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
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
Obsessions and compulsive (OC) behaviors are a frequent feature of behavioral variant frontotemporal dementia (bvFTD), but their structural correlates have not been definitively established.
Patients with bvFTD presenting to the Mayo Clinic Alzheimer’s Disease Research Center were recruited. Each patient’s caregiver was given the Yale-Brown Obsessive-Compulsive scale (YBOCS) to document the type and presence of OC behaviors and to rate their severity. All subjects underwent a standardized MRI which was evaluated using VBM. 17 patients with bvFTD were recruited and 11 were included in the study and compared to 11 age and gender matched controls. Six were excluded for lack of MRI at time of survey or a pre-existing neurodegenerative condition.
Nine of the 11 reported OC behaviors, with the most frequent compulsions being checking, hoarding, ordering/arranging, repeating rituals, and cleaning. In the VBM analysis, total YBOCS score correlated with grey matter loss in the bilateral globus pallidus, left putamen, and in the lateral temporal lobe, particularly the left middle and inferior temporal gyri (p<0.001 uncorrected for multiple comparisons).
Obsessive-compulsive behaviors were frequent among these patients. The correlation with basal ganglia atrophy may point to involvement of frontal subcortical neuronal networks. Left lateral temporal lobe volume loss likely reflects the number of MAPT mutation patients included but also provides additional data implicating temporal lobe involvement in OC behaviors.
Frontotemporal dementia; magnetic resonance imaging; obsessive behavior; compulsive behavior
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.
The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Tertiary care academic medical center.
The members of the family affected by the mutation with features of FTD and/or ALS.
Main Outcome Measures
Clinical, neuropsychological, and neuroimaging assessments.
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterized by loss of muscle atonia during REM sleep and is associated with dream enactment behaviour. RBD is often associated with α-synuclein pathology, and we examined if there is a relationship of RBD with cholinergic neuronal loss in the pedunculopontine/laterodorsal tegmental nucleus (PPN/LDT), compared to catecholaminergic neurons in a neighbouring nucleus, the locus coeruleus (LC).
This retrospective study, utilized human brain banked tissues of 11 Lewy body disease (LBD) cases with RBD, 10 LBD without RBD, 19 AD and 10 neurologically normal controls. Tissues were stained with choline acetyl transferase immunohistochemistry to label neurons of PPN/LDT and tyrosine hydroxylase for the LC. The burden of tau and α-synuclein pathology was measured in the same regions with immunohistochemistry.
Both the LC and PPN/LDT were vulnerable to α-synuclein pathology in LBD and tau pathology in AD, but significant neuronal loss was only detected in these nuclei in LBD. Greater cholinergic depletion was found in both LBD groups, regardless of RBD status, when compared with normals and AD. There were no differences in either degree of neuronal loss or burden of α-synuclein pathology in LBD with and without RBD.
Whether decreases in brainstem cholinergic neurons in LBD contribute to RBD is uncertain, but our findings indicate these neurons are highly vulnerable to α-synuclein pathology in LBD and tau pathology in AD. The mechanism of selective α-synuclein-mediated neuronal loss in these nuclei remains to be determined.
α-synuclein; cholinergic; Lewy body; laterodorsal tegmentum; locus coeruleus; pedunculopontine nucleus; REM behaviour disorder; tau
The clinical syndromes of frontotemporal lobar degeneration include behavioral variant frontotemporal dementia (bvFTD) and semantic (SV-PPA) and nonfluent variants (NF-PPA) of primary progressive aphasia. Using magnetic resonance imaging (MRI), tensor-based morphometry (TBM) was used to determine distinct patterns of atrophy between these three clinical groups.
Twenty-seven participants diagnosed with bvFTD, 16 with SV-PPA, and 19 with NF-PPA received baseline and follow-up MRI scans approximately 1 year apart. TBM was used to create three-dimensional Jacobian maps of local brain atrophy rates for individual subjects.
Regional analyses were performed on the three-dimensional maps and direct comparisons between groups (corrected for multiple comparisons using permutation tests) revealed significantly greater frontal lobe and frontal white matter atrophy in the bvFTD relative to the SV-PPA group (p < 0.005). The SV-PPA subjects exhibited significantly greater atrophy than the bvFTD in the fusiform gyrus (p = 0.007). The NF-PPA group showed significantly more atrophy in the parietal lobes relative to both bvFTD and SV-PPA groups (p < 0.05). Percent volume change in ventromedial prefrontal cortex was significantly associated with baseline behavioral symptomatology.
The bvFTD, SV-PPA, and NF-PPA groups displayed distinct patterns of progressive atrophy over a 1-year period that correspond well to the behavioral disturbances characteristic of the clinical syndromes. More specifically, the bvFTD group showed significant white matter contraction and presence of behavioral symptoms at baseline predicted significant volume loss of the ventromedial prefrontal cortex.
Frontotemporal dementia; Primary progressive aphasia; Longitudinal study; Magnetic resonance imaging; Tensor-based morphometry; White matter
To characterize the shape of the trajectories of Alzheimer’s Disease (AD) biomarkers as a function of MMSE.
Longitudinal registries from the Mayo Clinic and the Alzheimer’s Disease Neuroimaging Initiative (ADNI).
Two different samples (n=343 and n=598) were created that spanned the cognitive spectrum from normal to AD dementia. Subgroup analyses were performed in members of both cohorts (n=243 and n=328) who were amyloid positive at baseline.
Main Outcome Measures
The shape of biomarker trajectories as a function of MMSE, adjusted for age, was modeled and described as baseline (cross-sectional) and within-subject longitudinal effects. Biomarkers evaluated were cerebro spinal fluid (CSF) Aβ42 and tau; amyloid and fluoro deoxyglucose position emission tomography (PET) imaging, and structural magnetic resonance imaging (MRI).
Baseline biomarker values generally worsened (i.e., non-zero slope) with lower baseline MMSE. Baseline hippocampal volume, amyloid PET and FDG PET values plateaued (i.e., non-linear slope) with lower MMSE in one or more analyses. Longitudinally, within-subject rates of biomarker change were associated with worsening MMSE. Non-constant within-subject rates (deceleration) of biomarker change were found in only one model.
Biomarker trajectory shapes by MMSE were complex and were affected by interactions with age and APOE status. Non-linearity was found in several baseline effects models. Non-constant within-subject rates of biomarker change were found in only one model, likely due to limited within-subject longitudinal follow up. Creating reliable models that describe the full trajectories of AD biomarkers will require significant additional longitudinal data in individual participants.
Alzheimer’s disease biomarkers; Magnetic Resonance Imaging; cerebro spinal fluid; amyloid PET imaging; FDG PET imaging
A workgroup commissioned by the Alzheimer’s Association (AA) and the National Institute on Aging (NIA) recently published research criteria for preclinical Alzheimer’s disease (AD). We performed a preliminary assessment of these guidelines.
We employed Pittsburgh compound B positron emission tomography (PET) imaging as our biomarker of cerebral amyloidosis and 18fluorodeoxyglucose PET imaging and hippocampal volume as biomarkers of neurodegeneration. A group of 42 clinically diagnosed AD subjects was used to create imaging biomarker cut-points. A group of 450 cognitively normal (CN) subjects from a population based sample was used to develop cognitive cut-points and to assess population frequencies of the different preclinical AD stages using different cut-point criteria.
The new criteria subdivide the preclinical phase of AD into stages 1–3. To classify our CN subjects, two additional categories were needed. Stage 0 denotes subjects with normal AD biomarkers and no evidence of subtle cognitive impairment. Suspected Non-AD Pathophysiology (SNAP) denotes subjects with normal amyloid PET imaging, but abnormal neurodegeneration biomarker studies. At fixed cut-points corresponding to 90% sensitivity for diagnosing AD and the 10th percentile of CN cognitive scores, 43% of our sample was classified as stage 0; 16% stage 1; 12 % stage 2; 3% stage 3; and 23% SNAP.
This cross-sectional evaluation of the NIA-AA criteria for preclinical AD indicates that the 1–3 staging criteria coupled with stage 0 and SNAP categories classify 97% of CN subjects from a population-based sample, leaving just 3% unclassified. Future longitudinal validation of the criteria will be important.
Steroid-responsive encephalopathies can considered vasculitic or nonvasculitic. Clinicopathological studies of nonvasculitic steroid-responsive encephalopathy are unusual, but can explain the range of diagnoses consistent with a steroid responsive presentation in life.
To extend the range of clinical features and pathological findings consistent with steroid-responsive encephalopathy.
Design, Methods, and Patients
A clinicopathological case series of four patients (ages 54–71 years, 2 women) with steroid-responsive encephalopathy followed at this institution until the time of death.
Clinical features were suggestive of Creutzfeld-Jakob disease, dementia with Lewy Bodies, and parkinsonism, but pathological examination revealed only Alzheimer’s Disease-related findings without evidence of Lewy bodies or prion disease in all cases. All patients demonstrated marked, sustained improvement following steroid treatment, based on clinical, magnetic resonance imaging, and/or electroencephalogram studiesAlzheimer’s Disease was not diagnosed in life due to a lack of hippocampal atrophy on brain imaging and a dramatic symptomatic response to steroids.
Steroid-responsive encephalopathy is the clinical presentation of some patients with Alzheimer’s Disease related pathology at autopsy, and can be consistent with the clinical diagnoses of parkisonism, dementia with Lewy Bodies, or Creutzfeld-Jakob Disease in life.
Alzheimer’s Disease; corticosteroids; dementia; encephalopathy; Hashimoto’s encephalopathy; neuropathology
Numerous kindreds with familial frontotemporal dementia or amyotrophic lateral sclerosis or both have been linked to chromosome 9 (c9FTD/ALS), and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 (C9ORF72) was identified in the summer of 2011 as the pathogenic mechanism. An avalanche of papers on this disorder is in progress, and a relatively distinctive phenotype is taking form. In this review, we present an illustrative case and summarize the demographic, inheritance, clinical, and behavioral aspects and presumed pathologic underpinnings of c9FTD/ALS on the basis of the available data on more than 250 patients with frontotemporal lobar degeneration syndromes, parkinsonism, or ALS or a combination of these disorders.
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 and others have recently reported an association between ALS and single nucleotide polymorphisms on chromosome 9p21 in several populations. Here we show that the associated haplotype is the same in all populations and that several families previously shown to have genetic linkage to this region also share this haplotype. The most parsimonious explanation of these data is that there is a single founder for this form of disease.
Genetics; amyotrophic lateral sclerosis; frontotemporal dementia; Finland
To determine whether dementia with Lewy bodies with or without probable rapid eye movement sleep behavior disorder differ clinically or pathologically.
Patients with dementia with Lewy bodies who have probable rapid eye movement sleep behavior sleep disorder (n=71) were compared to those without it (n=19) on demographics, clinical variables (core features of dementia with Lewy bodies, dementia duration, rate of cognitive/motor changes) and pathologic indices (Lewy body distribution, neuritic plaque score, Braak neurofibrillary tangle stage).
Individuals with probable rapid eye movement sleep behavior disorder were predominantly male (82% versus 47%), and had a shorter duration of dementia (mean 8 years versus 10 years), earlier onset of parkinsonism (mean 2 years versus 5 years), and earlier onset of visual hallucinations (mean 3 years versus 6 years). These patients also had a lower Braak neurofibrillary tangle stage (Stage IV versus Stage VI) and lower neuritic plaque scores (18% frequent versus 85% frequent), but no difference in Lewy body distribution. When probable rapid eye movement sleep behavior disorder developed early (at or before dementia onset), the onset of parkinsonism and hallucinations was earlier and Braak neurofibrillary tangle stage was lower compared to those who developed the sleep disorder after dementia onset. Women with autopsy-confirmed DLB without a history of dream enactment behavior during sleep had a later onset of hallucinations and parkinsonism and a higher Braak NFT stage.
Probable rapid eye movement sleep behavior disorder is associated with distinct clinical and pathologic characteristics of dementia with Lewy bodies.
Parkinson’s disease; REM sleep behavior disorder; Dementia with Lewy bodies; Lewy body disease; Alzheimer’s disease
Patients with corticobasal degeneration can present with several different clinical syndromes, making ante-mortem diagnosis a challenge. Corticobasal syndrome is the clinical phenotype originally described for corticobasal degeneration, characterized by asymmetric rigidity and apraxia, cortical sensory deficits, dystonia and myoclonus. Some patients do not develop these features, but instead have clinical features consistent with the Richardson syndrome presentation of progressive supranuclear palsy, characterized by postural instability, early unexplained falls, vertical supranuclear gaze palsy, symmetric motor disability and dysphagia. The aim of this study was to identify differences in corticobasal degeneration presenting with corticobasal syndrome (n = 11) or Richardson syndrome (n = 15) with respect to demographic, clinical and neuropathological features. Corticobasal degeneration cases were also compared with patients with pathologically proven progressive supranuclear palsy with Richardson syndrome (n = 15). Cases with corticobasal degeneration, regardless of presentation, shared histopathological and tau biochemical characteristics, but they had differing densities of tau pathology in neuroanatomical regions that correlated with their clinical presentation. In particular, those with corticobasal syndrome had greater tau pathology in the primary motor and somatosensory cortices and putamen, while those with Richardson syndrome had greater tau pathology in limbic and hindbrain structures. Compared with progressive supranuclear palsy, patients with corticobasal degeneration and Richardson syndrome had less neuronal loss in the subthalamic nucleus, but more severe neuronal loss in the medial substantia nigra and greater atrophy of the anterior corpus callosum. Clinically, they had more cognitive impairment and frontal behavioural dysfunction. The results suggest that Richardson syndrome can be a clinicopathological presentation of corticobasal degeneration. Atrophy of anterior corpus callosum may be a potential neuroimaging marker to differentiate corticobasal degeneration from progressive supranuclear palsy in patients with Richardson syndrome.
pathology; immunocytochemistry; progressive supranuclear palsy; tau protein; corticobasal degeneration
To examine the association between computer use, physical exercise, aging, and mild cognitive impairment (MCI).
Patients and Methods
The Mayo Clinic Study of Aging is a population-based study of aging and MCI in Olmsted County, Minnesota. The study sample consists of a random sample of 926 nondemented individuals aged 70 to 93 years who completed self-reported questionnaires on physical exercise, computer use, and caloric intake within 1 year of the date of interview. The study was conducted from April 1, 2006, through November 30, 2008. An expert consensus panel classified each study participant as cognitively normal or having MCI on the basis of published criteria.
Using a multivariable logistic regression model, we examined the impact of the presence during the study period of 2 lifestyle factors (physical exercise and computer use) after adjusting for a third lifestyle factor (caloric intake) on aging and MCI. We also adjusted for age, sex, education, medical comorbidity, and depression. The median daily caloric intake was significantly higher in participants with MCI than in controls (odds ratio, 1.04; 95% confidence interval, 1.02-1.06; P=.001). Participants who engaged in both moderate physical exercise and computer use had significantly decreased odds of having MCI (odds ratio [95% confidence interval], 0.36 [0.20-0.68]) compared with the reference group. In the interaction analyses, there was an additive interaction (P=.012) but not multiplicative interaction (P=.780).
In this population-based sample, the presence of both physical exercise and computer use as assessed via survey was associated with decreased odds of having MCI, after adjustment for caloric intake and traditional confounders.
CDR, Clinical Dementia Rating; CI, confidence interval; MCI, mild cognitive impairment; OR, odds ratio
Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.