Maria da Graça Naffah-Mazzacoratti

Clinical distinction between dementia with Lewy bodies (DLB) and late-onset Alzheimer’s disease (AD) is difficult, while several features might affect the analyses of biomarkers. This study aimed to verify associations of anthropometric and demographic features with cerebrospinal fluid biomarkers, their ratios, and restructured traditional regression formulas in patients with DLB and AD, as well as in cognitively healthy controls. Consecutive outpatients with DLB were paired with outpatients with AD according to sex, dementia stage, and cognitive status, and with controls according to sex and age to investigate associations of sex, age, dementia duration, total sleep time, body mass index, alcohol use, smoking, sanitation, and APOE-ε4 alleles on the measurement of cerebrospinal fluid α-synuclein, biomarker ratios, and restructured traditional regression formulas involving amyloid-β (Aβ₄₂,Aβ₄₀,Aβ₃₈), tau, and phospho-tau Thr₁₈₁. Overall, 81 participants were included with DLB (n = 27;11 APOE-ε4 +) or AD (n = 27;12 APOE-ε4 +), and controls (n = 27;4 APOE-ε4 +); two thirds were women. Cerebrospinal fluid evidence of amyloidosis and tauopathy was more prevalent among women with AD, while Aβ₄₂/Aβ₃₈ could also discriminate men with DLB from men with AD. Restructured traditional regression formulas had higher diagnostic accuracy for women with AD. Aging, higher body mass index, and APOE-ε4 alleles were associated with amyloidosis in DLB, while only in AD were higher body mass index associated with lower tau pathology load, and more alcohol use associated with higher phospho-tau Thr₁₈₁/Aβ₄₂. These findings confirm the effects of anthropometric and demographic features on cerebrospinal fluid biomarkers, and also differences in aberrant amyloidosis and tauopathy between DLB and AD.

Background: Amyloid‐β‐degrading enzymes such as the angiotensin‐converting enzyme (ACE‐1) might be surrogates of the amyloid‐β load in the brain potentially triggering tauopathy and behavioral features in dementia.Methods: Consecutive outpatients with probable dementia with Lewy bodies (fourth consensus report of the DLB Consortium) were paired with outpatients with late‐onset Alzheimer’s dementia (AD, National Institute on Aging – Alzheimer’s Association) by sex, Clinical Dementia Rating and Mini‐Mental State Examination scores, and with cognitively healthy controls by sex and age (±1 year). Behavioral symptoms were assessed by way of the Neuropsychiatric Inventory. APOE genotyping (rs7412&rs429358) was undertaken with TaqMan® Real‐Time PCR technology, while conventional PCR was used for the ACE insertion/deletion polymorphism. Cerebrospinal fluid (CSF) amyloid‐β₄₂, amyloid‐β₃₈, ACE‐1, tau and phospho‐tau Thr₁₈₁ were quantified with enzyme‐linked immunosorbent assays, whereas CSF and plasma ACE‐1 activities were measured using a fluorescence method. Adjusted general linear models were used to examine relationships between log‐transformed behavioral symptoms and biomarkers of interest at pn = 27;78.48±9.0years‐old;eleven APOE‐ε4 carriers) were paired with participants with AD (n = 27;81.00±5.8years‐old;twelve APOE‐ε4 carriers) and controls (n = 27;78.48±8.7years‐old;four APOE‐ε4 carriers); two thirds were women. CSF ACE‐1 activity was associated with CSF ACE‐1 levels (pACE deletion allele was cumulatively associated with higher plasma ACE‐1 activity (p = 0.049). Use of ACE inhibitors did not affect CSF ACE‐1 levels. For APOE‐ε4 carriers with DLB, agitation was inversely associated with amyloid‐β₃₈, CSF and plasma ACE‐1 activities. For APOE‐ε4 non‐carriers with DLB, appetite and eating abnormalities were associated with CSF ACE‐1 levels and activity, tau and tau/phospho‐tau, and inversely associated with amyloid‐β₄₂/amyloid‐β₃₈. CSF ACE‐1, tau, tau/phospho‐tau, and tau/amyloid‐β₄₂ were associated with disinhibition for APOE‐ε4 carriers with AD, and with aberrant motor behavior for APOE‐ε4 non‐carriers with AD. For APOE‐ε4 carriers with AD, irritability was associated with CSF ACE‐1 and inversely associated with amyloid‐β₄₂. All other behavioral associations with ACE‐1 were independent of measures of amyloidosis or tauopathy.Conclusions: Biofluid activity and CSF levels of ACE‐1 may be surrogates for CSF amyloid‐β levels and tauopathy unevenly associated with behavioral symptoms across dementia syndromes.

There is currently no available drug to prevent the development of post-traumatic epilepsy. insufficient evidence regarding the effect of biperiden in preventing post-traumatic epilepsy after TBI. The combined effect of variables known to have an impact on the likelihood of developing late post-traumatic seizures and its unbalanced frequency in the different groups is an aspect to be considered and underpins the need for larger studies. Highlights: Prior research suggests anticholinergics may prevent post-traumatic epilepsy There was insufficient evidence on biperiden’s role in preventing PTE after TBI Variable impact on post-traumatic epilepsy underscores need for broader studies Graphical

Background: The study of vascular cognitive impairment and dementia (VCID) risk factors must be reproduced in every community so that disparities may be addressed. In South America, diverse levels of education, mixed ethnicity, genetic and cultural heterogeneity, and the burden of cerebrovascular risk are important features to be investigated for proper interventions.Methods: Observational and interventional VCID studies from South America will be discussed so that issues concerning potential barriers for participant recruitment and research effectiveness may be addressed.Results: Few South American institutions have studied risk factors for VCID. Older people suffer the effects of restrictions to female education that occurred a century ago. Cross‐sectional studies demonstrated that APOE‐ε4 carrier status predisposes to physical inactivity and has smaller effects over dementia onset than in studies from the Northern Hemisphere, possibly due to ethnical disparities, while the burden of combined cerebrovascular risk factors (and smoking in particular) in this regard is high. Foreigners living in Brazil had later dementia onset, unexplained by common genetic variants. While prevalent in almost half of the older population, and associated with earlier dementia onset particularly in women, depression could be a risk factor or a prodromal symptom. Late life prospective studies verified that cerebrovascular risk factors such as arterial hypertension, hypercholesterolemia and a higher coronary heart disease risk, or increased creatinine clearance for women only, may be neuroprotective against cognitive and functional decline, probably due to enhanced cerebral perfusion. Lifetime sanitary conditions and increasing late life body mass index may protect against frailty, while education is neuroprotective for women and APOE‐ε4 carriers (though associated with faster cognitive decline in some cohorts). Longitudinal pharmacogenetic studies demonstrated that potential benefits of cerebrovascular metabolism modulators such as angiotensin‐converting enzyme inhibitors and lipophilic statins depend upon epistatic interactions among specific genetic variants. Caregiver awareness of the need to control cerebrovascular risk is beneficial for patients.Conclusions: Genomic effects of cognitive reserve, cerebral perfusion, and hormonal changes interact on mechanisms of neurodegeneration. Adherence to lifestyle and pharmacological interventions in South America is highly dependent upon proper funding, public support, harmonization efforts, institutional expertise and leadership, and caregiver education. (Supported by FAPESP grant #2015/10109‐5)

Aim To explore associations of cerebrospinal fluid biomarkers of neurodegeneration and amyloidosis with caregiver burden, cognition and functionality in dementia with Lewy bodies (DLB) paired with late-onset Alzheimer’s disease (AD) and healthy older people. Methods Consecutive outpatients with DLB were matched with outpatients with AD according to sex, cognitive scores and dementia stage, and with cognitively healthy controls according to age and sex to investigate associations of cerebrospinal fluid amyloid-β (Aβ₄₂,Aβ₄₀,Aβ₃₈), tau, phospho-tau Thr₁₈₁, ubiquitin, α-synuclein and neurofilament light with caregiver burden, functionality, reverse digit span, a clock drawing test, Mini-Mental State Examination (MMSE) and Severe MMSE, adjusted for sex, age, education, dementia duration and APOE-ε4 alleles. Results Overall, 27 patients with DLB (78.98 ± 9.0 years-old; eleven APOE-ε4 +) were paired with 27 patients with AD (81.50 ± 5.8 years-old; twelve APOE-ε4 +) and 27 controls (78.98 ± 8.7 years-old; four APOE-ε4 +); two-thirds were women. In AD, Aβ₄₂/Aβ₃₈ and Aβ₄₂ were lower, while tau/Aβ₄₂ and phospho-tau Thr₁₈₁/Aβ₄₂ were higher; α-synuclein/Aβ₄₂ was lower in DLB and higher in AD. The following corrected associations remained significant: in DLB, instrumental functionality was inversely associated with tau/phospho-tau Thr₁₈₁ and tau/Aβ₄₂, and reverse digit span associated with α-synuclein; in AD, instrumental functionality was inversely associated with neurofilament light, clock drawing test scores inversely associated with phospho-tau Thr₁₈₁/Aβ₄₂ and α-synuclein/Aβ₄₂, and Severe MMSE inversely associated with tau/Aβ₄₂ and tau/phospho-tau Thr₁₈₁. Conclusions Cerebrospinal fluid phospho-tau Thr₁₈₁ in DLB was similar to AD, but not Aβ₄₂. In associations with test scores, biomarker ratios were superior to isolated biomarkers, while worse functionality was associated with axonal degeneration only in AD.

Temporal lobe epilepsy (TLE) is a chronic disease, characterized by severe and refractory seizures, triggered in the hippocampus and/or amygdala, disrupting the blood–brain barrier. This disruption can sustain, or aggravate, the epileptic condition. The aim of this study was to evaluate the activation of the kallikrein‐kinin system in patients with TLE, as it relates to the maintenance of blood–brain barrier. Human hippocampal sclerotic tissues removed after surgery for seizure control, plasma, and serum were used in the following assays: immunostaining for white blood cells in the TLE hippocampus, C‐reactive protein in serum, quantification of plasma kallikrein (PKal) and cathepsin B (CatB) activity in serum and plasma, quantification of C1‐inhibitor, analysis of high‐molecular‐weight kininogen (H‐kininogen) fragments, and activation of plasma prekallikrein for comparison with healthy controls. Infiltration of white blood cells in the sclerotic hippocampus and a significant increase in the neutrophil/lymphocyte ratio in the blood of TLE patients were observed. High levels of C‐reactive protein (TLE = 1.4 ± 0.3 µg/mL), PKal (TLE = 5.4 ± 0.4 U/mL), and CatB (TLE = 4.9 ± 0.4 U/mL) were also evident in the serum of TLE patients comparing to controls. A strong linear correlation was observed between active CatB and PKal in the serum of TLE patients (r = 0.88). High levels of cleaved H‐kininogen and free PKal, and low levels of C1‐inhibitor (TLE = 188 ± 12 µg/mL) were observed in the serum of TLE patients. Our data demonstrated that the plasma kallikrein‐kinin system is activated in patients with TLE.Open Science Badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. image

The underlying mechanisms by which renal denervation (RD) decreases blood pressure (BP) remain incompletely understood. In this study, we investigated the effects of ischemic kidney denervation on different sympathetic outflows, brain and renal expression of angiotensin-II receptors, oxidative stress and renal function markers in the 2-kidney, 1-clip (2K-1C) rat model. Surgical RD was performed in Wistar male rats 4–5 weeks after clip implantation. After 10 days of RD, BP, and the activity of sympathetic nerves projecting to the contralateral kidney (rSNA) and splanchnic region were partially reduced in 2K-1C rats, with no change in systemic renin-angiotensin system (RAS). To distinguish the effects of RD from the reduction in BP, 2K-1C rats were treated with hydralazine by oral gavage (25 mg/kg/day for 1 week). RD, but not hydralazine, normalized oxidative stress in the sympathetic premotor brain regions and improved intrarenal RAS, renal injury, and proteinuria. Furthermore, different mechanisms led to renal injury and oxidative stress in the ischemic and contralateral kidneys of 2K-1C rats. Injury and oxidative stress in the ischemic kidney were driven by the renal nerves. Although RD attenuated rSNA, injury and oxidative stress persisted in the contralateral kidney, probably due to increased BP. Therefore, nerves from the ischemic kidney at least partially contribute to the increase in BP, sympathetic outflows, brain oxidative stress, and renal alterations in rats with renovascular hypertension. Based on these findings, the reduction in oxidative stress in the brain is a central mechanism that contributes to the effects of RD on Goldblatt hypertension.

The aim of this work was to evaluate patients with chronic migraine treated with botulinum toxin A (BT-A) and compare this with low level laser therapy (LLLT), referencing: pain days, pain intensity, intake of drugs/self-medication, anxiety and sleep disorders. Methods: Patients were randomized into two groups: BT-A group (n = 18) and LLLT group (n = 18). Each patient kept three pain diaries: one before (baseline) (30 days), one during treatment (30 days) and one after the post-treatment phase (30 days). Repeated ANOVA plus the Bonferroni post-test, Student's t test, and factorial analysis were applied, and p < 0.05 was accepted as significant. Results: Our data showed that both treatments were able to reduce headache days, acute medication intake and decrease the intensity of pain. Anxiety was reduced in the BT-A group, while sleep disturbance was reduced in the LLLT group. Conclusion: Our data showed that both treatments can be used to treat chronic migraine, without notable differences between them.