Cancer in Parkinson Disease: an approximation to the main risk factors

Background: Many evidences suggest a pathological link between neurodegenerative diseases and cancer. In fact, several epidemiologic studies indicate a a decreased incidence of most cancer types in Parkinson's disease (PD) patients and some PD genes are involved in cancer networks. Objective : The aim of this study is to assess the influence of several factors in the risk of cancer in a cohort of 753 PD patients and to study how these variables interact with each other. Methods: We analyzed the effect of gender, tobacco, alcohol, type of PD (genetic (gPD) or idiopathic PD (iPD)) and two genetic variants, previouly associated with cancer, rs5848- GRN, rs1042522- TP53. Results: A higher age at PD onset was observed in patients that develop cancer before PD (p<0.001). Alcohol consumption was a risk factor to develop cancer in PD patients (p=0.011) while smoking was not a cancer risk factor in our cohort(p=0.098). Among the genetic factors, the genotype TT GRN-rs5848 was statistically more frequent in PD patients without cancer (p=0.05). Conclusions: Our study identified several factors, genetic and non-genetic, which contribute to the risk for cancer in PD.

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Impact of Depression and Anxiety on Dimensions of Health-Related Quality of Life in Subjects with Parkinson’s Disease Enrolled in an Association of Patients

Parkinson’s disease (PD) is a complex disorder characterized by a wide spectrum of symptoms. Depression and anxiety are common manifestations in PD and may be determinants of health-related quality of life (HRQoL). The objective of this study is to determine the association of depression and anxiety with the dimensions of HRQoL in subjects with PD enrolled in an association of patients. Ninety-five community-based patients with PD diagnosis at different disease stages were studied. HRQoL was assessed using the Parkinson’s Disease Questionnaire (PDQ-39); depression and anxiety were assessed using the Beck Depression Inventory (BDI-II) and the State-Trait Anxiety Inventory (STAI), respectively. Our results showed that depression and anxiety were negatively associated with HRQoL measured by PDSI. Higher motor dysfunction measured by Hoehn and Yahr (H&Y) staging was also associated with worse HRQoL. Depression was the most influential variable in the model. All PDQ-39 dimensions except social support and bodily discomfort were associated with depression. Anxiety was associated with the emotional well-being and bodily discomfort dimensions. These results suggest that physicians should pay attention to the presence of psychiatric symptoms and treat them appropriately.

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A series of cases with Huntington-like phenotype and intermediate repeats in HTT

Here we describe the larger series of clinical cases (n = 14) with HD-like phenotype and IAs published to date.  MRI and FDG-PET neuroimaging findings compatible with HD can be found in some patients with IA.  Larger and more detailed series are needed to assess the pathogenic role of IAs in HTT gene.

Intermediate Alleles (IAs) are expansions of CAG repeats in the HTT gene between 27 and 35 repeats which pathogenic meaning remains controversial. They are present in the general population but there is an increasing number of cases with Huntington-like phenotype reported.

We reviewed the medical records of cases in our centre where the neurologist suspected Huntington's disease (HD) as one of the feasible diagnoses and genetic testing showed the number of CAG repeats was in the “intermediate range”. We gathered the type of symptoms in all cases and the main neuroimaging findings when available.

We found 14 cases, 8 males and 6 females, with average age at onset at 64 years old. Most cases exhibited some type of extrapyramidal symptoms. Cognitive and/or behavioral symptoms were also present in most cases (being depression, anxiety and cognitive impairment the most frequent ones). In one case we found deposits of iron in the basal ganglia in the MRI, and in another case we found diffuse cortical hypometabolism with predominantly frontal bilateral involvement and bilateral focal deficit of both caudate and thalamus in the FDG-PET.

The clinical and neuroimaging findings of some cases with IA in this series are compatible with the clinical picture of HD but also with several other alternative diagnoses. Therefore we can not establish association between IA and HD. Larger series with more comprehensive diagnostic workout and neuropathological studies are needed to confirm or rule out whether IAs in the HTT gene may cause HD.

Patients with Parkinson’s Disease Show Alteration in their Visuospatial Abilities and in their Egocentric and Allocentric Spatial Orientation Measured by Card Placing Tests

Background: Visuospatial skills are impaired in Parkinson's disease (PD). Other related skills exist, such as spatial orientation have been poorly studied. The egocentric (based on internal cues) and allocentric frameworks (based on external cues) are used in daily spatial orientation. Depending on PD onset, the allocentric framework may have a higher level of impairment in tremor-dominant and the egocentric one in akinetic-rigid.

Objective: To evaluate spatial orientation and visuospatial functions in PD patients and controls, and to assess whether their performance is related to disease duration and the PD subtype (tremor-dominant and akinetic-rigid).

Methods: We evaluated egocentric and allocentric spatial orientation (Egocentric and Allocentric Spatial Memory Tasks) and visuospatial abilities, span and working memory in 59 PD patients and 51 healthy controls.

Results: Visuospatial skills, visuospatial span, and egocentric and allocentric orientation are affected in PD. Visuospatial skills and allocentric orientation undergo deterioration during the first 5 years of the disease progression, while egocentric orientation and visuospatial span do so at later stages (9-11 years). The akinetic-rigid subtype presents worse results in all the spatial abilities that were measured when compared to controls, and worse scores in visuospatial working memory, visuospatial abilities and allocentric orientation when compared to the tremor-dominant group. The tremor-dominant group performed worse than controls in egocentric and allocentric orientation.

Conclusion: PD patients show deficits in their visuospatial abilities and in their egocentric and allocentric spatial orientation compared to controls, specifically in akinetic-rigid PD. Only spatial orientation are affected in tremor-dominant PD patients. Allocentric orientation is affected earlier in the progression of the disease.

Reference: Fernandez-Baizan C, Paula Fernandez Garcia M, Diaz-Caceres E, Menendez-Gonzalez M, Arias JL, Mendez M. Patients with Parkinson's Disease Show Alteration in their Visuospatial Abilities and in their Egocentric and Allocentric Spatial Orientation Measured by Card Placing Tests. J Parkinsons Dis. 2020;10(4):1807-1816. doi: 10.3233/JPD-202122

Genetic variation in APOE, GRN and TP53 are phenotype modifiers in frontotemporal dementia

Frontotemporal dementia (FTD) is a clinical, genetic and pathological heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 frontotemporal dementia (FTD) patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p<0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (HR=4.12) and the PNFA group showed the highest onset-age (p=0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p=0.02) and survival (HR= 1.73) and rs5848 GRN with a significant shorter survival in CC homozygous patients (HR= 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 non carriers (p=0.022). Although validation of our findings is necessary, our results suggest that TP53,GRN and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials (full text).

A role for ATXN1, ATXN2 and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2 and HTT genes in several neurodegenerative diseases. The study included 1,126 Alzheimer disease (AD), 440 frontotemporal dementia (FTD) and 610 Parkinson's disease (PD) patients. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. Additionally, in the FTD cohort we determined the number of HTT CAG-repeats. The frequency of HTT IAs was higher in FTD patients (6.9%) vs controls (2.9%) and in the C9orf72 expansion non carriers (7.2%) vs. controls (2.9%), although the difference was non-significant after correction for multiple testing. Compared to controls, progressive non-fluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs ( 13.6% vs 2.9% controls). For the ATXN2 gene, we observed an IAs increased frequency in AD cases (AD 4.1% vs controls 1.8%) and in the behavioural FTD (bvFTD) group (4.8% vs 1.8%). For the ATXN1 gene we found a significant increase of IAs in PNFA patients (18.6%) vs controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.


The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population‐Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight

Background The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. 
Objectives To perform the largest PD genome‐wide association study restricted to a single country. 
Methods We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population‐specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease‐associated loci, heritability estimates, genetic correlations, and burden analyses. 
Results We identified a novel population‐specific genome‐wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome‐wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA‐DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non‐Spanish origin. Seventeen PD‐related genes showed functional consequence by two‐sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. 
 Conclusions Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine‐mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. 


Albumin Exchange in Alzheimer's Disease: Might CSF Be an Alternative Route to Plasma?

Amyloid β (Aβ) in brain parenchyma is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). Aβ is transported from the brain to the plasma via complex transport mechanisms at the blood-brain barrier (BBB). About 90–95% of plasma Aβ may be bound to albumin. Replacement of serum albumin in plasma has been proposed as a promising therapy for AD. However, the efficacy of this approach may be compromised by altered BBB Aβ receptors in AD, as well as multiple pools of Aβ from other organs in exchange with plasma Aβ, competing for albumin binding sites. The flow of interstitial fluid (ISF) into cerebrospinal fluid (CSF) is another major route of Aβ clearance. Though the concentration of albumin in CSF is much lower than in plasma, the mixing of CSF with ISF is not impeded by a highly selective barrier and, hence, Aβ in the two pools is in more direct exchange. Furthermore, unlike in plasma, Aβ in CSF is not in direct exchange with multiple organ sources of Aβ. Here we consider albumin replacement in CSF as an alternative method for therapeutic brain Aβ removal and describe the possible advantages and rationale supporting this hypothesis.

Reference: Front. Neurol., 18 October 2019 |

Prevalence of Depression and Anxiety in Parkinson Disease and Impact on Quality of Life: A Community-Based Study in Spain

Background: Identifying neuropsychiatric disorders is essential for prompt treatment to reduce morbidity. Among these disorders, anxiety and depression have been frequently associated with Parkinson disease (PD), particularly among elderly population. 
 Objective: The objective of this study is to determine the prevalence of anxiety and depression in a series of community-based PD cases in Spain, their relationship with different clinical and sociodemographic characteristics, and quality of life. 
 Methods: This is an observational, descriptive, survey-based study with 95 community-based patients with PD diagnosis at different disease stages. Anxiety and depression were assessed using the State-Trait Anxiety Inventory and the Beck Depression Inventory II, respectively. Quality of life was assessed using the Parkinson’s Disease Questionnaire 39. 
 Results: The prevalence of depression and anxiety was 32.63% and 68.42%, respectively. Concomitant depression and anxiety were observed in 31.58% of patients. Patients with longer than 10 years’ PD duration had an increased risk of depression. We found a relationship between the presence of anxiety, depression, and the patient’s quality of life. 
 Conclusions: Depression is present in one-third and anxiety in two-thirds of PD cases in community settings in Spain. Depression and anxiety have a very negative impact on quality of life in PD. Both anxiety and depression are independent from sociodemographic characteristics, patient’s comorbidities, or antiparkinsonian treatments; presenting as intrinsic symptoms in PD.

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Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders

Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype–phenotype correlations. Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype–phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype–phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.

Reference: Journal of Translational Medicine volume 17, Article number: 290 (2019) Full text

HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease

We have shown, for the first time, that the frequency of Intermediate alleles (IAs) of the HTT gene are higher in other neurodegenerative diseases different from Huntington's disease (HD). HD is an autosomal progressive neurodegenerative disorder caused by the expansion of CAG repeats in the HTT gene. Intermediate alleles (IAs) are in the range of 27-35 repeats and have been associated to a normal phenotype. The aim of this work was to analyze the association between intermediate huntingtin CAG-repeat alleles (IAs) and neurodegenerative diseases, other than HD. We screened the HTT CAG repeats in patients with Alzheimer's disease (AD) (n = 1126), Parkinson's disease (PD) (n = 610), and frontotemporal lobar degeneration (FTLD) (n = 225). We also studied 509 healthy controls (HCs). The relative frequency of IAs for each group was 6.03% in AD, 5.3% in FTLD, 3.5% in PD, and 2.9% in HCs. The frequency of IA was significantly higher among patients with AD when compared to HCs (p = 0.011, OR = 2.11, 95% CI = 1.19-3.74); no significant difference was observed in FTLD (p = 0.17; OR = 1.88, 95% CI = 0.85-4.03) and PD (p = 0.69; OR = 1.21; 95% CI (0.61-2.37) versus HCs. No atypical symptoms or clinical features distinctive of HD were found among carriers of IAs. We found 3 cases with CAG expansions within the pathological range, one diagnosed with AD, one with PD, and one with FTD. Results suggest that IAs might have a role in the pathogenesis of AD. In addition, HD patients might be misdiagnosed with other neurodegenerative diseases, particularly when CAG repeats are in the lower pathological range.

Reference: Menéndez-González M, Clarimón J, Rosas-Allende I, Blázquez M, San Martín ES,García-Fernández C, Lleó A, Dols-Icardo O, Illán-Gala I, Morís G, Ribacoba R, Álvarez V, Martínez C. HTT gene intermediate alleles in neurodegeneration: evidence for association with Alzheimer's disease. Neurobiol Aging. 2018 Nov 28. pii: S0197-4580(18)30415-9. doi: 10.1016/j.neurobiolaging.2018.11.014 (Full text).

Frontotemporal Lobe Degeneration as Origin of Scans Without Evidence of Dopaminergic Deficit

The term scans without evidence of dopaminergic deficit (SWEDD) can be associated with any patient diagnosed at first with Parkinson’s disease but with a negative dopamine transporter-single photon emission computed tomography (DaTSPECT), which does not confirm the presynaptic dopaminergic deficiency. Therefore, an alternative diagnosis should be sought to support parkinsonism as a clinical diagnosis. Parkinsonism is a well-known manifestation of frontotemporal lobar degeneration (FTLD), particularly frequent in those with positive DaTSPECT. Here, we reinforce previous observations that parkinsonism can be present in FTLD patients with negative DaTSPECT and therefore, FTLD may account for a percentage of patients with SWEDD. We gather the clinical observations supporting this hypothesis and describe a case report illustrating this idea. Studies suggest the result of DaTSPECT in FTLD may depend on the neuropathology and clinical subtype. However, most studies do not provide a clinical description of the clinical subtype or pathological features making the association between subtypes of FTLD and DaTSPECT results impossible at the moment. Further studies correlating clinical, neuropsychological, neuroimaging, genetic, and pathology findings are needed to better understand parkinsonism in FTLD.

Reference: Menéndez-González M, Álvarez-Avellón T, Salas-Pacheco JM, de Celis-Alonso B, Wyman-Chick KA and Arias-Carrión O (2018) Frontotemporal Lobe Degeneration as Origin of Scans Without Evidence of Dopaminergic Deficit. Front. Neurol. 9:335. doi: 10.3389/fneur.2018.00335 (Full text)

Neuropsychological Test Performance in Parkinsonism Without Dopaminergic Deficiency on [123I]-FP-CIT SPECT Imaging

Objectives: To examine neuropsychological test performance among individuals clinically diagnosed with Parkinson's disease (PD) without evidence of dopaminergic deficiency on [123]I-CIT single photon emission computed tomography imaging. Methods: Data were obtained from the Parkinson's Progression Marker Initiative. The sample included 59 participants with scans without evidence of dopaminergic deficiency (SWEDD), 412 with PD, and 114 healthy controls (HC). Tests included Judgment of Line Orientation, Letter-Number Sequencing, Symbol Digit Modalities, Hopkins Verbal Learning Test-Revised, and Letter and Category Fluency. Multivariate analysis of variance was used to compare standardized scores between the groups. Results: There was a statistically significant difference in performances between the groups, F(14,1155)=5.04; p<.001; partial η2=.058. Pairwise comparisons revealed significant differences in Category Fluency between SWEDD (M=0.22; SD=1.08) and HC (M=0.86; SD=1.15) and in Symbol Digit Modalities Test performance between SWEDD (M=45.09; SD=11.54) and HC (M=51.75; SD=9.79). No significant differences between SWEDD and PD were found. Using established criteria, approximately one in four participants in the SWEDD and PD groups met criteria for mild cognitive impairment (MCI). Conclusions: Individuals with SWEDD demonstrate significantly worse mental processing speed and semantic fluency than HC. The neuropsychological test performances and rates of MCI were similar between the SWEDD group and PD groups, which may reflect a common pathology outside of the nigrostriatal pathway.

Reference: Wyman-Chick KA, Martin PK, Minár M, Menéndez-González M, Erickson LO,Álvarez-Avellón T, Schroeder RW. Neuropsychological Test Performance in Parkinsonism Without Dopaminergic Deficiency on [123I]-FP-CIT SPECT Imaging. J Int Neuropsychol Soc. 2018:1-6. doi: 10.1017/S1355617718000164 

Couple of open access articles on the rationale of clearing target proteins from the CSF in neurodegenerative diseases

Parkinson's disease
Menéndez-González M, Padilla-Zambrano HS, Tomás-Zapico C, García BF. Clearing Extracellular Alpha-Synuclein from Cerebrospinal Fluid: A New Therapeutic Strategy in Parkinson's Disease. Brain Sci. 2018 Mar 23;8(4). pii: E52. doi: 10.3390/brainsci8040052
 Effects of intracellular and extracellular alpha-synuclein.

Alzheimer's disease
Menendez-Gonzalez M, Padilla-Zambrano HS, Alvarez G, Capetillo-Zarate E, Tomas-Zapico C and Costa A (2018) Targeting Beta-Amyloid at the CSF: A New Therapeutic Strategy in Alzheimer’s Disease. Front. Aging Neurosci. 10:100. doi: 10.3389/fnagi.2018.00100
Graph representing the evolution of Aβ in the different pools. On the left, evolution of Aβ levels across the different stages of a AD. On the right, predicted evolution of Aβ levels in a case of AD treated at presymptomatic stage. islSF, insoluble pool in the ISF; slSF, soluble pool in the ISF.

The role of innate immune system receptors in epilepsy research

Epilepsy is one of the most complex neurological disorders whose study requires a broad knowledge of neurology and neuroscience. It comprises a diverse group of neurological disorders that share the central feature of spontaneous recurrent seizures, and are often accompanied by cognitive deficits and mood disorder. This condition is one of the most common neurological disorders. Until recently, alterations of neuronal activities had been the focus of epilepsy research. This neurocentric emphasis did not address issues that arise in more complex models of epileptogenesis. An important factor in epilepsy that is not regulated directly by neurons is inflammation and the immune response of the brain. Recent evidence obtained in rodent epilepsy models supports the role of immune responses in the initiation and maintenance of epilepsy. Recognition of exogenous pathogens by the innate immune system is mediated by some pattern recognition receptors such as Toll-like receptors leading to cell activation and cytokine production. Currently, these receptors have been the focus of epilepsy studies looking to determine whether the innate immune activation is neuroprotective or neurotoxic for the brain. Here, we present the evidence in the literature of the involvement of key innate immune receptors in the development of epilepsy. We address some of the contradictory findings in these studies and also mention possible avenues for research into epilepsy treatments that target these receptors.

Reference: CNS & neurological disorders drug targets 16 · July 2017

Paired articles on liquorpheresis, an abandoned and forgotten therapeutic strategy in neurology

I have published a couple of papers in Cureus on liquorpheresis (CSF filtration), an abandoned and forgotten therapeutic strategy for some neurological conditions. Here I present new designs and new potential applications, particularly in the treatment of Alzheimer's disease.

Menéndez González M (February 10, 2017) Implantable Systems for Continuous Liquorpheresis and CSF Replacement. Cureus 9(2): e1022. doi:10.7759/cureus.1022
Menéndez González M (February 28, 2017) Mechanical Dilution of Beta-amyloid Peptide and Phosphorylated Tau Protein in Alzheimer's Disease: Too Simple to be True?. Cureus 9(2): e1062. doi:10.7759/cureus.1062

Comparison of extracellular and intracellular blood compartments highlights redox alterations in Alzheimer's and Mild Cognitive Impairment patients.

Many studies suggest oxidative stress as an early feature of Alzheimer's Disease (AD). However, evidence of established oxidative stress in AD peripheral cells is still inconclusive, possibly due to both, differences in the type of samples and the heterogeneity of oxidative markers used in different studies. Here we measured the activity of Superoxide Dismutase, Catalase and Glutathione Peroxidase both in the extracellular and the intracellular blood compartments of AD, MCI and control subjects. The amount of an open isoform of p53 protein (unfolded p53), resulting from oxidative modifications was also determined. Decreased SOD, increased GPx activity and higher p53 open isoform were found in both AD and MCI plasma compared to controls. In blood peripheral mononuclear cells, SOD activity was also decreased in both AD and MCI, and unfolded p53 increased exquisitely in younger AD males compared to controls. Overall, these data highlight the importance of considering both extracellular and intracellular compartments, in the determination of antioxidant enzyme activities as well as specific oxidation end-products, in order to identify peculiar systemic redox alterations in AD pathology. 

Reference: Arce-Varas N, Abate G, Prandelli C, Martínez C, Cuetos F, Menéndez M, Marziano M, Cabrera-García D, Fernández-Sánchez MT, Novelli A, Memo M, Uberti D. Comparison of extracellular and intracellular blood compartments highlights redox alterations in Alzheimer's and Mild Cognitive Impairment patients. Curr AlzheimerRes. 2016