The Interface between Depression and Alzheimer's Disease. A Comprehensive Approach.

Depression and Alzheimer's disease (AD) are frequent interacting diseases in the elderly with a negative impact on the quality of life of patients and caregivers. Late-life depression may be regarded either as an early symptom of AD or a risk factor for AD, depending on the context. This review was focused on the latest developments in the fields of the neurobiological basis and treatment of depression in AD. We found that some plausible hypotheses are emerging to correlate with depression in AD, such as neuroinflammation and dysimmune regulation. It seems that depression is not related to amyloid deposition, but this issue is not completely resolved. The response to antidepressants is controversial according to the evidence from 10 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression: four with sertraline, one with three arms (sertraline, mirtazapine, placebo), one with fluoxetine, one with imipramine, one with clomipramine, one with escitalopram, and one with vortioxetine. The total number of treated patients completing the trials was 638. The main criterion of a positive response was a reduction in the scores of clinical scales for depression of at least 50%. The weighted OR (odds ratio) was calculated with the method of Mantel-Haenszel: 1.29; 95% CI: 0.77-2.16. No significant differences were found compared with placebo. Antidepressants did not have a meaningful negative influence on cognition, which was measured with the mini-mental state examination (MMSE) in 18 clinical trials. Alternatives other than drugs are also discussed. Although there have been important advances in this field, pathophysiology and treatment deserve further research.

Frontal Dysexecutive Syndrome in Brain Tumors: A Pragmatic Insight to an Old Problem.

Brain tumors have long been considered one of the most prevalent causes of potentially reversible cognitive impairment. An accurate underlying cause of cognitive impairment due to brain tumor needs to be evaluated pragmatically. Patterns of cognitive impairment associated with brain tumors depend mainly on their location, lateralization, pathological classification and secondary effects of the treatment, as well as the structural plasticity and diaschisis. Hence, it is not rare that lesions with different locations and histologies may manifest with a similar pattern of cognitive impairment due to the complex interplay of determinants. We herein report 3 patients with brain tumors affecting different locations and with differing histologies, who shared a similar presentation as "frontal dysexecutive syndrome" masqueraded as psychiatric conditions. Detailed examination of saccades and pursuit along with eye movements and conventional motor examinations were essential not only to diagnose brain tumor as the potential cause of cognitive impairment, but also to rule out other coexisting etiologies with completely different underlying pathological mechanisms (i.e., Huntington's disease in 1 of the cases). A detailed neurological examination, including eye movement assessment, in patients with psychiatric symptoms provides not only important clues to delineate the underlying anatomical substrate involved, but also helps clinicians to make an accurate diagnosis and to select appropriate therapeutic options.

The effects of pregnancy on relapse rates, disability and peripartum outcomes in women with multiple sclerosis: a systematic review and meta-analysis.

Background: Although previous cohort studies of women with multiple sclerosis (MS) yielded a reduction in relapse rate during pregnancy, the effect size has not been quantified in a comprehensive manner. In addition, the effects on disability progression and peripartum outcomes have been controversial. The purpose of this work is to assess the effect of pregnancy on disease activity, and to assess the effects of MS on pregnancy as well. Materials & methods: We searched in PubMed, Cochrane Library and EMBASE for cohort studies dealing with the effects of pregnancy on relapse rates, disability progression and peripartum outcomes in women with MS. The evaluated outcomes were: changes in the annualized relapse rate (ARR) in pregnancy and puerperium, disability worsening compared with the year before pregnancy, and peripartum outcomes, which were compared with the ones of non-MS women. In the majority of cohorts included here, the women were not under disease modifying therapies during pregnancy. Results: We found 23 cohort studies measuring changes in the ARR during pregnancy and puerperium; 12 were prospective and 11 retrospective. In 17 cohorts there was significant reduction in the ARR during pregnancy compared with prepregnancy period. The pooled mean reduction in the ARR was -0.5 (95% CI: 0.67-0.38), p < 0.001, from 15 cohorts included in meta-analysis. In 18 cohorts the ARR increased in the 3-month puerperium relative to prepregnancy year period; the pooled mean increase in the ARR was 0.22 (95% CI: 0.11-0.33), p < 0.001, from 14 cohorts included in meta-analysis. Disability worsening was addressed in 18 cohorts, and in 14 of them there were no significant changes. Peripartum complications and obstetrical outcomes were assessed in 16 cohorts, of whom 13 were retrospective, without finding significant differences. Conclusion: Pregnancy is associated with lower disease activity, and puerperium with higher disease activity. Disability does not change significantly after pregnancy. The obstetrical outcomes are not very different from those of non-MS women in most cohorts.

The Risk of Symptomatic Intracranial Hemorrhage after Thrombolysis for Acute Stroke: Current Concepts and Perspectives.

BACKGROUND: Thrombolysis is the standard of treatment for acute ischemic stroke, with a time window of up to 4½ h from stroke onset. Despite the long experience with the use of recombinant tissue plasminogen activator and the adherence to protocols symptomatic intracranial hemorrhage (SICH) may occur in around 6% of cases, with high-mortality rate and poor-functional outcomes. Many patients are excluded from thrombolysis on the basis of an evaluation of known risk factors, but there are other less known factors involved. OBJECTIVE: The purpose of this work is to analyze the less known risk factors for SICH after thrombolysis. A search of articles related with this field has been undertaken in PubMed with the keywords (brain hemorrhage, thrombolysis, and acute ischemic stroke). Some risk factors for SICH have emerged such as previous microbleeds on brain magnetic resonance imaging, leukoaraiosis, and previous antiplatelet drug use or statin use. Serum matrix metalloproteinases have emerged as a promising biomarker for better selection of patients, but further research is needed. CONCLUSIONS: In addition to the already known risk factors considered in the standard protocols, an individualized evaluation of risks is needed to minimize the risk of brain hemorrhage after thrombolysis for ischemic stroke.

Magnetic resonance spectroscopy and brain volumetry in mild cognitive impairment. A prospective study.

OBJECTIVE: To assess the accuracy of magnetic resonance spectroscopy (1H-MRS) and brain volumetry in mild cognitive impairment (MCI) to predict conversion to probable Alzheimer's disease (AD). METHODS: Forty-eight patients fulfilling the criteria of amnestic MCI who underwent a conventional magnetic resonance imaging (MRI) followed by MRS, and T1-3D on 1.5 Tesla MR unit. At baseline the patients underwent neuropsychological examination. 1H-MRS of the brain was carried out by exploring the left medial occipital lobe and ventral posterior cingulated cortex (vPCC) using the LCModel software. A high resolution T1-3D sequence was acquired to carry out the volumetric measurement. A cortical and subcortical parcellation strategy was used to obtain the volumes of each area within the brain. The patients were followed up to detect conversion to probable AD. RESULTS: After a 3-year follow-up, 15 (31.2%) patients converted to AD. The myo-inositol in the occipital cortex and glutamate+glutamine (Glx) in the posterior cingulate cortex predicted conversion to probable AD at 46.1% sensitivity and 90.6% specificity. The positive predictive value was 66.7%, and the negative predictive value was 80.6%, with an overall cross-validated classification accuracy of 77.8%. The volume of the third ventricle, the total white matter and entorhinal cortex predict conversion to probable AD at 46.7% sensitivity and 90.9% specificity. The positive predictive value was 70%, and the negative predictive value was 78.9%, with an overall cross-validated classification accuracy of 77.1%. Combining volumetric measures in addition to the MRS measures the prediction to probable AD has a 38.5% sensitivity and 87.5% specificity, with a positive predictive value of 55.6%, a negative predictive value of 77.8% and an overall accuracy of 73.3%. CONCLUSION: Either MRS or brain volumetric measures are markers separately of cognitive decline and may serve as a noninvasive tool to monitor cognitive changes and progression to dementia in patients with amnestic MCI, but the results do not support the routine use in the clinical settings.

Cerebellar vermis: a vulnerable location of remote brain haemorrhages after thrombolysis for ischaemic stroke.

Extra-ischaemic (remote) brain heamorrhages after thrombolysis for ischaemic stroke occur in less than 3 % of treated patients, but it worsens prognosis. Little attention has been paid to the location of the haematomas. Among 12 patients with remote brain haemorrhage after thrombolysis, we report three patients with haemorrhage in the cerebellar vermis (25 %), with poor outcome. Previous hypertensive vasculopathy is deemed to be the most plausible cause.

Retinal nerve fiber layer and macular thickness in patients with schizophrenia: Influence of recent illness episodes.

Optical coherence tomography (OCT) has been recently used to investigate neuropsychiatric disorders. We aimed to study retinal OCT measures of patients with schizophrenia with respect to healthy controls, and to evaluate possible differences between recent illness episode (RIE) and non-recent illness episode (NRIE) patients. Thirty schizophrenia patients were classified as RIE (n=10) or NRIE (n=20), and compared with 30 matched controls. Statistical analyses included linear mixed-effects models to study the association between OCT measures and group membership. Multivariate models were used to control for potential confounders. In the adjusted linear mixed-effects regression model, patients had a significantly thinner retinal nerve fiber layer (RNFL) in overall measurements, and in the nasal, superior and inferior quadrants. Macular inner ring thickness and macular volume were also significantly smaller in patients than controls. Compared with controls, in the adjusted model only NRIE (but not RIE) patients had significantly reduced RNFL overall measures, superior RNFL, nasal RNFL, macular volume, and macular inner ring thickness. No significant correlation was found between illness duration and retinal measurements after controlling for age. In conclusion, retinal parameters observed using OCT in schizophrenia patients could be related to clinical status and merit attention as potential state biomarkers of the disorder.

Higher glutamate+glutamine and reduction of N-acetylaspartate in posterior cingulate according to age range in patients with cognitive impairment and/or pain.

RATIONALE AND OBJECTIVES: The aim of the study was to analyze 1) whether the metabolite levels in the posterior cingulate cortex (PCC) are different in healthy individuals compared to a group of patients with cognitive impairment and/or pain and 2) whether there exists a correlation between brain metabolites and the age of a patient. MATERIALS AND METHODS: Two hundred seven patients with cognitive impairment and/or pain (66 mild cognitive impairment, 54 fibromyalgia, 36 Alzheimer disease, 33 interictal migraine, 10 somatization disorder, and 8 after trigeminal neuralgia, and 193 healthy participants adjusted for gender and age. Proton magnetic resonance spectroscopy (MRS) of the brain was performed with the voxel placed in the ventral PCC and postprocessed with LCModel (Stephen Provencher, Oakville, Ontario, Canada). RESULTS: Using linear regression and adjusting for gender and age, mean brain metabolite values for the pathological group, when compared to healthy controls, were significantly lower in N-acetylaspartate (P=.003) and N-acetylaspartate/creatine (P=.015) and significantly greater in glutamate+glutamine (P<.001) and glutamate+glutamine/creatine (P<.000). All metabolites were significantly correlated with age: glutamate, glutamate+glutamine, N-acetylaspartate, and their creatine ratios exhibited a negative correlation, whereas myoinositol and choline exhibited a positive correlation. CONCLUSIONS: Although the number of patients is relatively small with heterogeneous state of disease, MRS in PCC may serve as a useful noninvasive tool for diagnostic of patients with cognitive impairment and pain.

Retinal alterations in mild cognitive impairment and Alzheimer's disease: an optical coherence tomography study.

Retinal nerve fiber layer thickness (RNFL) measured by means of Optical Coherence Tomography (OCT) has been used as a marker not only of ophthalmologic diseases but also of neurodegenerative diseases such as Alzheimer's disease (AD) and mild cognitive impairment (MCI). The purpose of this work was to demonstrate that patients with amnestic MCI show an intermediate RNFL thickness between normality and AD, and a macular volume and thickness as well. In a cross-sectional study we consecutively recruited 18 patients with AD, 21 with MCI, and 41 healthy controls. OCT was performed in all of them to measure circumpapillary RNFL thickness in µm, as well as macular volume and thickness. In the analysis of variance we saw that RNFL was thinner in MCI patients compared with controls, and it was also thinner in AD patients compared with MCI patients and controls. With regard to the macular measurements in mm(3), MCI patients had the greatest macular volume in comparison with AD patients and controls. In turn the controls had greater macular volume than AD patients. The decreased RNFL thickness in MCI and AD patients suggests loss of retinal neurons and their axons. The increased thickness and macular volume have never been reported before in aMCI. This finding could be explained by inflammation and/or gliosis in early stages of AD. OCT could be a useful marker of AD for early detection and monitoring progression.

Ataxia of Charlevoix-Saguenay: MR and Clinical Results in Lower-Limb Musculature.

OBJECTIVE: Peripheral neuropathy is a cardinal manifestation of the autosomal recessive spastic ataxia of Charlevoix- Saguenay (ARSACS), although its type of neuromuscular involvement has not been definitely established, and magnetic resonance imaging (MRI) plays an important role in the assessment of muscle and nerve diseases. The objective of this work has been to define the patterns of muscle weakness and of abnormal muscular MRI in ARSACS. PATIENTS AND METHODS: Five patients with a molecular diagnosis of ARSACS, aged 39 to 59 years, whose electrophysiological findings were consistent with an axonal neuropathy of distal distribution superimposed on a developmental defect of myelinization, underwent neurological and MRI lower-limb examinations. Conventional FSE T1-weighted and STIR sequences were performed, looking for fatty infiltration and oedema in the musculature of the thighs, legs and feet, together with their distribution along the longitudinal axis of the muscle bellies. RESULTS: On clinical examination, paralysis was apparent in foot muscles; moderate weakness, in leg musculature; and normal strength, in thigh muscles. MRI demonstrated massive fat deposition in the foot muscles and medial gastrocnemii in every case, distal fat infiltration and oedema in every leg muscle group, and preservation of thigh muscles, albeit with diffuse minimal non-specific fat infiltration. An inverse correlation between strength and degree of fat infiltration in lower-limb muscles became apparent. CONCLUSION: The preponderance of weakness and MRI abnormalities in distal muscle groups was concordant with the presence of a length-dependent axonopathy, as described in ARSACS.Ataxie de Charlevoix-Saguenay : IRM et observations cliniques au niveau de la musculature des membres inférieurs.

The predictive value of the memory impairment screen in patients with subjective memory complaints: a prospective study.

OBJECTIVE: The use of biomarkers in early Alzheimer's disease detection is growing. However, it is not clear whether sophisticated biomarker testing is more efficient than neuropsychological tests focused on memory. The goal of this study was to evaluate the predictive value of the Memory Impairment Screen (MIS), a simple and brief memory test, in elderly subjects with subjective memory loss. METHOD: A prospective cohort of 105 patients with subjective memory loss was followed up from December 2007 to April 2011 in Zaragoza, Spain. At baseline, the patients underwent neuropsychological examination with Mini-Examen-Cognoscivo (Spanish adaptation of the Mini-Mental State Examination), MIS, Clinical Dementia Rating scale, Blessed Dementia Rating Scale, and Geriatric Depression Scale. The final endpoint of the study was the conversion to dementia, mostly of probable Alzheimer's disease type according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association work group criteria. The patients were reevaluated every 6 months. RESULTS: After a mean follow-up of 2 years (range, 1-4 years), 57 patients developed Alzheimer's disease and 48 did not. A baseline score of 0 or 1 on the MIS predicted conversion to Alzheimer's disease, with a sensitivity of 42.9%, a specificity of 98%, and a positive predictive value of 96%. The area under the curve was 0.76 (95% CI, 0.66-0.83). CONCLUSIONS: In the clinical setting in patients referred for memory complaints, the MIS score at baseline (0 and 1) is useful to predict who may develop Alzheimer's disease within at least a year. The MIS would be more useful when combined with a higher sensitivity test.

Magnetic resonance imaging based clinical research in Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in elderly people in western countries. However important goals are unmet in the issue of early diagnosis and the development of new drugs for treatment. Magnetic resonance imaging (MRI) and volumetry of the medial temporal lobe structures are useful tools for diagnosis. Positron emission tomography is one of the most sensitive tests for making an early diagnosis of AD but the cost and limited availability are important caveats for its utilization. The importance of magnetic resonance techniques has increased gradually to the extent that most clinical works based on AD use these techniques as the main aid to diagnosis. However, the accuracy of structural MRI as biomarker of early AD generally reaches an accuracy of 80%, so additional biomarkers should be used to improve predictions. Other structural MRI (diffusion weighted, diffusion-tensor MRI) and functional MRI have also added interesting contribution to the understanding of the pathophysiology of AD. Magnetic resonance spectroscopy has proven useful to monitor progression and response to treatment in AD, as well as a biomarker of early AD in mild cognitive impairment.

Magnetic resonance spectroscopy in the prediction of early conversion from amnestic mild cognitive impairment to dementia: a prospective cohort study.

BACKGROUND: Mild cognitive impairment (MCI) of an amnestic type is a common condition in older people and highly predictive of Alzheimer's disease (AD). To date, there is no clear consensus regarding the best antecedent biomarker to predict early conversion to AD. OBJECTIVE: The aim of the study is to demonstrate that (1)H magnetic resonance spectroscopy (MRS) of the brain in MCI patients may predict early conversion to dementia within the 2-year period after baseline assessment. METHODS: A cohort of patients fulfilling the criteria of amnestic MCI were enrolled consecutively. At baseline the patients underwent neuropsychological examination, standard blood tests and APOE genotype. (1)H-MRS (1.5 T) of the brain was carried out by exploring two areas: the posteromedial bilateral parietal lobe and left medial occipital lobe. The patients were followed up to detect conversion to probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association group criteria. RESULTS: After a 2-year follow-up, 27 (38%) patients converted to AD. The mean N-acetyl-aspartate/creatine (NAA/Cr) ratio in the posteromedial bilateral parietal cortex was 1.38 in converters versus 1.49 in non-converters (p<0.0001). An NAA/Cr ratio equal to or lower than 1.43 in this area predicted conversion to probable AD at 74.1% sensitivity and 83.7% specificity (area under the curve: 0.84; 95% CI 0.73 to 0.92). The cross-validated accuracy of classification was 82%, which reaches 85% when the APOE4 genotype and memory test are included in the analysis. In the left medial occipital lobe, the predictive value was somewhat lower with 85.2% sensitivity and 61.4% specificity (area under the curve: 0.8; 95% CI 0.69 to 0.89). Neither the APOE4 genotype nor leuco-araiosis was predictive of conversion to dementia. CONCLUSION: MRS is a valuable biomarker to predict early conversion to dementia in patients with amnestic MCI.

Brain glutamate levels are decreased in Alzheimer's disease: a magnetic resonance spectroscopy study.

Glutamate (Glu) is the most abundant excitatory neurotransmitter in the central nervous system (CNS) and is involved in the pathophysiology of Alzheimer's disease (AD) in which there is an increased excitotoxicity. Biochemical composition of living tissues including the levels of Glu was analyzed by magnetic resonance spectroscopy (MRS). Previous reports point to decreased levels of Glu in AD. As Glu plays an important role in memory, we hypothesize that Glu levels are decreased in patients with AD when compared with controls. A consecutive sample of 30 patients with mild-to-moderate AD underwent H-MRS with the voxel placed in the bilateral posterior cingulate gyrus. For comparison purposes, we carried out the same technique in 68 patients with mild cognitive impairment (MCI) and in 26 controls. The healthy controls had higher metabolite levels of N-acetyl-aspartate (NAA) than patients with MCI and AD. In turn, patients with MCI and the controls had higher levels of Glu than in patients with AD. The differences were significant in the analysis of variance (ANOVA) test model corrected for age. In the post hoc analysis, the most remarkable differences were seen between patients with AD and the rest (patients with MCI and the controls). In AD, the levels of Glu and NAA are decreased in comparison with MCI and normality, which reflects loss of neurons.

Correlation of findings in advanced MRI techniques with global severity scales in patients with Parkinson disease.

RATIONALE AND OBJECTIVES: This work is aimed at determining whether magnetic resonance spectroscopy (MRS) and diffusion tensor imaging (DTI) may correlate with disease severity in a series of Parkinson disease (PD) patients. MATERIALS AND METHODS: We recruited a consecutive sample of 39 PD patients in several stages of the disease according to Hoehn and Yahr scale. There were 22 men, and the mean age was 74.5 years (SD 7.5). Disease severity was measured with the Unified Parkinson Disease Rating Scale (UPDRS). All of them underwent ¹H MRS in basal ganglia and the anterior cingulate area, as well as DTI in bilateral substantia nigra. Correlation was made between radiological findings and UPDRS. RESULTS: We found significant negative correlation between UPDRS scores and the Glx (glutamate+glutamine) levels in the right (r = -0.35; P = .03) and the left (r = -0.44; P = .006) lentiform nucleus; as well as with glutamate (r = -0.43; P = .008), the Glx/Cr ratio in the right (r = -0.41; P = .01), and in the left lentiform nucleus (r = -0.36; P = .02). We also found positive correlation between UPDRS scores and DTI in right rostral substantia nigra (r = 0.36; P = .02). Glx was increased in lentiform nucleus and fractional anisotropy was reduced in the rostral SN of subjects with PD in early stages. CONCLUSIONS: The results are consistent with the view that more than half the dopaminergic neurons in the nigrostriatal projection are lost before the onset of PD.

Longitudinal magnetic resonance spectroscopy as marker of cognitive deterioration in mild cognitive impairment.

OBJECTIVE: Amnestic mild cognitive impairment (MCI) is highly predictive of Alzheimer's disease but the pace of deterioration varies across patients. We hypothesize that magnetic resonance spectroscopy (MRS) could be a useful surrogate marker to monitor progression of cognitive impairment in patients with amnestic MCI. METHODS: A cohort of patients with amnestic MCI underwent single-voxel (1)H-MRS at baseline and at 2-year follow-up. We included 16 patients who converted to dementia of Alzheimer type and other 16 who did not. Changes in cognitive function were compared with the changes in the metabolite levels assessed in vivo. RESULTS: At baseline the converters had lower mean N-acetyl-aspartate (NAA)/creatine (Cr) ratios in the posteromedial parietal cortex (1.41) than nonconverters (1.47). Most patients tended to lose points in the Mini-Mental test after 2-year follow-up in parallel with decreases in NAA levels (r = .53; P = .002) in the posteromedial parietal cortex as well. The converters showed significant decreases in NAA levels and Cr ratios, whereas the nonconverters did not (P = .001 and .02, respectively) in this area. CONCLUSION: We conclude that MRS is a technique sensitive enough to monitor cognitive changes and progression to dementia in patients with amnestic MCI.

Depression in Alzheimer's disease. Pathophysiology, diagnosis, and treatment.

Depression is a comorbid condition in Alzheimer's disease (AD) with negative consequences in patients and caregivers. Pathophysiology and optimal treatment are matters to be elucidated. A search of articles dealing with depression in AD was conducted in MEDLINE with special attention to epidemiology, pathophysiology, and treatment. Depression may predate dementia and tends to occur in up to 50% of AD patients with a decrease of noradrenalin and serotonin in the brain being the most plausible cause. Only 7 small double-blind randomized placebo-controlled clinical trials with antidepressants in AD patients with depression were found: 4 with sertraline, 1 with fluoxetine, 1 with imipramine, and another one with clomipramine. The total number of treated patients was 318. The weighted odds ratio (OR) was calculated with the method of Mantel-Haenszel. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are better than placebo in treating depression in AD (weighted OR: 1.82, 95% CI: 1.13-2.96), with sertraline being one of the most used drugs. The differences were significant in 2 trials and not significant in four. The magnitude of effect is globally modest. Moreover, it is noteworthy mentioning the high rates of response to placebo in most studies. Depression is one of the most frequent behavioral symptoms in AD. Although antidepressants may work in AD, given the small number of patients treated, the effect is unclear. Further large randomized controlled clinical trials are warranted in order to know the best drug to begin with and the actual degree of efficacy.