the targeting sequence (TS) domain of DNMT1. These mutations cause premature degradation of mutant proteins, reduced methyltransferase activity and impaired heterochromatin binding during the G2 cell cycle phase, leading to global hypomethylation and site specific hypermethylation. Our study demonstrates DNMT1 mutations cause aberrant methylation implicated in complex pathogenesis. The discovered DNMT1 mutations provide a new framework for the study of neurodegenerative diseases.
Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer’s disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
The Dementia Rating Scale (DRS) is a widely used measure of global cognition, with age- and education-corrected norms derived from a cross-sectional sample of adults participating in Mayo's Older Americans Normative Studies (MOANS). In recent years, however, studies have indicated that cross-sectional normative samples of older adults represent an admixture of individuals who are indeed cognitively normal (i.e., disease-free) and individuals with incipient neurodegenerative disease. Theoretically, the “contamination” of cross-sectional normative samples with cases of preclinical dementia can lead to underestimation of the test mean and overestimation of the variance, thus reducing the clinical utility of the norms. Robust norming, in which dementia cases are removed from the normative cohort through longitudinal follow-up, is an alternative approach to norm development. The current study presents a reappraisal of the original MOANS DRS norms, provides robust and expanded norms based on a sample of 894 adults age 55 and over, and critically evaluates the benefits of robust norming.
Dementia Rating Scale; DRS; Alzheimer's disease; Robust; Norms
In the past 10 years, there has been a virtual explosion in the literature concerning the construct of mild cognitive impairment. The interest in this topic demonstrates the increasing emphasis on the identification of the earliest features of cognitive disorders such as Alzheimer’s disease and other dementias. Mild cognitive impairment represents the earliest clinical features of these conditions and, hence, has become a focus of clinical, epidemiological, neuroimaging, biomarker, neuropathological, disease mechanism and clinical trials research. This review summarizes the progress that has been made while also recognizing the challenges that remain.
Mild cognitive impairment; Alzheimer’s disease; Imaging; Cognitive decline
The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1–42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled ‘cognitively impaired’ subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory–Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1–42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1–42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.
Alzheimer's disease; mild cognitive impairment; CSF biomarkers; MRI; cognitive reserve
Frontotemporal lobar degeneration (FTLD) is a neurodegenerative disorder that affects language. We applied a computerized information-theoretic technique to assess the type and severity of language-related FTLD symptoms. Audio-recorded samples of 48 FTLD patients from three participating medical centers were elicited using the Cookie Theft picture stimulus. The audio was transcribed and analyzed by calculating two measures: a perplexity index and an out-of-vocabulary (OOV) rate. The perplexity index represents the degree of deviation in word patterns used by FTLD patients compared to patterns of healthy adults. The OOV rate represents the proportion of words used by FTLD patients that were not used by the healthy speakers to describe the stimulus. In this clinically well-characterized cohort, the perplexity index and the OOV rate were sensitive to spontaneous language manifestations of semantic dementia and the distinction between semantic dementia and progressive logopenic aphasia variants of FTLD. Our study not only supports a novel technique for the characterization of language-related symptoms of FTLD in clinical trial settings, it also validates the basis for the clinical diagnosis of semantic dementia as a distinct syndrome.
frontotemporal lobar degeneration; semantic dementia; perplexity; entropy; statistical language modeling