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BACKGROUND: PET imaging of the translocator protein (TSPO) is used to assess in vivo brain inflammation. One of the main methodological issues with this method is the allelic dependence of the radiotracer affinity. In Alzheimer's disease (AD), previous studies have shown similar clinical and patho-biological profiles between TSPO genetic subgroups. However, there is no evidence regarding the effect of the TSPO genotype on cerebrospinal-fluid biomarkers of glial activation, and synaptic and axonal damage. METHOD: We performed a trans-sectional study in early AD to compare cerebrospinal-fluid levels of GFAP, YKL-40, sTREM2, IL-6, IL-10, NfL and neurogranin between TSPO genetic subgroups. RESULTS: We recruited 33 patients with early AD including 16 (48%) high affinity binders, 13 (39%) mixed affinity binders, and 4/33 (12%) low affinity binders. No difference was observed in terms of demographics, and cerebrospinal fluid levels of each biomarker for the different subgroups. CONCLUSION: TSPO genotype is not associated with a change in glial activation, synaptic and axonal damage in early AD. Further studies with larger numbers of participants will be needed to confirm that the inclusion of specific TSPO genetic subgroups does not introduce selection bias in studies and trials of AD that combine TSPO imaging with cerebrospinal fluid biomarkers.
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Adiponectin is an adipokine playing a central role in the regulation of energy homeostasis, carbohydrate and lipid metabolism, as well as immunomodulation. The relationship between Alzheimer's disease (AD) and body composition has highlighted the bidirectional crosstalk between AD's pathophysiology and metabolic disorders. This review aimed to report the current state of knowledge about cellular and molecular mechanisms linking adiponectin and AD, in preclinical studies. Then, we reviewed human studies to assess the relationship between adiponectin levels and AD diagnosis. We also examined the risk of incident AD regarding the participants' baseline adiponectin level, as well as the relationship of adiponectin and cognitive decline in patients with AD. We conducted a systematic review, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline, of studies published over the last decade on MEDLINE and Cochrane databases. Overall, we reviewed 34 original works about adiponectin in AD, including 11 preclinical studies, two both preclinical and human studies and 21 human studies. Preclinical studies brought convincing evidence for the neuroprotective role of adiponectin on several key mechanisms of AD. Human studies showed conflicting results regarding the relationship between AD and adiponectin levels, as well as regarding the cross-sectional association between cognitive function and adiponectin levels. Adiponectin did not appear as a predictor of incident AD, nor as a predictor of cognitive decline in patients with AD. Despite solid preclinical evidence suggesting the protective role of adiponectin in AD, inconsistent results in humans supports the need for further research.
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Adiponectina , Enfermedad de Alzheimer , Animales , Humanos , Adipoquinas , Adiponectina/metabolismo , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico , Cognición , Estudios TransversalesRESUMEN
BACKGROUND: Metabolic dysfunction and dysregulation of leptin signaling have been linked to Alzheimer's disease (AD)'s pathophysiology. The objectives of this study were to examine the associations between plasma leptin, cerebrospinal fluid (CSF), beta-amyloid (Aß), and tau biomarkers (AT[N] status) and with the stage of cognitive impairment. METHODS: Cross-sectional analysis of data from cognitively impaired patients from a tertiary memory clinic. Plasma leptin levels were compared according to the stage of cognitive impairment and biomarker profiles, using the AT(N) classification. Linear regression models were performed to examine the relationship between leptin and CSF biomarkers. Results were adjusted for age, gender, body mass index (BMI), and APOE ε4. In a subgroup of A+T+ individuals, we compared the 2-year evolution of Mini-Mental State Examination scores, according to the participants' tertile of plasma leptin levels. RESULTS: We included 1 036 participants (age 68.7 ± 9.1, females = 54.1%). A+T+ and A+T- patients had significantly lower plasma leptin levels than amyloid negative participants (p < .01). CSF Aß concentration was significantly associated with lower plasma leptin ß = -4.3 (1.5), p = .005 unadjusted; and ß = -3.4 (1.6), p = .03 after adjustment for age, female gender, BMI, and APOE ε4. Patients with major neurocognitive disorder due to AD had a difference of leptin of -7.3 ng/mL 95% confidence interval (CI; -11.8; -2.8), p = .0002, compared to individuals with other causes of cognitive impairment. Leptin was not associated with the slope of cognitive decline. CONCLUSION: Plasma leptin levels were associated with CSF Aß and with the diagnosis of AD confirmed by CSF biomarkers, suggesting a molecular interplay between leptin metabolism and brain amyloid deposition.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Anciano , Enfermedad de Alzheimer/psicología , Apolipoproteína E4/genética , Estudios Transversales , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Amiloide , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
OBJECTIVE: To explore the accuracy of plasma neurofilament light chain (NfL) as a biomarker for diagnosis and staging of cognitive impairment, in a large cohort with of previously diagnosed patients in clinical practice. METHODS: Retrospective, cross-sectional, monocentric study, from a tertiary memory clinic. Patients underwent cerebrospinal fluid core Alzheimer's disease (AD) biomarker evaluation using ELISA or Elecsys methods, and plasma NfL analysis using the single molecule array technology. The patients' biomarker data were examined for associations with: i/cognitive status ii/presence of neurodegenerative disease and iii/diagnostic groups. Associations between core CSF biomarkers and plasma NfL were determined. RESULTS: Participants (N = 558, mean age = 69.2 ± 8.8, 56.5% women) were diagnosed with AD (n = 274, considering dementia and MCI stages), frontotemporal dementia (FTD, n = 55), Lewy body disease (LBD, n = 40, considering MCI and dementia stages), other neurodegenerative diseases, n = 57 (e.g Supranuclear Palsy, Corticobasal syndrome), non-neurodegenerative cognitive impairment (NND, n = 79, e.g. vascular lesions, epilepsy or psychiatric disorders) or subjective cognitive impairment (SCI, n = 53). Mean plasma NfL (log, pg/mL) levels were higher in neurodegenerative than non-neurodegenerative disorders (1.35 ± 0.2 vs 1.16 ± 0.23, p < 0.001), higher in all diagnostic groups than in SCI (1.06 ± 0.23) p < 0.001), and associated with the stage of cognitive impairment (p < 0.001). The addition of plasma NfL to a clinical model (age, MMSE and APOE ε4 carriership) marginally improved the discrimination of degenerative from non-degenerative disorders in ROC analysis (AUC clinical model: 0.81, 95% CI = [0.77;0.85] AUC clinical model + plasma NfL: AUC = 0.83 95% CI = [0.78;0.87], delta Akaike information criterion = -11.7). DISCUSSION: Plasma NfL could help discrimination between degenerative and non-degenerative cognitive disorders, albeit not better than comprehensive clinical evaluation.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Demencia Frontotemporal , Enfermedad por Cuerpos de Lewy , Enfermedades Neurodegenerativas , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores , Disfunción Cognitiva/líquido cefalorraquídeo , Estudios Transversales , Filamentos Intermedios , Proteínas de Neurofilamentos , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeo , Persona de Mediana Edad , AncianoRESUMEN
Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer's disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers.
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Enfermedad de Alzheimer , Enfermedad por Cuerpos de Lewy , Anciano , Humanos , Masculino , Persona de Mediana Edad , alfa-Sinucleína/líquido cefalorraquídeo , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Enfermedad por Cuerpos de Lewy/diagnóstico , Enfermedad por Cuerpos de Lewy/líquido cefalorraquídeo , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeo , FemeninoRESUMEN
In this translational study, we investigated the plasma tau protein, neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), which are established biomarkers of neurological injury, as predictive biomarkers of alcohol withdrawal-associated brain toxicity. In the clinical study, patients with severe alcohol use disorder (AUD) on D1 of hospitalization for alcohol cessation (AC) (N = 36) were compared to severe AUD patients with at least 3 months of abstinence (N = 16). Overall, patients were 40 men (76.9%), aged 49.8 years [SD ±9.9]. Tau, NfL, GFAP and UCHL1 levels were measured using SIMOA and analysed with a quasipoisson regression model adjusted for age and sex. The NfL level was higher in the AC group (p = 0.013). In the AC group, the tau (p = 0.021) and UCHL1 (p = 0.021) levels were positively associated with the dose of diazepam per weight, and the tau (p = 0.045), NfL (p = 4.9 × 10-3 ) and UCHL1 (p = 0.036) levels were higher in the presence of signs of Wernicke's encephalopathy (n = 9). In the preclinical study, NfL and GFAP levels were assessed in the alcohol deprivation effect (ADE) procedure (N = 17) and control Wistar rats (N = 15). Furthermore, ADE rats were prospectively assessed: after 24 h (T1) and 3 weeks of AC (T2) (paired-samples Wilcoxon and Mann-Whitney tests). The NfL level was higher in the ADE model than in the control rats at both T1 and T2 (p = 0.033 and p = 1.3 × 10-3 ) and higher at T2 than at T1 (p = 0.040). Plasma tau, NfL and UCHL1 are potential biomarkers of brain suffering during alcohol withdrawal.
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Alcoholismo , Síndrome de Abstinencia a Sustancias , Animales , Ratas , Proteínas de Neurofilamentos , Proteína Ácida Fibrilar de la Glía , Ubiquitina Tiolesterasa , Proyectos Piloto , Estudios de Cohortes , Ratas Wistar , Biomarcadores , EncéfaloRESUMEN
IMPORTANCE: Dementia with Lewy bodies (DLB) is a neurodegenerative disease linked to abnormal accumulation of phosphorylated α-synuclein. GBA1 is the gene encoding the lysosomal enzyme glucocerebrosidase (GCase), whose mutations are a risk factor of DLB. OBJECTIVE: To report all available data exploring the association between GBA1 mutations and DLB. EVIDENCE REVIEW: All publications focused on GCase and DLB in humans between 2003 and 2022 were identified on PubMed, Cochrane and ClinicalTrials.gov. FINDINGS: 29 studies were included and confirmed the strong association between GBA1 mutations and DLB (Odds Ratio [OR]: 8.28). GBA1 mutation carriers presented a more malignant phenotype, with earlier symptom onset, more severe motor and cognitive dysfunctions, more visual hallucinations and rapid eye movement sleep disorder. GBA1 mutations were associated with "purer" neuropathological DLB. No therapeutic recommendations exist and clinical trials targeting GCase are just starting in DLB patients. CONCLUSIONS AND RELEVANCE: This review reports a link between GBA1 mutations and the DLB phenotype with limited evidence due to the small number of studies.
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Enfermedad por Cuerpos de Lewy , Enfermedades Neurodegenerativas , Glucosilceramidasa/genética , Humanos , Enfermedad por Cuerpos de Lewy/genética , Mutación/genética , alfa-SinucleínaRESUMEN
BACKGROUND: Synaptic dysfunction is an early core feature of Alzheimer's disease (AD), closely associated with cognitive symptoms. Neuregulin 1 (NRG1) is a growth and differentiation factor with a key role in the development and maintenance of synaptic transmission. Previous reports have shown that changes in cerebrospinal fluid (CSF) NRG1 concentration are associated with cognitive status and biomarker evidence of AD pathology. Plasma biomarkers reflecting synaptic impairment would be of great clinical interest. OBJECTIVE: To measure plasma NRG1 concentration in AD patients in comparison with other neurodegenerative disorders and neurological controls (NC) and to study its association with cerebrospinal fluid (CSF) core AD and synaptic biomarkers. METHODS: This retrospective study enrolled 127 participants including patients with AD at mild cognitive impairment stage (AD-MCI, n = 27) and at dementia stage (n = 35), non-AD dementia (n = 26, Aß-negative), non-AD MCI (n = 19), and neurological controls (n=20). Plasma and CSF NRG1, as well as CSF core AD biomarkers (Aß 42/Aß 40 ratio, phospho-tau, and total tau), were measured using ELISA. CSF synaptic markers were measured using ELISA for GAP-43 and neurogranin and through immunoprecipitation mass spectrometry for SNAP-25. RESULTS: Plasma NRG1 concentration was higher in AD-MCI and AD dementia patients compared with neurological controls (respectively P = 0.005 and P < 0.001). Plasma NRG1 differentiated AD MCI patients from neurological controls with an area under the curve of 88.3%, and AD dementia patients from NC with an area under the curve of 87.3%. Plasma NRG1 correlated with CSF NRG1 (ß = 0.372, P = 0.0056, adjusted on age and sex). Plasma NRG1 was associated with AD CSF core biomarkers in the whole cohort and in Aß-positive patients (ß = -0.197-0.423). Plasma NRG1 correlated with CSF GAP-43, neurogranin, and SNAP-25 (ß = 0.278-0.355). Plasma NRG1 concentration correlated inversely with MMSE in the whole cohort and in Aß-positive patients (all, ß = -0.188, P = 0.038; Aß+: ß = -0.255, P = 0.038). CONCLUSION: Plasma NRG1 concentration is increased in AD patients and correlates with CSF core AD and synaptic biomarkers and cognitive status. Thus, plasma NRG1 is a promising non-invasive biomarker to monitor synaptic impairment in AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Proteína GAP-43 , Humanos , Neurregulina-1 , Neurogranina/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Estudios Retrospectivos , Proteínas tau/líquido cefalorraquídeoRESUMEN
PURPOSE OF REVIEW: Ketogenic diets (KD) are validated treatments of pharmacoresistant epilepsy. Their interest in neurodegenerative diseases such as Alzheimer's disease (AD) has been suggested, because ketone bodies may reduce neuroinflammation, improve neurotransmitters transport pathway, synaptic maintenance, and reduce brain ß-amyloid deposition. In this updated review, we aimed at critically examining the evidence of the past 2 years regarding KD or ketogenic supplements (KS) on cognitive and biological/neuropathological outcomes. We conducted our search in preclinical studies (animal models of AD) or in humans with or without cognitive impairment. RECENT FINDINGS: Overall, 12 studies were included: four in animal models of AD and eight in humans. In preclinical studies, we found additional evidence for a decrease in cerebral inflammation as well as in specific features of AD: ß-amyloid, aggregates of tau protein under KD/KS. Several AD mouse models experienced clinical improvements. Human studies reported significant cognitive benefits, improved brain metabolism and biomarkers change under KD/KS, despite rather short-term interventions. Adherence to KD or KS was acceptable with frequent, but minor gastrointestinal adverse effects. SUMMARY: The present review gathered additional evidence for both pathophysiological and clinical benefits of KS/KD in AD. Further studies are warranted with a biomarker-based selection of AD participants and long-term follow-up.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Dieta Cetogénica , Péptidos beta-Amiloides , Animales , Humanos , Cuerpos Cetónicos , RatonesRESUMEN
Alzheimer's disease (AD) is the most frequent age-related neurodegenerative disorder, with no curative treatment available so far. Alongside the brain deposition of ß-amyloid peptide and hyperphosphorylated tau, neuroinflammation triggered by the innate immune response in the central nervous system, plays a central role in the pathogenesis of AD. Glucose usually represents the main fuel for the brain. Glucose metabolism has been related to neuroinflammation, but also with AD lesions. Hyperglycemia promotes oxidative stress and neurodegeneration. Insulinoresistance (e.g., in type 2 diabetes) or low IGF-1 levels are associated with increased ß-amyloid production. However, in the absence of glucose, the brain may use another fuel: ketone bodies (KB) produced by oxidation of fatty acids. Over the last decade, ketogenic interventions i.e., ketogenic diets (KD) with very low carbohydrate intake or ketogenic supplementation (KS) based on medium-chain triglycerides (MCT) consumption, have been studied in AD animal models, as well as in AD patients. These interventional studies reported interesting clinical improvements in animals and decrease in neuroinflammation, ß-amyloid and tau accumulation. In clinical studies, KS and KD were associated with better cognition, but also improved brain metabolism and AD biomarkers. This review summarizes the available evidence regarding KS/KD as therapeutic options for individuals with AD. We also discuss the current issues and potential adverse effects associated with these nutritional interventions. Finally, we propose an overview of ongoing and future registered trials in this promising field.
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Introduction: Alzheimer's disease (AD) is neuropathologically marked by amyloid beta (Aß) plaques and neurofibrillary tangles. Little is known about isotopic compositions of human AD brains. Here we study this in comparison with control subjects for copper and zinc. Methods: We use mass-spectrometry methods, developed to study extraterrestrial materials, to compare the copper and zinc isotopic composition of 10 AD and 10 control brains. Results: Copper and zinc natural isotopic compositions of AD brains are statistically different compared to controls, and correlate with Braak stages. Discussion: The distribution of natural copper and zinc isotopes in AD is not affected by the diet, but is a consequence of Aß plaques and tau fibril accumulation. This is well predicted by the changes of the chemical bonding environment caused by the development of Aß lesions and accumulation of tau proteins. Future work will involve testing whether these changes affect brain functions and are propagated to body fluids.
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Abnormal activation of the transcriptional factor STAT3 (signal transducer and activator of transcription 3) was recently associated with Alzheimer Disease (AD). STAT3 phosphorylation is critical for cytokine secretion linked to neuroinflammation. Moreover, STAT3 may act as a transcriptional regulator of BACE1 (ß-APP cleaving enzyme-1), the key enzyme in amyloid ß (Aß) production. We have previously shown that neuroinflammation and increased brain BACE1 levels triggered by LPS-induced systemic inflammation in wild-type mice are associated with an enhanced STAT3 activation. Using this LPS model, the goal of this study was to investigate if a STAT3 inhibitor administration could be protective against neuroinflammation and abnormal BACE1 regulation. Our results show that intraperitoneal injection of Stattic, a molecule that selectively inhibits the activation of STAT3, decreases LPS-induced microglial activation in the hippocampus. In addition, STAT3 inhibition reduced brain levels of cytokines IL-6, IL-1ß and TNF-α triggered by LPS systemic administration. A significant reduction of BACE1 levels was observed in the hippocampus of mice treated with LPS and Stattic compared to those exposed to LPS alone. Taking together, our results show that Stattic can protect hippocampus against two pathological hallmarks of AD, and pave the way for further explorations of the therapeutic potential of STAT3 inhibition in AD.
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Secretasas de la Proteína Precursora del Amiloide/metabolismo , Antiinflamatorios/farmacología , Ácido Aspártico Endopeptidasas/metabolismo , Óxidos S-Cíclicos/farmacología , Hipocampo/efectos de los fármacos , Inflamación/tratamiento farmacológico , Microglía/efectos de los fármacos , Neuroinmunomodulación/efectos de los fármacos , Factor de Transcripción STAT3/antagonistas & inhibidores , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipocampo/enzimología , Hipocampo/inmunología , Inflamación/inducido químicamente , Inflamación/enzimología , Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Lipopolisacáridos , Masculino , Ratones Endogámicos C57BL , Microglía/enzimología , Microglía/inmunología , Fosforilación , Factor de Transcripción STAT3/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: The presynaptic protein neuregulin1 (NRG1) is cleaved by beta-site APP cleaving enzyme 1 (BACE1) in a similar way as amyloid precursor protein (APP) NRG1 can activate post-synaptic receptor tyrosine-protein kinase erbB4 (ErbB4) and was linked to schizophrenia. The NRG1/ErbB4 complex is neuroprotective, can trigger synaptogenesis and plasticity, increases the expression of NMDA and GABA receptors, and can induce neuroinflammation. This complex can reduce memory formation. In Alzheimer's disease (AD) brains, NRG1 accumulates in neuritic plaques. It is difficult to determine if NRG1 has beneficial and/or detrimental effects in AD. BACE1 levels are increased in AD brains and cerebrospinal fluid (CSF) and may lead to enhanced NRG1 secretion, but no study has assessed CSF NRG1 levels in AD and mild cognitive impairment (MCI) patients. METHODS: This retrospective study included 162 patients suffering from AD dementia (54), MCI with progression to AD dementia (MCI-AD) (27), non-AD MCI (30), non-AD dementias (30), and neurological controls (27). All patients had neurological examinations, brain MRI, and neuropsychological evaluations. After written informed consent and using enzyme-linked immunosorbent assays (ELISAs), CSF samples were evaluated for Aß1-42, Aß1-40, total tau (T-tau), phosphorylated tau on threonine 181 (P-tau), BACE1, growth-associated protein 43 (GAP 43), neurogranin (Ng), and NRG1. RESULTS: Levels of NRG1 were significantly increased in the CSF of AD (+ 36%) and MCI-AD (+ 28%) patients compared to neurological controls and also non-AD MCI and non-AD dementias. In addition, in AD and MCI-AD patients, NRG1 levels positively correlated with Aß1-42 but not with T-tau, P-tau, and BACE1 levels and negatively correlated with MMSE scores. A longitudinal follow-up study of AD patients revealed a trend (p = 0.08) between CSF NRG1 levels and cognitive decline. In the overall population, NRG1 correlated with MMSE and the synaptic biomarkers GAP 43 and neurogranin. CONCLUSIONS: Our results showed that CSF NRG1 levels are increased in AD and MCI-AD as compared to controls and other dementias. CSF NRG1 levels are associated with cognitive evolution, and a major outcome of our findings is that synaptic NRG1 could be involved in the pathophysiology of AD. Modulating brain NRG1 activity may represent a new therapeutic target in AD.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Secretasas de la Proteína Precursora del Amiloide , Péptidos beta-Amiloides , Ácido Aspártico Endopeptidasas , Biomarcadores , Cognición , Estudios de Seguimiento , Humanos , Neurregulina-1 , Fragmentos de Péptidos , Estudios Retrospectivos , Proteínas tauRESUMEN
BACKGROUND: Brain amyloid deposition and neurofibrillary tangles in Alzheimer's disease (AD) are associated with complex neuroinflammatory reactions such as microglial activation and cytokine production. Glucose metabolism is closely related to neuroinflammation. Ketogenic diets (KDs) include a high amount of fat, low carbohydrate and medium-chain triglyceride (MCT) intake. KDs lead to the production of ketone bodies to fuel the brain, in the absence of glucose. These nutritional interventions are validated treatments of pharmacoresistant epilepsy, consequently leading to a better intellectual development in epileptic children. In neurodegenerative diseases and cognitive decline, potential benefits of KD were previously pointed out, but the published evidence remains scarce. The main objective of this review was to critically examine the evidence regarding KD or MCT intake effects both in AD and ageing animal models and in humans. MAIN BODY: We conducted a review based on a systematic search of interventional trials published from January 2000 to March 2019 found on MEDLINE and Cochrane databases. Overall, 11 animal and 11 human studies were included in the present review. In preclinical studies, this review revealed an improvement of cognition and motor function in AD mouse model and ageing animals. However, the KD and ketone supplementation were also associated with significant weight loss. In human studies, most of the published articles showed a significant improvement of cognitive outcomes (global cognition, memory and executive functions) with ketone supplementation or KD, regardless of the severity of cognitive impairments previously detected. Both interventions seemed acceptable and efficient to achieve ketosis. CONCLUSION: The KD or MCT intake might be promising ways to alter cognitive symptoms in AD, especially at the prodromal stage of the disease. The need for efficient disease-modifying strategies suggests to pursue further KD interventional studies to assess the efficacy, the adherence to this diet and the potential adverse effects of these nutritional approaches.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Diabetes Mellitus Tipo 2 , Dieta Cetogénica , Adulto , Enfermedad de Alzheimer/dietoterapia , Animales , Cognición , Humanos , MasculinoRESUMEN
OBJECTIVES: New diagnostic criteria for Alzheimer's disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics. DESIGN: We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey. SETTING: 29 secondary and tertiary memory clinics in France. PARTICIPANTS: Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP. PRIMARY AND SECONDARY OUTCOME MEASURES: Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine. RESULTS: 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4). CONCLUSION: This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.
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Enfermedad de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico , Anciano , Enfermedad de Alzheimer/líquido cefalorraquídeo , Disfunción Cognitiva/líquido cefalorraquídeo , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Francia , Humanos , Masculino , Estudios Prospectivos , Encuestas y CuestionariosRESUMEN
Brain lesions in Alzheimer's disease (AD) include amyloid plaques made of Aß peptides and neurofibrillary tangles composed of hyperphosphorylated tau protein with synaptic and neuronal loss and neuroinflammation. Aß oligomers can trigger tau phosphorylation and neuronal alterations through activation of neuronal kinases leading to progressive cognitive decline. PKR is a ubiquitous pro-apoptotic serine/threonine kinase, and levels of activated PKR are increased in AD brains and AD CSF. In addition, PKR regulates negatively memory formation in mice. To assess the role of PKR in an AD in vivo model, we crossed 5xFAD transgenic mice with PKR knockout (PKRKO) mice and we explored the contribution of PKR on cognition and brain lesions in the 5xFAD mouse model of AD as well as in neuron-microglia co-cultures exposed to the innate immunity activator lipopolysaccharide (LPS). Nine-month-old double-mutant mice revealed significantly improved memory consolidation with the new object location test, starmaze test, and elevated plus maze test as compared to 5xFAD mice. Brain amyloid accumulation and BACE1 levels were statistically decreased in double-mutant mice. Apoptosis, neurodegeneration markers, and synaptic alterations were significantly reduced in double-mutant mice as well as neuroinflammation markers such as microglial load and brain cytokine levels. Using cocultures, we found that PKR in neurons was essential for LPS microglia-induced neuronal death. Our results demonstrate the clear involvement of PKR in abnormal spatial memory and brain lesions in the 5xFAD model and underline its interest as a target for neuroprotection in AD.
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Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Memoria Espacial , eIF-2 Quinasa/metabolismo , Enfermedad de Alzheimer/patología , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/patología , Células Cultivadas , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , eIF-2 Quinasa/deficienciaRESUMEN
Mutations of LRRK2, encoding leucine-rich repeat kinase 2 (LRRK2), are the leading cause of autosomal dominant Parkinson's disease (PD). The most frequent of these mutations, G2019S substitution, increases kinase activity, but it remains unclear how it causes PD. Recent studies suggest that LRRK2 modulates mitochondrial homeostasis. Mitochondrial dysfunction plays a key role in the pathogenesis of autosomal recessive PD forms linked to PARK2 and PINK1, encoding the cytosolic E3 ubiquitin-protein ligase Parkin and the mitochondrial kinase PINK1, which jointly regulate mitophagy. We explored the role of LRRK2 and its kinase activity in PINK1/Parkin-dependent mitophagy. LRRK2 increased mitochondrial aggregation and attenuated mitochondrial clearance in cells coexpressing Parkin and exposed to the protonophore carbonylcyanide m-chlorophenylhydrazone. Förster resonance energy transfer imaging microscopy showed that LRRK2 impaired the interactions between Parkin and Drp1 and their mitochondrial targets early in mitophagy. The inhibition of LRRK2 kinase activity by a 'kinase-dead' LRRK2 mutation or with a pharmacological inhibitor (LRRK2-IN-1) restored these interactions. The monitoring of mitophagy in human primary fibroblasts with the novel dual-fluorescence mtRosella reporter and a new hypothermic shock paradigm revealed similar defects in PD patients with the G2019S LRRK2 substitution or PARK2 mutations relative to healthy subjects. This defect was restored by LRRK2-IN-1 treatment in LRRK2 patients only. Our results suggest that PD forms due to LRRK2 and PARK2 mutations involve pathogenic mechanisms converging on PINK1/Parkin-dependent mitophagy.
Asunto(s)
Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genética , Enfermedad de Parkinson/genética , Proteínas Quinasas/genética , Ubiquitina-Proteína Ligasas/genética , Adulto , Anciano , Benzodiazepinonas/farmacología , Carbonil Cianuro m-Clorofenil Hidrazona/análogos & derivados , Carbonil Cianuro m-Clorofenil Hidrazona/farmacología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/patología , Transferencia Resonante de Energía de Fluorescencia , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Mitocondrias/genética , Mitocondrias/patología , Mitofagia/efectos de los fármacos , Mutación , Enfermedad de Parkinson/patología , Fosforilación , Cultivo Primario de Células , Pirimidinas/farmacologíaRESUMEN
Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in ParkinS65A/S65A neurons. Phenotypically, ParkinS65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN (PARK2) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.
Asunto(s)
Mitocondrias/metabolismo , Mitofagia , Enfermedad de Parkinson/metabolismo , Proteínas Quinasas/metabolismo , Ubiquitina-Proteína Ligasas , Animales , Humanos , Ratones , Ratones Transgénicos , Mitocondrias/genética , Mitocondrias/patología , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/patología , Fosforilación/genética , Proteínas Quinasas/genética , Serina/genética , Serina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Alzheimer's disease (AD) is marked by memory disturbances followed by aphasia, apraxia and agnosia. Brain lesions include the accumulation of the amyloid peptide in extracellular plaques, neurofibrillary tangles with abnormally phosphorylated tau protein and synaptic and neuronal loss. New findings have suggested that brain lesions could occur one or two decades before the first clinical signs. This asymptomatic preclinical phase could be an opportunity to put in place a secondary prevention but the detection of these brain lesions can only be achieved so far by cerebrospinal fluid (CSF) evaluation or molecular amyloid and tau PET imaging. There is an urgent need to find out simple and easily accessible new biomarkers to set up an efficient screening in adult and aging population. Neuropathological and biochemical studies have revealed that abnormal accumulations of potentially toxic kinases are present in the brains of AD patients. Kinase activation leads to abnormal tau phosphorylation, amyloid production, apoptosis and neuroinflammation. Increased levels of these kinases are present in the CSF of mild cognitive impairment (MCI) and AD patients. Over the last years the search for abnormal kinase levels was performed in the blood of patients. Glycogen synthase kinase 3 (GSK 3), protein kinase R (PKR), mamalian target of rapamycin (mTOR), dual specificity tyrosine-phosphorylation-regulated kinase 1A (DIRK1A), c-Jun N-terminal kinase (JNK), protein 70 kD ribosomal protein S6 kinase (P70S6K), ERK2 and other kinase concentrations were evaluated and abnormal levels were found in many studies. For example, GSK3 levels are increased in MCI and AD patients. PKR levels are also augmented in peripheral blood mononuclear cells (PBMC) of AD patients. In the future, the assessment of several blood kinase levels in large cohorts of patients will be needed to confirm the usefulness of this test at an early phase of the disease.