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We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.
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Lesiones Traumáticas del Encéfalo/terapia , Receptores CCR5/metabolismo , Accidente Cerebrovascular/terapia , Anciano , Anciano de 80 o más Años , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Espinas Dendríticas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones Endogámicos C57BL , Persona de Mediana Edad , Corteza Motora/metabolismo , Plasticidad Neuronal/fisiología , Neuronas/metabolismo , Receptores CCR5/fisiología , Rehabilitación de Accidente Cerebrovascular/métodosRESUMEN
Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty-one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three-way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio-temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio-temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. SIGNIFICANCE STATEMENT: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET-fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio-temporal disorientation and followed by late social disorientation, manifesting in task-evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response.
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Enfermedad de Alzheimer , Trastornos del Conocimiento , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Encéfalo/patología , Confusión/complicaciones , Confusión/patología , Neuroimagen , Trastornos del Conocimiento/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/complicaciones , Imagen por Resonancia MagnéticaRESUMEN
BACKGROUND: Sporadic Creutzfeldt-Jakob disease (s-CJD) is a rare, fatal neurodegenerative disorder. Familial cases of Creutzfeldt-Jakob disease (f-CJD) due to mutations in the PRNP gene are even rarer around the world; however, in Israel there is a focus of f-CJD patients carrying the E200K mutation. As the number of CJD E200K carriers in Israel is high and increasing, transmission of CJD to normal people was suspected. If such transmission occurs, the incidence of s-CJD would be expected to increase as well, resulting in changes of the ratio of familial/sporadic cases. METHODS: Using data from the National CJD Registry and official statistics on the Israeli population, we studied incidence rates of f-CJD and s-CJD for the period from 1985 to 2018 applying the Surveillance Epidemiology and End Results (SEER) statistical packet developed in the US National Cancer Institute. RESULTS: In total, 621 CJD patients (405 f-CJD and 216 s-CJD) cases are included in the registry. In the cohort of f-CJD patients, the mean age-adjusted annual incidence rate over the abovementioned period was 1.88 ± 0.09 (95% CI: 1.7-2.08) per 1,000,000. In the cohort of s-CJD patients, the mean age-adjusted incidence rate over the same period was 0.93 ± 0.06 (95% CI: 0.81-1.06) per 1,000,000 people. No significant time trends were found over the observation period in either s-CJD or f-CJD. The ratio f-CJD/s-CJD decreases over the observation period from 2.2 to 1.80. CONCLUSION: Israel has a high predominance of f-CJD compared to s-CJD. The mean incidence rate of s-CJD in Israel is similar to most countries. Between 1985 and 2018, the annual age-adjusted incidence rates for both forms of CJD remained stable. Thus, there is no evidence that CJD is transmitted from affected individuals to others.
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Síndrome de Creutzfeldt-Jakob , Enfermedades Neurodegenerativas , Priones , Humanos , Síndrome de Creutzfeldt-Jakob/epidemiología , Síndrome de Creutzfeldt-Jakob/genética , Priones/genética , MutaciónRESUMEN
BACKGROUND: Posttraumatic stress disorder (PTSD) can be triggered by life-threatening medical emergencies, such as stroke. Data suggest that up to 25% of stroke survivors will develop PTSD symptomatology, but little is known about predisposing factors. We sought to examine whether neuroimaging measures and coping styles are related to PTSD symptoms after stroke. METHODS: Participants were survivors of first-ever, mild-moderate ischemic stroke, or transient ischemic attack from the TABASCO study (Tel Aviv Brain Acute Stroke Cohort). All participants underwent a 3T magnetic resonance imaging at baseline and were examined 6, 12, and 24 months thereafter, using neurological, neuropsychological, and functional evaluations. At baseline, coping styles were evaluated by a self-reported questionnaire. PTSD symptoms were assessed using the PTSD checklist. Data were available for 436 patients. RESULTS: Forty-eight participants (11%) developed probable PTSD (PTSD checklist ≥44) during the first year after the stroke/transient ischemic attack. Stroke was more likely to cause PTSD than transient ischemic attack. Stroke severity, larger white matter lesion volume, and worse hippocampal connectivity were associated with PTSD severity, while infarct volume or location was not. In a multivariate analysis, high-anxious and defensive coping styles were associated with a 6.66-fold higher risk of developing poststroke PTSD ([95% CI, 2.08-21.34]; P<0.01) compared with low-anxious and repressive coping styles, after adjusting for age, education, stroke severity, brain atrophy, and depression. CONCLUSIONS: In our cohort, PTSD was a common sequela among stroke survivors. We suggest that risk factors for PTSD development include stroke severity, white matter damage, and premorbid coping styles. Early identification of at-risk patients is key to effective treatment.
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Ataque Isquémico Transitorio , Trastornos por Estrés Postraumático , Accidente Cerebrovascular , Adaptación Psicológica , Humanos , Ataque Isquémico Transitorio/complicaciones , Trastornos por Estrés Postraumático/diagnóstico por imagen , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/psicología , SobrevivientesRESUMEN
OBJECTIVE: To assess whether the Rey Auditory Verbal Learning Test (RAVLT) could differentiate deterioration from Mild Cognitive Impairment (MCI) to dementia. METHODS: Twenty-six participants who were diagnosed with MCI performed the RAVLT and the Mini Mental State Examination (MMSE) at baseline and after nearly a decade (M = 8.8 years, SD = 3.16), in order to evaluate whether they progressed to dementia. RESULTS: Twelve participants [5 males, 7 females; age M = 63.7 (7.7)] kept their diagnoses of MCI; 14 participants [11 males, 3 females; age M = 75.0 (6.5)] converted to dementia. Both groups had similar MMSE scores at baseline [26.6 (0.6); and 26.6 (0.7) respectively]. Significant differences between dementia and MCI groups were found on most measures of the RAVLT at baseline: Immediate memory [p = .04], delayed recall [p = .003], total learning [p = .01], learning rate [p = .002], retrieval efficiency [p = .004], and false alarms [p = .004]. Thus, the RAVLT results were significantly worse at baseline in those who later converted. The results remain the same when controlling for age. CONCLUSION: The results extend previous findings with follow-up of nearly a decade demonstrating that most of the RAVLT measures are sensitive to differentiate conversion from MCI to dementia.
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Disfunción Cognitiva , Demencia , Envejecimiento , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/epidemiología , Demencia/diagnóstico , Demencia/epidemiología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Pruebas de Memoria y Aprendizaje , Pruebas NeuropsicológicasRESUMEN
With newer research-based classification systems, the term Vascular Cognitive Impairment (VCI) is now preferred to vascular dementia. VCI is an umbrella term that includes all forms of cognitive deficits ranging from mild cognitive impairment of vascular origin (VaMCI) to vascular dementia (VaD). The new VCI construct takes into account the fact that in addition to single strategic infarcts, multiple infarcts, and leukoaraiosis, there are other mechanisms of cerebrovascular disease such as chronic hypoperfusion that might account for the pattern of cognitive deficits associated with vascular dementia. The key to defining the spectrum of VCI is neuropsychological testing, bedside or office-based clinical examination, and neuroimaging. The lack of specific cognitive tools that are sufficiently sensitive to detect subtle deficits makes the assessment of cognitive impairment difficult. Prospective cross-sectional and longitudinal studies of VCI from different settings are therefore required. Although there have been few published reports, behavioural and psychological symptoms (BPS) are inherently present in VCI from the onset and during the course of the disease. Besides the type of population (i.e. clinical, community or nursing-home settings), the definition of VCI/VaD and the instruments used, and differences in the prevalence and pattern of BPS between various studies, could be due to other, often unconsidered, factors such as gender, age, education, use of medication and VCI/VaD severity.
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Disfunción Cognitiva , Demencia Vascular , Cognición , Disfunción Cognitiva/diagnóstico , Estudios Transversales , Humanos , Estudios ProspectivosRESUMEN
It is currently incompletely understood whether inflammation and neurodegeneration are causally related in multiple sclerosis (MS). The sequence of a potential causal relationship is also unknown. Inflammation is present in rather all clinical stages of MS. Its role in the pathogenesis of MS is supported by histopathological analyses, genetic data, and numerous animal models of MS. All approved disease-modifying therapies that reduce clinical relapses and diminish the accumulation of lesions on neuroimaging are anti-inflammatory. Axonal loss and accelerated brain volume loss can also be detected from clinical disease onset throughout all stages. The expression of neurofilament light chain in cerebrospinal fluid and serum, a scaffolding protein in axons and dendrites, is a biomarker of neuronal injury associated with clinical relapses and reflects neuronal loss during episodes of acute inflammation. The recent association of human endogenous retrovirus (HERV) and its envelope proteins with MS illustrates a pathogenic pathway that causally links central nervous system (CNS)-intrinsic proinflammatory effects and inhibition of myelin repair and neuroregeneration. A review of current data on the causal relationship between inflammation and neurodegeneration in MS identified numerous plausible pathomechanisms that link the two events. Observations from most experimental models appear to favor a pathogenesis in which inflammation precedes neurodegeneration.
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Encefalomielitis Autoinmune Experimental , Inflamación/complicaciones , Esclerosis Múltiple/etiología , Degeneración Nerviosa/complicaciones , Animales , Humanos , Inflamación/diagnóstico , Esclerosis Múltiple/diagnóstico , Degeneración Nerviosa/diagnósticoRESUMEN
OBJECTIVES: We aimed to estimate the frequency of epileptic seizures (ES) and psychogenic nonepileptic seizures (PNES) with atypical duration in our epilepsy monitoring unit (EMU), in order to raise awareness of atypical durations of both types of events. MATERIALS & METHODS: We retrospectively reviewed all consecutive video-electroencephalogram (vEEG) recordings in our medical center's EMU from January 2013 to December 2017 and identified patients with seizures with atypical duration. Short PNES were defined as those lasting fewer than 2â¯min and long ES as those lasting for more than 5â¯min. RESULTS: The files of 830 adult (age >16â¯years) patients were reviewed, of whom 26 patients (3.1%, mean age: 33.3⯱â¯9.8â¯years, 12 females) were diagnosed as having an unusual seizure duration. Among 432 patients with ES during monitoring, fourteen patients [3.2% (95% confidence interval (CI): 1.5%-5.0%), mean age: 33.0⯱â¯12.2, 5 females [had long ES durations (exceeding 5â¯min). In 64% of patients with long ES, the events were provoked by antiepileptic drug (AED) withdrawal during vEEG, 62% had focal lesion on brain imaging, and 64% had a frontotemporal or a temporal seizure focus. Among 223 patients diagnosed with PNES, 12 patients [5.4% (95% CI: 2.2%-8.6%), mean age: 33.6⯱â¯6.6, 7 females] had short PNES durations (less than 2â¯min) and demonstrated motor (9/12, 75%), altered responsiveness (6/12, 50%), and vocalization (5/12, 42%) as the most prominent clinical features. CONCLUSIONS: The data from our case files highlight two main considerations in the diagnosis of paroxysmal events: prolonged event can be due to ES, while short events can be psychogenic.
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Encéfalo/fisiopatología , Electroencefalografía/tendencias , Trastornos Psicofisiológicos/fisiopatología , Convulsiones/fisiopatología , Grabación en Video/tendencias , Adolescente , Adulto , Anticonvulsivantes , Estudios de Cohortes , Electroencefalografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Trastornos Psicofisiológicos/diagnóstico , Estudios Retrospectivos , Convulsiones/diagnóstico , Convulsiones/psicología , Factores de Tiempo , Grabación en Video/métodos , Adulto JovenRESUMEN
BACKGROUND: The growing body of evidence indicating the heterogeneity of Alzheimer's disease (AD), coupled with disappointing clinical studies directed at a fit-for-all therapy, suggest that the development of a single magic cure suitable for all cases may not be possible. This calls for a shift in paradigm where targeted treatment is developed for specific AD subpopulations that share distinct genetic or pathological properties. Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor of AD, is expressed in more than half of AD patients and is thus an important possible AD therapeutic target. REVIEW: This review focuses initially on the pathological effects of apoE4 in AD, as well as on the corresponding cellular and animal models and the suggested cellular and molecular mechanisms which mediate them. The second part of the review focuses on recent apoE4-targeted (from the APOE gene to the apoE protein and its interactors) therapeutic approaches that have been developed in animal models and are ready to be translated to human. Further, the issue of whether the pathological effects of apoE4 are due to loss of protective function or due to gain of toxic function is discussed herein. It is possible that both mechanisms coexist, with certain constituents of the apoE4 molecule and/or its downstream signaling mediating a toxic effect, while others are associated with a loss of protective function. CONCLUSION: ApoE4 is a promising AD therapeutic target that remains understudied. Recent studies are now paving the way for effective apoE4-directed AD treatment approaches.
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Enfermedad de Alzheimer/tratamiento farmacológico , Apolipoproteína E4/metabolismo , Enfermedad de Alzheimer/patología , Animales , Humanos , RatonesRESUMEN
BACKGROUND: The concept of reserve was established to account for the observation that a given degree of neurodegenerative pathology may result in varying degrees of symptoms in different individuals. There is a large amount of evidence on epidemiological risk and protective factors for neurodegenerative diseases and dementia, yet the biological mechanisms that underpin the protective effects of certain lifestyle and physiological variables remain poorly understood, limiting the development of more effective preventive and treatment strategies. Additionally, different definitions and concepts of reserve exist, which hampers the coordination of research and comparison of results across studies. DISCUSSION: This paper represents the consensus of a multidisciplinary group of experts from different areas of research related to reserve, including clinical, epidemiological and basic sciences. The consensus was developed during meetings of the working groups of the first International Conference on Cognitive Reserve in the Dementias (24-25 November 2017, Munich, Germany) and the Alzheimer's Association Reserve and Resilience Professional Interest Area (25 July 2018, Chicago, USA). The main objective of the present paper is to develop a translational perspective on putative mechanisms underlying reserve against neurodegenerative disease, combining evidence from epidemiological and clinical studies with knowledge from animal and basic research. The potential brain functional and structural basis of reserve in Alzheimer's disease and other brain disorders are discussed, as well as relevant lifestyle and genetic factors assessed in both humans and animal models. CONCLUSION: There is an urgent need to advance our concept of reserve from a hypothetical model to a more concrete approach that can be used to improve the development of effective interventions aimed at preventing dementia. Our group recommends agreement on a common dictionary of terms referring to different aspects of reserve, the improvement of opportunities for data sharing across individual cohorts, harmonising research approaches across laboratories and groups to reduce heterogeneity associated with human data, global coordination of clinical trials to more effectively explore whether reducing epidemiological risk factors leads to a reduced burden of neurodegenerative diseases in the population, and an increase in our understanding of the appropriateness of animal models for reserve research.
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Enfermedad de Alzheimer/diagnóstico , Reserva Cognitiva/fisiología , Demencia/diagnóstico , Enfermedades Neurodegenerativas/diagnóstico , Investigación Biomédica Traslacional/métodos , Enfermedad de Alzheimer/patología , Animales , Consenso , Demencia/patología , Humanos , Enfermedades Neurodegenerativas/patología , Factores de RiesgoRESUMEN
Previous studies have suggested that disease duration in Creutzfeldt-Jakob disease (CJD) may be related to the radiological findings or cerebrospinal fluid (CSF) tau levels; however, it is not yet established whether clinical, radiological, and laboratory findings at diagnosis can predict survival or have a prognostic value. The aim of this study was to examine whether the disease duration is correlated with clinical, radiological, and laboratory variables. The study population consisted of consecutive familial CJD (fCJD) patients that were assessed within 1 week from the diagnosis including the CJD neurological scale (CJD-NS), Minimental Status Examination, Frontal Assessment Battery, NIH Stroke Scale, and the expanded disability status scale. In addition, a single MRI study was done and measurements of the extent of the cortical and subcortical involvement were performed. CSF was examined as part of the workout, and tau levels were determined. Sixty-nine fCJD patients were included in the study (43 males, mean age 59.3 ± 8.4, range 44-79 years). The mean disease duration was 7.3 ± 6.9 months (median 5.6 months, range 2-20 months). A significant correlation was found between the disease duration and the CJD-NS, the disease burden as reflected by the degree of cortical involvement by DWI, and the CSF tau levels. The findings of the current study reveal that several findings at disease onset including the disease severity, the cortical changes, and the tau levels are each individually correlated with disease duration and can be used by the clinician as a tool to predict the disease course and prognosis.
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Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/patología , Proteínas tau/líquido cefalorraquídeo , Adulto , Anciano , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Proteínas Priónicas/genética , PronósticoRESUMEN
OBJECTIVES: The epidemiology, manifestations, and course of Parkinson's disease (PD) may differ in men and women. Assessments of severity of the illness and quality of life (QoL), and the burden on their caregivers (CG) may change as the disease advances. We determined gender differences in assessment by patients with PD themselves and by their CGs. METHODS: Married couples in whom one of the partners was a PD patient and his/her spouse served as CG were separately evaluated. The patient completed the PD QoL Questionnaire (PDQ-39), and the spouse completed the Multidimensional Caregiver Strain Index (MCSI). Comparisons were performed using statistical tests. RESULTS: We studied 122 patient-CG pairs consisting of 86 (70.5%) male patients. Female patients reported reduced QoL due to depression and pain. Worsening of QoL in advanced PD was reported only by male patients. Female CGs felt exhaustion and damage to their health resulting from care twice as often as male CG. Social constraint and time limitations were more frequent in female CGs, whereas in male CGs it remained the same. With increasing disease severity female CGs reported that manipulations and excessive demands from their male spouses increased, while male CGs reported the same level in female patients. Male CGs, unexpectedly considered themselves more free as PD advanced in their spouses. CONCLUSIONS: Male and female PD patients and CGs assess differently the severity and burden of the disease. Clinicians and social workers should be aware of these factors in attempting to improve QoL of PD patients and CGs.
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Cuidadores/psicología , Enfermedad de Parkinson/psicología , Calidad de Vida , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which share many clinical, neurochemical, and morphological features, have been incorporated into DSM-5 as two separate entities of major neurocognitive disorders with Lewy bodies. Despite clinical overlap, their diagnosis is based on an arbitrary distinction concerning the time of onset of motor and cognitive symptoms, namely as early cognitive impairment in DLB and later onset following that of motor symptoms in PDD. Their morphological hallmarks - cortical and subcortical α-synuclein/Lewy body plus ß-amyloid and tau pathologies - are similar, but clinical differences at onset suggest some dissimilar profiles. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is provided herein. DISCUSSION: The clinical constellations of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and postmortem studies have revealed a more pronounced cortical atrophy, elevated cortical and limbic Lewy body pathologies, higher Aß and tau loads in cortex and striatum in DLB compared to PDD, and earlier cognitive defects in DLB. Conversely, multitracer PET studies have shown no differences in cortical and striatal cholinergic and dopaminergic deficits. Clinical management of both DLB and PDD includes cholinesterase inhibitors and other pharmacologic and non-drug strategies, yet with only mild symptomatic effects. Currently, no disease-modifying therapies are available. CONCLUSION: DLB and PDD are important dementia syndromes that overlap in many clinical features, genetics, neuropathology, and management. They are currently considered as subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), from incidental Lewy body disease and non-demented Parkinson's disease to PDD, DLB, and DLB with Alzheimer's disease at the most severe end. Cognitive impairment in these disorders is induced not only by α-synuclein-related neurodegeneration but by multiple regional pathological scores. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with Alzheimer's disease and other proteinopathies. While we prefer to view DLB and PDD as extremes on a continuum, there remains a pressing need to more clearly differentiate these syndromes and to understand the synucleinopathy processes leading to either one.
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Demencia/etiología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad de Parkinson/complicaciones , Anciano , Demencia/patología , Femenino , Humanos , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/patología , Masculino , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/patologíaRESUMEN
Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative disorders which have been pathologically classified as synucleinopathies, since they are associated with pathognomonic deposits of misfolded alpha-synuclein in cells of the nervous system. Recently PD, DLB, and MSA were also suggested to be prion-like disorders. Much controversy exists regarding this analogy between synucleinopathies and prion diseases. Here, we discuss what characterizes prion diseases and in which way synucleinopathies may be considered prion-like or -unlike. We critically review recent clinical and in vivo evidence from transmission studies to animals in support of or questioning the prion hypothesis of human synucleinopathies. We conclude that, although PD, DLB, and MSA fulfill many criteria of prion-likeness, they also still fail some of these criteria.
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Modelos Biológicos , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Priones/metabolismo , alfa-Sinucleína/metabolismo , HumanosRESUMEN
OBJECTIVE: To comprehensively describe the new syndrome of myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK), including cellular electrophysiological characterization of observed clinical improvement with fever. METHODS: We analyzed clinical, electroclinical, and neuroimaging data for 20 patients with MEAK due to recurrent KCNC1 p.R320H mutation. In vitro electrophysiological studies were conducted using whole cell patch-clamp to explore biophysical properties of wild-type and mutant KV 3.1 channels. RESULTS: Symptoms began at between 3 and 15 years of age (median = 9.5), with progressively severe myoclonus and rare tonic-clonic seizures. Ataxia was present early, but quickly became overshadowed by myoclonus; 10 patients were wheelchair-bound by their late teenage years. Mild cognitive decline occurred in half. Early death was not observed. Electroencephalogram (EEG) showed generalized spike and polyspike wave discharges, with documented photosensitivity in most. Polygraphic EEG-electromyographic studies demonstrated a cortical origin for myoclonus and striking coactivation of agonist and antagonist muscles. Magnetic resonance imaging revealed symmetrical cerebellar atrophy, which appeared progressive, and a prominent corpus callosum. Unexpectedly, transient clinical improvement with fever was noted in 6 patients. To explore this, we performed high-temperature in vitro recordings. At elevated temperatures, there was a robust leftward shift in activation of wild-type KV 3.1, increasing channel availability. INTERPRETATION: MEAK has a relatively homogeneous presentation, resembling Unverricht-Lundborg disease, despite the genetic and biological basis being quite different. A remarkable improvement with fever may be explained by the temperature-dependent leftward shift in activation of wild-type KV 3.1 subunit-containing channels, which would counter the loss of function observed for mutant channels, highlighting KCNC1 as a potential target for precision therapeutics. Ann Neurol 2017;81:677-689.
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Ataxia , Disfunción Cognitiva/etiología , Epilepsias Mioclónicas , Calor , Canales de Potasio Shaw/metabolismo , Adolescente , Adulto , Edad de Inicio , Ataxia/complicaciones , Ataxia/diagnóstico por imagen , Ataxia/genética , Ataxia/fisiopatología , Electroencefalografía , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/diagnóstico por imagen , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Femenino , Células HEK293 , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mutación , Linaje , Canales de Potasio Shaw/genética , Síndrome , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Poststroke cognitive impairment is a debilitating consequence of stroke. The aim of this study was to assess whether Actovegin confers cognitive benefit in patients who have had an ischemic stroke. METHODS: This was a 12-month, parallel-group, randomized, multicenter, double-blind, placebo-controlled study. Eligible patients were ≥60 years of age with a Montreal Cognitive Assessment test score of ≤25 points. Patients were randomized into 2 groups within 1 week of acute supratentorial ischemic stroke in a 1:1 ratio: Actovegin (a deproteinized hemoderivative of calf blood, 2000 mg/d for ≤20 intravenous infusions followed by 1200 mg/d orally) or placebo for 6 months. Patients were treated in accordance with standard clinical practice for a further 6 months. The primary end point was the change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version at 6 months. RESULTS: Two-hundred forty-eight patients were randomized to Actovegin and 255 patients to placebo. At month 6, the least squares mean change from baseline in Alzheimer's Disease Assessment Scale, cognitive subscale, extended version was -6.8 for Actovegin and -4.6 for placebo; the estimated treatment difference was -2.3 (95% confidence interval, -3.9, -0.7; P=0.005). Recurrent ischemic stroke was the most frequently reported serious adverse event, with a nonsignificantly higher number for Actovegin versus placebo. CONCLUSIONS: Actovegin had a beneficial effect on cognitive outcomes in patients with poststroke cognitive impairment. The safety experience was consistent with the known safety and tolerability profile of the drug. These results warrant confirmation in additional robustly designed studies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01582854.
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Antioxidantes/farmacología , Isquemia Encefálica/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Hemo/análogos & derivados , Evaluación de Resultado en la Atención de Salud , Accidente Cerebrovascular/complicaciones , Anciano , Anciano de 80 o más Años , Antioxidantes/administración & dosificación , Antioxidantes/efectos adversos , Disfunción Cognitiva/etiología , Método Doble Ciego , Femenino , Estudios de Seguimiento , Hemo/administración & dosificación , Hemo/efectos adversos , Hemo/farmacología , Humanos , Masculino , Persona de Mediana Edad , RecurrenciaRESUMEN
BACKGROUND AND PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with diseases of the brain, kidney, and vasculature. However, the relationship between T2DM, chronic kidney disease, brain alterations, and cognitive function after stroke is unknown. We aimed to evaluate the inter-relationship between T2DM, impaired renal function, brain pathology on imaging, and cognitive decline in a longitudinal poststroke cohort. METHODS: The TABASCO (Tel Aviv brain acute stroke cohort) is a prospective cohort of stroke/transient ischemic attack survivors. The volume and white matter integrity, ischemic lesions, and brain and hippocampal volumes were measured at baseline using 3-T MRI. Cognitive tests were performed on 507 patients, who were diagnosed as having mild cognitive impairment, dementia, or being cognitively intact after 24 months. RESULTS: At baseline, T2DM and impaired renal function (estimated creatinine clearance [eCCl] <60 mL/min) were associated with smaller brain and hippocampal volumes, reduced cortical thickness, and worse white matter microstructural integrity. Two years later, both T2DM and eCCl <60 mL/min were associated with poorer cognitive scores, and 19.7% of the participants developed cognitive decline (mild cognitive impairment or dementia). Multiple analysis, controlling for age, sex, education, and apolipoprotein E4, showed a significant association of both T2DM and eCCl <60 mL/min with cognitive decline. Having both conditions doubled the risk compared with patients with T2DM or eCCl <60 mL/min alone and almost quadrupled the risk compared with patients without either abnormality. CONCLUSIONS: T2DM and impaired renal function are independently associated with abnormal brain structure, as well as poorer performance in cognitive tests, 2 years after stroke. The presence of both conditions quadruples the risk for cognitive decline. T2DM and lower eCCl have an independent and additive effect on brain atrophy and the risk of cognitive decline. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01926691.
Asunto(s)
Disfunción Cognitiva/psicología , Demencia/psicología , Diabetes Mellitus Tipo 2/epidemiología , Insuficiencia Renal Crónica/epidemiología , Accidente Cerebrovascular/psicología , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Estudios de Cohortes , Comorbilidad , Demencia/diagnóstico por imagen , Demencia/epidemiología , Demencia/etiología , Función Ejecutiva , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/patología , Humanos , Israel/epidemiología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Destreza Motora , Pruebas Neuropsicológicas , Tamaño de los Órganos , Estudios Prospectivos , Factores de Riesgo , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/epidemiología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patologíaRESUMEN
We studied a consanguineous Palestinian Arab family segregating an autosomal recessive progressive myoclonus epilepsy (PME) with early ataxia. PME is a rare, often fatal syndrome, initially responsive to antiepileptic drugs which over time becomes refractory and can be associated with cognitive decline. Linkage analysis was performed and the disease locus narrowed to chromosome 19p13.3. Fourteen candidate genes were screened by conventional Sanger sequencing and in one, LMNB2, a novel homozygous missense mutation was identified that segregated with the PME in the family. Whole exome sequencing excluded other likely pathogenic coding variants in the linked interval. The p.His157Tyr mutation is located in an evolutionarily highly conserved region of the alpha-helical rod of the lamin B2 protein. In vitro assembly analysis of mutant lamin B2 protein revealed a distinct defect in the assembly of the highly ordered fibrous arrays typically formed by wild-type lamin B2. Our data suggests that disruption of the organisation of the nuclear lamina in neurons, perhaps through abnormal neuronal migration, causes the epilepsy and early ataxia syndrome and extends the aetiology of PMEs to include dysfunction in nuclear lamin proteins.
Asunto(s)
Ataxia/genética , Cromosomas Humanos Par 19/genética , Epilepsias Mioclónicas/genética , Lamina Tipo B/genética , Mutación Missense , Sustitución de Aminoácidos , Niño , Familia , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier. CONSENSUS AND SUGGESTIONS: Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied. CONCLUSION: A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.