Apolipoprotein E4, amyloid, and cognition in Alzheimer's and Lewy body disease.

The role of apolipoprotein E4 (APOE4) in the risk of Alzheimer's disease (AD) and Lewy body disease (LBD), and their relationship with ß-amyloid deposition and cognitive dysfunction, remain unclear. Using amyloid and dopamine transporter imaging, we enrolled 126 controls and 208 patients with typical AD (pure AD and Lewy body variant of AD), AD with dementia with Lewy bodies, or typical LBD (dementia with Lewy bodies with amyloid deposition and pure LBD). APOE4 was associated with an increased risk of all disease subtypes except pure LBD. APOE4 was associated with increased frontal ß-amyloid burden, and typical LBD was associated with increased occipital ß-amyloid levels through its interaction with APOE4. APOE4 was associated with deteriorated general cognition and memory dysfunction via its interaction with typical LBD and AD, respectively. In conclusion, the impact of APOE4 on disease risk depends on its effects on ß-amyloid deposition, and APOE4 is associated with ß-amyloid deposition regardless of the clinical diagnosis. However, it interacts with typical LBD to cause occipital ß-amyloid deposition.

Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI).

BACKGROUND: Dementia is a progressive global cognitive impairment syndrome. In 2010, more than 35 million people worldwide were estimated to be living with dementia. Some people with mild cognitive impairment (MCI) will progress to dementia but others remain stable or recover full function. There is great interest in finding good predictors of dementia in people with MCI. The Mini-Mental State Examination (MMSE) is the best-known and the most often used short screening tool for providing an overall measure of cognitive impairment in clinical, research and community settings. OBJECTIVES: To determine the accuracy of the Mini Mental State Examination for the early detection of dementia in people with mild cognitive impairment SEARCH METHODS: We searched ALOIS (Cochrane Dementia and Cognitive Improvement Specialized Register of diagnostic and intervention studies (inception to May 2014); MEDLINE (OvidSP) (1946 to May 2014); EMBASE (OvidSP) (1980 to May 2014); BIOSIS (Web of Science) (inception to May 2014); Web of Science Core Collection, including the Conference Proceedings Citation Index (ISI Web of Science) (inception to May 2014); PsycINFO (OvidSP) (inception to May 2014), and LILACS (BIREME) (1982 to May 2014). We also searched specialized sources of diagnostic test accuracy studies and reviews, most recently in May 2014: MEDION (Universities of Maastricht and Leuven, www.mediondatabase.nl), DARE (Database of Abstracts of Reviews of Effects, via the Cochrane Library), HTA Database (Health Technology Assessment Database, via the Cochrane Library), and ARIF (University of Birmingham, UK, www.arif.bham.ac.uk). No language or date restrictions were applied to the electronic searches and methodological filters were not used as a method to restrict the search overall so as to maximize sensitivity. We also checked reference lists of relevant studies and reviews, tracked citations in Scopus and Science Citation Index, used searches of known relevant studies in PubMed to track related articles, and contacted research groups conducting work on MMSE for dementia diagnosis to try to locate possibly relevant but unpublished data. SELECTION CRITERIA: We considered longitudinal studies in which results of the MMSE administered to MCI participants at baseline were obtained and the reference standard was obtained by follow-up over time. We included participants recruited and clinically classified as individuals with MCI under Petersen and revised Petersen criteria, Matthews criteria, or a Clinical Dementia Rating = 0.5. We used acceptable and commonly used reference standards for dementia in general, Alzheimer's dementia, Lewy body dementia, vascular dementia and frontotemporal dementia. DATA COLLECTION AND ANALYSIS: We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create two by two tables for dementia in general and other dementias. Two authors independently performed quality assessment using the QUADAS-2 tool. Due to high heterogeneity and scarcity of data, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic curve. MAIN RESULTS: In this review, we included 11 heterogeneous studies with a total number of 1569 MCI patients followed for conversion to dementia. Four studies assessed the role of baseline scores of the MMSE in conversion from MCI to all-cause dementia and eight studies assessed this test in conversion from MCI to Alzheimer´s disease dementia. Only one study provided information about the MMSE and conversion from MCI to vascular dementia. For conversion from MCI to dementia in general, the accuracy of baseline MMSE scores ranged from sensitivities of 23% to 76% and specificities from 40% to 94%. In relationship to conversion from MCI to Alzheimer's disease dementia, the accuracy of baseline MMSE scores ranged from sensitivities of 27% to 89% and specificities from 32% to 90%. Only one study provided information about conversion from MCI to vascular dementia, presenting a sensitivity of 36% and a specificity of 80% with an incidence of vascular dementia of 6.2%. Although we had planned to explore possible sources of heterogeneity, this was not undertaken due to the scarcity of studies included in our analysis. AUTHORS' CONCLUSIONS: Our review did not find evidence supporting a substantial role of MMSE as a stand-alone single-administration test in the identification of MCI patients who could develop dementia. Clinicians could prefer to request additional and extensive tests to be sure about the management of these patients. An important aspect to assess in future updates is if conversion to dementia from MCI stages could be predicted better by MMSE changes over time instead of single measurements. It is also important to assess if a set of tests, rather than an isolated one, may be more successful in predicting conversion from MCI to dementia.

TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy.

The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well understood. Here, we investigated the influence of genotypes at TMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions in C9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)-allele homozygotes at the TMEM106B locus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions. C9orf72 expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting for C9orf72 expansion status did not affect the relationship between TMEM106B genotype and TDP-43 pathology. To elucidate the direction of causality for this association, we directly manipulated TMEM106B levels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown of TMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.

Cerebrovascular disease, neurodegeneration, and clinical phenotype in dementia with Lewy bodies.

We investigated whether cerebrovascular disease contributes to neurodegeneration and clinical phenotype in dementia with Lewy bodies (DLB). Regional cortical thickness and subcortical gray matter volumes were estimated from structural magnetic resonance imaging (MRI) in 165 DLB patients. Cortical and subcortical infarcts were recorded and white matter hyperintensities (WMHs) were assessed. Subcortical only infarcts were more frequent (13.3%) than cortical only infarcts (3.1%) or both subcortical and cortical infarcts (2.4%). Infarcts, irrespective of type, were associated with WMHs. A higher WMH volume was associated with thinner orbitofrontal, retrosplenial, and posterior cingulate cortices, smaller thalamus and pallidum, and larger caudate volume. A higher WMH volume was associated with the presence of visual hallucinations and lower global cognitive performance, and tended to be associated with the absence of probable rapid eye movement sleep behavior disorder. Presence of infarcts was associated with the absence of parkinsonism. We conclude that cerebrovascular disease is associated with gray matter neurodegeneration in patients with probable DLB, which may have implications for the multifactorial treatment of probable DLB.

Detection of α-synuclein in CSF by RT-QuIC in patients with isolated rapid-eye-movement sleep behaviour disorder: a longitudinal observational study.

BACKGROUND: Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. METHODS: In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. FINDINGS: 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177). INTERPRETATION: In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein. FUNDING: Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.

What do we know about the risks of developing dementia after traumatic brain injury?

Traumatic brain injury (TBI) is a risk factor for the later development of dementia, but although the evidence dates back to the early 20th century, the nature of any association and its mechanistic pathways remain unclear. There has been greater focus on this subject over recent years, in part because of increasing reports around sports related TBIs, especially in the USA. Differences in research methods and clinical sampling remain the primary reason for the variable findings, although there is clearly increased prevalence of neurodegenerative disorders in general. Duration of follow up, definition of both TBI and dementia, and differences in the extent to which other dementia risk factors are controlled, as well as concerns about medical record accuracy are all issues yet to be resolved in TBI research, as is an absence pathological evidence. In addition, TBI has been reported to initiate a cascade of pathological processes related to several neurodegenerative disorders, and as such, it is likely that the risks vary between individuals. Given the evidence that dementia risk may increase with injury severity and frequency, a detailed account of age and type of injury, as well as lifetime TBI exposure is essential to document in future studies, and further longitudinal research with biomarker assessments are needed.

Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H ß-Synuclein.

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer's disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of ß-synuclein (ßS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which ßS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H ßS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H ßS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H ßS with αS. Collectively, we predict that ßS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H ßS Tg mice. Given that stimulation of αS evolvability by P123H ßS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered ßS were involved in the pathogenesis of sporadic DLB, the P123H ßS Tg mice could be used for investigating the mechanism and therapy of DLB.

Traumatic brain injury preceding clinically diagnosed α-synucleinopathies: A case-control study.

OBJECTIVE: To determine the association between traumatic brain injury (TBI) and any clinically diagnosed α-synucleinopathy including Parkinson disease (PD), dementia with Lewy bodies (DLB), PD dementia (PDD), and multiple system atrophy (MSA). METHODS: Using the medical records-linkage system of the Rochester Epidemiology Project, we identified incident cases of α-synucleinopathies in Olmsted County, Minnesota, from 1991 to 2010, matching by age (±1 year) at symptom onset and sex to controls. We reviewed records of cases and controls to detect TBI prior to clinical-motor onset of any α-synucleinopathies. We based severity (possible, probable, and definite) upon the Mayo Classification System for TBI Severity. Using conditional-logistic regression, we calculated the odds ratio (OR) of all α-synucleinopathies and type, adjusting for coffee intake and smoking. RESULTS: TBI frequency was lower among cases (7.0%) than controls (8.2%). No association was found between TBI and all α-synucleinopathies in multivariable analyses (OR 0.90, 95% confidence interval [CI] 0.54-1.52). No association presented when examining the number of TBIs, TBI severity, time between TBI exposure and index date, age at index date, or sex. When stratifying by each individual α-synucleinopathy, we did not identify any associations between TBI and PD, DLB, or PDD. Among the MSA group, 1 (6.4%) and 0 controls experienced a TBI (OR could not be estimated). CONCLUSIONS: In this nested case-control population-based analysis, TBI was not associated with subsequent α-synucleinopathies in general or any individual α-synucleinopathy. This did not change based on the temporality or the severity of the TBI. Our findings may be limited by the study power.

α-Synuclein oligomers mediate the aberrant form of spike-induced calcium release from IP3 receptor.

Emerging evidence implicates α-synuclein oligomers as potential culprits in the pathogenesis of Lewy body disease (LBD). Soluble oligomeric α-synuclein accumulation in cytoplasm is believed to modify neuronal activities and intraneural Ca2+ dynamics, which augment the metabolic burden in central neurons vulnerable to LBD, although this hypothesis remains to be fully tested. We evaluated how intracellular α-synuclein oligomers affect the neuronal excitabilities and Ca2+ dynamics of pyramidal neurons in neocortical slices from mice. Intracellular application of α-synuclein containing stable higher-order oligomers (αSNo) significantly reduced spike frequency during current injection, elongated the duration of spike afterhyperpolarization (AHP), and enlarged AHP current charge in comparison with that of α-synuclein without higher-order oligomers. This αSNo-mediated alteration was triggered by spike-induced Ca2+ release from inositol trisphosphate receptors (IP3R) functionally coupled with L-type Ca2+ channels and SK-type K+ channels. Further electrophysiological and immunochemical observations revealed that α-synuclein oligomers greater than 100 kDa were directly associated with calcium-binding protein 1, which is responsible for regulating IP3R gating. They also block Ca2+-dependent inactivation of IP3R, and trigger Ca2+-induced Ca2+ release from IP3R during multiple spikes. This aberrant machinery may result in intraneural Ca2+ dyshomeostasis and may be the molecular basis for the vulnerability of neurons in LBD brains.

Orthostatic Hypotension: An Important Risk Factor for Clinical Progression to Mild Cognitive Impairment or Dementia. The Amsterdam Dementia Cohort.

BACKGROUND: Orthostatic hypotension (OH) has been cross-sectionally and longitudinally related to dementia in the general population. Whether OH contributes to clinical progression to mild cognitive impairment (MCI) or dementia is less certain. Also, differences in risk of progression between patients with early OH (EOH) versus delayed and/or prolonged OH (DPOH) are unclear. OBJECTIVE: Assess the prevalence of EOH and DPOH, investigate the longitudinal association between EOH and DPOH and either incident MCI or dementia. METHODS: 1,882 patients from the Amsterdam Dementia Cohort [64±8 years; 43% female; n = 500 with subjective cognitive decline (SCD), n = 341 MCI, n = 758 Alzheimer's disease (AD), n = 49 vascular dementia (VaD), n = 146 frontotemporal dementia (FTD), n = 88 Lewy body dementia (DLB)]. Definition OH: systolic blood pressure (BP) drop≥20 mmHg and/or a diastolic BP drop≥10 mmHg at 1 and/or 3 minutes after standing. EOH: OH only at 1 minute, DPOH: OH at (1 and) 3 minutes. RESULTS: Prevalence OH: 19% SCD, 28% MCI, 41% dementia. Compared to SCD, odds of having OH were highest in patients with VaD and DLB; ORs (95% CI) were 2.6 (1.4-4.7) and 5.1 (3.1-8.4), respectively. After a mean (SD) follow-up of 2.2 (1.4) years, 105 (22%) of SCD or MCI patients showed clinical progression. Compared to patients without OH, those with DPOH had an increased risk of progression; hazard ratio (95% CI) was 1.7 (1.1-2.7), and those with EOH did not; 0.8 (0.3-1.9). CONCLUSION: Compared to SCD, prevalence of OH was higher in MCI and highest in dementia, particularly in VaD and DLB. DPOH, more likely associated with autonomic dysfunction, is a risk factor for incident MCI or dementia.

Association of brain heptachlor epoxide and other organochlorine compounds with lewy pathology.

BACKGROUND: Organochlorine pesticides are associated with an increased risk of Parkinson's disease. A preliminary analysis from the Honolulu-Asia Aging Study suggested that heptachlor epoxide, a metabolite from an organochlorine pesticide extensively used in Hawaii, may be especially important. This was a cross sectional analysis to evaluate the association of heptachlor epoxide and other organochlorine compounds with Lewy pathology in an expanded survey of brain organochlorine residues from the longitudinal Honolulu-Asia Aging Study. METHODS: Organochlorines were measured in frozen occipital or temporal lobes in 705 brains using gas chromatography with mass spectrometry. Lewy pathology was identified using hematoxylin and eosin- and α-synuclein immunochemistry-stained sections from multiple brain regions. RESULTS: The prevalence of Lewy pathology was nearly doubled in the presence versus the absence of heptachlor epoxide (30.1% versus 16.3%, P < 0.001). Although associations with other compounds were weaker, hexachlorobenzene (P = 0.003) and α-chlordane (P = 0.007) were also related to Lewy pathology. Most of the latter associations, however, were a result of confounding from heptachlor epoxide. Neither compound was significantly related to Lewy pathology after adjustment for heptachlor epoxide. In contrast, the association of heptachlor epoxide with Lewy pathology remained significant after adjustments for hexachlorobenzene (P = 0.013) or α-chlordane (P = 0.005). Findings were unchanged after removal of cases of PD and adjustment for age and other characteristics. CONCLUSIONS: Organochlorine pesticides are associated with the presence of Lewy pathology in the brain, even after exclusion of PD cases. Although most of the association is through heptachlor epoxide, the role of other organochlorine compounds is in need of clarification. © 2018 International Parkinson and Movement Disorder Society.

Neuroimaging findings and clinical trajectories of Lewy body disease in patients with MCI.

Elderly patients with mild cognitive impairment (MCI) may develop a Lewy body disease; their neuroimaging features at presentation are largely unknown. We present an intriguing group of 13 patients with MCI preceding (2.9 ± 1.9 years) parkinsonism (MCI-P), and eventually dementia 4.6 ± 1.6 years later (6 patients), whereas 7 patients remained dementia free after 4.7 ± 2.7 years. Neuropsychological tests, dopamine transporter (DAT) single photon emission computed tomography, and 18F-fluorodeoxyglucose positron emission tomography were compared with healthy controls and with cognitively normal patients with Parkinson's disease (PD-MOT). Compared to controls, MCI-P but not PD-MOT showed significant posterior temporo-parieto-occipital hypometabolism. Basal ganglia DAT uptake was similar between MCI-P and PD-MOT. Patients who converted to dementia were older, tended to have higher movement disorder society-unified Parkinson's disease rating scale scores and developed at least another clinical core feature fulfilling the criteria for probable dementia with Lewy bodies (DLB). Concurrent impairment of Corsi span and semantic verbal fluency, or of temporal lobe hypometabolism at baseline and reduced putamen-to-caudate ratio on DAT-SPECT at parkinsonism onset, both predicted (p < 0.001) the evolution to dementia. The constructs of Park cognitive subtype and prodromal Lewy body dementia partially overlap; functional imaging and neuropsychology may help in characterizing the patients and in tracking the risk toward dementia.

Increased Serum Levels of α-Synuclein in Patients With Major Depressive Disorder.

OBJECTIVE: Epidemiologic studies have demonstrated that depression is a risk factor for dementia. In particular, dementia with Lewy bodies (DLB) has been noted to be highly relevant to depression. It has been suggested that α-synuclein (α-syn), a major component of Lewy bodies, is related to the onset and progression of DLB. To investigate the relationship between depression and DLB, we compared serum α-syn levels of patients with depression to those of healthy subjects. METHODS: The subjects were 103 inpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), or DSM-5 major depressive disorder (MDD) and 132 healthy comparisons. Patients were recruited from Juntendo Koshigaya Hospital, Saitama, Japan, between June 2010 and November 2016. Serum α-syn levels were measured using an enzyme-linked immunosorbent assay kit. Serum α-syn levels were compared using a 2 (age group [<60 years versus ≥60 years]) × 2 (diagnosis [MDD versus comparison]) analysis of variance. RESULTS: There was no significant main effect of age (F = 1.167, df = 1, 231, p = 0.281). There was a significant main effect of diagnosis (F = 44.657, df = 1, 231, p <0.001), with higher α-syn levels in the MDD group versus the healthy comparison group, regardless of age. CONCLUSION: The present results suggest that depression may affect the metabolism of α-syn; there is a possibility that depression is not only a prodromal symptom of DLB but also a causal risk factor for DLB.

Effects of Novel Calpain Inhibitors in Transgenic Animal Model of Parkinson's disease/dementia with Lewy bodies.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders of the aging population characterized by the accumulation of α-synuclein (α-syn). The mechanisms triggering α-syn toxicity are not completely understood, however, c-terminus truncation of α-syn by proteases such as calpain may have a role. Therefore, inhibition of calpain may be of value. The main objective of this study was to evaluate the effects of systemically administered novel low molecular weight calpain inhibitors on α-syn pathology in a transgenic mouse model. For this purpose, non-tg and α-syn tg mice received the calpain inhibitors - Gabadur, Neurodur or a vehicle, twice a day for 30 days. Immunocytochemical analysis showed a 60% reduction in α-syn deposition using Gabadur and a 40% reduction using Neurodur with a concomitant reduction in c-terminus α-syn and improvements in neurodegeneration. Western blot analysis showed a 77% decrease in α-spectrin breakdown products (SBDPs) SBDPs with Gabadur and 63% reduction using Neurodur. There was a 65% reduction in the active calpain form with Gabadur and a 45% reduction with Neurodur. Moreover, treatment with calpain inhibitors improved activity performance of the α-syn tg mice. Taken together, this study suggests that calpain inhibition might be considered in the treatment of synucleinopathies.

Incidence and Comorbidity of Dementia with Lewy Bodies: A Population-Based Cohort Study.

BACKGROUND AND AIMS: Dementia with Lewy bodies (DLB) is the third most common form of dementia. Epidemiological studies of DLB in Taiwan are scarce. In this study, we estimated the incidence of DLB and comorbidity in the population of Taiwan. METHODS: Data were obtained from the Taiwan National Health Insurance Research Database (NHIRD). DLB patients between 2000 and 2013 were enrolled in assessments of incidence and comorbidity. RESULTS: The incidence of DLB was shown to be 7.10 per 100,000 person-years (95% CI = 6.63-7.59), which increased with age. The average age at diagnosis was 76.3, and this was higher for males than for females. The comorbidity rates of hypertension and hyperlipidemia in DLB patients were higher in females than in males. CONCLUSIONS: Epidemiologic data from large-scale retrospective studies is crucial to the prevention of DLB.

HIV Dementia with a Decreased Cardiac 123I-metaiodobenzylguanidine Uptake Masquerading as Dementia with Lewy Bodies.

Cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphy is a promising biomarker for dementia with Lewy bodies (DLB). However, we experienced a patient with cognitive decline, parkinsonism, and a decreased MIBG uptake who turned out to have HIV dementia. Normal dopamine transporter single-photon emission computed tomography reduced the possibility of comorbid Lewy body pathology causing the patient' s parkinsonism. The decreased MIBG uptake was most likely due to postganglionic sympathetic nerve denervation, which can also be caused by HIV. This case further emphasizes the importance of excluding other causes of autonomic neuropathy, including HIV infection, before interpreting MIBG scans.

Actualización en enfermedad con cuerpos de Lewy / Update in Lewy body disease

La enfermedad con cuerpos de Lewy incluye 2 entidades que podrían ser consideradas variantes clínicas de una misma patología: la demencia con cuerpos de Lewy y la demencia en enfermedad de Parkinson. Con la finalidad de describir correctamente lo que sucede en la evolución de la enfermedad se divide el cuadro en etapa prodrómica y de demencia propiamente dicha. La primera está clínicamente representada por aquel período en el cual, si bien el paciente exhibe algunos signos y síntomas propios de la enfermedad, no reúne criterios de demencia. A pesar de ser difícil de definir y por carecerse todavía de contundentes datos clínicos y biomarcadores, se caracteriza principalmente por deterioro leve selectivo en función atencional ­ visuoespacial, trastorno del sueño REM y disautonomía‒. La segunda etapa está claramente caracterizada en los criterios de consenso del año 2005. Recientemente hemos publicado la validación de un instrumento llamado ALBA Screening Instrument, que permite diagnosticar con alta sensibilidad y especificidad la enfermedad aun en etapas tempranas y diferenciarla de otras patologías semejantes. La tomografía por emisión de positrones (PET) para transportador de dopamina es el procedimiento de referencia (gold standard) del diagnóstico. El tratamiento sintomático con anticolinesterásicos y neurolépticos atípicos favorece una buena evolución de la enfermedad y es fundamental tener en cuenta evitar medicamentos que pueden dañar gravemente a los pacientes como los anticolinérgicos y antipsicóticos típicos. Los avances en el diagnóstico y la difusión del impacto de esta enfermedad en la población contribuirán a generar mayores esfuerzos de investigación para hallar un tratamiento eficaz, preventivo o curativo o de ambas características. (AU)

Lewy body disease includes 2 entities that could be considered clinical variants of the same pathology: Dementia with Lewy bodies and Parkinson's disease Dementia. Two stages of the disease are described in this review, a prodromal stage and one of explicit dementia. The first one is clinically represented by that period in which, the patient exhibits some typical features of the disease, but not dementia criteria. Despite being difficult to define the prodromal stage and that strong clinical data and biomarkers are still lacking, there is evidence to characterize it mainly by mild selective impairment in attention and visuo-spatial function, REM sleep disorder and dysautonomia. The second stage is clearly characterized in the known consensus criteria of 2005. We have recently published the validation of an instrument called ALBA Screening Instrument which showed a high sensitivity and specificity for diagnosis of the disease even in the early stages. It´s useful to differentiate the disease from other similar pathologies. Positron Emission Tomography for dopamine transporter is the gold standard of diagnosis in life. Symptomatic treatment with anticholinesterases and atypical neuroleptics help patients in their evolution of the disease. Anticholinergics and typical antipsychotics are agents to avoid in the treatmen of the disease because can severely damage patients. Future advances in the diagnosis and dissemination of the knowledge of the disease will contribute to generate greater research efforts to find an effective preventive and / or curative treatment. (AU)

Psychosocial therapy for Parkinson's-related dementia: study protocol for the INVEST randomised controlled trial.

INTRODUCTION: Parkinson's disease (PD) with mild cognitive impairment (MCI-PD) or dementia (PDD) and dementia with Lewy bodies (DLB) are characterised by motor and 'non-motor' symptoms which impact on quality of life. Treatment options are generally limited to pharmacological approaches. We developed a psychosocial intervention to improve cognition, quality of life and companion burden for people with MCI-PD, PDD or DLB. Here, we describe the protocol for a single-blind randomised controlled trial to assess feasibility, acceptability and tolerability of the intervention and to evaluate treatment implementation. The interaction among the intervention and selected outcome measures and the efficacy of this intervention in improving cognition for people with MCI-PD, PDD or DLB will also be explored. METHODS AND ANALYSIS: Dyads will be randomised into two treatment arms to receive either 'treatment as usual' (TAU) or cognitive stimulation therapy specifically adapted for Parkinson's-related dementias (CST-PD), involving 30 min sessions delivered at home by the study companion three times per week over 10 weeks. A mixed-methods approach will be used to collect data on the operational aspects of the trial and treatment implementation. This will involve diary keeping, telephone follow-ups, dyad checklists and researcher ratings. Analysis will include descriptive statistics summarising recruitment, acceptability and tolerance of the intervention, and treatment implementation. To pilot an outcome measure of efficacy, we will undertake an inferential analysis to test our hypothesis that compared with TAU, CST-PD improves cognition. Qualitative approaches using thematic analysis will also be applied. Our findings will inform a larger definitive trial. ETHICS AND DISSEMINATION: Ethical opinion was granted (REC reference: 15/YH/0531). Findings will be published in peer-reviewed journals and at conferences. We will prepare reports for dissemination by organisations involved with PD and dementia. TRIAL REGISTRATION NUMBER: ISRCTN (ISRCTN11455062).

A descriptive study of Lewy body dementia with functional imaging support in a Chinese population: a preliminary study.

INTRODUCTION: Lewy body dementia includes dementia with Lewy bodies and Parkinson's disease dementia. There have been limited clinical studies among Chinese patients with Lewy body dementia. This study aimed to review the presenting clinical features and identify risk factors for complications including falls, dysphagia, aspiration pneumonia, pressure sores, and mortality in Chinese patients with Lewy body dementia. We also wished to identify any difference in clinical features of patients with Lewy body dementia with and without an Alzheimer's disease pattern of functional imaging. METHODS: We retrospectively reviewed 23 patients with Lewy body dementia supported by functional imaging. Baseline demographics, presenting clinical and behavioural and psychological symptoms of dementia, functional and cognitive assessment scores, and complications during follow-up were reviewed. Patients with Lewy body dementia were further classified as having an Alzheimer's disease imaging pattern if functional imaging demonstrated bilateral temporoparietal hypometabolism or hypoperfusion with or without precuneus and posterior cingulate gyrus hypometabolism or hypoperfusion. RESULTS: The pre-imaging accuracy of clinical diagnosis was 52%. In 83% of patients, behavioural and psychological symptoms of dementia were evident. Falls, dysphagia, aspiration pneumonia, pressure sores, and death occurred in 70%, 52%, 26%, 26%, and 30% of patients, respectively with corresponding event rates per person-years of 0.32, 0.17, 0.18, 0.08, and 0.10. Patients with aspiration pneumonia compared with those without were more likely to have dysphagia (100% vs 35%; P=0.01). Deceased patients with Lewy body dementia, compared with alive patients, had a higher (median [interquartile range]) presenting Clinical Dementia Rating score (1 [1-2] vs 0.5 [0.5-1.0]; P=0.01), lower mean (± standard deviation) baseline Barthel index (13 ± 7 vs 18 ± 4; P=0.04), and were more likely to be prescribed levodopa (86% vs 31%; P=0.03). Patients with Lewy body dementia with an Alzheimer's disease pattern of functional imaging, compared with those without the pattern, were younger at presentation (mean ± standard deviation, 73 ± 6 vs 80 ± 6 years; P=0.02) and had a lower Mini-Mental State Examination score at 1 year (15 ± 8 vs 22 ± 6; P=0.05). CONCLUSIONS: Falls, dysphagia, aspiration pneumonia, and pressure sores were common among patients with Lewy body dementia. Those with an Alzheimer's disease pattern of functional imaging had a younger age of onset and lower 1-year Mini-Mental State Examination score.

Serum phosphorus levels and risk of incident dementia.

Higher serum phosphorous is associated with cerebral small vessel disease, an important driver of cognitive decline and dementia. Whether serum phosphorous, a potentially modifiable parameter, associates with risk of incident dementia is not known. We aimed to examine the association between serum phosphorous and risk of incident dementia and to determine if the association is modified by age. We used the United States Department of Veterans Affairs national databases to build a longitudinal observational cohort of US veterans without prior history of dementia and with at least one outpatient serum phosphorus between October 2008 and September 2010 and followed them until September 2014. Serum phosphorus was categorized into quintiles: ≤2.9, >2.9 to ≤3.2, >3.2 to ≤3.5, >3.5 to ≤3.9, >3.9 mg/dL. There were 744,235 participants in the overall cohort. Over a median follow-up of 5.07 years (Interquartile range [IQR]: 4.28, 5.63), adjusted Cox models show that compared to quintile 2, the risk of incident dementia was increased in quintile 4 (Hazard Ratio [HR] = 1.05; CI = 1.01-1.10) and quintile 5 (HR = 1.14; CI = 1.09-1.20). In cohort participants ≤60 years old, the risk of incident dementia was increased in quintile 4 (HR = 1.29; CI = 1.12-1.49) and 5 (HR = 1.45; CI = 1.26-1.68). In participants > 60 years old, the risk was not significant in quintile 4, and was attenuated in quintile 5 (HR = 1.10; CI = 1.05-1.16). Formal interaction analyses showed that the association between phosphorous and dementia was more pronounced in those younger than 60, and attenuated in those older than 60 (P for interaction was 0.004 and <0.0001 in quintiles 4 and 5; respectively). We conclude that higher serum phosphorous is associated with increased risk of incident dementia. This association is stronger in younger cohort participants. The identification of serum phosphorous as a risk factor for incident dementia has public health relevance and might inform the design and implementation of risk reduction strategies.