14-3-3θ phosphorylation at S232 reduces its interactome and regulates axonal trafficking

The Role of NAC in Amyloidogenesis in Alzheimer's Disease

Accepted September 14, 1998. From the Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; Veterans Administration Medical Center GRECC, Bedford, Massachusetts; and Departments of Neurology and Pathology, Boston University Medical School, Boston, Massachusetts. Address correspondence to Dr. Litvan, Neuropharmacology Unit, Defense and Veterans Head Injury Program, Henry M. Jackson Foundation, NINDS, NIH, Federal Building, Room 714, 7550 Wisconsin Avenue, Bethesda, MD 20892-9130; e-mail: litvan1@helix.nih.gov Copyright q 1999 American Psychiatric Press, Inc. Clinicopathologic Case Report

Convergence of Heat Shock Protein 90 with Ubiquitin in Filamentous α-Synuclein Inclusions of α-Synucleinopathies

Memantine for patients with Parkinson's disease dementia or dementia with Lewy bodies: a randomised, double-blind, placebo-controlled trial

MOLECULAR PERTURBATIONS IN SYNUCLEINOPATHY DISORDERS: INSIGHTS FROM PRE-CLINICAL TO HUMAN NEUROPATHOLOGY

Calpain-Cleavage of α-Synuclein: Connecting Proteolytic Processing to Disease-Linked Aggregation

Despite ongoing debate about whether Parkinson's disease (PD) dementia (PDD) and dementia with Lewy bodies (DLB) are separable diseases or a single Lewy body dementia (LBD) spectrum, there are limited investigations of differences between these conditions. We used fixel-based diffusion magnetic resonance imaging and plasma measures to examine white matter integrity and burden of amyloid pathology (using phosphorylated tau-217 [p-tau217]) in 47 patients with DLB, 21 with PDD, 29 with PD, and 23 age-matched controls. We show reduced fiber cross-section in LBD versus PD, and increased concentrations of plasma neurofilament light chain and p-tau217; with p-tau217 and fiber cross-section associated with cognition. Fiber density was reduced in PDD versus DLB, but neither plasma measures nor fiber cross-section differed between LBD subtypes. Our findings suggest that the presence of dementia in LBD is associated with poorer white matter macrostructure and may relate to pathological protein accumulation. Conversely, differences between DLB and PDD may be driven by other factors. Plasma neurofilament light and phosphorylated tau-217 were increased in Lewy body dementia (LBD) relative to Parkinson's disease (PD) and controls. Magnetic resonance imaging (MRI) white matter macrostructure (fiber cross-section) was reduced in LBD relative to PD. In contrast, MRI white matter microstructure (fiber density) was reduced in PD dementia compared to dementia with Lewy bodies. Differences between dementia with Lewy bodies and PD dementia were distinct compared with those between LBD and Parkinson's with normal cognition. Our findings suggest that dementia with Lewy bodies and Parkinson's dementia differ in underlying processes distinct from those driving dementia.

Are there morphological differences between Parkinson's disease-dementia and dementia with Lewy bodies?

This study investigated clinical and neuropathological differences between DLB and PDD. 52 PDD and 16 DLB cases from the Queen Square Brain Bank (QSBB) for Neurological disorders were included. Comprehensive clinical data of motor and cognitive features were obtained from medical records. Neuropathological assessment included examination of CAA, Lewy body and AD pathology. CAA was more common in DLB than in PDD (P=0.003). The severity of CAA was greater in DLB than in PDD (P=0.009), with significantly higher CAA scores in the parietal lobe (P=0.043), and the occipital lobe (P=0.008), in DLB than in PDD. The highest CAA scores were observed in cases with APOE ε4/4 and ε2/4. Survival analysis showed worse prognosis in DLB, as DLB reached each clinical milestone sooner than PDD. Absence of dyskinesia in DLB is linked to the significantly lower lifetime cumulative dose of levodopa in comparison with PDD. This is the first study which identified prominent concurrent CAA pathology as a pathological substrate of DLB. More prominent CAA and rapid disease progression as measured by clinical milestones distinguish DLB from PDD.

To investigate the extent of medial temporal lobe atrophy (MTA) on MRI in Parkinson disease (PD) with and without dementia compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB) and to determine whether MTA correlates with cognitive impairment in PD and PD dementia (PDD). Coronal T1-weighted MRI scans were acquired from control subjects (n = 39) and patients with PD (n = 33), PDD (n = 31), DLB (n = 25), and AD (n = 31), diagnosed according to standardized clinical diagnostic criteria. Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized (Scheltens) scale. More severe MTA was seen in PDD (p = 0.007), DLB (p < 0.001), and AD (p < 0.001) vs control subjects. PD subjects had greater hippocampal atrophy than control subjects (p = 0.015) but less than subjects with DLB and AD, though not with PDD. MTA correlated with CAMCOG score and memory scores in the DLB group and with age in control, PDD, and AD groups. There were no correlations between MTA and cognitive impairment in PD, PDD, and AD. PDD and DLB had a similar profile of cognitive impairment and MTA. Medial temporal lobe atrophy (MTA) was seen in cognitively intact older subjects with Parkinson disease (PD) and was not more pronounced in Parkinson disease dementia (PDD). Alzheimer disease (AD) and, to a lesser extent, dementia with Lewy bodies (DLB) showed more pronounced MTA. Results suggest early hippocampal involvement in PD and that when dementia develops in PD, anatomic structures apart from the hippocampus are predominantly implicated. Greater hippocampal involvement in AD vs PDD and DLB is consistent with clinical, cognitive, and pathologic differences between the disorders.

14-3-3θ phosphorylation exacerbates alpha-synuclein aggregation and toxicity.

Adult-onset neurodegenerative disorders, like Parkinson's disease (PD) and dementia with Lewy bodies (DLB), that share the accumulation of aggregated α-synuclein (αSynagg) as their hallmark molecular pathology are collectively known as α-synucleinopathies. Diagnosing α-synucleinopathies requires the post-mortem detection of αSynagg in various brain regions. Recent efforts to measure αSynagg in living patients include quantifying αSynagg in different biofluids as a biomarker for PD. We adopted the real-time quaking-induced conversion (RT-QuIC) assay to detect very low levels of αSynagg. We first optimized RT-QuIC for sensitivity, specificity, and reproducibility by using monomeric recombinant human wild-type αSyn as a substrate and αSynagg as the seed. Next, we exposed mouse microglia to αSyn pre-formed fibrils (αSynPFF) for 24h. RT-QuIC assay revealed that the αSynPFF is taken up rapidly by mouse microglia, within 30min, and cleared within 24h. We then evaluated the αSyn RT-QuIC assay for detecting αSynagg in human PD, DLB, and Alzheimer's disease (AD) post-mortem brain homogenates (BH) along with PD and progressive supranuclear palsy (PSP) cerebrospinal fluid (CSF) samples and then determined protein aggregation rate (PAR) for αSynagg. The PD and DLB BH samples not only showed significantly higher αSynagg PAR compared to age-matched healthy controls and AD, but RT-QuIC was also highly reproducible with 94% sensitivity and 100% specificity. Similarly, PD CSF samples demonstrated significantly higher αSynagg PAR compared to age-matched healthy controls, with 100% sensitivity and specificity. Overall, the RT-QuIC assay accurately detects αSynagg seeding activity, offering a potential tool for antemortem diagnosis of α-synucleinopathies and other protein-misfolding disorders. Graphical Abstract A schematic representation of αSyn RT-QuIC assay.

Although dementia with Lewy bodies (DLB) have Parkinsonism in common with Parkinson's disease (PD) or PD dementia (PDD), they have different neuropathologies that underlie Parkinsonism. Altered brain functional connectivity that may correspond to neuropathology has been reported in PD while never been studied in DLB. To identify the characteristic brain connectivity of Parkinsonism in DLB, we compared the resting state metabolic connectivity in striato-thalamo-cortical (STC) circuit, nigrostriatal pathway, and cerebello-thalamo-cortical motor (CTC) circuit in 27 patients with drug-naïve DLB and 27 age- and sex-matched normal controls using 18F-fluoro-2-deoxyglucose PET. We derived 118 regions of interest using the Automated Anatomical Labeling templates and the Wake Forest University Pick-Atlas. We applied the sparse inverse covariance estimation method to construct the metabolic connectivity matrix. Patients with DLB, with or without Parkinsonism, showed lower inter-regional connectivity between the areas included in the STC circuit (motor cortex–striatum, midbrain–striatum, striatum–globus pallidus, and globus pallidus–thalamus) than the controls. DLB patients with Parkinsonism showed less reduced inter-regional connectivity between the midbrain and the striatum than those without Parkinsonism, and higher inter-regional connectivity between the areas included in the CTC circuit (motor cortex–pons, pons–cerebellum, and cerebellum–thalamus) than those without Parkinsonism and the controls. The resting state metabolic connectivity in the STC circuit may be reduced in DLB. In DLB with Parkinsonism, the CTC circuit and the nigrostriatal pathway may be activated to mitigate Parkinsonism. This difference in the brain connectivity may be a candidate biomarker for differentiating DLB from PD or PDD.

Dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and Parkinson’s disease (PD) collectively known as Lewy body diseases (LBDs) are neuropathologically characterised by α-synuclein deposits (Lewy bodies and Lewy neurites). However, LBDs also exhibit pathology associated with Alzheimer’s disease (AD) (i.e. hyperphosphorylated tau and amyloid β (Aβ). Aβ can be deposited in the walls of blood vessels in the brains of individuals with AD, termed cerebral amyloid angiopathy (CAA). The aim of this study was to investigate the type and distribution of CAA in DLB, PDD, and PD and determine if this differs from AD. CAA type, severity, and topographical distribution was assessed in 94 AD, 30 DLB, 17 PDD, and 11 PD cases, and APOE genotype evaluated in a subset of cases where available. 96.3% AD cases, 70% DLB cases and 82.4% PDD cases exhibited CAA (type 1 or type 2). However only 45.5% PD cases had CAA. Type 1 CAA accounted for 37.2% of AD cases, 10% of DLB cases, and 5.9% of PDD cases, and was not observed in PD cases. There was a hierarchical topographical distribution in regions affected by CAA where AD and DLB displayed the same distribution pattern that differed from PDD and PD. APOE ε4 was associated with severity of CAA in AD cases. Topographical patterns and severity of CAA in DLB more closely resembled AD rather than PDD, and as type 1 CAA is associated with clinical dementia in AD, further investigations are warranted into whether the increased presence of type 1 CAA in DLB compared to PDD are related to the onset of cognitive symptoms and is a distinguishing factor between LBDs. Possible alignment of the the topographical distribution of CAA and microbleeds in DLB warrants further investigation. CAA in DLB more closely resembles AD rather than PDD or PD, and should be taken into consideration when stratifying patients for clinical trials or designing disease modifying therapies.

We examined the progression of extrapyramidal symptoms and signs in autopsy-confirmed dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), and Alzheimer's disease dementia (AD). Longitudinal data were obtained from Arizona Study of Aging and Neurodegenerative Disease, with PDD (n=98), AD (n=47) and DLB (n=48) further sub-grouped as with or without parkinsonism (DLB+ and DLB-). Within-group Unified Parkinson's Disease Rating Scale (UPDRS) -II and UPDRS-III trajectories were analyzed using non-linear mixed effects models. In DLB, 65.6% had parkinsonism. Baseline UPDRS-II and III scores (off-stage) were highest (P<0.001) for PDD (mean±SD 14.3±7.8 and 27.4±16.3), followed by DLB+ (6.0±8.8 and 17.2±17.1), DLB- (1.1±1.3 and 3.3±5.5) and AD (3.2±6.1 and 8.2±13.6). Compared to PDD, the DLB+ group had faster UPDRS-III progression over 8-years (Cohen's-d range 0.98 to 2.79, P<0.001), driven by gait (P<0.001) and limb bradykinesia (P=0.02) subscales. Motor deficits progress faster in DLB+ than PDD, providing insights about expected changes in motor function. Dementia with Lewy bodies has faster motor progression than Parkinson's disease dementia Linear and non-linear mixed modeling analysis of longitudinal data was utilized Findings have implications for clinical prognostication and trial design.