Lewy Type Research Articles

Predicting Post-Mortem α-Synuclein Pathology by the Combined Presence of Probable REM sleep behavior disorder and Hyposmia.

Idiopathic rapid eye movement sleep behavior disorder (RBD) is a strong known predictor of a final clinicopathological diagnosis of a Lewy type α-synucleinopathy (LTS). Olfactory dysfunction is an early symptom of synucleinopathies and has been repeatedly associated with the presence of post-mortem LTS. To assess the combined value of a clinician diagnosis of probable RBD (PRBD) and hyposmia in predicting the post-mortem presence of LTS in a broader, less-selected, volunteer elderly population. We studied 652 autopsied subjects from the Arizona Study of Aging and Neurodegenerative Disorders, which were evaluated for PRBD, had completed annual movement and cognitive assessments, and had at least one the University of Pennsylvania Smell Identification Test (UPSIT) olfactory test. Histological evidence of LTS was significantly more frequent in those who had PRBD (112/152: 73.7%) than those without (177/494: 35.8%) (P < 0.001). LTS was more frequent in cases with PRBD and a low UPSIT score (90.8%) compared to cases with PRBD only (73.7%) (P < 0.001) or cases with a low UPSIT score only (69.4%) (P < 0.001). Sensitivity of PRBD diagnosis for predicting LTS was 38.8% and specificity 88.8%, whereas sensitivity of a low UPSIT score was 74.4% and specificity 73.4% (Youden's index = 0.276 for PRBD, 0.478 for UPSIT). When combining both measures, sensitivity was 34.3% and specificity increased to 97.2%. PRBD, diagnosed without sleep study confirmation, combined with a reduced olfactory performance is highly specific for predicting post-mortem presence of LTS. The combination of both measures may provide a cost-effective means of predicting LTS in a broader community.

Study protocol on Alzheimer\u2019s disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions

BackgroundOne of the crucial challenges for the future of therapeutic approaches to Alzheimer’s disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions.MethodsA multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months.DiscussionThis study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns.Trial registrationNCT02052947.

Predicting alpha-synuclein pathology by REM sleep behavior disorder diagnosis

Inability to accurately diagnose Lewy type alpha-synucleinopathy (LTS) pre-mortem has been a major obstacle to clinical care and research. Probable REM sleep behavior disorder (PRBD) diagnosed with support of instruments such as the Mayo Sleep Questionnaire (MSQ) may provide a cost effective means of predicting LTS. Since 2007, 602 subjects in the Arizona Study of Aging and Neurodegenerative Disorders had clinician assessment for PRBD (298 with, 304 without support of the MSQ), completed cognitive and movement examinations, and had neuropathological assessment. Mean age at death was 84.8 years. Histological evidence of LTS was found in 80/101(79.2%) cases with PRBD and 198/501 (39.5%) without PRBD (p < 0.001). Overall sensitivity for predicting LTS by PRBD diagnosis was 28.8%, specificity 93.5%, positive predictive value (PPV) 79.2%, negative predictive value (NPV) 60.5%. Diagnosis of PRBD was less frequently present in subjects without LTS [4/105 (3.8%) of healthy controls, 42/255 (16.5%) AD, 2/33 (6.1%) progressive supranuclear palsy (PSP) without LTS] than in subjects with LTS [11/46 (23.9%) DLB, 58/104 (55.8%) PD, and 4/16 (25.0%) PSP with LTS.] PRBD was not present in any of 46 subjects with incidental Lewy body disease (ILBD). MSQ-supported diagnosis of PRBD appears useful for predicting LTS in manifest neurodegenerative disease, but not necessarily ILBD. Additional prospective autopsy research, including well-characterized polysomnogram-confirmed RBD subjects, is needed to elucidate the earliest tissue abnormalities in the “idiopathic” (premotor/pre-dementia) stage of RBD.

Association Between Pathology and Electroencephalographic Activity in Parkinson's Disease.

The key mechanisms that connect Parkinson's disease pathology with dementia are unclear. We tested the hypothesis that the quantitative spectral electroencephalographic measure, delta bandpower, correlates with Lewy type synucleinopathy on pathological examination in Parkinson's disease. As a corollary hypothesis, we analyzed whether there would be delta bandpower electroencephalographic differences between Parkinson's disease dementia cases with and without pathological criteria for Alzheimer's disease. We used pathological examination results from 44 Parkinson's disease subjects from our brain bank with various degrees of cognitive decline, who had undergone electroencephalography. Pathological grading for Lewy type synucleinopathy, plaques, tangles, and indications of vascular pathology in subcortical and cortical areas were correlated with the most associated electroencephalographic biomarker with Parkinson's disease dementia in our laboratory, delta bandpower. Group differences for all spectral electroencephalographic measures were also analyzed between cases with and without pathological criteria for Alzheimer's disease. Findings revealed significant correlations between delta bandpower with Lewy type synucleinopathy, whereas indications of Alzheimer's disease or vascular pathology had nonsignificant correlation. The strongest association was with delta bandpower and Lewy type synucleinopathy in the anterior cingulate region. Mean delta bandpower was higher in the group for Parkinson's disease dementia with Alzheimer's disease pathology criteria than without. Lewy type synucleinopathy severity appears to be more associated with increased delta bandpower than with Alzheimer's disease pathology or indications of vascular pathology over all cases. However, the presence of Alzheimer's pathology may associate with more cortex physiological disruption in a subset of cases.

Evaluation of alpha-synuclein immunohistochemical methods for the detection of Lewy-type synucleinopathy in gastrointestinal biopsies.

The observation showing that Lewy type synucleinopathy (LTS), the pathological hallmark of Parkinson’s disease (PD), is found in the gut of almost all PD subjects led to a substantial amount of research to develop a diagnostic procedure in living patients based on endoscopically obtained gastrointestinal biopsies. However, the existing studies have provided conflicting results regarding the sensitivity and specificity of gastrointestinal biopsies for the detection of LTS. We therefore undertook a multi-center staining and blinded judging of a common set of slides from colonic biopsies to determine the optimal protocol for the detection of LTS. Four different immunohistochemical methods, developed in four separate expert laboratories, were evaluated for their sensitivity and specificity to detect enteric LTS. Test sets of formalin-fixed, paraffin-embedded sections from biopsies of 9 PD subjects and 3 controls were stained with the 4 methods and graded by 4 different observers. Four types of staining morphology (granular staining in the lamina propria, perivascular/vascular wall staining in the submucosa, lacy-granular pattern in the submucosa and epithelial cell nuclear staining) were variably observed in the slides stained by the 4 methods. Positive alpha-synuclein staining was observed by all 5 judges in most of the slides from control cases, regardless of the staining methods that were used. Moreover, none of the tested method or staining pattern had a specificity and sensitivity more than 80 % regarding to PD. Overall, our study suggest that the tested methods are not adequate for the prediction of PD using gastrointestinal biopsies. Future studies are warranted to test new immunostaining methods.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0305-8) contains supplementary material, which is available to authorized users.

Peripheral Synucleinopathy in Early Parkinson's Disease: Submandibular Gland Needle Biopsy Findings.

Finding a peripheral tissue biopsy site to diagnose early PD would be of value for clinical care, biomarker validation, and as research enrollment criteria. Whereas autopsy and advanced PD studies suggest that the submandibular gland is an important biopsy site, there are no studies in early PD. The aim of this study was to determine whether needle biopsy of the submandibular gland reveals Lewy type alpha-synucleinopathy in early PD. Twenty-five early PD (duration < 5 years) and 10 controls underwent transcutaneous needle core biopsies of the submandibular gland. Tissue was stained for phosphorylated alpha-synuclein, reviewed blind to clinical diagnosis, and only nerve element staining was considered positive. Mean (standard deviation) age was 69.5 (8.3) for the PD group, 64.8 (8.0) years for controls, and disease duration 2.6 (1.1) years. Six PD and 1 control subject had inadequate glandular tissue. Positive staining was found in 14 of 19 (74%) PD and 2 of 9 (22%) control subjects. PD-positive and -negative cases did not differ clinically. Adverse events (mainly swelling and bruising) were common (77% of cases), but were minor and transient. Submandibular gland needle biopsies identified phosphorylated alpha-synuclein staining in 74% of early PD subjects. False positives may be true false positives or may represent prodromal PD. If confirmed in larger studies with eventual autopsy confirmation, the potential value of submandibular gland biopsies for early PD may be to aid in clinical trial inclusion/exclusion and eventually serve as a gold standard for biomarker studies short of autopsy confirmation.

Submandibular gland needle biopsy for the diagnosis of Parkinson disease

This study investigates salivary gland biopsies in living patients with Parkinson disease (PD). Patients with PD for ≥5 years underwent outpatient transcutaneous needle core biopsies (18-gauge or 16-gauge) of 1 submandibular gland. Minor salivary glands were removed via a small incision in the lower lip. Tissue was fixed in formalin and serial 6-µm paraffin sections were immunohistochemically stained for phosphorylated α-synuclein and reviewed for evidence of Lewy type α-synucleinopathy (LTS). Fifteen patients with PD were biopsied: 9 female/6 male, mean age 68.7 years, mean PD duration 11.8 years. Twelve of the needle core biopsies had microscopically evident submandibular gland tissue to assess and 9/12 (75%) had LTS. Only 1/15 (6.7%) minor salivary gland biopsies were positive for LTS. Five patients had an adverse event; all were minor and transient. This study demonstrates the feasibility of performing needle core biopsies of the submandibular gland in living patients with PD to assess LTS. Although this was a small study, this tissue biopsy method may be important for tissue confirmation of PD in patients being considered for invasive procedures and in research studies of other PD biomarkers.

Evaluation of β‐Alanine‐ and GABA‐Substituted Peptides as Inhibitors of Disease‐Linked Protein Aggregation

Inhibition of amyoid formation—the β-peptide way: Introducing β-amino acids into short peptides is presented as a novel method of preventing aggregation of amyloid proteins. The data suggest a common precursor to design agents to treat Lewy body disease, Alzheimer's and type 2 diabetes.

Neurodegenerative features in developmental brain disorders

The authors examined the occurrence of neurofibrillary tangles (NFT), senile plaques, spheroids in Goll's nucleus, grumose or foamy spheroid bodies (GFSB) in the basal ganglia, and hyaline inclusions in the brainstem nuclei in 62 patients under 40 years of age with non‐progressive developmental brain disorders. Five cases had demonstrated NFT, which tended to be confined to the subcortical nuclei, whereas no senile plaques were identified in any case. Spheroids in Goll's nucleus were significantly increased in three cases of congenital brain anomalies and five cases of perinatal hypoxic ischemic encephalopathy. The GFSB‐positive subjects were clinicopathologically divided into two subgroups consisting of four cases of congenital malformations, which were also associated with severe respiratory failure, and six cases of perinatal brain disorders in which the basal ganglia were severely affected. Eosinophilic intracytoplasmic inclusions, unlike the hyaline inclusions of the Lewy type, were found in the substantia nigra and/or locus ceruleus in two subjects. It is speculated that a variety of mechanisms, including accelerated aging and anoxic insults, may be involved in the increased occurrence of NFT and/or spheroids in non‐progressive developmental disorders. A detailed investigation is useful to clarify the neuronal changes secondary to the brain damages early in development.

Neurodegenerative features in developmental brain disorders.

The authors examined the occurrence of neurofibrillary tangles (NFT), senile plaques, spheroids in Goll's nucleus, grumose or foamy spheroid bodies (GFSB) in the basal ganglia, and hyaline inclusions in the brainstem nuclei in 62 patients under 40 years of age with non-progressive developmental brain disorders. Five cases had demonstrated NFT, which tended to be confined to the subcortical nuclei, whereas no senile plaques were identified in any case. Spheroids in Goll's nucleus were significantly increased in three cases of congenital brain anomalies and five cases of perinatal hypoxic ischemic encephalopathy. The GFSB-positive subjects were clinicopathologically divided into two subgroups consisting of four cases of congenital malformations, which were also associated with severe respiratory failure, and six cases of perinatal brain disorders in which the basal ganglia were severely affected. Eosinophilic intracytoplasmic inclusions, unlike the hyaline inclusions of the Lewy type, were found in the substantia nigra and/or locus ceruleus in two subjects. It is speculated that a variety of mechanisms, including accelerated aging and anoxic insults, may be involved in the increased occurrence of NFT and/or spheroids in non-progressive developmental disorders. A detailed investigation is useful to clarify the neuronal changes secondary to the brain damages early in development.

CR-MEROMORPHIC EXTENSION AND THE NONEMBEDDABILITY OF THE ANDREOTTI–ROSSI CR STRUCTURE IN THE PROJECTIVE SPACE

Let [Formula: see text] be a polynomially convex compact set and let M be a (2p-1) dimensional (p ≥ 2) maximally complex bounded scarred C1 submanifold of [Formula: see text], irreducible in the current sense. According to Harvey–Lawson [14] and Chirka [4], there exists a bounded irreducible analytic set [Formula: see text] such that [M]=±d[T]. In this paper, we prove that every CR-meromorphic map carrying M into a projective manifold V extends to a meromorphic map F:T → V. We extend the notion of CR-meromorphic maps to CR submanifolds of [Formula: see text] and give another proof of our extension theorem which extends to the greater codimensional case. We also apply our extension result to prove a Lewy type extension theorem for CR-meromorphic maps, a Hartogs type theorem in [Formula: see text] and the non embedding of the Andreotti–Rossi CR structure in [Formula: see text].

Structure of solutions for the Lewy type equations

Structure of solutions for the Lewy type equations

Idiopathic parkinsonism with lewy-type inclusions in cerebral cortex. A case report

A case of idiopathic parkinsonism showed specific neuropathological findings, namely, the diffuse appearances of intracytoplasmic inclusions of Lewy type in the cerebral cortex in addition to many Lewy bodies in the pigmented brain stem nuclei. The staining properties and the ultrastructure of the inclusions in the cerebral cortex had a strong resemblance to those of the Lewy bodies in the substantia nigra, though a few electron microscopical differences were observed. Almost all of these 'cortical inclusions' were homogeneous or had an obscure core in their center, and they gave the impression of immature Lewy bodies.

Hallervorden Spatz Disease Associated with Lewy Type Inclusions

Hallervorden Spatz Disease Associated with Lewy Type Inclusions

Diffuse intracytoplasmic ganglionic inclusions (Lewy type) associated with progressive dementia and quadriparesis in flexion.

Intraganglionic inclusion bodies of presumably non-viral ongm have been associated with a range of defined neurologic disturbances, including myoclonus epilepsy (1), Pick's disease (2), and Parkinson's disease (3). In each of these entities the inclusions present a pattern of characteristics (histochemical and histologic properties, topographical distribution and size) which permits a degree of diagnostic differentiation. In the Parkinsonian states, the inclusion is typically intracytoplasmic, and most frequently encountered in the pigmented neurons of the mesencephalic and rhombencephalic nuclei (4). Two elderly patients with progressive dementia associated with quadriparesis in flexion, and without any Parkinsonian stigmata, have been studied, demonstrating at autopsy widely disseminated intracytoplasmic ganglionic inclusions morphologically and histochemically indistinguishable from those initially described by Lewy in Parkinson's disease (paralysis agitans).

Estimates of the Friedrichs -Lewy type for a hyperbolic equation with three characteristics

Estimates of the Friedrichs -Lewy type for a hyperbolic equation with three characteristics