Nightmares without atonia as an early symptom of diffuse Lewy bodies disease

A male 70 years old patient with diffuse or ''pure'' Lewy body disease is described. The diagnosis was made based on clinical features of nightmares with no atonia, attention deficits with fluctuation in cognitive function, incapacity to find his way around the neighbourhood and other formerly familiar environments and mild neuropsychiatric symptoms. Neuropsychological assessment showed memory deficits, visuospatial and visuo-constructive disturbances. He had neither parkinsonism nor recurrent visual hallucinations typically well formed and detailled. Neuroimaging (computed tomography and magnetic resonance spectroscopy) showed mild diffuse cortical atrophy, mostly on the left temporal lobe and a decrease of N-acetil-aspartate levels. A cholinesterase inhibitor was prescribed to this patient during 6 months with clinically relevant behavioral effect. Diagnosis confirmation was made by post-mortem neuropathological findings. Macroscopical features were mild atrophy on the frontal, parietal and temporal lobes, notedly on the frontal lobes. Microscopically, there was neuronal loss and diffuse classic Lewy bodies. Brainstem (substantia nigra, raphe nucleus, locus coeruleus, pedunculopontine nucleus), limbic cortex, and neocortex (frontal, parietal and temporal) were the areas of predilection for Lewy bodies. Hematoxylin-eosin and Bielschowsky staining did not show neuronal swelling (balooned cell), argyrophilic inclusion (Pick's bodies), neurofibrillary tangles nor senile plaques. Immunohistochemical staining for anti-tau, anti-beta-amyloid, and anti-prion protein were negative. Antiubiquitine reaction was positive for Lewy body in the cerebral cortex and brainstem.

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Parkinson's Disease Dementia and Lewy Body Disease

Seminars in Neurology ◽

10.1055/s-0039-1678579 ◽

2019 ◽

Vol 39 (02) ◽

pp. 274-282 ◽

Cited By ~ 5

Author(s):

Mine Sezgin ◽

Basar Bilgic ◽

Sule Tinaz ◽

Murat Emre

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Body ◽

Functional Neuroimaging ◽

Neuropsychiatric Symptoms ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Behavioral Symptoms ◽

Cognitive Symptoms ◽

Parkinson’S Disease Dementia

AbstractDementia with Lewy bodies (DLB) and Parkinson's disease dementia (PD-D) are Lewy body-related neurodegenerative disorders sharing common clinical and neuropathological findings. The clinical features of both conditions include cognitive impairment, behavioral symptoms, autonomic dysfunction, sleep disorders, and parkinsonism. The cognitive profile of both disorders is characterized by particularly severe deficits in executive and visuospatial functions as well as attention. Clinical differentiation between DLB and PD-D is based on an arbitrary distinction between the time of onset of parkinsonism and cognitive symptoms; extrapyramidal symptoms precede dementia in PD-D, whereas it coincides with or follows dementia within 1 year in DLB. When the clinical picture is fully developed, DLB and PD-D are practically indistinguishable. Although the diagnosis is basically clinical, structural and functional neuroimaging as well as cerebrospinal fluid biomarkers may help the clinician in the diagnosis. Placebo-controlled randomized trials of the cholinesterase inhibitors have shown modest but significant benefits in cognition, global function, and neuropsychiatric symptoms in both disorders. Behavioral symptoms such as hallucinations and delusions should be treated with caution with antipsychotics, as they have the potential to worsen motor and cognitive symptoms.

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Aging & Dementia - 4 Risk Factors for Earlier Onset of Dementia in Pure Alzheimer’s Disease, Mixed Alzheimer’s with Lewy Bodies, and Pure Lewy Body Disease: Autopsy-Confirmed Cases from the National Alzheimer’s Coordinating Center

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acy060.04 ◽

2018 ◽

Vol 33 (6) ◽

pp. 692-702

Author(s):

J Schaffert ◽

C LoBue ◽

L Lacritz ◽

K Wilmoth ◽

T Nguyen ◽

...

Keyword(s):

Risk Factors ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Lewy Body ◽

Lewy Bodies ◽

Lewy Body Disease

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Clinical Aspects of Non-Alzheimer Disease Dementias

10.2310/fm.1336 ◽

2017 ◽

Author(s):

David Knopman

Keyword(s):

Cognitive Impairment ◽

Alzheimer Disease ◽

Cerebrovascular Disease ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Clinical Aspects ◽

Key Words Dementia ◽

Sleep Behavior

There are a relatively small number of disorders that account for the majority of dementia in the elderly that is not Alzheimer disease (AD): cerebrovascular disease, Lewy body disease (α-synucleinopathies), and the frontotemporal lobar degenerations. Cerebrovascular disease and Lewy body disease account for most non-AD dementia among persons in the eighth decade of life and beyond. These two frequently co-occur with AD but can occur in their pure forms rarely (in the case of dementia associated with cerebrovascular disease) or more commonly (in the case of Lewy body disease). There is no one cognitive or behavioral syndrome associated with cerebrovascular disease; however, attempts to isolate a common theme suggest that cognitive slowing is typical of cerebrovascular contributions to cognitive impairment. Cerebrovascular pathology relevant to cognitive impairment accumulates subclinically more commonly than it causes acute, strokelike declines in cognition. Dementia with Lewy bodies is a multidimensional disorder that includes a nonamnestic dementia, Parkinson disease or at least some parkinsonian features, a disorder of sleep and wakefulness, autonomic disturbances, and depression. The disorders of sleep prominently include rapid eye movement sleep behavior disorder, excessive daytime sleepiness, visual hallucinations, and marked fluctuations in level of alertness. The frontotemporal lobar degenerations are nearly as common as causes of dementia in persons under age 65 as is AD. The group of disorders includes two cognitive syndromes (primary progressive aphasia and behavior variant frontotemporal dementia) and two neuropathologic subtypes (tauopathy and TDP43 proteinopathy) and is associated with three major autosomal dominant genetic mutations (in MAPT, GRN, and C9ORF72). Key words: dementia with Lewy bodies, frontotemporal lobar degenerations, vascular cognitive impairment

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Diagnostic accuracy of dopaminergic imaging in prodromal dementia with Lewy bodies

Psychological Medicine ◽

10.1017/s0033291718000995 ◽

2018 ◽

Vol 49 (3) ◽

pp. 396-402 ◽

Cited By ~ 15

Author(s):

Alan J. Thomas ◽

Paul Donaghy ◽

Gemma Roberts ◽

Sean J. Colloby ◽

Nicky A. Barnett ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Lewy Body Disease ◽

High Specificity ◽

Diagnostic Confidence ◽

Neuropsychological Assessments ◽

Diagnostic Symptoms ◽

Prodromal Dementia

AbstractBackgroundDopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage.MethodsWe recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal.ResultsThe sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2–68.6], with a specificity of 89.0% (95% CI 70.8–97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5–77.4) and in possible MCI-LB was 40.0% (95% CI 16.4–67.7).ConclusionsDopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.

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18F-fluorodeoxyglucose positron emission tomography in dementia with Lewy bodies

Brain Communications ◽

10.1093/braincomms/fcaa040 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Jonathan Graff-Radford ◽

Timothy G Lesnick ◽

Rodolfo Savica ◽

Qin Chen ◽

Tanis J Ferman ◽

...

Keyword(s):

Lewy Body ◽

Dementia With Lewy Bodies ◽

Rating Scale ◽

Clinical Course ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Diffuse Lewy Body Disease ◽

18F Fluorodeoxyglucose ◽

Alzheimer’S Pathology ◽

Fluorodeoxyglucose Pet

Abstract Among individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether 18F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these 18F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease (n = 34) and a clinically diagnosed group of dementia with Lewy bodies (n = 87). A subset of the clinically diagnosed group was followed longitudinally (n = 51). We evaluated whether 18F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher 18F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.

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Fabry Disease With Concomitant Lewy Body Disease

Journal of Neuropathology & Experimental Neurology ◽

10.1093/jnen/nlz139 ◽

2019 ◽

Vol 79 (4) ◽

pp. 378-392 ◽

Cited By ~ 2

Author(s):

Kelly Del Tredici ◽

Albert C Ludolph ◽

Simone Feldengut ◽

Christian Jacob ◽

Heinz Reichmann ◽

...

Keyword(s):

Fabry Disease ◽

Lewy Body ◽

Neuronal Loss ◽

Lewy Body Disease ◽

Therapeutic Interventions ◽

Substantia Nigra Pars Compacta ◽

Lysosomal Storage ◽

Lewy Neurites ◽

Cerebrovascular Lesions ◽

Lewy Pathology

Abstract Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cognitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, α-synuclein, collagen IV) and neuropathological staging were performed on 100-µm sections. Tissue from the enteric or peripheral nervous system was unavailable. As controls, a second cognitively unimpaired 50-year-old male FD patient without LP or motor symptoms and 3 age-matched individuals were examined. Inclusion body pathology was semiquantitatively evaluated. Although Lewy neurites/bodies were not present in the 50-year-old individual or in controls, severe neuronal loss in the substantia nigra pars compacta and LP corresponding to neuropathological stage 4 of Parkinson disease was seen in the 58-year-old FD patient. Major cerebrovascular lesions and/or additional pathologies were absent in this individual. We conclude that Lewy body disease with parkinsonism can occur within the context of FD. Further studies determining the frequencies of both inclusion pathologies in large autopsy-controlled FD cohorts could help clarify the implications of both lesions for disease pathogenesis, potential spreading mechanisms, and therapeutic interventions.

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Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases

Acta Neuropathologica ◽

10.1007/s00401-020-02233-8 ◽

2020 ◽

Vol 141 (1) ◽

pp. 25-37

Author(s):

Zen-ichi Tanei ◽

Yuko Saito ◽

Shinji Ito ◽

Tomoyasu Matsubara ◽

Atsuko Motoda ◽

...

Keyword(s):

Nervous System ◽

Lewy Body ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Wide Distribution ◽

Esophageal Wall ◽

Motor Symptoms ◽

Aging Research ◽

Lewy Pathology ◽

Japanese Cohort

AbstractLewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson’s disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach’s plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner’s plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD.

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14-3-3 protein sigma isoform co-localizes with phosphorylated α-synuclein in lewy bodies and lewy neurites of patients with lewy body disease

Journal of the Neurological Sciences ◽

10.1016/j.jns.2017.08.2729 ◽

2017 ◽

Vol 381 ◽

pp. 969

Author(s):

T. Umahara ◽

K. Wakabayashi ◽

K. Hirokawa ◽

H. Hanyu ◽

T. Uchihara

Keyword(s):

Lewy Body ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Lewy Neurites

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Deubiquitinase Usp8 regulates α-synuclein clearance and modifies its toxicity in Lewy body disease

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1523597113 ◽

2016 ◽

Vol 113 (32) ◽

pp. E4688-E4697 ◽

Cited By ~ 52

Author(s):

Zoi Alexopoulou ◽

Johannes Lang ◽

Rebecca M. Perrett ◽

Myriam Elschami ◽

Madeleine E. D. Hurry ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Lewy Body ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Cell Loss ◽

Lysosomal Degradation ◽

Endosomal Membranes ◽

Locomotor Deficits ◽

Outstanding Question ◽

In Cells

In Parkinson’s disease, misfolded α-synuclein accumulates, often in a ubiquitinated form, in neuronal inclusions termed Lewy bodies. An important outstanding question is whether ubiquitination in Lewy bodies is directly relevant to α-synuclein trafficking or turnover and Parkinson’s pathogenesis. By comparative analysis in human postmortem brains, we found that ubiquitin immunoreactivity in Lewy bodies is largely due to K63-linked ubiquitin chains and markedly reduced in the substantia nigra compared with the neocortex. The ubiquitin staining in cells with Lewy bodies inversely correlated with the content and pathological localization of the deubiquitinase Usp8. Usp8 interacted and partly colocalized with α-synuclein in endosomal membranes and, both in cells and after purification, it deubiquitinated K63-linked chains on α-synuclein. Knockdown of Usp8 in the Drosophila eye reduced α-synuclein levels and α-synuclein–induced eye toxicity. Accordingly, in human cells, Usp8 knockdown increased the lysosomal degradation of α-synuclein. In the dopaminergic neurons of the Drosophila model, unlike knockdown of other deubiquitinases, Usp8 protected from α-synuclein–induced locomotor deficits and cell loss. These findings strongly suggest that removal of K63-linked ubiquitin chains on α-synuclein by Usp8 is a critical mechanism that reduces its lysosomal degradation in dopaminergic neurons and may contribute to α-synuclein accumulation in Lewy body disease.

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