The North American Prodromal Synucleinopathy (NAPS) Consortium: Baseline neuropsychological findings in 136 participants
Julie A. FieldsBradley F. BoeveLeah K. ForsbergErik K. St. LouisRuth KraftKevin M. NelsonPaul TimmLuke TeigenAlon Y. AvidanAdreanne RiveraRonald B. PostumaJean‐François GagnonAmélie PelletierMichael J. HowellCarlos H. SchenckJosh De KamKelly J. RybergRebekah L. S. SummersDonald L. BliwiseDaniel E. HuddlestonCathy Wood‐SiverioAleksandar VidenovićMatthew StauderSamantha HershSusan R. CriswellJennifer McLelandYo‐El S. Ju
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Abstract Background It is important to determine the natural history of individuals with RBD and generate clinical and neuropsychological data for planning disease‐modifying trials to delay or prevent phenoconversion of RBD to an overt synucleinopathy such as dementia with Lewy bodies, Parkinson’s disease, or multiple system atrophy. Our objective is to present initial neuropsychological data on 136 participants with REM sleep behavior disorder (RBD) without an overt synucleinopathy who are in the North American Prodromal Synucleinopathy (NAPS; R34AG056639) Consortium. Method As part of the NAPS protocol (www.naps‐rbd.org), investigators at 10 centers in North America are enrolling a target of 360 participants with RBD. A comprehensive clinical battery and a set of neuropsychological measures (using the National Alzheimer Coordinating Center Uniform Data Set version 3 or UDS3) are performed at each visit. Result Participants were 82% male, ranging in age from 35‐85 (Mean=65.9, SD=15.9) and education from 8‐20 years (Mean=15.9, SD=3.1). Only 17 participants (13%) were impairment‐free across all tests administered. The proportions of participants with impaired scores were tabulated as follows ( < ‐1.5 SD after adjustment for age, sex, and education): global cognition – 17%; attention/executive functioning – 10‐20% across measures; language – 14‐24% across measures; visuospatial – 16%; and episodic learning/memory – 18‐25% across measures. Of all participants, 79 (58%) showed impairments < ‐2 SD. Moreover, 53% of those with cognitive impairment involved impact in 2 domains, an additional 20% in 3 domains, and another 4% was impaired in all domains. The combination of attention/executive and language was most often observed. Conclusion Collection of a comprehensive set of clinical and neuropsychological measures is feasible and tolerated in RBD patients. Using the UDS3 neuropsychological test battery, impairment in one or more measures was present in 87% of participants, and 58% showed impairments greater than 2 SD below the mean in the absence of a clinical diagnosis of dementia. Impairments in > 2 domains was common, most frequently involving attention/executive and language. Future longitudinal assessments will be required to determine the predictive utility of neuropsychological performance for phenoconversion of RBD to an overt synucleinopathy.幻聴は精神科領域において最も一般的な症候の 1 つであり, その研究は主に統合失調症などの機能性精神疾患で論ぜられてきた。一方, 器質性精神疾患の幻覚は幻聴よりも幻視が特徴的であり, 幻視はレビー小体型認知症 (dementia with Lewy bodies : DLB) の中核症状の 1 つとして位置づけられている。 しかし DLB において幻聴は決して稀な症候ではなく, 我々の調査では, DLB 患者の約 3 人に 1 人が幻聴を有していた。また DLB の幻聴の大半は幻視とともに出現し, その多くが「幻視の人物が話す」という特徴を有していた。さらに幻聴の発現には, 妄想, うつ, 難聴, 女性などの因子が関与していた。DLB の幻聴は, そうした多様な因子が幻視に作用することによって引き起こされる可能性が考えられた。
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Lewy body
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Dementia with Lewy bodies (DLB) is currently diagnosed clinically by identifying dementia in combination with a number of hallmark features: REM sleep behavior disorder (RBD), prominent visual hallucinations, parkinsonism, and marked fluctuations of cognition and alertness.1 DLB is often underdiagnosed, suggesting a role for biomarkers. The main differential diagnosis of DLB is Alzheimer disease (AD); whereas both AD and DLB have amyloid deposition, DLB also has additional α-synuclein deposition (Lewy bodies and Lewy neurites). So, one way to establish DLB diagnosis might be to detect the α-synucleinopathy itself.
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Lewy body
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Familial cases of dementia with Lewy bodies (DLB) are rare. The authors describe two small kindreds with familial DLB: one with pure DLB meeting consensus criteria for DLB and one with coexistent AD pathology that did not fulfill DLB criteria. The authors call attention to the diverse features of DLB and suggest that current clinical criteria may not detect all cases. Familial DLB is clinically heterogeneous and occurs with or without coexistent AD, suggesting the relevance of LB pathology for the developing dementia.
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123I-FP-CIT SPECT can help in the discrimination of probable dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, its usefulness in more clinically uncertain “possible DLB” cases is unknown. The main aim of this study was to determine the diagnostic accuracy of 123I-FP-CIT SPECT in possible DLB cases, validated by final clinical diagnosis twelve months later. We undertook a twelve month follow-up of 325 subjects with probable or possible DLB or non-DLB dementia who had previously undergone 123I-FP-CIT SPECT as part of phase III multicentre study. A consensus panel established diagnosis at 12 months in 264 cases, blind to SPECT findings. In the overall study, SPECT scans had a mean sensitivity of 78% for detecting probable DLB, with a specificity of 93% for excluding non-DLB dementia. 44 possible DLB cases were followed-up, of whom 19 (43%) became probable DLB cases, 7 (16%) non-DLB and 18 (41%) remained possible cases. Of the 19 who became probable DLB, 12 had abnormal scans, while all 7 cases who became non-DLB had normal scans (sensitivity 63%, specificity 100%, positive predictive value 100%). Our findings suggest an important and clinically useful role 123I-FP-CIT SPECT in diagnostically more uncertain DLB cases, as an abnormal scan in a possible DLB subject is highly suggestive of future development of probable DLB.
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Background Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) is not straightforward, especially in the early stages of disease. We compared AD biomarkers (phospho-Tau 181 , total-Tau, Aβ42 and Aβ40) in cerebrospinal fluid (CSF) of patients with DLB and AD, focusing especially on the prodromal stage. Methods A total of 1221 CSF were collected in different memory centres (ePLM network) in France and analysed retrospectively. Samples were obtained from patients with prodromal DLB (pro-DLB; n=57), DLB dementia (DLB-d; n=154), prodromal AD (pro-AD; n=132) and AD dementia (n=783), and control subjects (CS; n=95). These centres use the same diagnostic procedure and criteria to evaluate the patients. Results In patients with pro-DLB, CSF Aβ42 levels appeared much less disrupted than in patients at the demented stage (DLB-d) (P<0.05 CS>pro-DLB; P<0.001 CS>DLB-d). On average, Aβ40 levels in patients with DLB (pro-DLB and DLB-d) were much below those in patients with pro-AD (P<0.001 DLB groups<pro-AD). The Aβ42/Aβ40 ratio in patients with pro-DLB remained close to that of CS. t-Tau and phospho-Tau 181 levels were unaltered in patients with DLB (pro-DLB and DLB-d). Conclusions Reduced levels of CSF Aβ42 were found in patients with DLB but rather at a later stage, reaching those of patients with AD, in whom Aβ42 levels were decreased even at the prodromal stage. At the prodromal stage of DLB, the majority of patients presented a normal CSF profile. CSF t-Tau and phospho-Tau 181 were the best biomarkers to discriminate between AD and DLB, whatever the stage of disease.
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123I-FP-CIT SPECT can help in the discrimination of probable dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). However, its usefulness in more clinically uncertain “possible DLB” cases is unknown. The main aim of this study was to determine the diagnostic accuracy of 123I-FP-CIT SPECT in possible DLB cases, validated by final clinical diagnosis twelve months later. We undertook a twelve month follow-up of 325 subjects with probable or possible DLB or non-DLB dementia who had previously undergone 123I-FP-CIT SPECT as part of phase III multicentre study. A consensus panel established diagnosis at 12 months in 264 cases, blind to SPECT findings. In the overall study, SPECT scans had a mean sensitivity of 78% for detecting probable DLB, with a specificity of 93% for excluding non-DLB dementia. 44 possible DLB cases were followed-up, of whom 19 (43%) became probable DLB cases, 7 (16%) non-DLB and 18 (41%) remained possible cases. Of the 19 who became probable DLB, 12 had abnormal scans, while all 7 cases who became non-DLB had normal scans (sensitivity 63%, specificity 100%, positive predictive value 100%). Our findings suggest an important and clinically useful role 123I-FP-CIT SPECT in diagnostically more uncertain DLB cases, as an abnormal scan in a possible DLB subject is highly suggestive of future development of probable DLB.
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Dementia with Lewy bodies (DLB) is the second commonest cause of dementia in the general population. Several researches have established an association between Down syndrome (DS) and Alzheimer’s disease. Very few studies have however showed such an association between dementia with Lewy bodies and Down syndrome. The occurrence of DLB in persons with DS is widely unrecognized. We report the first case of a person who fulfils the operational criteria for DLB and was also found to have Lewy bodies on neuropathological examination. It is important to make an early and accurate diagnosis as patients with DLB may respond differently than Alzheimer’s dementia patients to certain behavioural and medical treatments.
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Te lecture presents modern concept of the symptoms, diagnosis and treatment of dementia with Lewy bodies (DLB), which accounts for about 10% of cases of dementia. Te nosological status of DLB and the problem of ratio of DLB and Parkinson’s disease which, apparently, represent two phenotypic variants of one neurodegenerative process («diseases with Lewy bodies») are considered in historical aspect. Approaches to the diagnosis and coding of DLB in accordance with ICD-10 are proposed. Te role of cholinesterase inhibitors, antipsychotics, levodopa, rasagiline and other drugs in the treatment of patients with DLB is аnalyzed.
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