Outcome study of the Pipeline Vantage Embolization Device (second version) in unruptured (and ruptured) aneurysms (PEDVU(R) study).

BACKGROUND: The Pipeline Vantage Embolization Device (PEDV) is the fourth-generation pipeline flow diverter for intracranial aneurysm treatment. There are no outcome studies for the second PEDV version. We aimed to evaluate safety and efficacy outcomes. Primary and secondary objectives were to determine outcomes for unruptured and ruptured cohorts, respectively. METHODS: In this multicenter retrospective and prospective study, we analyzed outcome data from eight centers using core laboratory assessments. We determined 30-day and ≥3-month mortality and morbidity rates, and 6- and 18-month radiographic aneurysm occlusion rates for procedures performed during the period July 2021-March 2023. RESULTS: We included 121 consecutive patients with 131 aneurysms. The adequate occlusion rate for the unruptured cohort at short-term and medium-term follow up, and also for the ruptured cohort at short-term follow up, was >90%. Two aneurysms (1.5%) underwent retreatment. When mortality attributed to a palliative case in the unruptured cohort, or subarachnoid hemorrhage in the ruptured cohort, was excluded then the overall major adverse event rate in respective cohorts was 7.5% and 23.5%, with 0% mortality rates for each. When all event causes were included on an intention-to-treat basis, the major adverse event rates in respective cohorts were 8.3% and 40.9%, with 0.9% and 22.7% mortality rates. CONCLUSIONS: For unruptured aneurysm treatment, the second PEDV version appears to have a superior efficacy and similar safety profile to previous-generation PEDs. These are acceptable outcomes in this pragmatic and non-industry-sponsored study. Analysis of ruptured aneurysm outcomes is limited by cohort size. Further prospective studies, particularly for ruptured aneurysms, are needed.

Speech and phonological impairment across Alzheimer's disease severity.

INTRODUCTION: Phonetic-phonological impairments have been described in dementia due to Alzheimer's disease (AD). However, whether the likely phonological-linguistic changes progress with the evolution of the disease or whether phonetic-motor manifestations occur in all three stages of AD (mild, moderate, and severe) has not yet been clarified. Thus, the aim of this study was to verify whether phonological-linguistic and phonetic-motor speech manifestations occur in the mild, moderate, and severe stages of AD. METHODS: Thirty participants in each stage of probable AD (mild, moderate, and severe) and 30 healthy older adults underwent cognitive, instrumental activities of daily living and phonetic-phonological assessments. Phonetic-phonological manifestations were classified into three types: likely phonetic-motor, likely phonological-linguistic, and manifestations that may occur in disorders of both phonetic and phonological origin. RESULTS: The manifestations analyzed in this study occurred rarely. The manifestations that may occur in disorders of both phonetic and phonological origin were the most common in all stages of the disease. The likely phonetic-motor manifestations emerged during the mild stage of the disease (distortions, prolonged intersegment duration, and vowel prolongations), while the likely phonological-linguistic manifestations were present mainly in the moderate (substitutions and attempts at the word level) and severe stages (substitutions, attempts at the word level, self-corrections, and anticipations). The occurrence of phonetic-phonological manifestations increased with disease progression. CONCLUSIONS: The type of phonological and phonetic manifestations in the individuals with AD differed according to the dementia stage and were statistically more frequent as dementia worsened.

Early Outcomes of the Pipeline Vantage Flow Diverter : A Multicentre Study.

PURPOSE: The recently introduced Pipeline Vantage Embolization Device with Shield Technology is the fourth generation of Pipeline flow diverter devices. Due to the relatively high rate of intraprocedural technical complications, modifications were subsequently made to the device after a limited release of the device in 2020. This study aimed to evaluate the safety and efficacy of the modified version of this device. METHODS: This was a multicentre retrospective series. The primary efficacy endpoint was aneurysm occlusion in the absence of retreatment. The primary safety endpoint was any neurological morbidity or death. Ruptured and unruptured aneurysms were included in the study. RESULTS: A total of 52 procedures were performed for 60 target aneurysms. Treatment was performed on 5 patients with ruptured aneurysms. The technical success rate was 98%. The mean clinical follow-up time was 5.5 months. In patients presenting with unruptured aneurysms there were no deaths, 3 (6.4%) major complications and 7 (13%) minor complications. In the five patients presenting with subarachnoid haemorrhage there were 2 (40%) major complications with 1 (20%) of these resulting in death, and 1 (20%) minor complication. Of the patients 29 (56%) had undergone 6­monthly postprocedural angiographic imaging with a mean time of 6.6 months demonstrating that 83% of patients had achieved adequate occlusion (RROC1/2) of the aneurysm. CONCLUSIONS: In this non-industry-sponsored study, the occlusion rates and safety outcomes were similar to those seen in previously published studies with flow diverter devices and earlier generation Pipeline devices. Modifications to the device appear to have improved ease of deployment.

Dementia in the older population is associated with neocortex content of serum amyloid P component.

Despite many reported associations, the direct cause of neurodegeneration responsible for cognitive loss in Alzheimer's disease and some other common dementias is not known. The normal human plasma protein, serum amyloid P component, a constituent of all human fibrillar amyloid deposits and present on most neurofibrillary tangles, is cytotoxic for cerebral neurones in vitro and in experimental animals in vivo. The neocortical content of serum amyloid P component was immunoassayed in 157 subjects aged 65 or more with known dementia status at death, in the large scale, population-representative, brain donor cohort of the Cognitive Function and Ageing Study, which avoids the biases inherent in studies of predefined clinico-pathological groups. The serum amyloid P component values were significantly higher in individuals with dementia, independent of serum albumin content measured as a control for plasma in the cortex samples. The odds ratio for dementia at death in the high serum amyloid P component tertile was 5.24 (95% confidence interval 1.79-15.29) and was independent of Braak tangle stages and Thal amyloid-ß phases of neuropathological severity. The strong and specific association of higher brain content of serum amyloid P component with dementia, independent of neuropathology, is consistent with a pathogenetic role in dementia.

Language impairment in the moderate stage of dementia due to Alzheimer's disease.

BACKGROUND: During the moderate stage of dementia due to Alzheimer's disease (AD), language disorder is more evident and it impacts on communication. An overview of language impairment could be helpful to find compensatory communication strategies for these patients. OBJECTIVE: To identify all language impairments among patients with moderate-stage of AD. METHODS: 20 patients diagnosed with probable AD based on the criteria of the NINCDS-ARDRA, with a MMSE score of 13-23 points and CDR=2, who were undergoing treatment for AD with therapeutic doses of acetyl cholinesterase inhibitors, were assessed using the Boston Diagnostic Aphasia Examination (BDAE), a test that provides a broad assessment of language. The results were compared with the performance of a normal population. RESULTS: The patients assessed in this study presented normal scores for oral and written word recognition, repetition, mechanics of writing, primer-level dictation and spelling to dictation but also had impairment at most levels of linguistic processing, in oral and written comprehension and production. In general, as expected, the tasks relying on access to the mental lexicon were most significantly affected. However, they performed well in the naming task, in which semantic cues were presented. Moreover, the patients assessed in this study had better performance in written comprehension tasks than in oral ones. CONCLUSION: The severity of the language impairments was not homogenous, with some linguistic abilities more impaired than others. The abilities that were found to be preserved can help to guide strategies for aiding in communication at this stage of AD.

Language impairment in the moderate stage of dementia due to Alzheimer's disease / Alterações de linguagem na fase moderada da demência na doença de Alzheimer

ABSTRACT Background: During the moderate stage of dementia due to Alzheimer's disease (AD), language disorder is more evident and it impacts on communication. An overview of language impairment could be helpful to find compensatory communication strategies for these patients. Objective: To identify all language impairments among patients with moderate-stage of AD. Methods: 20 patients diagnosed with probable AD based on the criteria of the NINCDS-ARDRA, with a MMSE score of 13-23 points and CDR=2, who were undergoing treatment for AD with therapeutic doses of acetyl cholinesterase inhibitors, were assessed using the Boston Diagnostic Aphasia Examination (BDAE), a test that provides a broad assessment of language. The results were compared with the performance of a normal population. Results: The patients assessed in this study presented normal scores for oral and written word recognition, repetition, mechanics of writing, primer-level dictation and spelling to dictation but also had impairment at most levels of linguistic processing, in oral and written comprehension and production. In general, as expected, the tasks relying on access to the mental lexicon were most significantly affected. However, they performed well in the naming task, in which semantic cues were presented. Moreover, the patients assessed in this study had better performance in written comprehension tasks than in oral ones. Conclusion: The severity of the language impairments was not homogenous, with some linguistic abilities more impaired than others. The abilities that were found to be preserved can help to guide strategies for aiding in communication at this stage of AD.

RESUMO Introdução: Durante o estágio moderado da demência na doença de Alzheimer (DA), o distúrbio de linguagem se intensifica, afetando a comunicação. A identificação minuciosa das habilidades linguísticas mais comprometidas nessa fase da doença pode auxiliar no uso de estratégias facilitadoras para a comunicação. Este estudo visou identificar as alterações de linguagem em pacientes com DA na fase moderada. Métodos: 20 pacientes com o diagnóstico de DA provável com base nos critérios do NINCDS-ARDRA, MMSE entre 13 e 23 pontos, CDR=2 e em tratamento medicamentoso para DA foram submetidos à avaliação da global da linguagem por meio do teste de Boston para diagnóstico de Afasia. Os resultados obtidos foram comparados aos da população normal. Resultados: Os pacientes apresentaram escores normais nas tarefas de compreensão oral e escrita de palavras, repetição, mecânica da escrita, ditado do primeiro nível e soletração para o ditado, mas também apresentaram comprometimento em todos os níveis do processamento linguístico, tanto na compreensão quanto nas emissões oral e escrita. Em geral, como esperado, as tarefas envolvendo o acesso lexical foram mais afetadas, porém os pacientes obtiveram desempenho adequado para a nomeação responsiva em que a pista semântica é o eliciador para a resposta. Além disso, os pacientes tiveram melhor desempenho em tarefas de compreensão escrita do que oral. Conclusão: A gravidade da alteração linguística não foi homogênea com algumas habilidades linguísticas mais alteradas do que outras. As habilidades identificadas como preservadas podem contribuir para o uso de estratégias facilitadoras da comunicação nessa fase da DA.

Advanced Glycation End Product Formation in Human Cerebral Cortex Increases With Alzheimer-Type Neuropathologic Changes but Is Not Independently Associated With Dementia in a Population-Derived Aging Brain Cohort.

Diabetes mellitus is a risk factor for dementia, and nonenzymatic glycosylation of macromolecules results in formation of advanced glycation end-products (AGEs). We determined the variation in AGE formation in brains from the Cognitive Function and Ageing Study population-representative neuropathology cohort. AGEs were measured on temporal neocortex by enzyme-linked immunosorbent assay (ELISA) and cell-type specific expression on neurons, astrocytes and endothelium was detected by immunohistochemistry and assessed semiquantitatively. Fifteen percent of the cohort had self-reported diabetes, which was not significantly associated with dementia status at death or neuropathology measures. AGEs were expressed on neurons, astrocytes and endothelium and overall expression showed a positively skewed distribution in the population. AGE measures were not significantly associated with dementia. AGE measured by ELISA increased with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neurofibrillary tangle score (p = 0.03) and Thal Aß phase (p = 0.04), while AGE expression on neurons (and astrocytes), detected immunohistochemically, increased with increasing Braak tangle stage (p < 0.001), CERAD tangle score (p = 0.002), and neuritic plaques (p = 0.01). Measures of AGE did not show significant associations with cerebral amyloid angiopathy, microinfarcts or neuroinflammation. In conclusion, AGE expression increases with Alzheimer's neuropathology, particular later stages but is not independently associated with dementia. AGE formation is likely to be important for impaired brain cell function in aging and Alzheimer's.

TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort.

Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia.

Evaluation of macrolinguistic aspects of the oral discourse in patients with Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a degenerative syndrome that impairs cognitive functioning, including speech and language. Discourse can be used to analyze language processing, which is organized into microlinguistic and macrolinguistic dimensions. OBJECTIVES: To identify the occurrence of changes in the macrolinguistic dimension of oral discourse in AD patients. Design: This was developed as a cross-sectional study. Setting: Outpatient clinic of the Behavioural Neurology Division of São Paulo Federal University. PARTICIPANTS: 121 elderly patients, with ≥ 4 years of education, divided into AD and comparison groups. MEASUREMENTS: The subjects were asked to create a narrative based on seven figures that made up a story. The macrolinguistic aspects of the narratives were analyzed. RESULTS: The performance of the AD group was inferior to that of the comparison group on content-related, no-content-related complete and incomplete propositions as well as macropropositions, main information units, appropriated local and global coherence, cohesive devices and all subtypes, cohesive errors and some of their subtypes. Global coherence, macropropositions and ellipsis subtype of cohesive devices were the variables that best differentiated the groups. CONCLUSIONS: Changes were observed in most aspects of the macrolinguistic dimension of oral discourse in patients with AD.

Longitudinal diffusion tensor imaging changes in early Parkinson's disease: ICICLE-PD study.

OBJECTIVE: To investigate whether white matter microstructural changes can be used as a predictor of worsening of motor features or cognitive decline in patients with Parkinson's disease and verify whether white matter microstructural longitudinal changes differ between patients with Parkinson's disease with normal cognition and those with mild cognitive impairment. METHODS: We enrolled 120 newly diagnosed patients with early stage Parkinson's disease (27 with mild cognitive impairment and 93 with normal cognition) along with 48 controls. Participants were part of the incidence of cognitive impairment in cohorts with longitudinal evaluation in Parkinson's disease study and were assessed at baseline and 18 months later with cognitive, motor tests and diffusion tensor imaging. The relationships between fractional anisotropy and mean diffusivity with disease status, cognitive and motor function were investigated. RESULTS: At baseline, patients with early stage Parkinson's disease had significantly higher widespread mean diffusivity relative to controls, regardless of cognitive status. In patients with Parkinson's disease/mild cognitive impairment, higher mean diffusivity was significantly correlated with lower attention and executive function scores. At follow-up frontal mean diffusivity increased significantly when comparing patients with Parkinson's disease/mild cognitive impairment with those with normal cognition. Baseline mean diffusivity was a significant predictor of worsening of motor features in Parkinson's disease. CONCLUSIONS: Mean diffusivity represents an important correlate of cognitive function and predictor of motor impairment in Parkinson's disease: DTI is potentially a useful tool in stratification of patients into clinical trials and to monitor the impact of treatment on motor function.

Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population.

Hippocampal neuron loss is a common neuropathological feature in old age with various underlying etiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43 kDa (TDP-43) aggregations. Its etiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n = 642/672, 96%) donated for the population-based Cambridge City over-75s Cohort and the Cognitive Function and Ageing Study. HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP-43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, P = 0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher's exact, P < 0.001) and high Braak stage (Fisher's exact, P = 0.001). Hippocampal neuron loss in CA4-CA2 was not associated with TDP-43. We conclude that hippocampal neuron loss patterns are associated with different etiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than "end-stage" HS-Aging only.

Neuropathology of White Matter Lesions, Blood-Brain Barrier Dysfunction, and Dementia.

BACKGROUND AND PURPOSE: We tested whether blood-brain barrier dysfunction in subcortical white matter is associated with white matter abnormalities or risk of clinical dementia in older people (n=126; mean age 86.4, SD: 7.7 years) in the MRC CFAS (Medical Research Council Cognitive Function and Ageing Study). METHODS: Using digital pathology, we quantified blood-brain barrier dysfunction (defined by immunohistochemical labeling for the plasma marker fibrinogen). This was assessed within subcortical white matter tissue samples harvested from postmortem T2 magnetic resonance imaging (MRI)-detected white matter hyperintensities, from normal-appearing white matter (distant from coexistent MRI-defined hyperintensities), and from equivalent areas in MRI normal brains. Histopathologic lesions were defined using a marker for phagocytic microglia (CD68, clone PGM1). RESULTS: Extent of fibrinogen labeling was not significantly associated with white matter abnormalities defined either by MRI (odds ratio, 0.90; 95% confidence interval, 0.79-1.03; P=0.130) or by histopathology (odds ratio, 0.93; 95% confidence interval, 0.77-1.12; P=0.452). Among participants with normal MRI (no detectable white matter hyperintensities), increased fibrinogen was significantly related to decreased risk of clinical dementia (odds ratio, 0.74; 95% confidence interval, 0.58-0.94; P=0.013). Among participants with histological lesions, increased fibrinogen was related to increased risk of dementia (odds ratio, 2.26; 95% confidence interval, 1.25-4.08; P=0.007). CONCLUSIONS: Our data suggest that some degree of blood-brain barrier dysfunction is common in older people and that this may be related to clinical dementia risk, additional to standard MRI biomarkers.

Neuropsychological profiles of vascular disease and risk of dementia: implications for defining vascular cognitive impairment no dementia (VCI-ND).

Background: vascular cognitive impairment no dementia (VCI-ND) defines a preclinical phase of cognitive decline associated with vascular disorders. The neuropsychological profile of VCI-ND may vary according to different vascular conditions. Objective: to determine the neuropsychological profile of individuals with no dementia and vascular disorders, including hypertension, peripheral vascular disease (PVD), coronary heart disease (CHD), diabetes and stroke. Risk of 2-year incident dementia in individuals with disease and cognitive impairment was also tested. Methods: participants were from the Cognitive Function and Ageing Study. At baseline, 13,004 individuals aged ≥65 years were enrolled into the study. Individuals were grouped by baseline disorder status (present, absent) for each condition. Cognitive performance was assessed using the Mini Mental State Examination (MMSE) and the Cambridge Cognitive Examination (CAMCOG). Dementia was assessed at 2 years. Results: in the cross-sectional analysis, hypertension, PVD and CHD were not associated with cognitive impairment. Stroke was associated with impaired global (MMSE) and CAMCOG sub-scale (including memory and non-memory) scores. Diabetes was associated with impairments in global cognitive function (MMSE) and abstract thinking. In the longitudinal analysis, cognitive impairments were associated with incident dementia in all groups. Conclusion: the neuropsychological profile in individuals with vascular disorders depends on the specific condition investigated. In all conditions cognitive impairment is a risk factor for dementia. A better understanding of which cognitive domains are affected in different disease groups could help improve operationalisation of the neuropsychological criteria for VCI-ND and could also aid with the development of dementia risk prediction models in persons with vascular disease.

Metaflammasome components in the human brain: a role in dementia with Alzheimer's pathology?

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome ("metaflammasome") in mediating chronic inflammation in peripheral organs implicating IKKß (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKß [pSer176/180 ], IRS1 [pS312 ], JNK [pThr183 /Tyr185 ] and PKR [pT451 ]. The data were analyzed to investigate whether the proteins were expressed together and in relation with metabolic disorders, dementia, Alzheimer's pathology and APOE genotype. We observed a change from a positive to a negative association between the proteins and hypertension according to the dementia status. Type-2 diabetes was negatively related with the proteins among participants without dementia; whereas participants with dementia and AD pathology showed a positive association with JNK. A significant association between IKKß and JNK in participants with dementia and AD pathology was observed, but not in those without dementia. Otherwise, weak to moderate associations were observed among the protein loads. The presence of dementia was significantly associated with JNK and negatively associated with IKKß and IRS1. Cognitive scores showed a significant positive relationship with IKKß and a negative with IRS1, JNK and PKR. The proteins were significantly associated with pathology in Alzheimer's participants with the relationship being inverse or not significant in participants without dementia. Expression of the proteins was not related to APOE genotype. These findings highlight a role for these proteins in AD pathophysiology but not necessarily as a complex.

Sensorimotor speech disorders in Parkinson's disease: Programming and execution deficits / Distúrbios sensórios-motores da fala na doença de Parkinson

ABSTRACT Introduction: Dysfunction in the basal ganglia circuits is a determining factor in the physiopathology of the classic signs of Parkinson's disease (PD) and hypokinetic dysarthria is commonly related to PD. Regarding speech disorders associated with PD, the latest four-level framework of speech complicates the traditional view of dysarthria as a motor execution disorder. Based on findings that dysfunctions in basal ganglia can cause speech disorders, and on the premise that the speech deficits seen in PD are not related to an execution motor disorder alone but also to a disorder at the motor programming level, the main objective of this study was to investigate the presence of sensorimotor disorders of programming (besides the execution disorders previously described) in PD patients. Methods: A cross-sectional study was conducted in a sample of 60 adults matched for gender, age and education: 30 adult patients diagnosed with idiopathic PD (PDG) and 30 healthy adults (CG). All types of articulation errors were reanalyzed to investigate the nature of these errors. Interjections, hesitations and repetitions of words or sentences (during discourse) were considered typical disfluencies; blocking, episodes of palilalia (words or syllables) were analyzed as atypical disfluencies. We analysed features including successive self-initiated trial, phoneme distortions, self-correction, repetition of sounds and syllables, prolonged movement transitions, additions or omissions of sounds and syllables, in order to identify programming and/or execution failures. Orofacial agility was also investigated. Results: The PDG had worse performance on all sensorimotor speech tasks. All PD patients had hypokinetic dysarthria. Conclusion: The clinical characteristics found suggest both execution and programming sensorimotor speech disorders in PD patients.

RESUMO Introdução: Na doença de Parkinson (DP) a disfunção dos circuitos dos núcleos da base é um fator determinante na fisiopatologia dos sinais clássicos da DP e a disartria hipocinética é uma das manifestações da doença. No que se refere aos distúrbios da fala associados à DP, os modelos recentes de processamento de fala complicam a visão antiga da disartria como um déficit apenas de execução motora. Baseado nos achados de que as disfunções nos gânglios basais podem causar alterações de fala e que os distúrbios não estão apenas relacionados aos déficits de execução motora, mas também de programação motora, o objetivo deste estudo foi investigar a presença de distúrbios sensórios-motores da programação motora além dos de execução motora já descritos na fala de pacientes com DP. Métodos: O estudo é transversal e se baseou numa amostra composta por 60 adultos pareados por sexo, idade e escolaridade: 30 adultos diagnosticados com DP idiopática e 30 adultos sadios (grupo controle). Dados obtidos em um estudo prévio que analisou alterações de fluência em indivíduos com DP foram reanalisados acrescentando-se todos os tipos de manifestações/erros na fala, a fim de verificar falhas de programação e/ou execução motora. Os pacientes também realizaram avaliação da apraxia orofacial. Resultados: Todos os pacientes tinham disartria hipocinética. O grupo com DP obteve pior desempenho em todas as tarefas de fala. Conclusão: As características clínicas das manifestações/erros de fala encontrados em pacientes com DP são sugestivas de déficits de execução e de programação motora.

Microglial immunophenotype in dementia with Alzheimer's pathology.

BACKGROUND: Genetic risk factors for Alzheimer's disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. METHODS: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer's pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). RESULTS: The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0.007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer's pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer's pathology was negative or not significant, and positive in participants with dementia and Alzheimer's pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). CONCLUSIONS: Our findings raise the possibility that in dementia with Alzheimer's pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer's pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aß and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.

Epidemiological pathology of Tau in the ageing brain: application of staging for neuropil threads (BrainNet Europe protocol) to the MRC cognitive function and ageing brain study.

INTRODUCTION: Deposition of abnormally phosphorylated tau (phospho-tau) occurs in Alzheimer's disease but also with brain ageing. The Braak staging scheme focused on neurofibrillary tangles, but abundant p-tau is also present in neuropil threads, and a recent scheme has been proposed by the BrainNet Europe consortium for staging tau pathology based on neuropil threads. We determined the relationship of threads to tangles, and the value of staging for threads in an unselected population-representative ageing brain cohort. We also determined the prevalence of astroglial tau pathologies, and their relationship to neuronal tau. Phospho-tau pathology was determined by immunohistochemistry (AT8 antibody) in the MRC-CFAS neuropathology cohort. Neuropil threads were staged using the BrainNet Europe protocol for tau pathology, and compared with Braak tangle stages. Astroglial tau pathology was assessed in neo-cortical, mesial temporal and subcortical areas. RESULTS: Cases conformed well to the hierarchical neuropil threads staging of the BrainNet Europe protocol and correlated strongly with Braak staging (r=0.84, p < 0.001). Based on the areas under the receiver operator curves (AUC), incorporating either threads or tangle staging significantly improved dementia case identification to a similar degree over age alone (Braak stage X (2)(1)=10.1, p=0.002; BNE stage X (2)(1)=9.7, p=0.002). Thorn-shaped astrocytes, present in 40 % of cases, were most common in mesial temporal lobe, then brainstem, and were associated with subpial tau-positive neurites (mesial temporal: X (2)(1)=61.3, p < 0.001; brainstem: X (2)(1)=47.9, p < 0.001). Adding thorn astrocytes did not improve dementia prediction (AUC: X (2)(1)=0.77, p=0.381), but there was a weak relationship between numbers of areas involved and staging for threads or tangles (r=0.17, p=0.023). Neuropil threads develop hierarchically in parallel with neurofibrillary tangles. CONCLUSIONS: The BrainNet Europe staging protocol is straightforward to apply, and offers similar predictive value for dementia to Braak tangle staging. Astroglial tauopathy, particularly thorn shaped astrocyte formation, does not relate to dementia status, but the association with phospho-tau neurites may suggest a pathogenic relationship to neuronal tau pathology.

Sensorimotor speech disorders in Parkinson's disease: Programming and execution deficits.

INTRODUCTION: Dysfunction in the basal ganglia circuits is a determining factor in the physiopathology of the classic signs of Parkinson's disease (PD) and hypokinetic dysarthria is commonly related to PD. Regarding speech disorders associated with PD, the latest four-level framework of speech complicates the traditional view of dysarthria as a motor execution disorder. Based on findings that dysfunctions in basal ganglia can cause speech disorders, and on the premise that the speech deficits seen in PD are not related to an execution motor disorder alone but also to a disorder at the motor programming level, the main objective of this study was to investigate the presence of sensorimotor disorders of programming (besides the execution disorders previously described) in PD patients. METHODS: A cross-sectional study was conducted in a sample of 60 adults matched for gender, age and education: 30 adult patients diagnosed with idiopathic PD (PDG) and 30 healthy adults (CG). All types of articulation errors were reanalyzed to investigate the nature of these errors. Interjections, hesitations and repetitions of words or sentences (during discourse) were considered typical disfluencies; blocking, episodes of palilalia (words or syllables) were analyzed as atypical disfluencies. We analysed features including successive self-initiated trial, phoneme distortions, self-correction, repetition of sounds and syllables, prolonged movement transitions, additions or omissions of sounds and syllables, in order to identify programming and/or execution failures. Orofacial agility was also investigated. RESULTS: The PDG had worse performance on all sensorimotor speech tasks. All PD patients had hypokinetic dysarthria. CONCLUSION: The clinical characteristics found suggest both execution and programming sensorimotor speech disorders in PD patients.

INTRODUÇÃO: Na doença de Parkinson (DP) a disfunção dos circuitos dos núcleos da base é um fator determinante na fisiopatologia dos sinais clássicos da DP e a disartria hipocinética é uma das manifestações da doença. No que se refere aos distúrbios da fala associados à DP, os modelos recentes de processamento de fala complicam a visão antiga da disartria como um déficit apenas de execução motora. Baseado nos achados de que as disfunções nos gânglios basais podem causar alterações de fala e que os distúrbios não estão apenas relacionados aos déficits de execução motora, mas também de programação motora, o objetivo deste estudo foi investigar a presença de distúrbios sensórios-motores da programação motora além dos de execução motora já descritos na fala de pacientes com DP. MÉTODOS: O estudo é transversal e se baseou numa amostra composta por 60 adultos pareados por sexo, idade e escolaridade: 30 adultos diagnosticados com DP idiopática e 30 adultos sadios (grupo controle). Dados obtidos em um estudo prévio que analisou alterações de fluência em indivíduos com DP foram reanalisados acrescentando-se todos os tipos de manifestações/erros na fala, a fim de verificar falhas de programação e/ou execução motora. Os pacientes também realizaram avaliação da apraxia orofacial. RESULTADOS: Todos os pacientes tinham disartria hipocinética. O grupo com DP obteve pior desempenho em todas as tarefas de fala. CONCLUSÃO: As características clínicas das manifestações/erros de fala encontrados em pacientes com DP são sugestivas de déficits de execução e de programação motora.

Neuronal DNA damage response-associated dysregulation of signalling pathways and cholesterol metabolism at the earliest stages of Alzheimer-type pathology.

AIMS: Oxidative damage and an associated DNA damage response (DDR) are evident in mild cognitive impairment and early Alzheimer's disease, suggesting that neuronal dysfunction resulting from oxidative DNA damage may account for some of the cognitive impairment not fully explained by Alzheimer-type pathology. METHODS: Frontal cortex (Braak stage 0-II) was obtained from the Medical Research Council's Cognitive Function and Ageing Study cohort. Neurones were isolated from eight cases (four high and four low DDR) by laser capture microdissection and changes in the transcriptome identified by microarray analysis. RESULTS: Two thousand three hundred seventy-eight genes were significantly differentially expressed (1690 up-regulated, 688 down-regulated, P < 0.001) in cases with a high neuronal DDR. Functional grouping identified dysregulation of cholesterol biosynthesis, insulin and Wnt signalling, and up-regulation of glycogen synthase kinase 3ß. Candidate genes were validated by quantitative real-time polymerase chain reaction. Cerebrospinal fluid levels of 24(S)-hydroxycholesterol associated with neuronal DDR across all Braak stages (rs = 0.30, P = 0.03). CONCLUSIONS: A persistent neuronal DDR may result in increased cholesterol biosynthesis, impaired insulin and Wnt signalling, and increased GSK3ß, thereby contributing to neuronal dysfunction independent of Alzheimer-type pathology in the ageing brain.

Differential Expression of Ribosomal Genes in Brain and Blood of Alzheimer's Disease Patients.

Changes in rRNA and rDNA expression have been associated with cellular and organism aging and have been linked to Alzheimer's disease (AD) pathogenesis. In this study, we investigated the mRNA expression of ribosomal genes (28S/18S) and ß-amyloid precursor protein (APP) in different post mortem brain tissue regions (the entorhinal and auditory cortices and the hippocampus) of AD patients and elderly control subjects and also evaluated the extent of expression in peripheral blood from young, healthy, elderly, and Alzheimer's disease patients in order to investigate whether these individuals experienced the effects of aging. The comparative threshold cycle (CT) method via Real Time Polymerase Chain Reaction and the Polymerase Chain Reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) were used to analyze gene expression and the Apolipoprotein E (APOE) genotype, respectively. When the brain areas were analyzed collectively, we observed a significant decrease in APP expression and a significant increase in levels of mRNA of 18S and 28S in Alzheimer's disease patients compared to healthy elderly individuals. Furthermore, there was a significant upregulation of 28SrRNA in the entorhinal cortex and hippocampus, but not in the auditory cortex of patients with AD. On the other hand, tests of blood samples verified a decreased expression of 28S rRNA in patients with AD. These results support the hypothesis that changes in rRNA are present in AD patients, are tissue-specific, and seem to occur independently and differently in each tissue. However, the next challenge is to discover the mechanisms responsible for the differences in expression observed in the blood and the brain in both healthy elderly individuals and Alzheimer's disease patients, as well as the impact of these genes on AD pathogenesis.