The new criteria for preclinical Alzheimer’s Disease (AD) proposed 3 stages: abnormal levels of β-amyloid (stage 1); stage 1 plus evidence of brain injury (stage 2); and stage 2 plus subtle cognitive changes (stage 3). However, a large group of subjects with normal β-amyloid biomarkers have evidence of brain injury; we labeled them as “suspected non-Alzheimer pathway” (sNAP) group. The characteristics of the sNAP group are poorly understood.
Using the preclinical AD classification, 430 cognitively normal subjects from the Mayo Clinic Study of Aging who underwent brain MR, 18fluorodeoxyglucose (FDG) and Pittsburgh compound B (PiB) positron emission tomography (PET) were evaluated with FDG PET regional volumetrics, MR regional brain volumetrics, white matter hyperintensity (WMH) volume and number of infarcts. We examined cross-sectional associations across AD preclinical stages, those with all biomarkers normal, and the sNAP group.
The sNAP group had a lower proportion (14%) with APOE ε4 genotype than the preclinical AD stages 2 + 3. The sNAP group did not show any group differences compared to stages 2 + 3 of the preclinical AD group on measures of FDG PET regional hypometabolism, MR regional brain volume loss, cerebrovascular imaging lesions, vascular risk factors, imaging changes associated with α-synucleinopathy or physical findings of parkinsonism.
Cognitively normal persons with brain injury biomarker abnormalities, with or without abnormal levels of β-amyloid, were indistinguishable on a variety of imaging markers, clinical features and risk factors. The initial appearance of brain injury biomarkers that occurs in cognitively normal persons with preclinical AD may not depend on β-amyloidosis.
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
To model the temporal trajectory of β-amyloid accumulation using serial amyloid PET imaging.
Participants, aged 70–92 years, were enrolled in either the Mayo Clinic Study of Aging (n = 246) or the Mayo Alzheimer's Disease Research Center (n = 14). All underwent 2 or more serial amyloid PET examinations. There were 205 participants classified as cognitively normal and 55 as cognitively impaired (47 mild cognitive impairment and 8 Alzheimer dementia). We measured baseline amyloid PET-relative standardized uptake values (SUVR) and, for each participant, estimated a slope representing their annual amyloid accumulation rate. We then fit regression models to predict the rate of amyloid accumulation given baseline amyloid SUVR, and evaluated age, sex, clinical group, and APOE as covariates. Finally, we integrated the amyloid accumulation rate vs baseline amyloid PET SUVR association to an amyloid PET SUVR vs time association.
Rates of amyloid accumulation were low at low baseline SUVR. Rates increased to a maximum at baseline SUVR around 2.0, above which rates declined—reaching zero at baseline SUVR above 2.7. The rate of amyloid accumulation as a function of baseline SUVR had an inverted U shape. Integration produced a sigmoid curve relating amyloid PET SUVR to time. The average estimated time required to travel from an SUVR of 1.5–2.5 is approximately 15 years.
This roughly 15-year interval where the slope of the amyloid SUVR vs time curve is greatest and roughly linear represents a large therapeutic window for secondary preventive interventions.
REM sleep behavior disorder (RBD) is usually characterized by
potentially injurious dream enactment behaviors (DEB). RBD treatment aims to
reduce DEBs and prevent injury, but outcomes require further elucidation. We
surveyed RBD patients to describe longitudinal treatment outcomes with
melatonin and clonazepam.
We surveyed and reviewed records of consecutive RBD patients seen at
Mayo Clinic between 2008–2010 to describe RBD-related injury
frequency/severity as well as RBD Visual Analog Scale (VAS) ratings,
medication dosage, and side effects. Statistical analyses were performed
with appropriate non-parametric matched pairs tests before and after
treatment, and with comparative group analyses for continuous and
categorical variables between treatment groups. The primary outcome
variables were RBD VAS ratings and injury frequency.
Forty-five (84.9%) of 53 respondent surveys were analyzed.
Mean age was 65.8 years and 35 (77.8%) patients were men.
Neurodegenerative disorders were seen in 24 (53%) patients, and 25
(56%) received antidepressants. Twenty-five patients received
melatonin, 18 received clonazepam, and 2 received both as initial treatment.
Before treatment, 27 patients (60%) reported an RBD associated
injury. Median dosages were melatonin 6 mg and clonazepam 0.5 mg. RBD VAS
ratings were significantly improved following both treatments
Melatonin-treated patients reported significantly reduced injuries
(pm=.001, pc=.06) and fewer
adverse effects (p=0.07). Mean durations of treatment were no
different between groups (for clonazepam 53.9 +/− 29.5
months, and for melatonin 27.4 +/− 24 months,
p=0.13) and there were no differences in treatment retention, with
28% of melatonin and 22% of clonazepam-treated patients
discontinuing treatment (p=0.43).
Melatonin and clonazepam were each reported to reduce RBD behaviors
and injuries and appeared comparably effective in our naturalistic practice
experience. Melatonin-treated patients reported less frequent adverse
effects than those treated with clonazepam. More effective treatments that
would eliminate injury potential and evidence-based treatment outcomes from
prospective clinical trials for RBD are needed.
REM sleep behavior disorder; parasomnia; melatonin; clonazepam; treatment; side effects; tolerability; retention; injury; falls; synucleinopathy
Non-amnestic mild cognitive impairment (naMCI), a putative precursor of vascular and other non-Alzheimer’s disease dementias, is hypothesized to have a vascular etiology. We investigated the association of cardiac disease with amnestic (aMCI) and non-amnestic (naMCI) MCI.
A prospective, population-based, cohort study with a median 4.0 years of follow-up.
Olmsted County, Minnesota.
Participants were evaluated at baseline and every 15 months using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing. A diagnosis of normal cognition, MCI, or dementia was made by consensus. Cardiac disease at baseline was assessed from the participant’s medical records.
Main outcome measures
Incident MCI, aMCI, naMCI.
Among 1,450 subjects free of MCI or dementia at baseline, 366 developed MCI. Cardiac disease was associated with an increased risk of naMCI (hazard ratio [HR] 95% confidence interval; 1.77 [1.16–2.72]). However, the association varied by sex (P for interaction = .02). Cardiac disease was associated with an increased risk of naMCI (HR, 3.07 [1.58–5.99]) in women, but not in men (HR, 1.16 [0.68–1.99]. Cardiac disease was not associated with any MCI or aMCI.
Cardiac disease is an independent risk factor for naMCI, within sex comparisons showed a stronger association in women. Prevention and management of cardiac disease and vascular risk factors may reduce the risk of naMCI.
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
We aimed to assess associations between clinical, imaging, pathological and genetic features and frontal lobe asymmetry in behavioral variant frontotemporal dementia (bvFTD). Volumes of the left and right dorsolateral, medial and orbital frontal lobes were measured in 80 bvFTD subjects and subjects were classified into three groups according to the degree of asymmetry (asymmetric left, asymmetric right, symmetric) using cluster analysis. The majority of subjects were symmetric (65%), with 20% asymmetric left and 15% asymmetric right. There were no clinical differences across groups, although there was a trend for greater behavioral dyscontrol in right asymmetric compared to left asymmetric subjects. More widespread atrophy involving the parietal lobe was observed in the symmetric group. Genetic features differed across groups with symmetric frontal lobes associated with C9ORF72 and tau mutations, while asymmetric frontal lobes were associated with progranulin mutations. These findings therefore suggest that neuroanatomical patterns of frontal lobe atrophy in bvFTD are influenced by specific gene mutations.
Frontotemporal dementia; frontal lobes; MRI; asymmetry; microtubule associated protein tau; progranulin; C9ORF72; pathology
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A–D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.
TDP-43 type C; corticospinal tract; MRI; semantic dementia; right temporal lobe
The appearance of β-amyloidosis and brain injury biomarkers in cognitively normal (CN) persons is thought to define risk for the future development of cognitive impairment due to Alzheimer’s disease (AD), but their interaction is poorly understood.
To test the hypothesis that the joint presence of β-amyloidosis and brain injury biomarkers would lead to more rapid neurodegeneration.
Longitudinal Cohort Study
Population-based Mayo Clinic Study of Aging.
191 CN persons (median age 77, range 71–93) in the Mayo Clinic Study of Aging who underwent MR, FDG PET and PiB PET imaging at least twice 15 months apart. Subjects were grouped according to the recommendations of the NIA-AA Preclinical AD criteria, based on the presence of β-amyloidosis, defined as a PiB PET SUVr >1.5, alone (Stage 1) or with brain injury (stage 2+3), defined as hippocampal atrophy or FDG hypometabolism. We also studied a group of MCI (n=17) and dementia (n=9) patients from the Mayo Clinic Study of Aging or the Mayo Alzheimer Center with similar follow-up times who had had comparable imaging and who all had PiB PET SUVr >1.5.
Main Outcome Measures
Rate of change of cortical volume on volumetric MR scans and rate of change of glucose metabolism on FDG PET scans.
There were 25 CN subjects with both high PiB retention and low hippocampal volume or FDG hypometabolism at baseline (Preclinical AD stages 2+3). On follow-up scans, the Preclinical AD stages 2+3 subjects had greater loss of medial temporal lobe volume and greater glucose hypometabolism in the medial temporal lobe compared to other CN groups. The changes were similar to the cognitively impaired participants. Extra-temporal regions did not show similar changes.
Higher rates of medial temporal neurodegeneration occurred in CN individuals who, on their initial scans, had abnormal levels of both β-amyloid and brain injury biomarkers.
Alzheimer’s disease; PET imaging; MR imaging; Epidemiology
Pallido-ponto-nigral degeneration (PPND), caused by an N279K mutation of the MAPT gene, is 1 of a family of disorders collectively referred to as frontotemporal dementia and parkinsonism linked to chromosome 17. This study aims to characterize the nature of the sleep disturbance in PPND and compare these findings to those in other progressive neurological illnesses. Pathological findings are also provided.
Ten subjects were recruited from the PPND kindred; 5 affected and 5 unaffected. The subjects underwent clinical assessment, polysomnography, and wrist actigraphy. Available sleep-relevant areas (pedunculopontine/laterodorsal tegmentum, nucleus basalis of Meynert, thalamus, and locus ceruleus) of affected subjects were analyzed postmortem.
The affected group's total sleep time was an average of 130.8 minutes compared to 403.6 minutes in the control group (p < 0.01). Initial sleep latency was significantly longer in affected subjects (range, 58–260 minutes vs 3–34 minutes). Affected subjects also had an increase in stage I sleep (8.5% vs 1%), and less stage III/IV sleep (8.5% vs 17%). At the time of autopsy, all cases had severe neuronal tau pathology in wake-promoting nuclei, as well as decreases in thalamic cholinergic innervations. There was no difference in orexinergic fiber density in nucleus basalis of Meynert or locus ceruleus compared to controls.
The PPND kindred showed severe sleep disturbance. Sleep abnormalities are common in neurodegenerative illnesses, but this is the first study of sleep disorders in PPND. Unlike most neurodegenerative conditions, PPND is characterized by decreased total sleep time, increased sleep latency, and decreased sleep efficiency, without daytime hypersomnolence.
In a population-based case-control study, we examined whether moderate and high caloric intakes are differentially associated with the odds of having mild cognitive impairment (MCI). The sample was derived from the Mayo Clinic Study of Aging in Olmsted County, Minnesota. Non-demented study participants aged 70–92 years (1,072 cognitively normal persons and 161 subjects with MCI) reported their caloric consumption within 1 year of the date of interview by completing a Food Frequency Questionnaire. An expert consensus panel classified each subject as either cognitively normal or having MCI based on published criteria. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age, sex, education, depression, medical comorbidity, and body mass index. We also conducted stratified analyses by apolipoprotein E ε4 genotype status. Analyses were conducted in tertiles of caloric intake: 600 to <1,526 kcals per day (reference group); 1,526 to 2,143 kcals per day (moderate caloric intake group); and >2,143 kcals per day (high caloric intake group). In the primary analysis, there was no significant difference between the moderate caloric intake group and the reference group (OR 0.87, 95% CI 0.53–1.42, p = 0.57). However, high caloric intake was associated with a nearly two-fold increased odds of having MCI (OR 1.96, 95% CI 1.26–3.06, p = 0.003) as compared to the reference group. Therefore, high caloric intake was associated with MCI but not moderate caloric intake. This association is not necessarily a cause-effect relationship.
aging; APOE ε4 genotype; caloric intake; mild cognitive impairment; population-based
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
Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers.
Amyotrophic lateral sclerosis; Frontotemporal Dementia; C9ORF72; Repeat-expansion disease; Association study
Hexanucleotide repeat expansions in C9ORF72 underlie a significant fraction of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study investigates the frequency of C9ORF72 repeat expansions in clinically diagnosed late-onset Alzheimer’s disease (AD).
Design, setting and patients
This case-control study genotyped the C9ORF72 repeat expansion in 872 unrelated familial AD cases and 888 controls recruited as part of the NIA-LOAD cohort, a multi-site collaboration studying 1000 families with two or more individuals clinically diagnosed with late-onset-AD.
Main Outcome Measure
We determined the presence or absence of the C9ORF72 repeat expansion by repeat-primed PCR, the length of the longest non-expanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers.
Three families showed large C9ORF72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the NIA-LOAD series, the C9ORF72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions.
C9ORF72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and highlight the necessity of screening “FTD genes” in clinical AD cases with strong family history.
Recently, we evaluated two patients with corticobasal syndrome (CBS) who reported symptom onset after limb immobilization. Our objective was to investigate the association between trauma, immobilization and CBS.
The charts of forty-four consecutive CBS patients seen in the Mayo Clinic Alzheimer Disease Research Center were reviewed with attention to trauma and limb immobilization.
10 CBS patients (23%) had immobilization or trauma on the most affected limb preceding the onset or acceleration of symptoms. The median age at onset was 61. Six patients manifested their first symptoms after immobilization from surgery or fracture with one after leg trauma. Four patients had pre-existing symptoms of limb dysfunction but significantly worsened after immobilization or surgery.
23 percent of patients had immobilization or trauma of the affected limb. This might have implications for management of CBS, for avoiding injury, limiting immobilization and increasing movement in the affected limb.
Corticobasal syndrome; plasticity; immobilization
To investigate the effect of intellectual and physical activity on biomarkers of Alzheimer’s disease (AD) pathophysiology and cognition in a non-demented elderly population. The biomarkers evaluated were brain Aβ-amyloid load via PIB-PET, neuronal dysfunction via FDG-PET and neurodegeneration via Structural-MRI.
We studied 515 non-demented (428 cognitively normal and 87 MCI) participants in the population based Mayo Clinic Study of Aging who completed a 3T MRI, PET scans, APOE genotype, had lifestyle activity measures and cognition data available. The imaging measures computed were global PiB-PET uptake; global FDG-PET and MRI based hippocampal volume. We consolidated activity variables into lifetime intellectual, current intellectual and current physical activities. We used a global cognitive Z-score as a measure of cognition. We applied two independent methods – partial correlation analysis adjusted for age and gender and path analysis using structural equations to evaluate the associations between lifestyle activities, imaging biomarkers and global cognition.
None of the lifestyle variables correlated with the biomarkers and the path associations between lifestyle variables and biomarkers were not significant (p>0.05). On the other hand, all the biomarkers were correlated with global cognitive Z-score (p<0.05) and the path associations between (lifetime and current) intellectual activities and global Z-score were significant (p<0.01).
Intellectual and physical activity lifestyle factors were not associated with AD biomarkers but intellectual lifestyle factors explained variability in the cognitive performance in this non-demented population. This study provides evidence that lifestyle activities may delay the onset of dementia but do not significantly influence the expression of AD pathophysiology.
Alzheimer’s disease; Imaging biomarkers; Lifestyle Activities
Secondary prevention trials in subjects with preclinical Alzheimer disease may require documentation of brain amyloidosis. The identification of inexpensive and noninvasive screening variables that can identify individuals who have significant amyloid accumulation would reduce screening costs.
A total of 483 cognitively normal (CN) individuals, aged 70–92 years, from the population-based Mayo Clinic Study of Aging, underwent Pittsburgh compound B (PiB)–PET imaging. Logistic regression determined whether age, sex, APOE genotype, family history, or cognitive performance was associated with odds of a PiB retention ratio >1.4 and >1.5. Area under the receiver operating characteristic curve (AUROC) evaluated the discrimination between PiB-positive and -negative subjects. For each characteristic, we determined the number needed to screen in each age group (70–79 and 80–89) to identify 100 participants with PiB >1.4 or >1.5.
A total of 211 (44%) individuals had PiB >1.4 and 151 (31%) >1.5. In univariate and multivariate models, discrimination was modest (AUROC ∼0.6–0.7). Multivariately, age and APOE best predicted odds of PiB >1.4 and >1.5. Subjective memory complaints were similar to cognitive test performance in predicting PiB >1.5. Indicators of PiB positivity varied with age. Screening APOE ε4 carriers alone reduced the number needed to screen to enroll 100 subjects with PIB >1.5 by 48% in persons aged 70–79 and 33% in those aged 80–89.
Age and APOE genotype are useful predictors of the likelihood of significant amyloid accumulation, but discrimination is modest. Nonetheless, these results suggest that inexpensive and noninvasive measures could significantly reduce the number of CN individuals needed to screen to enroll a given number of amyloid-positive subjects.
ApoE ε4 is associated with adverse health conditions that negatively impact the quality of life (QOL). The relationship between ApoE ε4 and QOL has not been explored in the oldest old. Our study aimed to examine ApoE in the oldest old, and explore its association with QOL.
Cross-sectional cohort study.
A medium sized community in Olmsted County, Minnesota, USA.
90–99 year old individuals living independently or in long term care environments.
We collected demographic information and measured cognitive function (Short Test of Mental Status [STMS], Mini-Mental State Examination [MMSE], Mattis Dementia Rating Scale [DRS]), QOL (Linear Analogue Self Assessment [LASA]) and ApoE distribution. Subjects were classified as cognitively normal, mild cognitive impairment (MCI), dementia (DEM), or dementia with stroke and/or parkinsonism (DEMSP). Regression model was used to assess the predictors of QOL.
121 subjects (45 cognitively normal, 13 MCI, 34 DEM, 29 DEMSP) aged 90–99,106 (87.6 %) females, were included. Frequency of ApoE ε3 allele was highest [194 (80.2%): ε2/3 18, ε3/3 77, ε3/4 22] followed by ApoE ε4 [25 (10.3%): ε2/4 3, ε3/4 22] and ApoE ε2 [23 (9.5%; ε2/2 1, ε2/3 18, ε2/4 3]. None of the subjects carried ApoE ε4/4 genotype. QOL was similar between ApoE ε4 carrier and non-carriers. Physical well-being, emotional well-being, intellectual well-being, social connectedness and coping ability were positively associated with QOL, whereas male gender, DEMSP, pain frequency and pain severity were negatively associated.
The most common ApoE in the oldest old was ε3/3 genotype and ε3 allele. No association was found between ApoE ε4 and QOL. However, those with high physical, emotional and intellectual well being, social connectedness and coping ability had the highest overall QOL.
Well being; oldest old; apolipoprotein E
Atypical variants of Alzheimer’s disease (AD) have been pathologically defined based on the distribution of neurofibrillary tangles; hippocampal sparing (HpSp) AD shows minimal involvement of the hippocampus and limbic predominant (LP) AD shows neurofibrillary tangles restricted to the medial temporal lobe. We aimed to determine whether MRI patterns of atrophy differ across HpSp AD, LP AD and typical AD, and whether imaging could be a useful predictor of pathological subtype during life.
In this case-control study, we identified 177 patients who had been prospectively followed in the Mayo Clinic Alzheimer’s Disease Research Center, were demented during life, had AD pathology at autopsy (Braak stage ≥ IV, intermediate-high probability AD) and an antemortem MRI. Cases were assigned to one of three pathological subtypes (HpSp n=19, typical n=125, or LP AD n=33) based on neurofibrillary tangle counts and their ratio in association cortices to hippocampus, without reference to neuronal loss. Voxel-based morphometry and atlas-based parcellation were used to compare patterns of grey matter loss across groups, and to controls.
The severity of medial temporal and cortical grey matter atrophy differed across subtypes. The most severe medial temporal atrophy was observed in LP AD, followed by typical AD, and then HpSp AD. Conversely, the most severe cortical atrophy was observed in HpSp AD, followed by typical AD, and then LP AD. A ratio of hippocampal-to-cortical volume provided the best discrimination across all three AD subtypes. The majority of typical AD (98/125;78%) and LP AD (31/33;94%) subjects, but only 8/19 (42%) of the HpSp AD subjects, presented with a dominant amnestic syndrome.
Patterns of atrophy on MRI differ across the pathological subtypes of AD, suggesting that MR regional volumetrics reliably track the distribution of neurofibrillary tangle pathology and can predict pathological subtype during life.
US National Institutes of Health (National Institute on Aging)
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.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
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
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by
repeated episodes of dream enactment behavior and REM sleep without atonia (RSWA) during
polysomnography recording. RSWA is characterized by increased phasic or tonic muscle activity seen
on polysomnographic electromyogram channels. RSWA is a requisite diagnostic feature of RBD, but may
also be seen in patients without clinical symptoms or signs of dream enactment as an incidental
finding in neurologically normal individuals, especially in patients receiving antidepressant
therapy. RBD may be idiopathic or symptomatic. Patients with idiopathic RBD often later develop
other neurological features including parkinsonism, orthostatic hypotension, anosmia, or cognitive
impairment. RSWA without clinical symptoms as well as clinically overt RBD also often occurs
concomitantly with the α-synucleinopathy family of neurodegenerative disorders, which
includes idiopathic Parkinson disease, Lewy body dementia, and multiple system atrophy. This review
article considers the epidemiology of RBD, clinical and polysomnographic diagnostic standards for
both RBD and RSWA, previously reported associations of RSWA and RBD with neurodegenerative disorders
and other potential causes, the pathophysiology of which brain structures and networks mediate
dysregulation of REM sleep muscle atonia, and considerations for the effective and safe management
REM sleep behavior disorder; REM sleep without atonia; Parasomnia; α-synucleinopathy; Parkinsonism; Neurodegeneration; Braak staging; Melatonin; Clonazepam; Treatment; Neuropsychological testing; Neurological disease
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
To determine whether MRI measurements observed in the Alzheimer's Disease Neuroimaging Initiative (ADNI; convenience-sample) differ from those observed in the Mayo Clinic Study of Aging (MCSA; population-based sample).
Comparison of two samples.
59 recruiting sites for the ADNI in US/Canada, and the MCSA, a population-based cohort in Olmsted County, MN.
Cognitively normal (CN) subjects and amnestic mild cognitive impairment (aMCI) subjects were selected from the ADNI convenience cohort and MCSA population-based cohort. Two samples were selected; the first was a simple random sample of subjects from both cohorts in the same age range, and the second applied matching for age, sex, education, apolipoprotein E genotype, and Mini-Mental State Examination.
Main outcome measures
Baseline hippocampal volumes and annual percent decline in hippocampal volume.
In the population-based sample, MCSA subjects were older, less educated, performed worse on MMSE, and less often had family history of AD than ADNI subjects. Baseline hippocampal volumes were larger in ADNI compared to MCSA CN subjects in the random sample, although no differences were observed after matching. Rates of decline in hippocampal volume were greater in ADNI compared to MCSA for both CN and aMCI, even after matching.
Rates of decline in hippocampal volume suggest that ADNI subjects have more aggressive brain pathology than MCSA subjects, and hence may not be representative of the general population. These findings have implications for treatment trials that employ ADNI-like recruitment mechanisms and for studies validating new diagnostic criteria for AD in its various stages.