The CORCOBIA study: Cut-off points of Alzheimer's disease CSF biomarkers in a clinical cohort.

INTRODUCTION: The analysis of the core biomarkers of Alzheimer's Disease (AD) in the cerebrospinal fluid (CSF) is recommended in the clinical units where it is available. Because of the absence of universal validated values, the determination of specific cut-off points for each center and its population is recommended. The main objective of the CORCOBIA study was to determine the cut-off points of core AD CSF biomarkers for several centers (Parc de Salut Mar, Barcelona and Hospital General de Granollers), which work with the same reference laboratory (Laboratori de Referència de Catalunya). METHODS: Prospective study including cognitively unimpaired individuals (CU, n = 42), subjects with amnestic mild cognitive impairment (aMCI, n = 35) and patients with dementia due to Alzheimer's Disease (AD, n = 48), in whom clinical and neuropsychological assessment, neuroimaging, APOE genotyping and lumbar puncture to analyse amyloid beta peptides (Aß42, Aß40), total tau (tTau) and phosphorylated Tau (pTau181) using the Lumipulse G600II (Fujirebio) was performed. The values of sensitivity (SE), specificity (SP), predictive values and area under the curve (AUC) were calculated, determining the cut-off point according to the Youden index by comparing the CU and AD groups. RESULTS: The resulting cut-offs and their AUC were the following: Aß42 750 pg/mL (AUC 0.809); Aß42/Aß40 0.062 (AUC 0.78); pTau181 69.85 pg/mL (AUC 0.81); tTau 522.0 pg/mL (AUC 0.79); Aß42/tTau 1.76 (AUC 0.86); Aß42/pTau181 10.25 (AUC 0.86). CONCLUSIONS: The determination of cut-off points of core AD CSF biomarkers for the participating centers allows a better diagnostic accuracy. The ratio CSF Aß42/pTau181 shows the highest AUC and better balance between sensitivity and specificity.

[New mutation in the PSEN1 (E120G) gene associated with early onset Alzheimer's disease]. / Nueva mutación en el gen PSEN1 (E120G) asociada a enfermedad de Alzheimer de inicio precoz.

OBJECTIVE: To describe a novel mutation in exon 5 of the presenilin 1 gene (E120G)associated with early-onset autosomal dominant Alzheimer's disease (AD). PATIENT AND METHODS: The proband was a man who began with memory loss and progressive cognitive decline at the age of 34. His father and his sister suffered from early-onset cognitive decline. The genetic study performed on the blood sample using the single strand conformation polymorphism (SSCP) technique did not detect any abnormality suggestive of the presence of a mutation in PSEN1, PSEN2, and APP. In the last stage of the disease the patient had seizures and gait alteration. He died at the age of 44. Coding exons 3-12 of PSEN1 were studied by direct sequencing using isolated DNA from frozen brain tissue of the proband. RESULTS: The neuropathological examination showed the presence of frequent amyloid plaques and neurofibrillary tangles and severe amyloid angiopathy. The direct sequencing of the PSEN1 gene disclosed the presence of the E120G mutation. CONCLUSIONS: E120G is a novel mutation in PSEN1 that probably causes early-onset autosomal dominant AD. Absence of genetic alterations in screening techniques (SSCP) does not rule out the presence of mutations. We recommend direct sequencing for the genetic study of patients with early-onset autosomal dominant AD.

Exposure to lead appears to selectively alter metabolism of cortical gray matter.

OBJECTIVE: The effects of lead poisoning on the development of children have been examined primarily in the context of behavioral and neuropsychological studies. The purpose of this study was to examine the in vivo use of magnetic resonance spectroscopy (MRS) for the evaluation of the neurotoxic effects of lead on the nervous system. MRS has the ability to monitor brain metabolism by detecting a number of neurochemicals among which is N-acetylaspartate, a metabolite shown to decrease in processes that involve neuronal loss. METHODS: In the present study we evaluated the metabolism of gray and white matter of frontal cortex using MRS in individuals with elevated blood lead levels and compared the results with those obtained on nonlead-exposed controls. RESULTS: Although all of the participants had normal MRI examinations of the brain, the lead-exposed individuals exhibited a significant reduction in the N-acetylaspartate/creatine and phosphocreatine ratios in frontal gray matter compared with the nonlead-exposed controls. CONCLUSIONS: The findings of this study suggest that lead has an effect on brain metabolites as detected by MRS in vivo. More specifically, we have found statistically significant reduced levels of brain metabolites in gray but not white matter in lead-exposed individuals. These results imply that MRS is able to detect metabolic abnormalities in individuals with lead poisoning.

A randomized placebo-controlled comparative trial of gabapentin and propranolol in essential tremor.

BACKGROUND: New medication is needed to treat essential tremor. Preliminary evidence suggests that gabapentin may be effective in the treatment of this disorder. OBJECTIVE: To study the effects of gabapentin in a comparative, double-blind, crossover, placebo-controlled trial of patients who have essential tremor. PATIENTS AND METHODS: 16 patients with essential tremor (6 with a new onset and 10 with a 2-week washout period of previous treatment with propranolol hydrochloride) received gabapentin (Neurontin), 400 mg 3 times daily; propranolol hydrochloride, 40 mg 3 times daily; and placebo for 15 days with a 1-week washout period between treatments. MAJOR OUTCOME MEASURES: Major outcome evaluations consisted of a Tremor Clinical Rating Scale, accelerometric recordings, and a self-reported disability scale obtained before drug intake on study days 1 and 15 of each treatment period. In addition, the initial (day 1) and superimposed (day 15) drug effects were studied before and 2, 4, 6, and 8 hours after drug intake. RESULTS: At day 15, both gabapentin and propranolol demonstrated significant and comparable efficacy in reducing tremor from baseline in all tremor measures. The initial drug effects evaluated through accelerometry revealed no significant changes with the use of a placebo, but gabapentin and propranolol use significantly reduced tremor power. CONCLUSION: Gabapentin may be useful for the treatment of essential tremor.

A six-month study of pergolide and levodopa in de novo Parkinson's disease patients.

Formal studies examining the antiparkinsonian efficacy of levodopa and pergolide monotherapy in de novo Parkinson's disease (PD) are lacking. The authors conducted a preliminary, 6-month, open-label parallel experimental study with de novo consecutive PD patients who were randomly assigned to three daily doses of pergolide (n = 10; mean age, 63.7 years; mean Hohen & Yahr score, 1.5; mean final dose, 2.8 mg daily) or levodopa (n = 10; mean age, 67.3 years; mean Hohen & Yahr score, 1.8; mean final dose, 435 mg daily). Doses were titrated individually according to patients' evaluation of their own functional ability, known side-effects, and a monthly administration of the Unified Parkinson's Disease Rating Scale (UPDRS) by a clinician blind to the treatment regime. All patients completed the study. There were no significant basal differences between groups and no significant treatment ortreatment-by-time effects in UPDRS scores (according to two-way ANOVA). A clear time effect was observed for most of the functional and motor variables (p < 0.001), with significant improvement during the first month that was maintained for the duration of the study in both groups. Side effects were mild, transient, and comparable. In this preliminary study, pergolide and levodopa exhibited similar symptomatic efficacy and incidence of side effects in the short-term treatment of de novo PD patients at their usual age of clinical manifestation.

Magnetic resonance imaging and spectroscopy of regional brain structure in a 10-year-old boy with elevated blood lead levels.

OBJECTIVE: The effects of elevated blood lead levels on the development of children have been examined only in the context of behavioral and neuropsychological evaluations. No studies have examined the effects of lead on brain metabolism in vivo or on structural and/or functional correlates of brain function in children. In the human brain, magnetic resonance spectroscopy (MRS) provides a noninvasive, risk-free method to monitor the biochemistry of acute and chronic stages of disease. The purpose of this study was to examine in vivo the use of MRS for the evaluation of the neurotoxic effects of lead on the nervous system, by detection of brain metabolism, especially N-acetylaspartate, a metabolite shown to decrease in processes that involve neuronal loss. METHODOLOGY: Two male cousins who live in the same household and share the same socioeconomic background and home environment were studied. The subject, a 10-year-old boy, had elevated blood lead levels. His cousin, a 9-year-old boy, was not exposed to lead. Both underwent a comprehensive neuropsychological evaluation and both were evaluated using the magnetic resonance imaging (MRI) and MRS at the University of Pennsylvania Medical Center. High-resolution MRI and MRS were performed using a 3-in surface coil. Localized proton spectra were obtained from contiguous 6 x 6 x 10-mm voxels using one-dimensional phase encoding, with a 2000-millisecond repetition time and a 31-millisecond echo time. RESULTS: Neuropsychological evaluation demonstrated areas of impairment in the lead-exposed child, including difficulties in academic skills of reading, writing, and arithmetic, as well as deficient linguistic skills and attentional mechanism. By contrast, studies of the cousin, who was not exposed to lead, showed overall neuropsychological functioning within normal limits. Although both children had a normal MRI examination of the brain, studies of the lead-exposed boy showed a significant alteration in brain metabolites, with a reduction in the N-acetylaspartate:creatine ratio for both gray and white matter on the MRS examination, compared with his cousin. CONCLUSIONS: The present study is a first attempt to determine in vivo metabolic differences in the brain of a child exposed to lead compared with a healthy control subject. This is a unique case because these children were matched on a number of variables usually regarded as confounders in behavioral lead studies, and therefore can be regarded as matched controls. The present study demonstrates that MRS is a feasible, noninvasive technique for in vivo examination of the brains of children exposed to lead. We were able to obtain high-quality spectra from voxels as small as 0.36 cm at 1.5T. The spatial resolution used in the present study is sufficient to obtain spectra from voxels almost exclusively composed of gray matter. The one-dimensional phase-encoding approach used presents the advantage of obtaining several spectra simultaneously in a relatively short time. The present study has allowed us to examine the spectroscopic patterns of frontal gray and white matter after lead exposure relative to the normal pattern seen in healthy children and adults. The MRS study of the healthy, nonlead-exposed cousin demonstrated spectra entirely consistent with the spectral pattern reported in previous studies of healthy individuals. By contrast, the spectra obtained from the lead-exposed child deviated from the expected pattern in all metabolite ratios analyzed. Because N-acetylaspartate has been shown as a measure of neuronal viability, the level of N-acetylaspartate may enable us to evaluate the degree of neuronal loss in children exposed to lead. The MRI examination indicated no structural abnormalities or cortical thinning, and no abnormal findings in either case. By contrast, MRS indicated a significant change from normal values for the lead-exposed child. This supports the idea that lead neurodevelopmental toxicity may be related to inter

Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy.

We have developed a proton magnetic resonance spectroscopy method that selectively can sample cortical gray matter and adjacent white matter in the frontal lobe. We have used this approach to study a group of patients (n = 7) infected with HIV and clinical manifestations of the AIDS dementia complex (ADC), a group of patients (n = 8) infected with HIV without any indications of ADC, and seven controls. The patients without ADC had a statistically significant increase in the ratio of myo-inositol to creatine in white matter compared with normal controls. In contrast, the group of patients with ADC had almost normal levels of myo-inositol to creatine in both gray matter and white matter and showed a statistically significant decrease in the N-acetylaspartate to creatine ratio in gray matter compared with either the normal controls or the patients without ADC. Patterns of spectral abnormalities correlated with neuropsychological measures of frontal lobe dysfunction, suggesting that the evaluation of frontal lobe metabolism by magnetic resonance spectroscopy can play a role in the early detection of ADC, in determining its progression, and in assessing responses to therapeutic interventions.

[Initial treatment of Parkinson's disease]. / Tratamiento inicial de la enfermedad de Parkinson.

The initial treatment of Parkinson's disease should be addressed to improve symptoms, slow down the progression of the illness and avoid long and short term complications. Drugs currently available for symptomatic treatment are levodopa, dopaminergic agonists, anticholinergics and amantadine. Levodopa is still the goldstandard. Both the standard preparations of carbidopa/levodopa or benserazide/levodopa and the slow release preparations are suitable for initial treatment. However, when to start levodopa remains controversial. Dopaminergic agonists are useful symptomatic drugs. They can be used in monotherapy, but usually require the addition of levodopa to obtain a satisfactory long term therapeutic response. Used as adjuvant treatment to levodopa, they help lowering the dosage of levodopa. Anticholinergic drugs effectively improve symptoms such as tremor and rigidity but their use is limited by their side effects, particularly in older people. Amantadine may be a useful drug for initial treatment of Parkinson's disease when symptoms are not severe. Symptomatic treatment should be considered individually in each patient. If there is only slight disability, treatment may be started with amantadine alone or with a dopaminergic agonist. If there is greater disability, levodopa or the simultaneous use of levodopa and a dopaminergic agonist should be considered. Anticholinergic drugs should be reserved for young patients with tremor as the main symptom. The newer dopamine agonists and inhibitors of catachol-o-methyltransferase (COMT) are coming therapeutic options. Selegiline, a MAOB inhibitor with a possible neuroprotective effect, should also be considered as initial option for Parkinson's disease.

[Psychogenic tremor: clinical, electrophysiologic and psychopathologic assessment]. / Temblor psicógeno: análisis clínico, electrofisiológico y psicopatológico.

There are few studies analyzing the incidence, clinical characteristics and diagnostic work-up of psychogenic tremor. We studied the clinical and electrophysiological characteristics and the associated psychopathology in a series of patients with psychogenic tremor. All patients (n = 8) diagnosed with documented or clinically established psychogenic tremor in the movement disorders section of our Department of Neurology in a two-years period were analysed. Psychogenic tremor was diagnosed in 9.5% of the patients that consulted for postural or action tremor of the upper limbs. In all cases tremor had a variable frequency and amplitude and improvement with distraction. Electrophysiological studies revealed asynchronic muscle activity and considerable variation of the dominant frequency when weight was added to the patient hands. Six patients were initially misdiagnosed of essential tremor (n = 3); Parkinson's disease (n = 1); and cerebrovascular disease (n = 2). Final psychiatric diagnoses were depression (n = 4); conversive disorder (n = 2); and malignering (n = 2). Psychogenic tremor is a relatively frequent cause of tremor in a Movement Disorders Clinic and has a characteristic clinical and electrophysiological pattern.

Post-irradiation neuromyotonia in bilateral facial and trigeminal nerve distribution.

We describe a patient with episodic involuntary contraction in the lower facial and masseter muscles, in whom we recorded neuromyotonic discharges. The neuromyotonia was a delayed effect of radiation therapy and responded to carbamazepine therapy.

High spatial resolution MRI and proton MRS of human frontal cortex.

High-resolution MR imaging (312 microns in plane resolution) and MR spectroscopy (0.36 cm3 nominal voxel) have been performed on human frontal cortex using a 3 in surface coil. Localized proton spectra have been obtained from contiguous 6 x 6 x 10 mm voxels using one-dimensional phase encoding, TR 2000 ms and TE 31 ms. Seven healthy subjects were studied using this approach. The spectra from frontal gray matter showed a reproducible pattern characterized by a choline to creatine and N-acetylaspartate to creatine ratio significantly lower than those from cortical white matter. These metabolite ratio differences reflect the lower choline and higher creatine content in gray matter. These preliminary results show the potential of this high spatial-resolution approach for studying brain cortex.

Neuropsychological alterations in patients with computed tomography-detected basal ganglia calcification.

OBJECTIVE: To investigate the cognitive and mental status of patients with basal ganglia calcification on a computed tomographic scan. DESIGN: Eighteen ambulatory patients with basal ganglia calcification and without other radiological findings who were identified from the computed tomography records of a general hospital in a 2-year period and 16 control subjects who were matched for age, education, sex, and premorbid IQ estimation consented to participate. All subjects underwent a neurological evaluation, a comprehensive neuropsychological battery, and tests with psychiatric rating scales. RESULTS: Significant differences for the control group were found in tests that evaluated motor speed and executive, visuospatial, and some memory functions. Four patients (22%) met criteria for organic mood disorder (minor depression, three patients; bipolar depression, one patient) according to the Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, whereas six other patients (33%) met diagnostic criteria for obsessive-compulsive disorder. CONCLUSIONS: These results indicate that patients with basal ganglia calcifications frequently have a subcortical pattern of neuropsychological dysfunction and behavioral changes that are known to be associated with alterations of the frontal-limbic-basal ganglia circuits. The pattern of neuropsychological impairment is consistent with basal ganglia damage. However, poor performance in other neuropsychological tests suggest additional involvement of other connected networks.

Lactate production by human monocytes/macrophages determined by proton MR spectroscopy.

Elevated brain lactate has been observed by in vivo proton MRS in different pathological situations. The origin of this lactate remains controversial. The possibility that it was produced by the metabolism of phagocytic cells has been proposed. To investigate this hypothesis, the authors have employed high-resolution proton MRS to monitor changes in glucose, lactate, and other metabolites in the medium used to culture human monocyte-derived macrophages in vitro. Results show that the differentiation of human monocytes/macrophages in the presence of physiological stimulating factors (M-CSF or GM-CSF) was associated with an increase in lactate production and glucose utilization. The present results are consistent with the hypothesis that lactate detected by proton MRS in vivo may be produced by the metabolism of macrophages when infiltrates of these cells are present. The possible extrapolation of the authors' finding to the in vivo situation and its relevance are discussed.