Patterns of amygdala region pathology in LATE-NC: subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies.

Transactive response (TAR) DNA-binding protein 43 kDa (TDP-43) pathology is a hallmark of limbic-predominant age-related TDP-43 encephalopathy (LATE). The amygdala is affected early in the evolution of LATE neuropathologic change (LATE-NC), and heterogeneity of LATE-NC in amygdala has previously been observed. However, much remains to be learned about how LATE-NC originates and progresses in the brain. To address this, we assessed TDP-43 and other pathologies in the amygdala region of 184 autopsied subjects (median age = 85 years), blinded to clinical diagnoses, other neuropathologic diagnoses, and risk genotype information. As previously described, LATE-NC was associated with older age at death, cognitive impairment, and the TMEM106B risk allele. Pathologically, LATE-NC was associated with comorbid hippocampal sclerosis (HS), myelin loss, and vascular disease in white matter (WM). Unbiased hierarchical clustering of TDP-43 inclusion morphologies revealed discernable subtypes of LATE-NC with distinct clinical, genetic, and pathologic associations. The most common patterns were: Pattern 1, with lamina II TDP-43 + processes and preinclusion pathology in cortices of the amygdala region, and frequent LATE-NC Stage 3 with HS; Pattern 2, previously described as type-ß, with neurofibrillary tangle-like TDP-43 neuronal cytoplasmic inclusions (NCIs), high Alzheimer's disease neuropathologic change (ADNC), frequent APOE ε4, and usually LATE-NC Stage 2; Pattern 3, with round NCIs and thick neurites in amygdala, younger age at death, and often comorbid Lewy body disease; and Pattern 4 (the most common pattern), with tortuous TDP-43 processes in subpial and WM regions, low ADNC, rare HS, and lower dementia probability. TDP-43 pathology with features of patterns 1 and 2 were often comorbid in the same brains. Early and mild TDP-43 pathology was often best described to be localized in the "amygdala region" rather than the amygdala proper. There were also important shared attributes across patterns. For example, all four patterns were associated with the TMEM106B risk allele. Each pattern also demonstrated the potential to progress to higher LATE-NC stages with confluent anatomical and pathological patterns, and to contribute to dementia. Although LATE-NC showed distinct patterns of initiation in amygdala region, there was also apparent shared genetic risk and convergent pathways of clinico-pathological evolution.

Neuroinflammation is highest in areas of disease progression in semantic dementia.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

Sleep-Disordered Breathing and Idiopathic Normal-Pressure Hydrocephalus: Recent Pathophysiological Advances.

PURPOSE OF REVIEW: Idiopathic normal-pressure hydrocephalus (iNPH) is characterized clinically by ventriculomegaly, abnormal gait, falls, incontinence, and cognitive decline. This article reviews recent advances in the pathophysiology of iNPH concerning sleep-disordered breathing (SDB) and glymphatic circulation during deep sleep. RECENT FINDINGS: The authors found iNPH frequently associated with obstructive sleep apnea (OSA). A critical factor in iNPH is intracranial venous hypertension delaying drainage of cerebrospinal fluid (CSF) into the cerebral venous sinuses. CSF-venous blood circulates in the jugular veins and finally drains into the heart. During SDB, repeated reflex attempts to breathe induce strong respiratory efforts against a closed glottis thereby increasing the negative intrathoracic pressure. This causes atrial distortion and decreases venous return to the heart resulting in retrograde intracranial venous hypertension. Additionally, repeated awakenings from OSA impede sleep-associated circulation of interstitial CSF into the glymphatic circulation contributing to hydrocephalus. Sleep has become a critical element in the cognitive changes of aging including iNPH.

Epigenetic Factors in Late-Onset Alzheimer's Disease: MTHFR and CTH Gene Polymorphisms, Metabolic Transsulfuration and Methylation Pathways, and B Vitamins.

DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer's disease (LOAD). Methylenetetrahydrofolate reductase (MTHFR) gene mutations occur in most elderly patients with memory loss. MTHFR is critical for production of S-adenosyl-l-methionine (SAM), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase (CTH) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine (tHcy) or hyperhomocysteinemia-a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins. We emphasize the importance of supplementing vitamin B12 (methylcobalamin), vitamin B9 (folic acid), vitamin B6 (pyridoxine), and SAM to patients in early stages of LOAD.

Differential Methylation in APOE (Chr19; Exon Four; from 44,909,188 to 44,909,373/hg38) and Increased Apolipoprotein E Plasma Levels in Subjects with Mild Cognitive Impairment.

BACKGROUND: Biomarkers are essential for identification of individuals at high risk of mild cognitive impairment (MCI) for potential prevention of dementia. We investigated DNA methylation in the APOE gene and apolipoprotein E (ApoE) plasma levels as MCI biomarkers in Colombian subjects with MCI and controls. METHODS: In total, 100 participants were included (71% women; average age, 70 years; range, 43⁻91 years). MCI was diagnosed by neuropsychological testing, medical and social history, activities of daily living, cognitive symptoms and neuroimaging. Using multivariate logistic regression models adjusted by age and gender, we examined the risk association of MCI with plasma ApoE and APOE methylation. RESULTS: MCI was diagnosed in 41 subjects (average age, 66.5 ± 9.6 years) and compared with 59 controls. Elevated plasma ApoE and APOE methylation of CpGs 165, 190, and 198 were risk factors for MCI (p < 0.05). Higher CpG-227 methylation correlated with lower risk for MCI (p = 0.002). Only CpG-227 was significantly correlated with plasma ApoE levels (correlation coefficient = -0.665; p = 0.008). CONCLUSION: Differential APOE methylation and increased plasma ApoE levels were correlated with MCI. These epigenetic patterns require confirmation in larger samples but could potentially be used as biomarkers to identify early stages of MCI.

Progress toward standardized diagnosis of vascular cognitive impairment: Guidelines from the Vascular Impairment of Cognition Classification Consensus Study.

INTRODUCTION: Progress in understanding and management of vascular cognitive impairment (VCI) has been hampered by lack of consensus on diagnosis, reflecting the use of multiple different assessment protocols. A large multinational group of clinicians and researchers participated in a two-phase Vascular Impairment of Cognition Classification Consensus Study (VICCCS) to agree on principles (VICCCS-1) and protocols (VICCCS-2) for diagnosis of VCI. We present VICCCS-2. METHODS: We used VICCCS-1 principles and published diagnostic guidelines as points of reference for an online Delphi survey aimed at achieving consensus on clinical diagnosis of VCI. RESULTS: Six survey rounds comprising 65-79 participants agreed guidelines for diagnosis of VICCCS-revised mild and major forms of VCI and endorsed the National Institute of Neurological Disorders-Canadian Stroke Network neuropsychological assessment protocols and recommendations for imaging. DISCUSSION: The VICCCS-2 suggests standardized use of the National Institute of Neurological Disorders-Canadian Stroke Network recommendations on neuropsychological and imaging assessment for diagnosis of VCI so as to promote research collaboration.

Defective cholesterol metabolism in amyotrophic lateral sclerosis.

As neurons die, cholesterol is released in the central nervous system (CNS); hence, this sterol and its metabolites may represent a biomarker of neurodegeneration, including in amyotrophic lateral sclerosis (ALS), in which altered cholesterol levels have been linked to prognosis. More than 40 different sterols were quantified in serum and cerebrospinal fluid (CSF) from ALS patients and healthy controls. In CSF, the concentration of cholesterol was found to be elevated in ALS samples. When CSF metabolite levels were normalized to cholesterol, the cholesterol metabolite 3ß,7α-dihydroxycholest-5-en-26-oic acid, along with its precursor 3ß-hydroxycholest-5-en-26-oic acid and product 7α-hydroxy-3-oxocholest-4-en-26-oic acid, were reduced in concentration, whereas metabolites known to be imported from the circulation into the CNS were not found to differ in concentration between groups. Analysis of serum revealed that (25R)26-hydroxycholesterol, the immediate precursor of 3ß-hydroxycholest-5-en-26-oic acid, was reduced in concentration in ALS patients compared with controls. We conclude that the acidic branch of bile acid biosynthesis, known to be operative in-part in the brain, is defective in ALS, leading to a failure of the CNS to remove excess cholesterol, which may be toxic to neuronal cells, compounded by a reduction in neuroprotective 3ß,7α-dihydroxycholest-5-en-26-oic acid.

The Vascular Impairment of Cognition Classification Consensus Study.

INTRODUCTION: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. METHODS: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. RESULTS: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. DISCUSSION: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research.

The prevalence of epilepsy and association with traumatic brain injury in veterans of the Afghanistan and Iraq wars.

OBJECTIVE: To examine the association of epilepsy with traumatic brain injury (TBI) in Afghanistan and Iraq (Operation Enduring Freedom [OEF]/Operation Iraqi Freedom [OIF]) Veterans. DESIGN: Cross-sectional observational study. PARTICIPANTS: A total 256 284 OEF/OIF Veterans who received inpatient and outpatient care in the Veterans Health Administration in fiscal years 2009-2010. MAIN OUTCOME MEASURES: We used algorithms developed for use with International Classification of Diseases, Ninth Revision, Clinical Modification, codes to identify epilepsy, TBI (penetrating TBI [pTBI]/other TBI), and other risk factors for epilepsy (eg, stroke). TBI and other risk factors were identified prior to the index date (first date of seizure or October 1, 2009) for primary analyses. RESULTS: Epilepsy prevalence was 10.6 per 1000 (N = 2719) in fiscal year 2010; age-adjusted prevalence was 6.1. Of 37 718 individuals with a diagnosis of TBI, 29 297 Veterans had a diagnosis of TBI prior to the index date. Statistically significant associations were found between epilepsy and prior TBI diagnosis (pTBI: adjusted odds ratio = 18.77 [95% confidence interval, 9.21-38.23]; other TBI: adjusted odds ratio = 1.64 [1.43-1.89]). CONCLUSIONS: Among OEF/OIF Veterans, epilepsy was associated with previous TBI diagnosis, with pTBI having the strongest association. Because war-related epilepsy in Vietnam War Veterans with TBI continued 35 years postwar, a detailed, prospective study is needed to understand the relationship between epilepsy and TBI severity in OEF/OIF Veterans.

Association of gestational maternal hypothyroxinemia and increased autism risk.

OBJECTIVE: Transient gestational hypothyroxinemia in rodents induces cortical neuronal migration brain lesions resembling those of autism. We investigated the association between maternal hypothyroxinemia (gestational weeks 6-18) and autistic symptoms in children. METHODS: The mother-and-child cohort of the Generation R Study (Rotterdam, the Netherlands) began prenatal enrollment between 2002 and 2006. At a mean gestational age of 13.4 weeks (standard deviation=1.9, range=5.9-17.9), maternal thyroid function tests (serum thyrotropin [TSH], free thyroxine [fT4], and thyroid peroxidase [TPO] antibodies) were assessed in 5,100 women. We defined severe maternal hypothyroxinemia as fT4<5th percentile with normal TSH. Six years later, parents reported behavioral and emotional symptoms in 4,039 children (79%) using the Pervasive Developmental Problems (PDP) subscale of the Child Behavior Checklist and/or the Social Responsiveness Scale (SRS). We defined a probable autistic child by a PDP score>98th percentile and SRS score in the top 5% of the sample (n=81, 2.0%). RESULTS: Severe maternal hypothyroxinemia (n=136) was associated with an almost 4-fold increase in the odds of having a probable autistic child (adjusted odds ratio=3.89, 95% confidence interval [CI]=1.83-8.20, p<0.001). Using PDP scores, children of mothers with severe hypothyroxinemia had higher scores of autistic symptoms by age 6 years (adjusted B=0.23, 95% CI=0.03-0.37); SRS results were similar. No risk was found for children of TPO-antibody-positive mothers (n=308). INTERPRETATION: We found a consistent association between severe, early gestation maternal hypothyroxinemia and autistic symptoms in offspring. Findings are concordant with epidemiological, biological, and experimental data on autism. Although these findings cannot establish causality, they open the possibility of preventive interventions.

Why U.S. epilepsy hospital stays rose in 2006.

OBJECTIVE: We observed a substantial increase in age-adjusted hospitalization rates in the United States National Hospital Discharge Survey data from 1996 to 2010. We aimed to assess reasons for this increase. METHODS: The National Hospital Discharge Survey collected data on a national sample of short-term hospital stays in nonfederal hospitals. We determined epilepsy-related discharge diagnoses by age, gender, and region using weighted analysis, and estimated age-adjusted rates and annual percent changes using regression analysis. We also looked at epilepsy as the principal discharge diagnosis in the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project. RESULTS: In the United States, on average, nearly 110,000 more admissions were reported each year with epilepsy as the principal discharge diagnosis in 2006-2010 than in 1996-2005, a 2.7-fold increase in hospitalization rates from epilepsy. During this period, there were more hospitalizations with principal discharge diagnosis of epilepsy not otherwise specified, and among older patients. The number of discharges with seizure not otherwise specified dropped dramatically after 2006, and was more evident among pediatric patients. The age-adjusted rates of hospital stays combining discharges with any mention of epilepsy (345.XX) or seizures unspecified (780.39) in seven discharge diagnoses, were similar in 1996-2005 and 2006-2010. SIGNIFICANCE: We postulate that the excess in hospitalizations with epilepsy as first discharge diagnosis in 2006-2010 in the United States was related to the changes in coding in 2006. Any use of U.S. hospital discharge data with epilepsy-related diagnosis after that date will require further validation. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Vascular cognitive disorders and depression after first-ever stroke: the Fogarty-Mexico Stroke Cohort.

BACKGROUND AND PURPOSE: Stroke is the major cause of vascular behavior and cognitive disorders worldwide. In developing countries, there is a dearth of information regarding the public health magnitude of stroke. The aim of the Fogarty-Mexico cohort was to assess the prevalence of vascular behavioral and cognitive disorders, ranging from mild vascular cognitive impairment (VCI) to vascular dementia (VaD), in a cohort of acute first-ever symptomatic stroke patients in Mexico. METHODS: A total of 165 consecutive, first-ever stroke patients admitted to the National Institute of Neurology and Neurosurgery in Mexico City, were included in the cohort. Patients were eligible if they had an ischemic stroke, primary intracerebral hemorrhage, or cerebral venous thrombosis (CVT). Stroke diagnosis required the presence of an acute focal deficit lasting more than 24 h, confirmed by a corresponding lesion on CT/MRI. Stroke severity was established with the NIH Stroke Scale. The pre-stroke functional status was determined by the IQCODE. Three months after the occurrence of stroke, 110 survivor patients returned for follow-up and were able to undergo functional outcome (modified Rankin scale, Barthel index), along with neurological, psychiatric, neuropsychological, laboratory, and imaging assessments. We compared depression, demographic, and clinical and imaging features between patients with and without dementia, and between patients with VCI and those with intact cognition. RESULTS: Of the 110 patients (62% men, mean age 56 ± 17.8, education 7.7 ± 5.2 years) 93 (84%) had ischemic strokes, 14 (13%) intracerebral hemorrhage, and 3 (3%) CVT. The main risk factors were hypertension (50%), smoking (40%), hypercholesterolemia (29%), hyperhomocysteinemia (24%), and diabetes (22%). Clinical and neuropsychological evaluations demonstrated post-stroke depression in 56%, VCI in 41%, and VaD in 12%; 17% of the latter had pre-stroke functional impairment (IQCODE >3.5). Cognitive deficits included executive function in 69%, verbal memory in 49%, language in 38%, perception in 36%, and attention in 38%. Executive dysfunction occurred in 36% of non-demented subjects, 65% of them with mild-moderate deficits in daily living activities. Female gender (p ≤ 0.054), older age (mean age 65.6 years vs. 49.3, p < 0.001), diabetes (p ≤ 0.004), illiteracy and lower education (p ≤ 0.001), and PSD (p = 0.03) were significantly higher in VCI-VaD compared with cognitively intact post-stroke subjects. We could not demonstrate an association with lesion site and distribution of the cognitive deficits. CONCLUSIONS: The Fogarty-Mexico cohort recruited relatively young acute stroke patients, compared with other Mexican stroke cohorts. PSD and VCI occurred frequently but prevalence of VaD (12%) was lower than expected. A high prevalence of treatable stroke risk factors suggests that preventive interventions are advisable.

Diagnostic criteria for vascular cognitive disorders: a VASCOG statement.

BACKGROUND: Several sets of diagnostic criteria have been published for vascular dementia since the 1960s. The continuing ambiguity in vascular dementia definition warrants a critical reexamination. METHODS: Participants at a special symposium of the International Society for Vascular Behavioral and Cognitive Disorders (VASCOG) in 2009 critiqued the current criteria. They drafted a proposal for a new set of criteria, later reviewed through multiple drafts by the group, including additional experts and the members of the Neurocognitive Disorders Work Group of the fifth revision of Diagnostic and Statistical Manual (DSM-5) Task Force. RESULTS: Cognitive disorders of vascular etiology are a heterogeneous group of disorders with diverse pathologies and clinical manifestations, discussed broadly under the rubric of vascular cognitive disorders (VCD). The continuum of vascular cognitive impairment is recognized by the categories of Mild Vascular Cognitive Disorder, and Vascular Dementia or Major Vascular Cognitive Disorder. Diagnostic thresholds are defined. Clinical and neuroimaging criteria are proposed for establishing vascular etiology. Subtypes of VCD are described, and the frequent cooccurrence of Alzheimer disease pathology emphasized. CONCLUSIONS: The proposed criteria for VCD provide a coherent approach to the diagnosis of this diverse group of disorders, with a view to stimulating clinical and pathologic validation studies. These criteria can be harmonized with the DSM-5 criteria such that an international consensus on the criteria for VCD may be achieved.

Long-term treatment with citicoline may improve poststroke vascular cognitive impairment.

BACKGROUND: Cognitive decline after stroke is more common than stroke recurrence. Stroke doubles the risk of dementia and is a major contributor to vascular cognitive impairment and vascular dementia. Nonetheless, few pharmacological studies have addressed vascular cognitive impairment after stroke. We assessed the safety of long-term administration and its possible efficacy of citicoline in preventing poststroke cognitive decline in patients with first-ever ischemic stroke. METHODS: Open-label, randomized, parallel study of citicoline vs. usual treatment. All subjects were selected 6 weeks after suffering a qualifying stroke and randomized by age, gender, education and stroke type into parallel arms of citicoline (1 g/day) for 12 months vs. no citicoline (control group). Medical management was similar otherwise. All patients underwent neuropsychological evaluation at 1 month, 6 months and 1 year after stroke. Tests results were combined to give indexes of 6 neurocognitive domains: attention and executive function, memory, language, spatial perception, motor speed and temporal orientation. Using adjusted logistic regression models we determined the association between citicoline treatment and cognitive decline for each neurocognitive domain at 6 and 12 months. RESULTS: We recruited 347 subjects (mean age 67.2 years, 186 male (56.6%), mean education 5.7 years); 172 (49.6%) received citicoline for 12 months (no significant differences from controls n = 175). Demographic data, risk factors, initial stroke severity (NIHSS), clinical and etiological classification were similar in both groups. Only 37 subjects (10.7%) discontinued treatment (10.5% citicoline vs. 10.9% control) at 6 months; 30 (8.6%) due to death (16 (9.3%) citicoline vs. 14 (8.0%) control, p = 0.740), 7 lost to follow-up or incorrect treatment, and 4 (2.3%) had adverse events from citicoline without discontinuation. 199 patients underwent neuropsychological evaluation at 1 year. Cognitive functions improved 6 and 12 months after stroke in the entire group but in comparison with controls, citicoline-treated patients showed better outcome in attention-executive functions (OR 1.721, 95% CI 1.065-2.781, p = 0.027 at 6 months; OR 2.379, 95% CI 1.269-4.462, p = 0.007 at 12 months) and temporal orientation (OR 1.780, 95% CI 1.020-3.104, p = 0.042 at 6 months; OR 2.155, 95% CI 1.017-4.566, p = 0.045 at 12 months) during the follow-up. Moreover, citicoline group showed a better functional outcome (modified Rankin scale ≤2) at 12 months (57.3 vs. 48.7%) without statistically significant differences (p = 0.186). CONCLUSIONS: Citicoline treatment for 12 months in patients with first-ever ischemic stroke is safe and probably effective in improving poststroke cognitive decline. Citicoline appears to be a promising agent to improve recovery after stroke. Large clinical trials are needed to confirm the net benefit of this therapeutic approach.

[Liver enzymes elevation: etiologic study and efficiency of a single-act office visit]. / Elevación de las enzimas de función hepática en nuestro medio: estudio etiológico y de la eficacia de una consulta de acto único.

BACKGROUND: Liver enzyme (LE) elevation is a common finding in routine blood analysis. There is very little information on the most prevalent causes of these alterations in our population. In addition, a number of tests and several visits to the specialist are required to reach a diagnosis. For these reasons, we designed a protocol to streamline the evaluation of patients with LE elevations in a single-act office visit. METHODS: From March 2008 until June 2010, we studied all patients with incidental LE elevation (isolated transaminase elevation, combined elevation of alkaline phosphatase [FA] and gamma-glutamyl transpeptidase [GGT], or isolated elevation of GGT) who were referred by their primary care physicians. At the time of referral, a complete biochemistry analysis was performed (LE, viral serology, autoantibodies, ceruloplasmin, iron metabolism, alpha-1-antitrypsin and thyroid hormones) and the patients underwent an abdominal ultrasound scan on the day of the office evaluation by the hepatologist. RESULTS: A total of 427 patients were included in our study. The most common cause of transaminase elevation was non-alcoholic fatty liver disease (NAFLD) (40%), followed by alcohol intake (17%), and hepatitis C virus infection (13%). Elevated GGT levels were most commonly related to NAFLD (30%), closely followed by alcohol intake (27%), and hepatotoxicity (8%). Combined elevation of GGT and FA was associated with NAFLD (21%), alcohol (17%), and hepatotoxicity (11%). Self-limited elevation was seen in 9% of the patients and we could not identify a definite cause in 11%. A definitive diagnosis was reached in 79% of the patients. CONCLUSIONS: The single-act office visit has proven to be efficient, yielding a diagnosis in most of the patients. The most common cause of elevated LE was NAFLD. Transaminase elevation must be confirmed before a more thorough work-up is started.

Tropical spastic paraparesis.

A large number of causative agents can result in spinal cord disorders in the tropics including etiologies similar to those of temperate regions such as trauma, spinal bone and disc lesions, tumors, epidural abscess, and congenital malformations. Yet infectious and nutritional disorders differ in their higher prevalence in tropical regions including Pott's disease; brucellosis; neuroborreliosis; various parasitic diseases such as schistosomiasis, neurocysticercosis, and eosinophilic meningitis. Notably, the retrovirus HTLV-1 is the causeof tropical spastic paraparesis/paraplegia or TSP. Nutritional causes of TSP include vitamin B and folate deficiencies, while endemic clusters of konzo and tropical ataxic myeloneuropathy occur in Africa, along with malnutrition and excessive consumption of cyanide-containing bitter cassava. Other toxic etiologies of TSP include lathyrism and fluorosis. Nutritional forms of myelopathy are associated often with optic and sensory neuropathy, hence the name tropical myeloneuropathies. Acute transverse myelopathy, seen in association with vaccination, infections, and fibrocartilaginous embolism of the nucleus pulposus, can be ubiquitous. Multiple sclerosis and optic myelopathy occur in the tropics but with lesser prevalence than in temperate regions. The advent of modern imaging in the tropics, including computed tomography and magnetic resonance imaging, has allowed better diagnosis and treatment of these conditions that are a frequent cause of death and disability. This chapter provides an overview of TSP emphasizing the most common causes with clues to diagnosis and effective therapy.

Environmental neurology: Concepts and short history of an interdisciplinary approach to etiology, treatment and prevention.

Environmental Neurology (EN), a sub-discipline of Neurology and Neurological Sciences, favors an interdisciplinary collaboration allowing a holistic approach to understanding the impact of environmental factors on the nervous system and their relationship with neurological diseases. Several examples of diseases and conditions show the large scope of subjects addressed by EN. The EN sub-discipline focuses on both individual and population issues thus joining patient care and public health, respectively. Neuropathogenesis is addressed by several major questions: How do the environment and nervous system interact? Which exogenous factors can trigger neurological disease? When, where and how do they act? What are the therapeutic implications, and how can these disorders be controlled or prevented. To answer such questions, we address the incentive for, philosophy of and methods developed by EN, which seeks to safeguard Brain Health and, thus, the quality of life.

A phase 1 open-label pilot study of low-dose interleukine-2 immunotherapy in patients with Alzheimer's disease.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05821153, Registered April 20 2023, Retrospectively registered, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05821153.

Translating current knowledge into dementia prevention.

Considerable knowledge has been gained from epidemiologic studies and randomized clinical trials regarding risk factors for dementia, including Alzheimer disease (AD) and vascular dementia (VaD). Most identified risk factors for dementia are similar to vascular disease risk factors for heart disease and stroke. In 2010, the National Institutes of Health Conference concluded that there are no validated modifiable factors to reduce the incidence of AD or to change its course. This research perspective specifically concerning AD disregards the fact that in community-dwelling elderly, the most common forms of dementia involve the cerebral macrovasculature and microvasculature, manifesting as VaD and mixed dementia (the combination of VaD and AD) in autopsy-confirmed cases. Thus, prevention of dementia in clinical practice should be considered from this broader and more relevant view and not just a research perspective on "pure" AD. Practicing clinicians can reasonably state to patients that, although more definitive research is clearly needed, the management and treatment of vascular disease risk factors are likely beneficial not only to prevent heart disease and stroke, but also common forms of dementia in the community.