Novel clinicopathological characteristics differentiate dementia with Lewy bodies from Parkinson's disease dementia

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) known as Lewy body dementias have overlapping clinical and neuropathological features. Neuropathology in both includes combination of Lewy body and Alzheimer's disease (AD) pathology. Cerebral amyloid angiopathy (CAA), often seen in AD, is increasingly recognised for its association with dementia. AIMS: This study investigated clinical and neuropathological differences between DLB and PDD. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

Lower nucleus accumbens α-synuclein load and D3 receptor levels in Parkinson's disease with impulsive compulsive behaviours

Impulsive compulsive behaviours in Parkinson’s disease have been linked to increased dopaminergic release in the ventral striatum and excessive stimulation of dopamine D3 receptors. Thirty-one patients with impulsive compulsive behaviours and Parkinson’s disease who donated their brains to the Queen Square Brain Bank for Neurological Disorders were assessed for α-synuclein neuropathological load and tyrosine hydroxylase levels in the nucleus accumbens, dorsal putamen and caudate using immunohistochemistry. Dopamine D2 and dopamine D3 receptors protein levels in the nucleus accumbens, frontal cortex and putamen were determined using western blotting. Results were compared to 29 Parkinson’s disease cases without impulsive compulsive behaviours matched by age, sex, disease duration, age at Parkinson’s disease onset and disease duration. The majority of patients with impulsive compulsive behaviours had dopamine dysregulation syndrome. Patients with Parkinson’s disease and impulsive compulsive behaviours had lower α-synuclein load and dopamine D3 receptor levels in the nucleus accumbens. No differences were seen between groups in the other brain areas and in the analysis of tyrosine hydroxylase and dopamine D2 receptor levels. Lower α-synuclein load in the nucleus accumbens of individuals with Parkinson’s disease and impulsive compulsive behaviours was confirmed on western blotting. Downregulation of the dopamine D3 receptor levels may have occurred either as a consequence of the degenerative process or of a pre-morbid trait. The lower levels of α-synuclein may have contributed to an excessive stimulation of the ventral striatum resulting in impulsive compulsive behaviours

Effect of Fluorinert on the Histological Properties of Formalin-Fixed Human Brain Tissue

Fluorinert (perfluorocarbon) represents an inexpensive option for minimizing susceptibility artifacts in ex vivo brain MRI scanning, and provides an alternative to Fomblin. However, its impact on fixed tissue and histological analysis has not been rigorously and quantitatively validated. In this study, we excised tissue blocks from 2 brain regions (frontal pole and cerebellum) of 5 formalin-fixed specimens (2 progressive supranuclear palsy cases, 3 controls). We excised 2 blocks per region per case (20 blocks in total), one of which was subsequently immersed in Fluorinert for a week and then returned to a container with formalin. The other block from each region was kept in formalin for use as control. The tissue blocks were then sectioned and histological analysis was performed on each, including routine stains and immunohistochemistry. Visual inspection of the stained histological sections by an experienced neuropathologist through the microscope did not reveal any discernible differences between any of the samples. Moreover, quantitative analysis based on automated image patch classification showed that the samples were almost indistinguishable for a state-of-the-art classifier based on a deep convolutional neural network. The results showed that Fluorinert has no effect on subsequent histological analysis of the tissue even after a long (1 week) period of immersion, which is sufficient for even the lengthiest scanning protocols

Solving random boundary heat model using the finite difference method under mean square convergence

"This is the peer reviewed version of the following article: Cortés, J. C., Romero, J. V., Roselló, M. D., Sohaly, MA. Solving random boundary heat model using the finite difference method under mean square convergence. Comp and Math Methods. 2019; 1:e1026. https://doi.org/10.1002/cmm4.1026 , which has been published in final form at https://doi.org/10.1002/cmm4.1026. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] This contribution is devoted to construct numerical approximations to the solution of the one-dimensional boundary value problem for the heat model with uncertainty in the diffusion coefficient. Approximations are constructed via random numerical schemes. This approach permits discussing the effect of the random diffusion coefficient, which is assumed a random variable. We establish results about the consistency and stability of the random difference scheme using mean square convergence. Finally, an illustrative example is presented.Spanish Ministerio de Economía y Competitividad. Grant Number: MTM2017-89664-PCortés, J.; Romero, J.; Roselló, M.; Sohaly, M. (2019). Solving random boundary heat model using the finite difference method under mean square convergence. Computational and Mathematical Methods. 1(3):1-15. https://doi.org/10.1002/cmm4.1026S11513Han, X., & Kloeden, P. E. (2017). Random Ordinary Differential Equations and Their Numerical Solution. Probability Theory and Stochastic Modelling. doi:10.1007/978-981-10-6265-0Villafuerte, L., Braumann, C. A., Cortés, J.-C., & Jódar, L. (2010). Random differential operational calculus: Theory and applications. Computers & Mathematics with Applications, 59(1), 115-125. doi:10.1016/j.camwa.2009.08.061Logan, J. D. (2004). Partial Differential Equations on Bounded Domains. Undergraduate Texts in Mathematics, 121-171. doi:10.1007/978-1-4419-8879-9_4Cannon, J. R. (1964). A Cauchy problem for the heat equation. Annali di Matematica Pura ed Applicata, 66(1), 155-165. doi:10.1007/bf02412441LinPPY.On The Numerical Solution of The Heat Equation in Unbounded Domains[PhD thesis].New York NY:New York University;1993.Li, J.-R., & Greengard, L. (2007). On the numerical solution of the heat equation I: Fast solvers in free space. Journal of Computational Physics, 226(2), 1891-1901. doi:10.1016/j.jcp.2007.06.021Han, H., & Huang, Z. (2002). Exact and approximating boundary conditions for the parabolic problems on unbounded domains. Computers & Mathematics with Applications, 44(5-6), 655-666. doi:10.1016/s0898-1221(02)00180-3Han, H., & Huang, Z. (2002). A class of artificial boundary conditions for heat equation in unbounded domains. Computers & Mathematics with Applications, 43(6-7), 889-900. doi:10.1016/s0898-1221(01)00329-7Strikwerda, J. C. (2004). Finite Difference Schemes and Partial Differential Equations, Second Edition. doi:10.1137/1.9780898717938Kloeden, P. E., & Platen, E. (1992). Numerical Solution of Stochastic Differential Equations. doi:10.1007/978-3-662-12616-5Øksendal, B. (2003). Stochastic Differential Equations. Universitext. doi:10.1007/978-3-642-14394-6Holden, H., Øksendal, B., Ubøe, J., & Zhang, T. (2010). Stochastic Partial Differential Equations. doi:10.1007/978-0-387-89488-1El-Tawil, M. A., & Sohaly, M. A. (2012). Mean square convergent three points finite difference scheme for random partial differential equations. Journal of the Egyptian Mathematical Society, 20(3), 188-204. doi:10.1016/j.joems.2012.08.017Cortés, J.-C., Navarro-Quiles, A., Romero, J.-V., Roselló, M.-D., & Sohaly, M. A. (2018). Solving the random Cauchy one-dimensional advection–diffusion equation: Numerical analysis and computing. Journal of Computational and Applied Mathematics, 330, 920-936. doi:10.1016/j.cam.2017.02.001Cortés, J. C., Jódar, L., Villafuerte, L., & Villanueva, R. J. (2007). Computing mean square approximations of random diffusion models with source term. Mathematics and Computers in Simulation, 76(1-3), 44-48. doi:10.1016/j.matcom.2007.01.020Cortés, J. C., Jódar, L., & Villafuerte, L. (2009). Random linear-quadratic mathematical models: Computing explicit solutions and applications. Mathematics and Computers in Simulation, 79(7), 2076-2090. doi:10.1016/j.matcom.2008.11.008Henderson, D., & Plaschko, P. (2006). Stochastic Differential Equations in Science and Engineering. doi:10.1142/580

Immunohistochemical and Molecular Investigations Show Alteration in the Inflammatory Profile of Multiple System Atrophy Brain

Multiple system atrophy (MSA) is an adult-onset neurodegenerative disease characterized by aggregation of α-synuclein in oligodendrocytes to form glial cytoplasmic inclusions. According to the distribution of neurodegeneration, MSA is subtyped as striatonigral degeneration (SND), olivopontocerebellar atrophy (OPCA), or as combination of these 2 (mixed MSA). In the current study, we aimed to investigate regional microglial populations and gene expression in the 3 different MSA subtypes. Microscopy with microglial marker Iba-1 combined with either proinflammatory marker CD68 or anti-inflammatory marker Arginase-1 was analyzed in control, SND, and OPCA cases (n = 5) using paraffin embedded sections. Western immunoblotting and cytokine array were used to determine protein expression in MSA and control brain regions. Gene expression was investigated using the NanoString nCounter Human Inflammation panel v2 mRNA Expression Assay. Analysis of neuropathological subtypes of MSA demonstrated a significant increase in microglia in the substantia nigra of OPCA cases. There was no difference in the microglial activation state in any region. Cytokine expression in MSA was comparable with controls. Decreased expression of CX3CL1 precursor protein and significantly greater CX3CR1 protein was found in MSA. NanoString analysis revealed the >2-fold greater expression of ARG1, MASP1, NOX4, PTGDR2, and C6 in MSA

Identification of multiple system atrophy mimicking Parkinson's disease or progressive supranuclear palsy

WWe studied a subset of patients with autopsy-confirmed multiple system atrophy who presented a clinical picture that closely resembled either Parkinson’s disease or progressive supranuclear palsy. These mimics are not captured by the current diagnostic criteria for multiple system atrophy. Among 218 autopsy-proven multiple system atrophy cases reviewed, 177 (81.2%) were clinically diagnosed and pathologically confirmed as multiple system atrophy (i.e. typical cases), while the remaining 41 (18.8%) had received an alternative clinical diagnosis, including Parkinson’s disease (i.e. Parkinson’s disease mimics; n = 16) and progressive supranuclear palsy (i.e. progressive supranuclear palsy mimics; n = 17). We also reviewed the clinical records of another 105 patients with pathologically confirmed Parkinson’s disease or progressive supranuclear palsy, who had received a correct final clinical diagnosis (i.e. Parkinson’s disease, n = 35; progressive supranuclear palsy-Richardson syndrome, n = 35; and progressive supranuclear palsy-parkinsonism, n = 35). We investigated 12 red flag features that would support a diagnosis of multiple system atrophy according to the current diagnostic criteria. Compared with typical multiple system atrophy, Parkinson’s disease mimics more frequently had a good levodopa response and visual hallucinations. Vertical gaze palsy and apraxia of eyelid opening were more commonly observed in progressive supranuclear palsy mimics. Multiple logistic regression analysis revealed an increased likelihood of having multiple system atrophy [Parkinson’s disease mimic versus typical Parkinson’s disease, odds ratio (OR): 8.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.3] if a patient developed any one of seven selected red flag features in the first 10 years of disease. Severe autonomic dysfunction (orthostatic hypotension and/or urinary incontinence with the need for a urinary catheter) was more frequent in clinically atypical multiple system atrophy than other parkinsonian disorders (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.1; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 8.8). The atypical multiple system atrophy cases more frequently had autonomic dysfunction within 3 years of symptom onset than the pathologically confirmed patients with Parkinson’s disease or progressive supranuclear palsy (Parkinson’s disease mimic versus typical Parkinson’s disease, OR: 4.7; progressive supranuclear palsy mimic versus typical progressive supranuclear palsy, OR: 2.7). Using all included clinical features and 21 early clinical features within 3 years of symptom onset, we developed decision tree algorithms with combinations of clinical pointers to differentiate clinically atypical cases of multiple system atrophy from Parkinson’s disease or progressive supranuclear palsy

Managing lifestyle change to reduce coronary risk: a synthesis of qualitative research on peoples’ experiences

Background Coronary heart disease is an incurable condition. The only approach known to slow its progression is healthy lifestyle change and concordance with cardio-protective medicines. Few people fully succeed in these daily activities so potential health improvements are not fully realised. Little is known about peoples’ experiences of managing lifestyle change. The aim of this study was to synthesise qualitative research to explain how participants make lifestyle change after a cardiac event and explore this within the wider illness experience. Methods A qualitative synthesis was conducted drawing upon the principles of meta-ethnography. Qualitative studies were identified through a systematic search of 7 databases using explicit criteria. Key concepts were identified and translated across studies. Findings were discussed and diagrammed during a series of audiotaped meetings. Results The final synthesis is grounded in findings from 27 studies, with over 500 participants (56% male) across 8 countries. All participants experienced a change in their self-identity from what was ‘familiar’ to ‘unfamiliar’. The transition process involved ‘finding new limits and a life worth living’ , ‘finding support for self’ and ‘finding a new normal’. Analyses of these concepts led to the generation of a third order construct, namely an ongoing process of ‘reassessing past, present and future lives’ as participants considered their changed identity. Participants experienced a strong urge to get back to ‘normal’. Support from family and friends could enable or constrain life change and lifestyle changes. Lifestyle change was but one small part of a wider ‘life’ change that occurred. Conclusions The final synthesis presents an interpretation, not evident in the primary studies, of a person-centred model to explain how lifestyle change is situated within ‘wider’ life changes. The magnitude of individual responses to a changed health status varied. Participants experienced distress as their notion of self identity shifted and emotions that reflected the various stages of the grief process were evident in participants’ accounts. The process of self-managing lifestyle took place through experiential learning; the level of engagement with lifestyle change reflected an individual’s unique view of the balance needed to manage ‘realistic change’ whilst leading to a life that was perceived as ‘worth living’. Findings highlight the importance of providing person centred care that aligns with both psychological and physical dimensions of recovery which are inextricably linked

Parkinson's disease without nigral degeneration: a pathological correlate of scans without evidence of dopaminergic deficit (SWEDD)?

Objective To describe 5 cases of Parkinson's disease lacking any detectable histopathology. Background The diagnosis of Parkinson's disease is supported histologically by the findings of α-synuclein immunopositive Lewy bodies and neurites and severe substantia nigra cell loss. Bradykinesia as defined by slowness of initiation of movement and a progressive reduction in speed and amplitude on finger tapping is a clinical correlate of pars compacta nigral degeneration. There are very few published cases of Parkinson's disease in which no pathological abnormality was found, and some of these cases were in hindsight thought to have probably been cases of indeterminate senile tremor or dystonic tremor. Methods Retrospective case notes review of the Queen Square Brain Bank archival collection and detailed neuropathological analysis of the selected cases. Results 5 cases considered to have Parkinson's disease by neurologists throughout the entirety of their illness that lacked any histopathological findings known to be associated with Parkinson's syndromes were identified out of a total number of 773 brains with a final clinical diagnosis of Parkinson's disease in the Queen Square Brain Bank. Retrospective case note analysis did not suggest dystonic tremor or indeterminate tremor in any of them. There was a reduction in tyrosine hydroxylase (TH) density in the striatum in these cases when compared with healthy controls, but not in the substantia nigra. Conclusions Striatal dopamine deficiency without nigral cell loss is the most likely explanation for the clinical findings; other possible explanations include slowness due to comorbidities misinterpreted as bradykinesia, a tardive syndrome related to undisclosed previous neuroleptic exposure, or ‘soft age-related’ parkinsonian signs. These cases emphasise the need to regularly review the diagnosis in cases of suspected Parkinson's disease and highlight the need for precision in the neurological examination particularly of elderly patients. These cases may represent a distinct entity of diagnostic exclusion and may be considered one explanation for the radiological phenomenon of SWEDD (scans without evidence of dopaminergic deficit)