RESUMO
Expansions of repeat DNA tracts cause >70 diseases, and ongoing expansions in brains exacerbate disease. During expansion mutations, single-stranded DNAs (ssDNAs) form slipped-DNAs. We find the ssDNA-binding complexes canonical replication protein A (RPA1, RPA2, and RPA3) and Alternative-RPA (RPA1, RPA3, and primate-specific RPA4) are upregulated in Huntington disease and spinocerebellar ataxia type 1 (SCA1) patient brains. Protein interactomes of RPA and Alt-RPA reveal unique and shared partners, including modifiers of CAG instability and disease presentation. RPA enhances in vitro melting, FAN1 excision, and repair of slipped-CAGs and protects against CAG expansions in human cells. RPA overexpression in SCA1 mouse brains ablates expansions, coincident with decreased ATXN1 aggregation, reduced brain DNA damage, improved neuron morphology, and rescued motor phenotypes. In contrast, Alt-RPA inhibits melting, FAN1 excision, and repair of slipped-CAGs and promotes CAG expansions. These findings suggest a functional interplay between the two RPAs where Alt-RPA may antagonistically offset RPA's suppression of disease-associated repeat expansions, which may extend to other DNA processes.
Assuntos
Proteína de Replicação A , Expansão das Repetições de Trinucleotídeos , Animais , Humanos , Camundongos , DNA/genética , Reparo de Erro de Pareamento de DNA , Doença de Huntington/genética , Proteínas/genética , Ataxias Espinocerebelares/genética , Proteína de Replicação A/metabolismoRESUMO
Huntington's disease (HD) is a neurodegenerative disorder that severely affects the basal ganglia and regions of the cerebral cortex. While astrocytosis and microgliosis both contribute to basal ganglia pathology, the contribution of gliosis and potential factors driving glial activity in the human HD cerebral cortex is less understood. Our study aims to identify nuanced indicators of gliosis in HD which is challenging to identify in the severely degenerated basal ganglia, by investigating the middle temporal gyrus (MTG), a cortical region previously documented to demonstrate milder neuronal loss. Immunohistochemistry was conducted on MTG paraffin-embedded tissue microarrays (TMAs) comprising 29 HD and 35 neurologically normal cases to compare the immunoreactivity patterns of key astrocytic proteins (glial fibrillary acidic protein, GFAP; inwardly rectifying potassium channel 4.1, Kir4.1; glutamate transporter-1, GLT-1; aquaporin-4, AQP4), key microglial proteins (ionised calcium-binding adapter molecule-1, IBA-1; human leukocyte antigen (HLA)-DR; transmembrane protein 119, TMEM119; purinergic receptor P2RY12, P2RY12), and indicators of proliferation (Ki-67; proliferative cell nuclear antigen, PCNA). Our findings demonstrate an upregulation of GFAP+ protein expression attributed to the presence of more GFAP+ expressing cells in HD, which correlated with greater cortical mutant huntingtin (mHTT) deposition. In contrast, Kir4.1, GLT-1, and AQP4 immunoreactivity levels were unchanged in HD. We also demonstrate an increased number of IBA-1+ and TMEM119+ microglia with somal enlargement. IBA-1+, TMEM119+, and P2RY12+ reactive microglia immunophenotypes were also identified in HD, evidenced by the presence of rod-shaped, hypertrophic, and dystrophic microglia. In HD cases, IBA-1+ cells contained either Ki-67 or PCNA, whereas GFAP+ astrocytes were devoid of proliferative nuclei. These findings suggest cortical microgliosis may be driven by proliferation in HD, supporting the hypothesis of microglial proliferation as a feature of HD pathophysiology. In contrast, astrocytes in HD demonstrate an altered GFAP expression profile that is associated with the degree of mHTT deposition.
Assuntos
Astrócitos , Proliferação de Células , Doença de Huntington , Microglia , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Microglia/metabolismo , Microglia/patologia , Astrócitos/metabolismo , Astrócitos/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Proliferação de Células/fisiologia , Adulto , Idoso , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteínas de Ligação ao Cálcio/metabolismo , Gliose/metabolismo , Gliose/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Proteínas de Membrana , Proteínas dos MicrofilamentosRESUMO
OBJECTIVE: Patients with Huntington's disease can present with variable difficulties of motor functioning, mood, and cognition. Neurodegeneration occurs in the anterior cingulate cortex of some patients with Huntington's disease and is linked to the presentation of mood symptomatology. Neuroinflammation, perpetrated by activated microglia and astrocytes, has been reported in Huntington's disease and may contribute to disease progression and presentation. This study sought to quantify the density of mutant huntingtin protein and neuroinflammatory glial changes in the midcingulate cortex of postmortem patients with Huntington's disease and determine if either correlates with the presentation of mood, motor, or mixed symptomatology. METHODS: Free-floating immunohistochemistry quantified 1C2 immunolabeling density as an indicative marker of mutant huntingtin protein, and protein and morphological markers of astrocyte (EAAT2, Cx43, and GFAP), and microglial (Iba1 and HLA-DP/DQ/DR) activation. Relationships among the level of microglial activation, mutant huntingtin burden, and case characteristics were explored using correlative analysis. RESULTS: We report alterations in activated microglia number and morphology in the midcingulate cortex of Huntington's disease cases with predominant mood symptomatology. An increased proportion of activated microglia was observed in the midcingulate of all Huntington's disease cases and positively correlated with 1C2 burden. Alterations in the astrocytic glutamate transporter EAAT2 were observed in the midcingulate cortex of patients associated with mood symptoms. INTERPRETATION: This study presents pathological changes in microglia and astrocytes in the midcingulate cortex in Huntington's disease, which coincide with mood symptom presentation. These findings further the understanding of neuroinflammation in Huntington's disease, a necessary step for developing inflammation-targeted therapeutics. ANN NEUROL 2023;94:895-910.
Assuntos
Giro do Cíngulo , Doença de Huntington , Humanos , Microglia/metabolismo , Astrócitos/metabolismo , Proteína Huntingtina/genética , Doença de Huntington/patologia , Doenças NeuroinflamatóriasRESUMO
Huntington's disease (HD) is caused by a CAG repeat expansion mutation in the gene encoding the huntingtin (Htt) protein, with mutant Htt protein subsequently forming aggregates within the brain. Mutant Htt is a current target for novel therapeutic strategies for HD, however, the lack of translation from preclinical research to disease-modifying treatments highlights the need to improve our understanding of the role of Htt protein in the human brain. This study aims to undertake an immunohistochemical screen of 12 candidate antibodies against various sequences along the Htt protein to characterize Htt distribution and expression in post-mortem human brain tissue microarrays (TMAs). Immunohistochemistry was performed on middle temporal gyrus TMAs comprising of up to 28 HD and 27 age-matched control cases, using 12 antibodies specific to various sequences along the Htt protein. From this study, six antibodies directed to the Htt N-terminus successfully immunolabeled human brain tissue. Htt aggregates and Htt protein expression levels for the six successful antibodies were subsequently quantified with a customized automated image analysis pipeline on the TMAs. A 2.5-12 fold increase in the number of Htt aggregates were detected in HD cases using antibodies MAB5374, MW1, and EPR5526, despite no change in overall Htt protein expression compared to control cases, suggesting a redistribution of Htt into aggregates in HD. MAB5374, MW1, and EPR5526 Htt aggregate numbers were positively correlated with CAG repeat length, and negatively correlated with the age of symptom onset in HD. However, the number of Htt aggregates did not correlate with the degree of striatal degeneration or the degree of cortical neuron loss. Together, these results suggest that longer CAG repeat lengths correlate with Htt aggregation in the HD human brain, and greater Htt cortical aggregate deposition is associated with an earlier age of symptom onset in HD. This study also reinforces that antibodies MAB5492, MW8, and 2B7 which have been utilized to characterize Htt in animal models of HD do not specifically immunolabel Htt aggregates in HD human brain tissue exclusively, thereby highlighting the need for validated means of Htt detection to support drug development for HD.
Assuntos
Doença de Huntington , Animais , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Corpo Estriado/metabolismo , Encéfalo/metabolismo , MutaçãoRESUMO
OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by variable motor and behavioral symptoms attributed to major neuropathology of mainly the basal ganglia and cerebral cortex. The role of the cerebellum, a brain region involved in the coordination of movements, in HD neuropathology has been controversial. This study utilizes postmortem human brain tissue to investigate whether Purkinje cell degeneration in the neocerebellum is present in HD, and how this relates to disease symptom profiles. METHODS: Unbiased stereological counting methods were used to quantify the total number of Purkinje cells in 15 HD cases and 8 neurologically normal control cases. Based on their predominant symptoms, the HD cases were categorized into 2 groups: "motor" or "mood." RESULTS: The results demonstrated a significant 43% loss of Purkinje cells in HD cases with predominantly motor symptoms, and no cell loss in cases showing a major mood phenotype. There was no significant correlation between Purkinje cell loss and striatal neuropathological grade, postmortem delay, CAG repeat in the IT15 gene, or age at death. INTERPRETATION: This study shows a compelling relationship between Purkinje cell loss in the HD neocerebellum and the HD motor symptom phenotype, which, together with our previous human brain studies on the same HD cases, provides novel perspectives interrelating and correlating the variable cerebellar, basal ganglia, and neocortical neuropathology with the variability of motor/mood symptom profiles in the human HD brain. ANN NEUROL 2019;85:396-405.
Assuntos
Cerebelo/patologia , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Doença de Huntington/psicologia , Células de Purkinje/patologia , Adulto , Idoso , Autopsia , Encéfalo/patologia , Estudos de Casos e Controles , Contagem de Células , Corpo Estriado/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/patologia , FenótipoRESUMO
INTRODUCTION: Community knowledge and stroke awareness is crucial for primary prevention of stroke and timely access to stroke treatments including acute reperfusion therapies. We conducted a national telephone survey to quantify the level of community stroke awareness. METHODS: A random sample of 400 adults in New Zealand (NZ), stratified by the 4 main ethnic groups, was surveyed. Eligible participants answered stroke awareness questions using both unprompted (open-ended) and prompted questions (using a list). Proportional odds logistic regression models were used to identify factors associated with stroke awareness. RESULTS: Only 1.5% of participants named stroke as a major cause of death. The stroke signs and symptoms most frequently identified from a list were sudden speech difficulty (94%) and sudden 1-sided weakness (92%). Without prompting, 78% of participants correctly identified at least 1 risk factor, 62% identified at least 2, and 35% identified 3 or more. When prompted with the list, scores increased 10-fold compared with unprompted responses. Ethnic disparities were observed, with Pacific peoples having the lowest level of awareness among the 4 ethnic groups. Higher education level, higher income, and personal experience of stroke were predictive of greater awareness (P ≤ .05). CONCLUSIONS: Stroke was not recognized as a major cause of death. Although identification of stroke risk factors was high with prompting, awareness was low without prompting, particularly among those with lower education and income. Nationwide, culturally tailored public awareness campaigns are necessary to improve knowledge of stroke risk factors, recognition of stroke in the community and appropriate actions to take in cases of suspected stroke.
Assuntos
Conscientização , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Havaiano Nativo ou Outro Ilhéu do Pacífico/psicologia , Acidente Vascular Cerebral/etnologia , Adulto , Causas de Morte , Características Culturais , Assistência à Saúde Culturalmente Competente/etnologia , Feminino , Promoção da Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Nova Zelândia/epidemiologia , Prognóstico , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Acidente Vascular Cerebral/terapiaRESUMO
OBJECTIVE: Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology. METHODS: Stereology was used to measure regional atrophy, neuronal loss, and soma neuronal atrophy in 3 components of the GP-the external segment (GPe), internal segment (GPi), and ventral pallidum (VP)-in 8 HD cases compared with 7 matched control cases. The findings in the HD patients were compared with HD striatal neuropathological grade, and symptom scores of motor impairment, chorea, cognition, and mood. RESULTS: Relative to controls, in the HD patients the GPe showed a 54% overall volume decline, 60% neuron loss, and 34% reduced soma volume. Similarly, the VP was reduced in volume by 31%, with 48% neuron loss and 64% reduced soma volume. In contrast, the GPi was less affected, with a 38% reduction in overall volume only. The extent of GP neurodegeneration correlated with increasing striatal neuropathological grade. Decreasing GPe and VP volumes were associated with poorer cognition and increasing motor impairments, but not chorea. In contrast, decreasing GPi volumes were associated with decreasing levels of irritability. INTERPRETATION: The HD gene mutation produces variable degrees of GP segment degeneration, highlighting the differential vulnerability of striato-GP target projections. The relationship established between clinical symptom scores and pallidal degeneration provides a novel contribution to understanding the clinicopathological associations in HD. Ann Neurol 2016;80:185-201.
Assuntos
Globo Pálido/patologia , Doença de Huntington/patologia , Degeneração Neural/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Atrofia/complicações , Atrofia/patologia , Estudos de Casos e Controles , Transtornos Cognitivos/complicações , Transtornos Cognitivos/patologia , Feminino , Humanos , Proteína Huntingtina/genética , Doença de Huntington/complicações , Humor Irritável , Masculino , Pessoa de Meia-Idade , Transtornos Motores/complicações , Transtornos Motores/patologia , Degeneração Neural/complicações , Índice de Gravidade de Doença , Repetições de Trinucleotídeos/genéticaRESUMO
Task-related functional connectivity (fc-MRI) indexes the interaction of brain regions during cognitive tasks. Two general classes of methods exist to investigate fc-MRI: the most widely-used method calculates temporal correlations between voxels/regions within subjects, and then determines if within-subject correlations are reliable across subjects (ws-fcMRI); the other calculates the average (BOLD) signal within voxels/regions and then performs correlations across subjects (as-fcMRI). That is, while both methods rely on correlational techniques, the level at which correlations are calculated is fundamentally different. While conceptually distinct, it is not known how well these two methods of fc-MRI analyses converge on the same findings. The current study addresses this question across a number of analyses. First, using default-mode network regions as seeds, we show that as-fcMRI does not strongly predict ws-fcMRI during episodic simulation tasks. Next, we show that the relationship between as-fcMRI and ws-fcMRI is contingent on whether correlations are calculated between regions from the same functional network (default mode or dorsal attention networks) or between regions from different functional networks. Lastly, we compare seed partial least squares (PLS) - a well-established as-fcMRI method - with a novel version of seed PLS that combines the multivariate approach of PLS analyses and within-subject correlations. The results showed that while many regions exhibited congruent as-fcMRI and ws-fcMRI effects, in some regions the two analyses produced effects in opposite directions. Results are discussed in relation to the Simpson's Paradox, a phenomenon in which across-subject correlations are reversed within individuals present in a sample. Overall, our results suggest that the findings of as-fcMRI do not always map onto those from ws-fcMRI. We end by discussing the advantages associated with using ws-fcMRI to assess the task-related interactions between brain regions.
Assuntos
Artefatos , Encéfalo/fisiologia , Cognição/fisiologia , Conectoma/métodos , Interpretação Estatística de Dados , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Algoritmos , Feminino , Humanos , Aumento da Imagem/métodos , Masculino , Rede Nervosa/fisiologia , Sensibilidade e Especificidade , Estatística como Assunto , Adulto JovemRESUMO
BACKGROUND: Huntington's disease (HD) is characterised by variable symptoms and neuropathology of the basal ganglia and cortex. Previously, we have shown that the pattern of pyramidal cell loss in 8 different cortical regions correlates with the phenotypic variability in HD. In the primary motor and anterior cingulate cortices, the pattern of interneuron degeneration correlates with pyramidal cell death and variable HD symptom profiles. OBJECTIVES: This study aimed to examine the pattern of interneuron degeneration in 3 further regions of the HD cortex (primary sensory, superior frontal, superior parietal cortices) to determine whether HD neuropathogenesis was characterised by a general fundamental pattern of cortical interneuron loss, and explore the relationship between cortical interneuron loss with previously determined pyramidal cell loss and clinical heterogeneity. METHODS: Stereological counting was used to quantify 3 sub-populations of calcium-binding protein containing interneurons in 3 cortical human brain regions of 14 HD and 13 control cases as used in our previous studies (Nana et al., 2014; Kim et al., 2014). The HD cases were grouped according to their predominant symptom profile ("motor", "mood", "mixed"). RESULTS: The present results demonstrated a heterogeneous loss of interneurons across the 3 cortical regions which, when compared with our previous studies, mirrored the pattern of pyramidal cell loss in the same cortical areas. Most interestingly, the pattern of neuronal loss in these regions correlated with the variable HD symptom profiles. CONCLUSION: The overall findings in our present and previous cortical studies establish a clear correlative pattern of variable cortical neuronal degeneration in HD pathogenesis, which mirrors the heterogeneity of HD symptom phenotypes.
Assuntos
Córtex Cerebral/patologia , Doença de Huntington/complicações , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Adulto , Idoso , Autopsia , Morte Celular , Feminino , Humanos , Doença de Huntington/genética , Interneurônios/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: The tendency to generate overgeneral past or future events is characteristic of individuals with a history of depression. Although much research has investigated the contribution of rumination and avoidance to the reduced specificity of past events, comparatively little research has examined (1) whether the specificity of future events is differentially reduced in depression and (2) the role of executive functions in this phenomenon. Our study aimed to redress this imbalance. METHODS: Participants with either current or past experience of depressive symptoms ('depressive group'; N = 24) and matched controls ('control group'; N = 24) completed tests of avoidance, rumination, and executive functions. A modified Autobiographical Memory Test was administered to assess the specificity of past and future events. RESULTS: The depressive group were more ruminative and avoidant than controls, but did not exhibit deficits in executive function. Although overall the depressive group generated significantly fewer specific events than controls, this reduction was driven by a significant group difference in future event specificity. Strategic retrieval processes were correlated with both past and future specificity, and predictive of the future specificity, whereas avoidance and rumination were not. CONCLUSIONS: Our findings demonstrate that future simulation appears to be particularly vulnerable to disruption in individuals with current or past experience of depressive symptoms, consistent with the notion that future simulation is more cognitively demanding than autobiographical memory retrieval. Moreover, our findings suggest that even subtle changes in executive functions such as strategic processes may impact the ability to imagine specific future events. PRACTITIONER POINTS: Future simulation may be particularly vulnerable to executive dysfunction in individuals with current/previous depressive symptoms, with evidence of a differential reduction in the specificity of future events. Strategic retrieval abilities were associated with the degree of future event specificity whereas levels of rumination and avoidance were not. Given that the ability to generate specific simulations of the future is associated with enhanced psychological wellbeing, problem solving and coping behaviours, understanding how to increase the specificity of future simulations in depression is an important direction for future research and clinical practice. Interventions focusing on improving the ability to engage strategic processes may be a fruitful avenue for increasing the ability to imagine specific future events in depression. The autobiographical event tasks have somewhat limited ecological validity as they do not account for the many social and environmental cues present in everyday life; the development of more clinically-relevant tasks may be of benefit to this area of study.
Assuntos
Sinais (Psicologia) , Depressão/psicologia , Transtorno Depressivo/psicologia , Função Executiva , Imaginação , Memória Episódica , Adaptação Psicológica , Adulto , Feminino , Humanos , Masculino , Resolução de ProblemasRESUMO
OBJECTIVE: The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons. METHODS: We undertook a double-blind study using stereological cell counting methods to quantify the 3 major types of γ-aminobutyric acidergic interneurons (calbindin-D28k, calretinin, parvalbumin) in 13 HD cases of variable motor/mood symptomatology and 15 matched control cases in the primary motor and anterior cingulate cortices. RESULTS: In the primary motor cortex, there was a significant loss (57% reduction) of only calbindin interneurons (p=0.022) in HD cases dominated by motor symptoms, but no significant interneuron loss in cases with a dominant mood phenotype. In contrast, the anterior cingulate cortex showed a major significant loss in all 3 interneuron populations, with 71% loss of calbindin (p=0.001), 60% loss of calretinin (p=0.001), and 80% loss of parvalbumin interneurons (p=0.005) in HD cases with major mood disorder, and no interneuron loss was observed in cases with major motor dysfunction. INTERPRETATION: These findings suggest that region-specific degeneration of cortical interneurons is a key component in understanding the neural basis of symptom heterogeneity in HD.
Assuntos
Córtex Cerebral/patologia , Doença de Huntington/diagnóstico , Interneurônios/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células/métodos , Método Duplo-Cego , Feminino , Humanos , Doença de Huntington/epidemiologia , Doença de Huntington/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
AIM: To explore the training, involvement and confidence of healthcare professionals involved in decision-making capacity (DMC) assessments, and to compare any differences between those conducting and those involved in, but not conducting DMC assessments. METHOD: A 10-minute anonymous, online survey was conducted with both closed and open questions. A total of 78 participants completed the survey. RESULTS: Training was lacking in quantity and adequacy. Only 14.1% received formal training during and post their qualification and only 38.5% reported the right amount of training. Just over 55% reported having the right amount of involvement, with 18% having too much and 27% having not enough involvement. A significantly higher response was given for having too much involvement by those conducting DMC assessments (p=0.006), while those not conducting felt they do not have enough involvement (p<0.001). Only 25.6% (n=20) were very confident in being able to explain DMC to a patient. CONCLUSIONS: Healthcare professionals working in this area urgently require support in the form of formal training and defined roles. Given what can be at stake for an individual undergoing a DMC assessment, it is imperative that improvements are made to upskill the workforce and utilise expertise of all healthcare professionals.
Assuntos
Tomada de Decisões , Pessoal de Saúde , Humanos , Nova Zelândia , Emoções , Atenção à SaúdeRESUMO
AIM: To examine the approaches that are being used in New Zealand when conducting decision-making capacity (DMC) assessments among the healthcare professionals that commonly conduct DMC assessments and those that are involved in, but do not conduct, the assessments. METHOD: An online quantitative survey was conducted, lasting 10 minutes, including a mix of closed- and open-ended questions. The survey garnered responses from a total of n=78 participants. RESULTS: Bedside cognitive tests were found to be the most commonly reported tool used to assess DMC among those conducting and those contributing to DMC assessments. Nearly a third (31.9%) of participants conducting DMC assessments used a structured clinical interview as one of their most common approaches while 27.5% of this same group reported not being aware of this approach. It was reported by both those conducting and those contributing to DMC assessments that the current standards lack quality and consistency, with partial capacity being poorly understood and identified, and supported decision making often being overlooked for substitute decision making. CONCLUSIONS: Current approaches to DMC assessment lack standardisation and consistency, with assessment approaches being widely varied. This article serves as a call for the development of and adherence to nationally recognised standards for DMC assessments.
Assuntos
Tomada de Decisões , Competência Mental , Humanos , Nova Zelândia , Inquéritos e Questionários , Pessoal de Saúde , Masculino , FemininoRESUMO
Healthy aging is associated with a shift away from the retrieval of specific episodic autobiographical memories (AMs), towards more general and semanticized memories. Younger adults modulate activity in the default mode network according to the episodic specificity of AM retrieval. However, little is known about whether aging disrupts this neural modulation. In the current study we examine age-related changes in the modulation of whole-brain networks in response to three tasks falling along a gradient of episodic specificity. Younger and older adults retrieved specific (unique) AMs, general (routine) AMs, and semantic (general knowledge) memories. We found that both younger and older adults modulated default mode regions in response to varying episodic specificity. In addition, younger adults upregulated activity in several default mode regions with increasing episodic specificity, while older adults either did not modulate these regions, or downregulated activity in these regions. In contrast, older adults upregulated activity in the left temporal pole for tasks with higher episodic specificity. These brain activation patterns converge with prior findings that specific AMs are diminished in episodic richness with age, but are supplemented with conceptual and general information. Age-related reductions in the modulation of default mode regions might contribute to the shift away from episodic retrieval and towards semantic retrieval, resulting in reduced episodic specificity of personal memories.
Assuntos
Memória Episódica , Humanos , Idoso , Rememoração Mental/fisiologia , Mapeamento Encefálico , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Envelhecimento/fisiologia , Imageamento por Ressonância MagnéticaRESUMO
Huntingtin protein, mutated in Huntington's disease, is implicated in nucleic acid-mediated processes, yet the evidence for direct huntingtin-nucleic acid interaction is limited. Here, we show wild-type and mutant huntingtin copurify with nucleic acids, primarily RNA, and interact directly with G-rich RNAs in in vitro assays. Huntingtin RNA-immunoprecipitation sequencing from patient-derived fibroblasts and neuronal progenitor cells expressing wild-type and mutant huntingtin revealed long noncoding RNA NEAT1 as a significantly enriched transcript. Altered NEAT1 levels were evident in Huntington's disease cells and postmortem brain tissues, and huntingtin knockdown decreased NEAT1 levels. Huntingtin colocalized with NEAT1 in paraspeckles, and we identified a high-affinity RNA motif preferred by huntingtin. This study highlights NEAT1 as a huntingtin interactor, demonstrating huntingtin's involvement in RNA-mediated functions and paraspeckle regulation.
Assuntos
Proteína Huntingtina , Doença de Huntington , RNA Longo não Codificante , Proteínas de Ligação a RNA , Humanos , Proteína Huntingtina/metabolismo , Proteína Huntingtina/genética , RNA Longo não Codificante/metabolismo , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Doença de Huntington/metabolismo , Doença de Huntington/genética , Doença de Huntington/patologia , Ligação Proteica , Fibroblastos/metabolismo , MutaçãoRESUMO
INTRODUCTION: Loss of blood-brain barrier (BBB) integrity is hypothesised to be one of the earliest microvascular signs of Alzheimer's disease (AD). Existing BBB integrity imaging methods involve contrast agents or ionising radiation, and pose limitations in terms of cost and logistics. Arterial spin labelling (ASL) perfusion MRI has been recently adapted to map the BBB permeability non-invasively. The DEveloping BBB-ASL as a non-Invasive Early biomarker (DEBBIE) consortium aims to develop this modified ASL-MRI technique for patient-specific and robust BBB permeability assessments. This article outlines the study design of the DEBBIE cohorts focused on investigating the potential of BBB-ASL as an early biomarker for AD (DEBBIE-AD). METHODS AND ANALYSIS: DEBBIE-AD consists of a multicohort study enrolling participants with subjective cognitive decline, mild cognitive impairment and AD, as well as age-matched healthy controls, from 13 cohorts. The precision and accuracy of BBB-ASL will be evaluated in healthy participants. The clinical value of BBB-ASL will be evaluated by comparing results with both established and novel AD biomarkers. The DEBBIE-AD study aims to provide evidence of the ability of BBB-ASL to measure BBB permeability and demonstrate its utility in AD and AD-related pathologies. ETHICS AND DISSEMINATION: Ethics approval was obtained for 10 cohorts, and is pending for 3 cohorts. The results of the main trial and each of the secondary endpoints will be submitted for publication in a peer-reviewed journal.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Marcadores de Spin , Imageamento por Ressonância Magnética/métodos , Disfunção Cognitiva/diagnóstico por imagem , Biomarcadores , Estudos Observacionais como AssuntoRESUMO
Although dystonia represents a major source of motor disability in Huntington's disease (HD), its pathophysiology remains unknown. Because recent animal studies indicate that loss of parvalbuminergic (PARV+) striatal interneurons can cause dystonia, we investigated if loss of PARV+ striatal interneurons occurs during human HD progression, and thus might contribute to dystonia in HD. We used immunolabeling to detect PARV+ interneurons in fixed sections, and corrected for disease-related striatal atrophy by expressing PARV+ interneuron counts in ratio to interneurons co-containing somatostatin and neuropeptide Y (whose numbers are unaffected in HD). At all symptomatic HD grades, PARV+ interneurons were reduced to less than 26% of normal abundance in rostral caudate. In putamen rostral to the level of globus pallidus, loss of PARV+ interneurons was more gradual, not dropping off to less than 20% of control until grade 2. Loss of PARV+ interneurons was even more gradual in motor putamen at globus pallidus levels, with no loss at grade 1, and steady grade-wise decline thereafter. A large decrease in striatal PARV+ interneurons, thus, occurs in HD with advancing disease grade, with regional variation in the loss per grade. Given the findings of animal studies and the grade-wise loss of PARV+ striatal interneurons in motor striatum in parallel with the grade-wise appearance and worsening of dystonia, our results raise the possibility that loss of PARV+ striatal interneurons is a contributor to dystonia in HD.
Assuntos
Corpo Estriado/patologia , Distonia/patologia , Doença de Huntington/patologia , Degeneração Neural/patologia , Neurônios/patologia , Parvalbuminas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Corpo Estriado/metabolismo , Distonia/metabolismo , Feminino , Humanos , Doença de Huntington/metabolismo , Masculino , Pessoa de Meia-Idade , Degeneração Neural/metabolismo , Neurônios/metabolismoRESUMO
Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the Huntington gene (HD) also known as IT15. Despite the disease being caused by dysfunction ofa single gene, expressed as an expanded polyglutamine in the huntingtin protein, there is a major variability in the symptom profile of patients with Huntington's disease as well as great variability in the neuropathology. The symptoms vary throughout the course of the disease and vary greatly between cases. These symptoms present as varying degrees of involuntary movements, mood, personality changes, cognitive changes and dementia. To determine whether there is a morphological basis for this symptom variability, recent studies have investigated the cellular and neurochemical changes in the striatum and cerebral cortex in the human brain to determine whether there is a link between the pathology in these regions and the symptomatology shown by individual cases. These studies together revealed that cases showing mainly mood symptom profiles correlated with marked degeneration in the striosomal compartment of the striatum, or in the anterior cingulate gyrus of the cerebral cortex. In contrast, in cases with mainly motor symptoms neurodegeneration was especially marked in the primary motor cortex with variable degeneration in both the striosomes and matrix compartments of the striatum. These studies suggest that the variable degeneration of the striatum and cerebral cortex correlates with the variable profiles of Huntington's disease.
Assuntos
Corpo Estriado/fisiopatologia , Giro do Cíngulo/fisiopatologia , Doença de Huntington/genética , Doença de Huntington/fisiopatologia , Córtex Motor/fisiopatologia , Proteínas do Tecido Nervoso/genética , Expansão das Repetições de Trinucleotídeos , Afeto/classificação , Mapeamento Encefálico , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Variação Genética , Giro do Cíngulo/metabolismo , Giro do Cíngulo/patologia , Humanos , Proteína Huntingtina , Doença de Huntington/patologia , Córtex Motor/metabolismo , Córtex Motor/patologia , Peptídeos/genética , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: This study investigated whether previously identified modifiable risk factors for dementia were associated with cognitive change in Maori (indigenous people of New Zealand) and non-Maori octogenarians of LiLACS NZ (Life and Living in Advanced Age; a Cohort Study in New Zealand), a longitudinal study. METHOD: Multivariable repeated-measure mixed effect regression models were used to assess the association between modifiable risk factors and sociodemographic variables at baseline, and cognitive change over 6 years, with p values of <.05 regarded as statistically significant. RESULTS: Modifiable factors associated with cognitive change differed between ethnic groups. Depression was a negative factor in Maori only, secondary education in non-Maori was protective, and obesity predicted better cognition over time for Maori. Diabetes was associated with decreased cognition for both Maori and non-Maori. CONCLUSION: Our results begin to address gaps in the literature and increase understanding of disparities in dementia risk by ethnicity. These findings have implications for evaluating the type and application of culturally appropriate methods to improve cognition.