Association study between the DNMT3A -448A>G polymorphism and risk of Alzheimer's disease in Caucasians of Italian origin

Increasing evidence points to an epigenetic contribution in Alzheimer's disease (AD) pathogenesis. In this regard, variants and polymorphisms of DNA methyltransferase genes (DNMTs) are being investigated for their contribution to cognitive decline and dementia, but results are still scarce or controversial. In the present study we genotyped 710 Caucasian subjects of Italian descent, including 320 late-onset AD (LOAD) patients, 70 individuals with amnestic Mild Cognitive Impairment (MCI), and 320 matched healthy controls, for the presence of a functional DNMT3A -448A>G (rs1550117) polymorphism, searching for association with disease risk. In addition, we searched for correlation between the studied polymorphism and circulating levels of folate, homocysteine (hcy) and vitamin B12, all involved in DNA methylation reactions and available from 189 LOAD patients and 186 matched controls. Both allele and genotype frequencies of rs1550117 were closely similar between MCI, LOAD and control subjects, and no association with dementia or pre-dementia conditions was observed. Plasma hcy levels were significantly higher (p = 0.04) and serum folate levels significantly lower (p = 0.01) in LOAD than in controls, but no difference in circulating folate, hcy or vitamin B12 levels was seen between carriers and non-carriers of the minor DNMT3A -448A allele. Collectively, present results confirmed previous associations of increased hcy and decreased folate with LOAD risk, but do not support an association between the DNMT3A -448A>G polymorphism and AD in our population

Cerebellar Ataxia with Complete Clinical Recovery and Resolution of MRI Lesions Related to Central Pontine Myelinolysis: Case Report and Literature Review

There are several reports of central pontine myelinolysis (CPM) in a setting of malnutrition, alcoholism, and chronic debilitating illness associated with electrolyte abnormalities, especially hyponatremia. The cause of myelinolysis is still under debate, and, although osmotic effects are thought to be responsible in most cases, alternative pathological factors should be considered [King et al.: Am J Med Sci 2010;339:561–567]. We report a case of CPM in a patient with recent chemotherapy for colon cancer without electrolyte unbalance and otherwise unexplained causes. Moreover, the present case is an example of the unusual clinical ataxic variant, followed by complete recovery without any specific treatment. The diagnosis was confirmed by MRI, which showed a characteristic hyperintense signal abnormality in the central part of the pons with an unaffected outer rim. One month later, we observed complete resolution of clinical and radiological symptoms

Reversible MRI abnormalities in mesial temporal lobe epilepsy: a case report

The question regarding the existence of abnormalities in the neuroimaging exams immediately after status epilecticus or epileptic seizures, but showing complete reversibility after a proper antiepileptic therapy, has long been debated. The first reports attempting to demonstrate their existence date back to the 1980s, and relied upon computed tomography as the imaging method of choice. After the introduction of MRI, a more appropriate characterization of these abnormalities was obtained along with the description of their most frequent features: (a) T2 signal hyperintensity in the white matter and, occasionally, (b) reduced apparent diffusion coefficient (ADC) and increased signal in DWI sequences.The MRI abnormalities induced by epileptic activity pose a broad differential diagnosis including infections, inflammatory autoimmune encephalopathies, neoplasms. It remains a diagnosis of exclusion and requires proper diagnostic iter in order to reduce the risk of misdiagnosis and unnecessary intervention.In this case report, a thorough presentation will be outlined about MRI alterations in the left mesial temporal lobe, which resulted completely reversible after a proper antiepileptic therapy

Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and its degeneration is considered to be key in the pathogenesis of neurodegenerative diseases. In the last 15 years,MRI has been used to assess LC in vivo, both in healthy subjects and in patients suffering from neurological disorders. In this review, we summarize the main findings of LC-MRI studies, interpreting them in light of preclinical and histopathological data, and discussing its potential role as diagnostic and experimental tool

What Does the Brain Have to Keep Working at Its Best? Resilience Mechanisms Such as Antioxidants and Brain/Cognitive Reserve for Counteracting Alzheimer's Disease Degeneration

here we performed a narrative review highlighting the effect of brain/cognitive reserve and natural/synthetic antioxidants in exerting a neuroprotective effect against cognitive deterioration during physiological and pathological aging. Particularly, we discussed pathogenesis of Alzheimer’s disease, brain and cognitive reserve as means of resilience towards deterioration, and evidence from the literature about antioxidants’ role in sustaining cognitive functioning in the preclinical phase of dementia. During aging, the effects of disease-related brain changes upon cognition are reduced in individuals with higher cognitive reserve, which might lose its potential with emerging cognitive symptoms in the transitional phase over the continuum normal aging-dementia (i.e., Mild Cognitive Impairment). Starting from this assumption, MCI should represent a potential target of intervention in which antioxidants effects may contribute—in part—to counteract a more severe brain deterioration (alongside to cognitive stimulation) causing a rightward shift in the trajectory of cognitive decline, leading patients to cross the threshold for clinical dementia later

Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry

Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices

Brain-Derived Neurotrophic Factor (BDNF) and Serotonin Transporter (SERT) in Platelets of Patients with Mild Huntington’s Disease: Relationships with Social Cognition Symptoms

Peripheral biological correlates of early-stage Huntington’s disease (HD) are currently attracting much interest given their possible use as prognostic predictors of later neurodegeneration. Since deficits in social-cognition processing are present among the initial disease symptoms, aim of this work was to appraise, in blood platelets, Brain-Derived Neurotrophic Factor (BDNF) and serotonin (5-HT) transporter (SERT), two proteins involved in human adaptive behavior as potential biochemical correlates of such disabilities in mild-HD. Thirteen gene positive and symptomatic patients (9M/4W, HD-stage II, age> 40y) together 11 gender/age matched controls without a concurrent diagnosis of psychiatric disorders, underwent a blood test to determine BDNF storage and membrane-bound SERT in platelets by ELISA immune-enzyme and [3H]-paroxetine ([3H]-PAR) binding assays, respectively. Concomitantly, all subjects were examined through a battery of socio-cognitive and emotion recognition questionnaires. Results showed moderately increased intra-platelet BDNF amounts (+20-22%) in patients versus controls, whereas [3H]-PAR binding parameters, maximum density (Bmax) and dissociation constant (KD), did not appreciably vary between the two groups. While patients displaying significantly reduced cognitive/emotion abilities, biochemical parameters and clinical features or psychosocial scores did not correlate each other, except for platelet BDNF and the illness duration, positively correlated, or for SERT KDs and angry voice recognition ability, negatively correlated in both controls and patients. Therefore, in this pilot investigation, platelet BDNF and SERT did not specifically underlie psychosocial deficits in stage II-HD. Higher platelet BDNF storage in patients showing lasting-mild symptoms would derive from compensatory mechanisms. Thus, supplementary investigations are warranted by also comparing patients in other illness’s phases

Observational study of sleep-related disorders in Italian patients with Parkinson's disease: usefulness of the Italian version of Parkinson's disease sleep scale.

Sleep disturbances are common in patients with Parkinson's disease (PD). We aimed to evaluate prevalence and severity of nighttime sleep disturbances in Italian PD patients and to validate the Italian version of the Parkinson's disease sleep scale. A total of 221 PD patients and 57 healthy controls participated in a cross-sectional study with retest. PDSS, Epworth Sleepiness Scale (ESS), Hamilton Depression Rating Scale, Unified Parkinson's Disease Rating Scale (UPDRS), and Hoehn and Yahr staging were applied. PDSS total and individual items scores from patients were significantly lower than those in controls. Internal consistency of PDSS scale was satisfactory and intraclass correlation coefficient for test-retest reliability was 0.96 for total PDSS score. A significant negative correlation was found between total PDSS and ESS scores, and between total PDSS and HDRS scores. PDSS scores were also related to UPDRS sections II, III and IV, and H&Y stage. PDSS and ESS scores were not related to levodopa equivalent dose. Daytime sleepiness, depressive symptoms and disease severity correlate with sleep disturbances in Italian PD patients. The PDSS is a valid and reliable tool to evaluate sleep disturbances in Italian patients. © 2011 Springer-Verlag

The Neuroanatomy of the Reticular Nucleus Locus Coeruleus in Alzheimer's Disease.

Alzheimer's Disease (AD) features the accumulation of β-amyloid and Tau aggregates, which deposit as extracellular plaques and intracellular neurofibrillary tangles (NFTs), respectively. Neuronal Tau aggregates may appear early in life, in the absence of clinical symptoms. This occurs in the brainstem reticular formation and mostly within Locus Coeruleus (LC), which is consistently affected during AD. LC is the main source of forebrain norepinephrine (NE) and it modulates a variety of functions including sleep-waking cycle, alertness, synaptic plasticity, and memory. The iso-dendritic nature of LC neurons allows their axons to spread NE throughout the whole forebrain. Likewise, a prion-like hypothesis suggests that Tau aggregates may travel along LC axons to reach out cortical neurons. Despite this timing is compatible with cross-sectional studies, there is no actual evidence for a causal relationship between these events. In the present mini-review, we dedicate special emphasis to those various mechanisms that may link degeneration of LC neurons to the onset of AD pathology. This includes the hypothesis that a damage to LC neurons contributes to the onset of dementia due to a loss of neuroprotective effects or, even the chance that, LC degenerates independently from cortical pathology. At the same time, since LC neurons are lost in a variety of neuropsychiatric disorders we considered which molecular mechanism may render these brainstem neurons so vulnerable