Expression Levels of an Alpha-Synuclein Transcript in Blood May Distinguish between Early Dementia with Lewy Bodies and Parkinson's Disease.

Lewy body diseases (LBD) including dementia with Lewy bodies (DLB) and Parkinson disease (PD) are characterized by alpha-synuclein pathology. DLB is difficult to diagnose and peripheral biomarkers are urgently needed. Therefore, we analyzed the expression of five alpha-synuclein gene (SNCA) transcripts, SNCAtv1, SNCAtv2, SNCAtv3, SNCA126, and SNCA112, in 45 LBD and control temporal cortex samples and in the blood of 72 DLB, 59 PD, and 54 control subjects. The results revealed overexpression of SNCAtv1 and SNCA112 in DLB, and SNCAtv2 in PD temporal cortices. In DLB blood, diminution of all SNCA transcripts was observed. SNCAtv1 and SNCAtv2 were diminished in PD with disease onset before 70 years. SNCAtv3, driven by its own promoter, showed opposite expression in early DLB and PD, suggesting that its amount may be an early, DLB specific biomarker. Correlation between blood transcript levels and disease duration was positive in DLB and negative in PD, possibly reflecting differences in brain alpha-synuclein aggregation rates associated with differences in disease courses. In conclusion, SNCA transcripts showed a disease-specific increase in the brain and were diminished in blood of LBD patients. SNCAtv3 expression was decreased in early DLB and increased in early PD and could be a biomarker for early DLB diagnosis.

Frontotemporal Dementia Caused by the P301L Mutation in the MAPT Gene: Clinicopathological Features of 13 Cases from the Same Geographical Origin in Barcelona, Spain.

BACKGROUND/AIMS: We identified and studied 13 patients carrying the P301L mutation in the MAPT gene from the same area (Baix Llobregat County) in Barcelona, Spain. METHODS: The demographic and clinical features were reviewed retrospectively. Detailed neuropathological characterization was obtained in 9 subjects. To investigate the origin of the P301L mutation in these families, 20 single nucleotide polymorphisms (SNPs) in the MAPT gene were analyzed. RESULTS: The mean age at disease onset was 51 years and the mean disease duration was 7 years. The most common initial symptoms were behavioral changes (54%), followed by language disturbances (31%) and memory loss (15%). 46% developed parkinsonism. Neuropathology showed an extensive neuronal and glial 4-repeat (4R) tauopathy with "mini-Pick"-like bodies in the dentate gyrus as the characteristic underlying pathology in all cases. In 1 subject, additional 4R globular glial inclusions were observed. All the mutation carriers showed the same haplotype for the SNPs analyzed, suggesting a common ancestor. CONCLUSION: These findings suggest a relative homogeneous clinicopathological phenotype in P301L MAPT mutation carriers in our series. This phenotype might help in the differential diagnosis from other tauopathies and be a morphological hint for genetic testing. The haplotype analysis results suggest a founder effect of the P301L mutation in this area.

GBA Mutations Are Associated With Earlier Onset and Male Sex in Dementia With Lewy Bodies.

BACKGROUND: Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by similar pathological features. Several studies have shown a relation between alterations in the glucocerebrosidase gene (GBA) and the development of LB diseases. Here, we explored the role of GBA mutations in Spanish DLB patients. METHODS: GBA mRNA sequences were analyzed in a neuropathological (50 DLB, 43 PD, and 34 control brains) and in a clinical cohort (47 DLB patients and 131 unaffected individuals). RESULTS: Sixteen GBA mutation carriers were identified, 5 of which were brains with pure DLB. The most common mutation, E326K, was strongly associated with pure DLB and PD with dementia. GBA mutations were overrepresented in men and associated with earlier DLB onset. CONCLUSIONS: GBA mutations are also an important risk factor for DLB development in the Spanish population, are associated with earlier disease onset, and are more prevalent in men. © 2015 International Parkinson and Movement Disorder Society.

Multiple organ involvement by alpha-synuclein pathology in Lewy body disorders.

Lewy body (LB) diseases are characterized by alpha-synuclein (AS) aggregates in the central nervous system (CNS). Involvement of the peripheral autonomic nervous system (pANS) is increasingly recognized, although less studied. The aim of this study was to systematically analyze the distribution and severity of AS pathology in the CNS and pANS. Detailed postmortem histopathological study of brain and peripheral tissues from 28 brain bank donors (10 with Parkinson's disease [PD], 5 with dementia with LB [DLB], and 13 with non-LB diseases including atypical parkinsonism and non-LB dementia). AS aggregates were found in the pANS of all 15 LB disease cases (PD, DLB) in stellate and sympathetic ganglia (100%), vagus nerve (86.7%), gastrointestinal tract (86.7%), adrenal gland and/or surrounding fat (53.3%), heart (100%), and genitourinary tract (13.3%), as well as in 1 case of incidental Lewy body disease (iLBD). A craniocaudal gradient of AS burden in sympathetic chain and gastrointestinal tract was observed. DLB cases showed higher amounts of CNS AS aggregates than PD cases, but this was not the case in the pANS. No pANS AS aggregates were detected in Alzheimer's disease (AD) cases with or without CNS AS aggregates. All pathologically confirmed LB disease cases including 1 case of iLBD had AS aggregates in the pANS with a craniocaudal gradient of pathology burden in sympathetic chain and gastrointestinal tract. AS was not detected in the pANS of any AD case. These findings may help in the search of peripheral AS aggregates in vivo for the early diagnosis of PD.

Effective connectivity of the locus coeruleus in patients with late-life Major Depressive Disorder or mild cognitive impairment.

INTRODUCTION: We compared effective connectivity from the locus coeruleus (LC) during the resting-state in patients with late-life Major Depressive Disorder (MDD), individuals with amnestic Mild Cognitive Impairment (aMCI), and Healthy Controls (HCs). PARTICIPANTS: 23 patients with late-life MDD, 22 patients with aMCI, and 28 HCs. MATERIAL AND METHODS: Participants were assessed in two time-points, 2 years apart. They underwent a resting-state functional magnetic resonance imaging and a high-resolution anatomical acquisition, as well as clinical assessments. Functional imaging data were analyzed with dynamic causal modeling, and parametric empirical Bayes model was used to map effective connectivity between 7 distinct nodes: 4 from the locus coeruleus and 3 regions displaying gray matter decreases during the two-year follow-up period. RESULTS: Longitudinal analysis of structural data identified three clusters of larger over-time gray matter volume reduction in patients (MDD+aMCI vs. HCs): the right precuneus, and the visual association and parahippocampal cortices. aMCI patients showed decreased effective connectivity from the left rostral to caudal portions of the LC, while connectivity from the left rostral LC to the parahippocampal cortex increased. In MDD, there was a decline in effective connectivity across LC caudal seeds, and increased connectivity from the left rostral to the left caudal LC seed over time. Connectivity alterations with cortical regions involved cross-hemisphere increases and same-hemisphere decreases. CONCLUSIONS: Our discoveries provide insight into the dynamic changes in effective connectivity in individuals with late-life MDD and aMCI, also shedding light on the mechanisms potentially contributing to the onset of neurodegenerative disorders.

The missing link between faces and names: evidence from Alzheimer's disease patients.

Retrieval of proper names is a cause of concern and complaint among elderly adults and it is an early symptom of patients suffering from neurodegenerative diseases such as Alzheimer's disease (AD). While it is well established that AD patients have deficits of proper name retrieval, the nature of such impairment is not yet fully understood. Specifically, it is unknown whether this deficit is due to a degradation of the links between faces and proper names, or due to deficits in intentionally accessing and retrieving proper names from faces. Here, we aim to investigate the integrity of the links between famous faces and proper names in AD while minimizing the impact of the explicit retrieval. We compare the performances of AD patients and elderly controls in a face-name priming task. We assess the integrity of the link between faces and names at two different levels: identity level - the name and face belong to the same person; and semantic level - the name and face belong to the same category (e.g., politicians). Our results reveal that AD patients compared with controls show intact semantic priming but reduced priming for person identity. This suggests that the deficits in intentionally retrieving proper names in AD are the result of a partial disruption of the network at the identity level, i.e., the links between known faces and proper names.

Complex visual manifestations of posterior cortical atrophy.

We describe 5 patients with complex visual disturbances in the absence of ocular pathology who were ultimately diagnosed with posterior cortical atrophy (PCA). The presence of visual cortical symptoms, neuroimaging findings and clinical evolution led to the diagnosis 1-5 years after the onset of visual symptoms. Age of onset ranged from 50-66 years. In 3 cases, magnetic resonance imaging (MRI) of the brain demonstrated predominantly right posterior cortical atrophy. The other 2 patients had nonspecific MRI findings but the diagnosis was established given the findings on clinical examination and positron emission tomography (PET). All progressed to global dementia and an autopsy confirmed the diagnosis of Alzheimer disease in one patient. The possibility of PCA should be considered when a patient presents with complex visual symptoms in the absence of ocular pathology. Early neurological assessment may avoid diagnostic delay.

Errorless Learning Therapy in Semantic Variant of Primary Progressive Aphasia.

BACKGROUND: The semantic variant of primary progressive aphasia (svPPA) is characterized by a progressive loss of semantic knowledge impairing the ability to name and to recognize the meaning of words. OBJECTIVE: We aimed to evaluate the immediate and short-term effect of errorless learning speech therapy on the naming and recognition of commonly used words in patients with svPPA. METHODS: Eight participants diagnosed with svPPA received 16 sessions of intensive errorless learning speech therapy. Naming and word comprehension tasks were evaluated at baseline, immediately postintervention, and at follow-up after 1, 3, and 6 months. These evaluations were performed using two item sets (a trained list and an untrained list). RESULTS: In the naming tasks, patients showed a significant improvement in trained items immediately after the intervention, but that improvement decayed progressively when therapy ended. No improvements were found either in trained comprehension or in untrained tasks. CONCLUSION: Errorless learning therapy could improve naming ability in patients with svPPA. This effect may be due to the relative preservation of episodic memory, but the benefit is not maintained over time, presumably because there is no consolidation.

Platelet miRNA Biosignature Discriminates between Dementia with Lewy Bodies and Alzheimer's Disease.

Dementia with Lewy bodies (DLB) is one of the most common causes of degenerative dementia, after Alzheimer's disease (AD), and presents pathological and clinical overlap with both AD and Parkinson's disease (PD). Consequently, only one in three DLB cases is diagnosed correctly. Platelets, previously related to neurodegeneration, contain microRNAs (miRNAs) whose analysis may provide disease biomarkers. Here, we profiled the whole platelet miRNA transcriptome from DLB patients and healthy controls. Differentially expressed miRNAs were further validated in three consecutive studies from 2017 to 2019 enrolling 162 individuals, including DLB, AD, and PD patients, and healthy controls. Results comprised a seven-miRNA biosignature, showing the highest diagnostic potential for the differentiation between DLB and AD. Additionally, compared to controls, two miRNAs were down-regulated in DLB, four miRNAs were up-regulated in AD, and two miRNAs were down-regulated in PD. Predictive target analysis identified three disease-specific clusters of pathways as a result of platelet-miRNA deregulation. Our cross-sectional study assesses the identification of a novel, highly specific and sensitive platelet-associated miRNA-based biosignature, which distinguishes DLB from AD.

Lower Locus Coeruleus MRI intensity in patients with late-life major depression.

BACKGROUND: The locus coeruleus (LC) is the major noradrenergic source in the central nervous system. Structural alterations in the LC contribute to the pathophysiology of different neuropsychiatric disorders, which may increase to a variable extent the likelihood of developing neurodegenerative conditions. The characterization of such alterations may therefore help to predict progression to neurodegenerative disorders. Despite the LC cannot be visualized with conventional magnetic resonance imaging (MRI), specific MRI sequences have been developed to infer its structural integrity. METHODS: We quantified LC signal Contrast Ratios (LCCRs) in late-life major depressive disorder (MDD) (n = 37, 9 with comorbid aMCI), amnestic Mild Cognitive Impairment (aMCI) (n = 21, without comorbid MDD), and healthy controls (HCs) (n = 31), and also assessed the putative modulatory effects of comorbidities and other clinical variables. RESULTS: LCCRs were lower in MDD compared to aMCI and HCs. While no effects of aMCI comorbidity were observed, lower LCCRs were specifically observed in patients taking serotonin/norepinephrine reuptake inhibitors (SNRIs). CONCLUSION: Our results do not support the hypothesis that lower LCCRs characterize the different clinical groups that may eventually develop a neurodegenerative disorder. Conversely, our results were specifically observed in patients with late-life MDD taking SNRIs. Further research with larger samples is warranted to ascertain whether medication or particular clinical features of patients taking SNRIs are associated with changes in LC neurons.

Frontal and associative visual areas related to visual hallucinations in dementia with Lewy bodies and Parkinson's disease with dementia.

Visual Hallucinations (VH) are among the core features of Dementia with Lewy Bodies (DLB), but are also very frequent in demented patients with Parkinson's Disease (PDD). The purpose of this study was to investigate the pattern of gray matter and cognitive impairment underlying VH in DLB and PDD. We applied voxel-based morphometry and behavioral assessment to 12 clinically diagnosed DLB patients and 15 PDD patients. Subjects with VH showed greater gray matter loss than non-hallucinators, specifically in the right inferior frontal gyrus (BA 45) in the DLB patients and in the left orbitofrontal lobe (BA 10) in the PDD patients. Comparing the two subgroups with VH, DLB patients had greater decrease of the bilateral premotor area (BA 6) than PDD patients. Furthermore, decreased volume in associative visual areas, namely left precuneus and inferior frontal lobe, correlated with VH in the DLB but not in PDD patients. VH were related to impaired verbal fluency, inhibitory control of attention and visuoperception in the DLB group and to visual memory in the PDD group. In conclusion, DLB and PDD patients with VH had more frontal gray matter atrophy than non-hallucinators, the impairment being greater in the DLB group. The patterns of structural and functional correlations were different in both pathologies.

Central apnea in a sporadic case of Creutzfeldt-Jakob disease with brainstem involvement.

We report a patient with Creutzfeldt-Jakob disease with somnolence as an initial manifestation and sleep apneas as a prominent sign. A respiratory polygraphy revealed the presence of a continuous Cheyne-Stokes pattern both awake and during sleep with central apneas. The neuropathology showed PrP deposition in brainstem involving respiratory nuclei. Central apnea is a rare manifestation of CJD that can be observed from early stages and may be related with PrP deposition in brainstem structures.

Active bilingualism delays the onset of mild cognitive impairment.

Lifelong bilingualism may contribute to cognitive reserve (CR) in neurodegenerative diseases as shown by a delay of the age at symptom onset in bilinguals with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI). However, some studies have failed to show this bilingual advantage, suggesting that it might depend on the type and degree of bilingualism. In the present study, we tested the hypothesis that active bilingualism, defined as the continuous use of the two languages as opposed to second language exposition only, may protect against cognitive decline. Moreover, we investigated whether bilingualism as a CR factor may be explained by an advantage within the executive control (EC) system. To do so, we collected clinical measures (age at onset of cognitive symptoms, age at the first medical visit for cognitive impairments, and age at diagnosis) in patients with MCI and patients with AD with different degrees of language experience and usage of Catalan and Spanish. Additionally, all participants were tested on four EC tasks and one long-term memory recognition task. First, results from multiple regression analyses showed that active bilingualism was a significant predictor of delay in the age at onset for all the clinical measures in MCI, but not AD patients. Second, the effect of active bilingualism was independent of occupation, educational level and job attainment across the individuals' lifespan. Finally, although we did not find an effect of active bilingualism across all EC tasks, we did find an effect for conflict resolution. These results are discussed in the context of CR hypotheses, suggesting that compensatory mechanisms may play a role in protecting against cognitive decline.

Correlations between gray matter reductions and cognitive deficits in dementia with Lewy Bodies and Parkinson's disease with dementia.

There is controversy regarding whether Dementia with Lewy Bodies (DLB) and Parkinson's disease with dementia (PDD) may or not be different manifestations of the same disorder. The purpose of the present study was to investigate possible correlations between brain structure and neuropsychological functions in clinically diagnosed patients with DLB and PDD. The study sample consisted of 12 consecutively referred DLB patients, 16 PDD patients, and 16 healthy control subjects recruited from an outpatient setting, who underwent MRI and neuropsychological assessment. Voxel-based morphometry results showed that DLB patients had greater gray matter atrophy in the right superior frontal gyrus, the right premotor area and the right inferior frontal lobe compared to PDD. Furthermore, the anterior cingulate and prefrontal volume correlated with performance on the Continuous Performance Test while the right hippocampus and amygdala volume correlated with Visual Memory Test in the DLB group. In conclusion, DLB patients had more fronto-temporal gray matter atrophy than PDD patients and these reductions correlated with neuropsychological impairment.

Prevalence of dementia and major dementia subtypes in Spanish populations: a reanalysis of dementia prevalence surveys, 1990-2008.

BACKGROUND: This study describes the prevalence of dementia and major dementia subtypes in Spanish elderly. METHODS: We identified screening surveys, both published and unpublished, in Spanish populations, which fulfilled specific quality criteria and targeted prevalence of dementia in populations aged 70 years and above. Surveys covering 13 geographically different populations were selected (prevalence period: 1990-2008). Authors of original surveys provided methodological details of their studies through a systematic questionnaire and also raw age-specific data. Prevalence data were compared using direct adjustment and logistic regression. RESULTS: The reanalyzed study population (aged 70 year and above) was composed of Central and North-Eastern Spanish sub-populations obtained from 9 surveys and totaled 12,232 persons and 1,194 cases of dementia (707 of Alzheimer's disease, 238 of vascular dementia). Results showed high variation in age- and sex-specific prevalence across studies. The reanalyzed prevalence of dementia was significantly higher in women; increased with age, particularly for Alzheimer's disease; and displayed a significant geographical variation among men. Prevalence was lowest in surveys reporting participation below 85%, studies referred to urban-mixed populations and populations diagnosed by psychiatrists. CONCLUSION: Prevalence of dementia and Alzheimer's disease in Central and North-Eastern Spain is higher in females, increases with age, and displays considerable geographic variation that may be method-related. People suffering from dementia and Alzheimer's disease in Spain may approach 600,000 and 400,000 respectively. However, existing studies may not be completely appropriate to infer prevalence of dementia and its subtypes in Spain until surveys in Southern Spain are conducted.

Comprehensive proteomic profiling of plasma-derived Extracellular Vesicles from dementia with Lewy Bodies patients.

Proteins and nucleic acids contained in extracellular vesicles (EVs) are considered a feasible source of putative biomarkers for physiological and pathological conditions. Within the nervous system, not only neurons but also other brain cells are able to produce EVs, which have been involved in their physiological processes and also in the development and course of several neurodegenerative diseases. Among these, dementia with Lewy bodies (DLB) is the second cause of dementia worldwide, though most cases are missed or misdiagnosed as Alzheimer's disease (AD) due to the important clinical and pathological overlap between both diseases. In an attempt to find reliable biomarkers for DLB diagnosis, our group characterized the proteome of plasma-derived EVs from DLB patients compared to aged-matched healthy controls (HCs) using two different proteomic LC-MS/MS approaches. Remarkably, we found that gelsolin and butyrylcholinesterase were differentially identified between DLB and HCs. Further validation of these results using conventional ELISA techniques, and including an additional group of AD patients, pointed to decreased levels of gelsolin in plasma-EVs from DLB compared to HCs and to AD samples. Thus, gelsolin may be considered a possible biomarker for the differentiation between DLB and AD.

Exploratory study on microRNA profiles from plasma-derived extracellular vesicles in Alzheimer's disease and dementia with Lewy bodies.

BACKGROUND: Because of the increasing life expectancy in our society, aging-related neurodegenerative disorders are one of the main issues in global health. Most of these diseases are characterized by the deposition of misfolded proteins and a progressive cognitive decline. Among these diseases, Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are the most common types of degenerative dementia. Although both show specific features, an important neuropathological and clinical overlap between them hampers their correct diagnosis. In this work, we identified molecular biomarkers aiming to improve the misdiagnosis between both diseases. METHODS: Plasma extracellular vesicles (EVs) -from DLB, AD and healthy controls- were isolated using size-exclusion chromatography (SEC) and characterized by flow cytometry, Nanoparticle Tracking Analysis (NTA) and cryo-electron microscopy. Next Generation Sequencing (NGS) and related bibliographic search was performed and a selected group of EV-associated microRNAs (miRNAs) was analysed by qPCR. RESULTS: Results uncovered two miRNAs (hsa-miR-451a and hsa-miR-21-5p) significantly down-regulated in AD samples respect to DLB patients, and a set of four miRNAs (hsa-miR-23a-3p, hsa-miR-126-3p, hsa-let-7i-5p, and hsa-miR-151a-3p) significantly decreased in AD respect to controls. The two miRNAs showing decreased expression in AD in comparison to DLB provided area under the curve (AUC) values of 0.9 in ROC curve analysis, thus suggesting their possible use as biomarkers to discriminate between both diseases. Target gene analysis of these miRNAs using prediction online tools showed accumulation of phosphorylation enzymes, presence of proteasome-related proteins and genes involved in cell death among others. CONCLUSION: Our data suggest that plasma-EV associated miRNAs may reflect a differential profile for a given dementia-related disorder which, once validated in larger cohorts of patients, could help to improve the differential diagnosis of DLB versus AD.

A unique common ancestor introduced P301L mutation in MAPT gene in frontotemporal dementia patients from Barcelona (Baix Llobregat, Spain).

The County of Baix Llobregat (Barcelona, Catalonia, Spain) presents a high prevalence of familial frontotemporal dementia (FTD) in the presence of P301L mutation in the MAPT gene. To evaluate a possible unique founder effect of P301L, and its age, the analysis of 20 single-nucleotide polymorphisms covering 50 kb and 12 single-nucleotide polymorphisms located along 30 Mb around the mutation was performed by developing 2 multiplex single-base extension reactions. In addition, families with affected and healthy individuals from France and Italy were analyzed. The FTD-affected individuals from Barcelona carried the same 50-kb haplotype linked to P301L mutation, suggesting a unique common ancestor, as opposed to French patients. Italian patients are also probably descendants of a unique ancestor, which would be different from that of Barcelona. Diversity of 30-Mb haplotypes found in Barcelona and the inference of the mutation age in these populations, among other reasons, suggest that prevalence of FTD linked to P301L MAPT mutation is the result of a locally originated mutation.

Category-specific semantic deficits in Alzheimer's disease: a semantic priming study.

Category-specific semantic deficits in individuals suffering brain damage after relatively focal lesions provide an important source of evidence about the organization of semantic knowledge. However, whether Alzheimer's disease (AD), in which the brain damage is more widespread, affects semantic categories to a different extent is still controversial. In the present study, we assess this issue by means of the semantic priming technique. AD patients with a mild impairment of their semantic knowledge showed comparable priming effects to that of controls for the categories of animals and artifacts. Interestingly, however, patients with a moderate impairment of their semantic knowledge showed a normal priming effect for animals but a very reduced priming effect (if any) for artifacts. These results reveal that AD may affect the semantic knowledge of different semantic categories to a different extent. The implications of this observation for current theoretical accounts of semantic representation in the brain are discussed.

Glucocerebrosidase mRNA is Diminished in Brain of Lewy Body Diseases and Changes with Disease Progression in Blood.

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by abnormal alpha-synuclein deposits and overlapping pathological features in the brain. Several studies have shown that glucocerebrosidase (GBA) deficiency is involved in the development of LB diseases. Here, we aimed to find out if this deficiency starts at the transcriptional level, also involves alternative splicing, and if GBA expression changes in brain are also detectable in blood of patients with LB diseases. The expression of three GBA transcript variants (GBAtv1, GBAtv2 and GBAtv5) was analyzed in samples from 20 DLB, 25 PD and 17 control brains and in blood of 20 DLB, 26 PD patients and 17 unaffected individuals. Relative mRNA expression was determined by real-time PCR. Expression changes were evaluated by the ΔΔCt method. In brain, specific expression profiles were identified in the temporal cortex of DLB and in the caudate nucleus of PD. In blood, significant GBA mRNA diminution was found in both DLB and PD patients. Early PD and early-onset DLB patients showed lowest GBA levels which were normal in PD patients with advanced disease and DLB patients who developed disease after 70 years of age. In conclusion, disease group specific GBA expression profiles were found in mostly affected areas of LBD. In blood, GBA expression was diminished in LB diseases, especially in patients with early onset DLB and in patients with early PD. Age of disease onset exerts an opposite effect on GBA expression in DLB and PD.