•Genetic leukodystrophies mimic autoimmune and inflammatory diseases.•Non-genetic leukoencephalopathies have rapid disease progression.•Rapid, subacute progression should prompt CSF analysis, antibody tests.•Oligoclonal bands in CSF may signal an inflammatory cause.•Identification of GFAP antibodies should prompt cancer screening.

Creutzfeldt–Jakob disease (CJD) is a rare, uniformly fatal prion disease. Although CJD commonly presents with rapidly progressive dementia, ataxia, and myoclonus, substantial clinicopathological heterogeneity is observed in clinical practice. Unusual and predominantly cognitive clinical manifestations of CJD mimicking common dementia syndromes are known to pose as an obstacle to early diagnosis and prognosis. We report a series of three patients with probable or definite CJD (one male and two females, ages 52, 58 and 68) who presented to our tertiary behavioral neurology clinic at Mayo Clinic Rochester that met criteria for a newly defined progressive dysexecutive syndrome. Glucose hypometabolism patterns assessed by 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) strongly resembled those of dysexecutive variant of Alzheimer’s disease (dAD). However, magnetic resonance imaging (MRI) demonstrated restricted diffusion in neocortical areas and deep nuclei, while cerebrospinal fluid biomarkers indicated abnormal levels of 14-3-3, total-tau, and prion seeding activity (RT-QuIC), establishing the diagnosis of CJD. Electroencephalogram (EEG) additionally revealed features previously documented in atypical cases of CJD. This series of clinical cases demonstrates that CJD can present with a predominantly dysexecutive syndrome and FDG-PET hypometabolism typically seen in dAD. This prompts for the need to integrate information on clinical course with multimodal imaging and fluid biomarkers to provide a precise etiology for dementia syndromes. This has important clinical implications for the diagnosis and prognosis of CJD in the context of emerging clinical characterization of progressive dysexecutive syndromes in neurodegenerative diseases like dAD.

Abstract Posterior cortical atrophy is a neurodegenerative syndrome with a heterogeneous clinical presentation due to variable involvement of the left, right, dorsal and ventral parts of the visual system, as well as inconsistent involvement of other cognitive domains and systems. 18F-fluorodeoxyglucose (FDG)-PET is a sensitive marker for regional brain damage or dysfunction, capable of capturing the pattern of neurodegeneration at the single-participant level. We aimed to leverage these inter-individual differences on FDG-PET imaging to better understand the associations of heterogeneity of posterior cortical atrophy. We identified 91 posterior cortical atrophy participants with FDG-PET data and abstracted demographic, neurologic, neuropsychological and Alzheimer’s disease biomarker data. The mean age at reported symptom onset was 59.3 (range: 45–72 years old), with an average disease duration of 4.2 years prior to FDG-PET scan, and a mean education of 15.0 years. Females were more common than males at 1.6:1. After standard preprocessing steps, the FDG-PET scans for the cohort were entered into an unsupervised machine learning algorithm which first creates a high-dimensional space of inter-individual covariance before performing an eigen-decomposition to arrive at a low-dimensional representation. Participant values (‘eigenbrains’ or latent vectors which represent principle axes of inter-individual variation) were then compared to the clinical and biomarker data. Eight eigenbrains explained over 50% of the inter-individual differences in FDG-PET uptake with left (eigenbrain 1) and right (eigenbrain 2) hemispheric lateralization representing 24% of the variance. Furthermore, eigenbrain-loads mapped onto clinical and neuropsychological data (i.e. aphasia, apraxia and global cognition were associated with the left hemispheric eigenbrain 1 and environmental agnosia and apperceptive prosopagnosia were associated with the right hemispheric eigenbrain 2), suggesting that they captured important axes of normal and abnormal brain function. We used NeuroSynth to characterize the eigenbrains through topic-based decoding, which supported the idea that the eigenbrains map onto a diverse set of cognitive functions. These eigenbrains captured important biological and pathophysiologic data (i.e. limbic predominant eigenbrain 4 patterns being associated with older age of onset compared to frontoparietal eigenbrain 7 patterns being associated with younger age of onset), suggesting that approaches that focus on inter-individual differences may be important to better understand the variability observed within a neurodegenerative syndrome like posterior cortical atrophy.

Impaired olfaction has been associated with neurodegenerative diseases and may be a useful tool to aid in diagnosis or track disease progression. We sought to compare olfaction in participants with the clinical diagnoses of idiopathic REM sleep behavior disorder (RBD), dementia with Lewy bodies (DLB), or Alzheimer’s disease dementia (AD).

Tuesday, April 28April 14, 2020Free AccessAge of Onset of Cognitive Impairment and the Core Features of Dementia with Lewy Bodies (1738)Parichita Choudhury, Tanis Ferman, Jonathan Graff-Radford, Jeremiah Aakre, Danielle Brushaber, David Jones, David Knopman, … Show All … , Kejal Kantarci, Rodolfo Savica, Neill Graff-Radford, Daniel Drubach, Julie Fields, Mary Machulda, Leah Forsberg, Laura Allen, Toji Miyagawa, Otto Pedraza, Erik St Louis, Michael Silber, Walter Kremers, Ronald Petersen, and Bradley Boeve Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.1738 Letters to the Editor

AbstractBackgroundDementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia but the evolution of the core clinical features of DLB has not been clearly defined. The objective of this study was to identify the temporal relationship between each core feature from the estimated onset of cognitive symptoms.MethodParticipants include 485 patients with probable DLB who were evaluated at the Mayo Clinic Alzheimer Disease Research Center with neurologic and neurocognitive assessment. Each core clinical feature was compared using Kaplan‐Meier (KM) curves with the sentinel event representing age at which each core feature developed, or time from estimated cognitive onset.ResultThe sample was disproportionately male (76%). Patients were followed longitudinally, with 84% followed until death. Mean MMSE at the last evaluation was 18.3 ± 7.8. KM curves for age of onset and cumulative incidence for DLB core features as time from cognitive onset are provided. REM‐sleep behavior disorder (RBD) developed earliest and in 77% of our sample with a median KM survival estimate of 69 years (95% CI: 67.6–70.8). RBD was present in greater than 50% of patients at cognitive symptom onset. The median KM survival estimate for cognitive symptom onset was 70.2 years (95% CI: 69.3‐71.0). Parkinsonism developed in 89% with a median KM survival estimate of 73.7 years (95% CI: 72.7‐74.7). 76% had fluctuations with a similar median KM survival estimate of 74.6 years (95% CI: 73.7‐75.8). Visual hallucinations (VH) were present in 70% emerging at a median KM survival estimate of 80.2 years (95% CI: 79.5‐ 81.3). Cumulative incidence estimates for median time from cognitive onset to parkinsonism, fluctuations and VH were 2 years (95% CI: 2.0‐2.5), 2.3 years (95% CI: 2.0‐3.2) and 4.3 years (95% CI: 4.0‐4.8 years), respectively.ConclusionIn this DLB cohort, RBD was most likely to precede cognitive onset. The evolution of the other core features after cognitive onset was parkinsonism and fluctuations and then VH. While VH occur about 4 years after cognitive symptom onset, parkinsonism and fluctuations occur within the first 2 years.

We report a group of patients presenting with a progressive dementia syndrome characterized by predominant dysfunction in core executive functions, relatively young age of onset and positive biomarkers for Alzheimer's pathophysiology. Atypical frontal, dysexecutive/behavioural variants and early-onset variants of Alzheimer's disease have been previously reported, but no diagnostic criteria exist for a progressive dysexecutive syndrome. In this retrospective review, we report on 55 participants diagnosed with a clinically defined progressive dysexecutive syndrome with 18F-fluorodeoxyglucose-positron emission tomography and Alzheimer's disease biomarkers available. Sixty-two per cent of participants were female with a mean of 15.2 years of education. The mean age of reported symptom onset was 53.8 years while the mean age at diagnosis was 57.2 years. Participants and informants commonly referred to initial cognitive symptoms as 'memory problems' but upon further inquiry described problems with core executive functions of working memory, cognitive flexibility and cognitive inhibitory control. Multi-domain cognitive impairment was evident in neuropsychological testing with executive dysfunction most consistently affected. The frontal and parietal regions which overlap with working memory networks consistently demonstrated hypometabolism on positron emission tomography. Genetic testing for autosomal dominant genes was negative in all eight participants tested and at least one APOE ε4 allele was present in 14/26 participants tested. EEG was abnormal in 14/17 cases with 13 described as diffuse slowing. Furthermore, CSF or neuroimaging biomarkers were consistent with Alzheimer's disease pathophysiology, although CSF p-tau was normal in 24% of cases. Fifteen of the executive predominate participants enrolled in research neuroimaging protocols and were compared to amnestic (n = 110), visual (n = 18) and language (n = 7) predominate clinical phenotypes of Alzheimer's disease. This revealed a consistent pattern of hypometabolism in parieto-frontal brain regions supporting executive functions with relative sparing of the medial temporal lobe (versus amnestic phenotype), occipital (versus visual phenotype) and left temporal (versus language phenotype). We propose that this progressive dysexecutive syndrome should be recognized as a distinct clinical phenotype disambiguated from behavioural presentations and not linked specifically to the frontal lobe or a particular anatomic substrate without further study. This clinical presentation can be due to Alzheimer's disease but is likely not specific for any single aetiology. Diagnostic criteria are proposed to facilitate additional research into this understudied clinical presentation.

Background Posterior cortical atrophy and dementia with Lewy bodies are 2 distinct clinical syndromes, yet they can overlap in symptoms and occipital hypometabolism. Patients with dementia with Lewy bodies often have overlapping Alzheimer's disease pathology. Similarly, Lewy bodies can be found in patients with posterior cortical atrophy. We investigated differences in the distribution and magnitude of F18-AV-1451 uptake in patients with these 2 syndromes. Methods Consecutive patients with probable dementia with Lewy bodies (n = 33), posterior cortical atrophy (n = 18), and cognitively unimpaired controls (n = 100) underwent F-18-AV-1451 positron emission tomography. Regional differences in AV-1451 uptake were assessed using voxel-wise and an atlas-based approach. The greatest differences in AV-1451 uptake between patient groups were identified using area under receiver operating curve statistics, and a composite region was derived. Results AV-1451 uptake in both patient groups was predominantly localized to the lateral occipital regions, but the magnitude of uptake was markedly greater in posterior cortical atrophy compared with dementia with Lewy bodies. The posterior cortical atrophy group showed the greatest AV-1451 uptake throughout all the gray matter compared with that in other groups. The occipital composite region, consisting of superior, middle, and inferior occipital cortices, distinguished posterior cortical atrophy from dementia with Lewy bodies (area under the curve >0.97; P < 0.001, Bonferroni-corrected) with excellent sensitivity (88%) and specificity (100%). Conclusions Posterior cortical atrophy and dementia with Lewy bodies can share clinical features, and although the pattern of AV-1451 uptake in occipital cortices overlaps between these 2 syndromes, its magnitude is significantly higher in posterior cortical atrophy. (c) 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Reduced striatonigral uptake on ioflupane SPECT reflects dopamine deficiency, and this finding can be seen in patients with Lewy body disease (LBD) pathology. The patients with idiopathic REM sleep behavior disorder (iRBD) tend to have underlying LBD pathology, and a high percentage ultimately develop clinically-diagnosed dementia with Lewy bodies (DLB) or Parkinson's disease. We analyze ioflupane SPECT findings in patients with iRBD compared to Alzheimer's disease dementia (ADem; uptake tends to be normal) and DLB (uptake tends to be abnormal, using z-scores from DaTQUANT software (GE Healthcare). The mean DaTQUANT z-scores of the caudate and putamen for iRBD, ADem and DLB who had undergone ioflupane SPECT at the Mayo Alzheimer's Disease Research Center were analyzed and compared. Data on 22 iRBD patients (mean age 62.8 ± 7.6 years, 14 male) were analyzed and compared to 16 ADem and 40 DLB patients. The mean z-scores for each group of interest was iRBD - putamen: −0.19 ± 1.35 and caudate −0.09 ± 1.39; ADem - putamen: 0.47 ± 1.80 and caudate 0.89 ± 2.02, DLB - putamen: −1.99 ± 1.28 and caudate −2.40 ± 1.41. iRBD had z-scores which did not differ from ADem (putamen P=0.21, caudate p=0.08), but which were higher than DLB scores (putamen P<0.001, caudate P<0.001). Two (9%) iRBD patients had at least one z-score value <−1.5, compared to 1 (6%) for ADem (this patient had mixed LBD and Alzheimer's disease pathology) and 32 (80%) for DLB. The striatonigral uptake using DaTQUANT quantitation is reduced in a minority of iRBD patients. Analyses using longitudinal ioflupane SPECT and associated quantitation may provide insights on those iRBD patients who are evolving to DLB or Parkinson's disease. Supported by NIH grants (P50 AG016574, U01 AG006786, R01 AG015866, U01 NS100620), grant from GE Healthcare, Mayo Clinic Dorothy and Harry T. Mangurian Jr. Lewy Body Dementia Program, Deal Family Foundation and the Little Family Foundation.

The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [18F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration.

The aims of this study were: to examine regional rates of change in tau-PET uptake and grey matter volume in atypical Alzheimer's disease (AD); to investigate the role of age in such changes; to describe multimodal regional relationships between tau accumulation and atrophy. Thirty atypical AD patients underwent baseline and one-year follow-up MRI, [18F]AV-1451 PET and PiB PET. Region- and voxel-level rates of tau accumulation and grey matter atrophy relative to cognitively unimpaired individuals, and the influence of age on such rates, were assessed. Univariate and multivariate analyses were performed between baseline measurements and rates of change, between baseline tau and atrophy, and between the two rates of change. Regional patterns of change in tau and volume differed, with highest rates of tau accumulation in frontal lobe and highest rates of atrophy in temporoparietal regions. Age had a negative effect on disease progression, predominantly on tau, with younger patients having a more rapid accumulation. Baseline tau uptake and regions of tau accumulation were disconnected, with high baseline tau uptake across the cortex correlated with high rates of tau accumulation in frontal and sensorimotor regions. In contrast, baseline volume and atrophy were locally related in the occipitoparietal regions. Higher tau uptake at baseline was locally related to higher rates of atrophy in frontal and occipital lobes. Tau accumulation rates positively correlated with rates of atrophy. In summary, our study showed that tau accumulation and atrophy presented different regional patterns in atypical AD, with tau spreading into the frontal lobes while atrophy remains in temporoparietal and occipital cortex, suggesting a temporal disconnect between protein deposition and neurodegeneration.

IC-02-02 LONGITUDINAL EVALUATION OF TAU 18 PROPAGATION USING [ F]MK-6240 Tharick A. Pascoal, Mira Chamoun, Min Su Kang, Andrea Lessa Benedet, Joseph Therriault, Melissa Savard, Sulantha Mathotaarachchi, Cecile Tissot, Muhammad Naveed Iqbal Qureshi, Firoza Zubeida Lussier, Marlee Parson, Gassan Massarweh, Jean-Paul Soucy, Serge Gauthier, Pedro Rosa-Neto, McGill University, Montreal, QC, Canada; McGill Center for Studies in Aging, Montreal, QC, Canada; McGill Center for Research in Aging, Montreal, QC, Canada; Translational Neuroimaging LaboratoryMcGill University, Verdun, QC, Canada; McGill University Research Centre for Studies in Aging, Montreal, QC, Canada; Translational Neuroimaging Laboratory, Verdun, QC, Canada; McGill University Research Centre for Studies in Aging, Verdun, QC, Canada; Montreal Neurological Institute, Montreal, QC, Canada; PERFORM Centre, Concordia University, Montr eal, QC, Canada; Douglas Hospital Research Centre, Verdun, QC, Canada. Contact e-mail: tharick.alipascoal@mail. mcgill.ca

Patients with mild cognitive impairment (MCI) with visual hallucinations, REM-sleep behavior disorder, parkinsonism or fluctuations may have prodromal dementia with Lewy bodies (DLB), but they often have overlapping Alzheimer's disease-related pathology as well. Identifying the imaging findings associated with prodromal DLB is necessary for understanding the disease progression and predicting who will progress to probable DLB in the near future. We investigated the distribution and magnitude of regional brain atrophy rates in prodromal DLB. Using AV-1451 PET, we assessed the association of tau-related pathology and atrophy rates. Patients with MCI (mean age=70) with one or more clinical features of DLB (n=56), who either progressed to probable DLB (n=28) or remained stable (n=28), and age- and sex-matched cognitively unimpaired adults (CU; n=112) who underwent at least two serial MRIs (average follow-up=18 months) were included. Regional gray matter atrophy rates were measured using Tensor-based morphometry with Symmetric Diffeomorphic Normalization. Regional and voxel-wise atrophy rates were compared among DLB-progressors, MCI-stable, and CU. In a subset of MCI patients (n=24), we estimated regional correlations between atrophy rates and AV-1451 uptake on PET at the time of MRIs. DLB-progressors showed greater atrophy rates in multiple subcortical and cortical regions compared to CU: caudate, thalamus, lateral temporal, parahippocampal/entorhinal, posterior cingulate, precuneus and orbital-frontal (p<0.001), and also lateral occipital, fusiform and middle frontal cortices (p<0.05), but the atrophy rates in the amygdala (p=0.072) and hippocampus (p=0.18) were low. DLB-progressors, compared to MCI-stables, showed also greater atrophy rates in caudate, thalamus, lateral temporal, posterior cingulate and orbito-frontal cortices (p<0.05). MCI-stables, compared to CU, showed slightly greater atrophy rates in lateral temporal, parahippocampus/entorhinal, fusiform and middle frontal cortices (p<0.05). Higher AV-1451 uptake correlated with a greater atrophy rate in the amygdala (r=0.62; p=0.001) but not elsewhere.

Reduced striatonigral uptake on ioflupane-SPECT reflects dopamine deficiency, and this finding is typical of dementia with Lewy bodies (DLB) using classic mean putamen to occipital ratio quantitation. This method relies on manual drawing of regions of interest, which introduces variability. Quantitative methods using computerized algorithms are increasingly being used. In this report, we compare ioflupane-SPECT findings between patients with DLB and Alzheimer's disease dementia (ADem) using z-scores from DaTQUANT software (GE Healthcare). The mean DaTQUANT z-scores of the caudate and putamen for each patient with DLB and ADem in the Mayo Alzheimer's Disease Research Center who had undergone ioflupane-SPECT were analyzed and compared. Data on those who had undergone autopsy were also analyzed. Data on 58 patients (mean age 67 ± 9.9 years, 45 male) were analyzed, of whom 40 had DLB and 18 had ADem (Figure). DLB had lower z-scores than ADem. Mean z-scores for each disorder were putamen: −1.99 ± 1.28 and caudate: −2.40 ± 1.41 for DLB; putamen: 0.52 ± 1.70 and caudate: 0.84 ± 1.90 for ADem (putamen P<0.001, caudate P<0.001). Among those with autopsy [N=19; 12 with Lewy body disease (LBD) pathology, 5 with Alzheimer's disease (AD) pathology and 2 with mixed LBD/AD pathology], the mean z-score for the LBD +/- AD pathology group was putamen: −3.06 ± 1.59 and caudate: −2.78 ± 1.47, while the AD only pathology group had mean z-scores as follows - putamen: 0.67 ± 0.71 and caudate 0.44 ± 0.20 (putamen P<0.001, caudate P <0.001).

Reduced striatonigral uptake on ioflupane SPECT reflects dopamine deficiency, and this finding is typical in patients with Lewy body disease (LBD) pathology. Patients with nonamnestic mild cognitive impairment (naMCI) and/or REM sleep behavior disorder (RBD) tend to have underlying LBD pathology, whereas those with amnestic MCI (aMCI) and those without RBD tend to have Alzheimer's disease or other non-LBD pathologies. In this study, we analyzed ioflupane SPECT findings in patients with aMCI vs naMCI, and MCI with (+RBD) vs without RBD (-RBD), using z-scores from DaTQUANT software (GE Healthcare). The mean DaTQUANT z-scores of the caudate and putamen for each patient with MCI who had undergone ioflupane SPECT were analyzed and compared. Data on 36 MCI patients (mean age 70.6 ± 7.7 years, 29 males) were analyzed, of whom 13 had naMCI and 23 had aMCI, and 26 of all MCI had RBD. The mean z-scores for each subgroup of interest were naMCI - putamen: −1.08 ± 1.83 and caudate −0.87 ± 1.40; aMCI - putamen: −0.36 ± 1.99 and caudate −0.23 ± 1.91; MCI+RBD - putamen: −1.05 ± 1.80 and caudate −0.84 ± 1.54; MCI-RBD - putamen: 0.49 ± 1.92 and caudate 0.52 ± 1.96 (Figure). There were no differences between naMCI and aMCI (putamen p<0.29, caudate p<0.30), but MCI+RBD had lower z-scores than MCI-RBD (putamen p<0.03 and caudate p<0.03).

The clinical characteristics of prodromal Lewy body disease (LBD) preceding the phenotype of dementia with Lewy bodies (DLB) are still being defined. Antemortem data were analyzed from autopsied patients with either limbic-transitional or diffuse-neocortical LBD diagnosed with mild cognitive impairment (MCI) and followed prospectively through the Mayo Alzheimer's Disease Research Center. Patients were compared based on absence vs. presence of neocortical neurofibrillary tangles (NFT) (Braak stages 0 to 3 vs. stages 4 to 6). The sample included 74 patients (34 transitional, 40 diffuse). There were no clinical or demographic differences based on distribution of Lewy-related pathology. At the first MCI evaluation, the mean MMSE was 27±2, age of cognitive decline onset was 71±9 years, and death age was 81±8 years. During the MCI stage, 69% had at least one core DLB feature and 45% had two features. Probable REM sleep behavior disorder (RBD) was evident in 55%, parkinsonism in 35%, visual hallucinations in 24%, and fluctuations in 26%. When distinguished by the absence (n=36) vs. presence (n=38) of neocortical NFT, the latter group had greater amyloid-β neuritic plaque density (p<0.01) and fewer males (58% vs. 86%, p<0.01). One or more core DLB features during the MCI stage was more likely in LBD without neocortical NFT (83% vs. 55%, p<0.01). Specifically, before dementia was diagnosed, those without neocortical NFT were more likely to have RBD (72% vs. 40%, p=0.005), parkinsonism (47% vs. 24%, p=0.03), and visual hallucinations (36% vs. 13%, p=0.02) but fluctuations were equally likely (31% vs. 21%, p=0.35). All but 5 patients developed dementia with a mean duration from MCI to dementia of 2±1 years. By the end of life, 92% had at least one core DLB feature, and 80% had two or more core features, with greater frequency in LBD without comorbid neocortical NFT (97% vs. 63%, p<0.01). In the MCI stage of evolving DLB, 69% had at least one core DLB feature. Patients with neocortical NFT were less likely to have core features in the pre-dementia stage. These findings underscore the need for biomarkers that are sensitive and specific to Lewy-related pathology.