A comparison of early diagnostic utility of Alzheimer disease biomarkers in brain magnetic resonance and cerebrospinal fluid.

INTRODUCTION: The goals of this study were to compare the early diagnostic utility of Alzheimer disease biomarkers in the CSF with those in brain MRI in conditions found in our clinical practice, and to ascertain the diagnostic accuracy of both techniques used together. METHODS: Between 2008 and 2009, we included 30 patients with mild cognitive impairment (MCI) who were examined using 1.5 Tesla brain MRI and AD biomarker analysis in CSF. MRI studies were evaluated by 2 radiologists according to the Korf́s visual scale. CSF biomarkers were analysed using INNOTEST reagents for Aß1-42, total-tau and phospho-tau181p. We evaluated clinical changes 2 years after inclusion. RESULTS: By 2 years after inclusion, 15 of the original 30 patients (50%) had developed AD (NINCDS-ADRA criteria). The predictive utility of AD biomarkers in CSF (RR 2.7; 95% CI, 1.1-6.7; P<.01) was greater than that of MRI (RR 1.5; 95% CI 95%, 0.7-3.4; P<.2); using both techniques together yielded a sensitivity and a negative predictive value of 100%. Normal results on both complementary tests ruled out progression to AD (100%) within 2 years of inclusion. CONCLUSIONS: Our results show that the diagnostic accuracy of biomarkers in CSF is higher than that of biomarkers in MRI. Combined use of both techniques is highly accurate for either early diagnosis or exclusion of AD in patients with MCI.

[Patients with mild cognitive impairment and a reduced CSF Aß1₋42 protein progress rapidly to Alzheimer's disease]. / Pacientes con deterioro cognitivo leve y reducción de la proteína Aß(1-42) en LCR evolucionan rápidamente a enfermedad de Alzheimer.

INTRODUCTION: Some studies have shown that CSF amyloid-beta 1-42 (Aß1₋42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau(181p)) proteins are useful diagnostic markers for distinguishing between clinically stable mild cognitive impairment (MCI) patients and those who will develop Alzheimers disease (AD). Our objective was to test the ability of this technique to discriminate in our cohort of MCI patients, according to the clinical outcome, one year after the lumbar puncture. MATERIAL AND METHODS: A total of 36 MCI patients were included from the local hospital memory clinic. Using INNO-BIA Alzbio-3 reagents from Innogenetics, we measured CSF Aß1₋42, T-tau and P-tau(181p) proteins, and calculated the T-tau/Aß1₋42 y P-tau(181p)/Aß1₋42 ratios. This project was approved by the local ethics committee. RESULTS: One year after the lumbar puncture, 14 MCI patients (38%) developed AD. These patients had lower Aß1₋42 protein levels (285.3 vs 377 ng/ml, P<.02) and higher P-tau(181p)/Aß1₋42 ratio (0,25 vs 0,16, p<.02) than the clinically stable patients. CONCLUSIONS: Our MCI patients with lower Aß1₋42 protein levels and an increased P-tau(181p) /Aß1₋42 ratio progressed quickly to AD. These results may help to identify those MCI patients with a poorer prognosis.

Biomarkers of Alzheimer's disease in the cerebrospinal fluid of Spanish patients with mild cognitive impairment.

The study of biomarkers in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment (MCI) is a technique used with increasing frequency in the early diagnosis of Alzheimers disease (AD). Our objectiv was to gain an own experience while evaluating the reliability, sensitivity, and reproducibility of this technique in Spanish patients. Thirty-seven patients with MCI and twenty-four control subjects were studied by means of AD biomarker analysis in CSF. xMAP Luminex and INNO-BIA Alzbio3 reagents of Innogenetics were used. The study variables assessed were levels of Aß(1-42), T-tau and P-tau(181p) proteins as well as the ratios of T-tau/Aß(1-42) and P-tau(181p)/Aß(1-42). Samples from nineteen patients were examined twice. Intra-class correlation coefficients for the three biomarkers used showed values higher than 0.95. We observed significant differences between the control group and the MCI groups. In the 6 months following lumbar puncture (LP), eleven (29%) patients with MCI developed AD. These patients showed significant lower levels in Aß(1-42) protein (276.35 ± 78 vs. 367.13 ± 123.49, P < 0.03) and higher ratios (T-tau/Aß(1-42) [0.38 ± 0.2 vs. 0.22 ± 0.14, P < 0.01] and P-tau(181p)/Aß(1-42) [0.27 ± 0.13 vs. 0.16 ± 0.1, P < 0.008]) to those in the same group who remained stable. We obtained similar results to those in the most recent reliable literature with our ROC curves, especially with our P-tau(181p) values and T-tau/Aß(1-42) ratio in order to differentiate between control and AD groups. Our experience showed that the analysis of CSF-AD biomarkers in patients with MCI is reliable, sensitive and reproducible. In our knowledge, this is the first experience in Spanish patients.

Spanish expert consensus on the use of safinamide in Parkinson's disease.

Safinamide is a new add-on drug to levodopa for the treatment of Parkinson's disease (PD) with motor fluctuations. Due to the recent incorporation of safinamide into routine clinical practice, no post-authorisation phase IV studies on the safety of safinamide have been conducted to date. This study provides clinical management guidelines for safinamide based on the opinion of a group of experts in movement disorders. This project was developed in 2 phases: 16 local meetings in phase 1 and a national meeting in phase 2. The meetings followed a pre-established agenda. The present clinical practice guidelines are based on the main conclusions reached during the national meeting. The group concluded that safinamide is effective in reducing motor and non-motor fluctuations. PD patients with mild-to-moderate fluctuations benefit most from treatment, although the drug may also improve the clinical status of patients with advanced PD. The dose of other dopaminergic drugs may be reduced after introducing safinamide, which would contribute to reducing such adverse reactions as impulse control disorder. At doses higher than those usually prescribed, safinamide may also improve dyskinesia. The experts agreed that safinamide is well tolerated and causes few adverse reactions when compared with placebo.

[Frequent involvement of the amyloid pathway in prodromal dementia with Lewy bodies]. / Frecuente alteracion de la via amiloide en la demencia con cuerpos de Lewy prodromica.

INTRODUCTION: Lewy body dementia (LBD) is the most frequent of the degenerative dementias, after Alzheimer's disease. AIM: To analyse the core biomarkers of Alzheimer's disease in the cerebrospinal fluid of exclusively Hispanic patients with prodromal LBD, in order to determine whether there is involvement of the amyloid pathway or the tau pathway. PATIENTS AND METHODS: Between 2008 and 2017 we included 430 patients with mild cognitive impairment according to Petersen criteria, from three hospitals in the province of Alicante. They underwent clinical check-ups every 6-12 months to evaluate their clinical stability or their progression to dementia using current clinical criteria. Among other complementary tests, biomarkers for Alzheimer's disease in the cerebrospinal fluid were analysed. RESULTS: Of all the patients included, 26 developed LBD and 29 remained stable for at least five years, and were thus considered as a reference. In this group only five (17%) had Abeta(1-42) protein values below normal, whereas 16 (55%) of the patients with LBD had altered levels. No differences were found in the levels of tau protein. On comparing the LBD groups with and without amyloidosis, differences were only found in the levels of Abeta(1-42) protein. CONCLUSIONS: We highlight the frequent presence of amyloid pathology in prodromal LBD in our population, and the probable involvement of different metabolic pathways in the same clinically defined dementia.

TITLE: Frecuente alteracion de la via amiloide en la demencia con cuerpos de Lewy prodromica.Introduccion. La demencia con cuerpos de Lewy (DCLW) es la mas frecuente de las degenerativas, despues de la enfermedad de Alzheimer. Objetivo. Analizar los biomarcadores core de la enfermedad de Alzheimer en el liquido cefalorraquideo de pacientes exclusivamente hispanos con DCLW prodromica, para conocer si existe alteracion de la via amiloide o de la via tau. Pacientes y metodos. Entre 2008-2017 incluimos a 430 pacientes con deterioro cognitivo leve segun los criterios de Petersen, procedentes de tres hospitales de la provincia de Alicante. Se les realizaron revisiones clinicas cada 6-12 meses para evaluar su estabilidad clinica o la progresion a demencia utilizando los criterios clinicos vigentes. Entre otras pruebas complementarias se analizaron los biomarcadores de enfermedad de Alzheimer en el liquido cefalorraquideo. Resultados. Entre todos los pacientes incluidos, 26 desarrollaron DCLW y 29 se mantuvieron estables durante al menos cinco años, por lo que los consideramos como referencia. En este grupo solamente cinco (17%) tenian valores de proteina Abeta(1-42) inferiores a la normalidad, mientras que 16 (55%) de los pacientes con DCLW tenian niveles alterados. No se encontraron diferencias en los niveles de las proteinas tau. Al comparar los grupos con DCLW con y sin amiloidosis solamente encontramos diferencias en los niveles de proteina Abeta(1-42). Conclusiones. Destacamos la frecuente presencia de patologia amiloidea en la DCLW prodromica en nuestra poblacion y la probable alteracion de diferentes vias metabolicas en una misma demencia clinicamente definida.

Spanish expert consensus on the use of safinamide in Parkinson's disease. / Consenso de expertos españoles sobre el uso de la safinamida en la enfermedad de Parkinson.

Safinamide is a new add-on drug to levodopa for the treatment of Parkinson's disease (PD) with motor fluctuations. Due to the recent incorporation of safinamide into routine clinical practice, no post-authorisation phase IV studies on the safety of safinamide have been conducted to date. This study provides clinical management guidelines for safinamide based on the opinion of a group of experts in movement disorders. This project was developed in 2 phases: 16 local meetings in phase 1 and a national meeting in phase 2. The meetings followed a pre-established agenda. The present clinical practice guidelines are based on the main conclusions reached during the national meeting. The group concluded that safinamide is effective in reducing motor and non-motor fluctuations. PD patients with mild-to-moderate fluctuations benefit most from treatment, although the drug may also improve the clinical status of patients with advanced PD. The dose of other dopaminergic drugs may be reduced after introducing safinamide, which would contribute to reducing such adverse reactions as impulse control disorder. At doses higher than those usually prescribed, safinamide may also improve dyskinesia. The experts agreed that safinamide is well tolerated and causes few adverse reactions when compared with placebo.

[A study of personality in Parkinson's disease: the influence of motor and non-motor factors]. / Estudio de la personalidad en la enfermedad de Parkinson: influencia de factores motores y no motores.

INTRODUCTION: The literature on Parkinson's disease (PD) has acknowledged the existence of certain characteristic features in the personality and moods of patients which could be caused by the disease or may be a consequence of the functional disability produced by the condition. AIM: To compare the variables personality, depression, anxiety and cognitive functions between a group of patients with PD and a control group with a similar functional disability. PATIENTS AND METHODS: The study involved a sample made up of 55 patients with PD and 55 patients with rheumatologic or orthopaedic diseases, who were paired by age, sex and functional disability according to the Schwab and England scale. Personality tests (personality questionnaire for adults adapted to the Spanish population, sensation-seeking questionnaire, rigidity questionnaire, coping strategies questionnaire), Hamilton Depression Scale, State-Trait Anxiety Inventory and tests for cognitive functions (Minimental and Progressive Matrixes Test). RESULTS: Patients with PD score significantly higher than control subjects on the Hamilton Depression Scale. No significant differences were found in any of the variables in the three personality tests that were used, on the anxiety scale or in the cognitive functioning tests. CONCLUSIONS: No differential personality traits were found between our patients and the control subjects, which would therefore not support the existence of a characteristic personality in PD. Our patients with PD show more symptoms of depression than is to be expected in relation to their functional disability, and this could influence the results obtained by other authors in studies on this subject.

Diagnostic Validity Comparison Between Criteria Based on CSF Alzheimer's Disease Biomarkers.

AIM: To compare the diagnostic validity of NIA-AA criteria, for AD CSF biomarkers, with our own new criteria. MATERIALS AND METHODS: Between 2008 and 2011, 170 patients with Mild Cognitive Impairment (MCI) were included. CSF levels of Aß1-42, T-tau, P-tau181, and ratios of T-tau/Aß1-42 and P-tau181/Aß1-42 were analyzed. In our criteria, we considered 3 or more abnormal variables indicative of a high likelihood of MCI due to AD. RESULTS: After a clinical follow-up of 4.5 ± 1.2 years, 44 patients remained stable, 95 developed AD, 15 other forms of dementia, 7 died and 9 received other diagnoses. Using the NIA-AA criteria and our own criteria, the diagnostic validity of the CSF biomarkers was 58% versus 85%, specificity 84% versus 72%, PPV 82% versus 79% and NPV 61% versus 79%. CONCLUSION: The inclusion of the ratios in diagnostic criteria increases sensitivity and NPV for the diagnosis of MCI due to AD.

[Levodopa and cognitive disorders in Parkinson's disease]. / Levodopa y alteraciones cognitivas en la enfermedad de Parkinson.

AIMS: Most of the patients with Parkinson's disease evaluated in formal neuropsychological studies are found to have cognitive disorders similar to those of patients with lesions in the prefrontal cortex. A large number of anatomical, physiological, pharmacological and clinical data indicate that dopamine transmission plays an important role in frontal cortical functions. We review the main types of cognitive impairment in Parkinson's disease and their response to treatment with levodopa. DEVELOPMENT: In studies involving the acute administration of levodopa, the results obtained with regard to the cognitive functions have been heterogeneous, since improvements, exacerbations and the absence of any changes have all been observed. This heterogeneity is affected by methodological problems deriving from the disease itself, the treatment administered and the way evaluation is carried out. Longitudinal studies show a pattern of initial improvement, followed by stability, or maintenance, over a period of 2 or 3 years and then renewed exacerbation with no response to levodopa. On occasions, patients may only respond after a certain period of continued treatment. Generally speaking, the more severe the cognitive impairment is, the poorer the response to levodopa will be. CONCLUSIONS: Therapy with levodopa modifies, in one sense or another, the cognitive disorders in Parkinson's disease, which indicates that the dopaminergic deficit unquestionably plays a role in these disorders. The absence of response in some patients or in some cognitive functions or the fact that it 'wears off' in most patients suggests that the dopaminergic deficit is only one of the factors in the aetiopathogenesis of the cognitive dysfunction found in Parkinson's disease.

Influence of APOE Genotype on Alzheimer's Disease CSF Biomarkers in a Spanish Population.

OBJECTIVES: To evaluate the association between apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) levels of Alzheimer's disease (AD) biomarkers and to study the influence of APOE genotype on the development of AD in a Spanish population. MATERIAL AND METHODS: The study comprised 29 amnestic mild cognitive impairment (MCI) patients and 27 control subjects. Using ELISA methodology, CSF biomarkers and tau/Aß ratios were obtained. ANOVA and adjusted odds ratios were calculated. RESULTS: We observed the effect of APOE genotype and age on CSF AD variables. The progression to AD was more clearly influenced by CSF AD variables than by age or APOE status. CONCLUSIONS: APOE status influences CSF AD variables. However, the presence of APOE ε4 does not appear to be a deterministic factor for the development of AD, because CSF variables have a greater influence on progression to the disease. These results confirm previous observations and, to our knowledge, are the first published in a Spanish population.

[Intracerebral hematoma: clinical and prognostic correlations (author's transl)]. / Hematoma intracerebral: correlaciones clínicas y pronósticas.

Forty-eight patients with intracranial hematomas are reviewed. In all cases diagnosis was established by CT scan. Volume was calculated with the Steiner method. Treatment was supportive for all patients. Mortality rate was 33%. Arterial hypertension was an associated factor in 58.33%. Clinical evolution was influenced by age of patient, volume and site of the hematoma. Mortality rate was highest in the cases with thalamic hematomas. Early coma or hemiplegia also carried a poor prognosis.

[Neurologic manifestations in Wolfram's syndrome]. / Complications neurologiques au cours du syndrome de Wolfram.

Wolfram's syndrome, also known as DIDMOAD syndrome, includes juvenile diabetes mellitus and optic atrophy variously associated with diabetes insipidus and deafness. We describe the neurological findings in 5 patients with Wolfram's syndrome. All patients had a neurological examination and were subjected electrophysiological and brain imaging including CT scan and, in one patient, MRI. There were two pairs of brothers and a sporadic case with paternal consanguinity suggesting recessive inheritance. Neurological abnormalities were found in four patients including dysarthria, seizures, anosmia, nystagmus, ataxia and changes in the electroencephalograms, electroretinograms and evoked potentials. In contrast with previous reports, four patients had abnormal brain CT scan with prominent atrophy of the brainstem. In the patient studied with NMR, severe brainstem and cerebellar atrophy was found. These neuroradiological findings are reminiscent of those described in olivopontocerebellar atrophy and are in agreement with previous pathological studies. We conclude that Wolfram's syndrome includes phenotypical manifestations of olivopontocerebellar atrophy. This reinforces the opinion that olivopontocerebellar atrophy is a nonspecific syndrome of varied causes.

[Neurological involvement following triple virus vaccine]. / Implicación neurológica tras immunización con vacuna triple vírica.

INTRODUCTION: Prophylactic immunization against measles, rubella and mumps is carried out using a trivalent vaccine. The second dose is recommended at 11-12 years-old. Neurological complications have been described after vaccination for measles and rubella. All cases occurred several days after vaccination. CLINICAL CASES: We describe four girls aged between 10 and 11 years old who were vaccinated on the same day. Almost immediately they complained of symptoms in the vaccinated arm. These were pain, paresthesia, coldness, pallor and sweating of the hand. On the following days there was loss of strength and alterations in sensation. All laboratory, radiological, neurophysiological and psychiatric studies were normal. Immunological study showed changes in the immunohumeral response to the vaccine. Complete recovery was made. CONCLUSIONS: The different types of post-vaccination complications described to date are reviewed, together with conditions showing features such as those described, particularly the reflex sympathetic syndrome. Possible reasons for the poor immunohumoral response to the vaccine in these patients are discussed.

[Peduncular hallucinosis associated with a space occupying lesion of the brain stem]. / Alucinosis peduncular asociada a un proceso expansivo del tronco cerebral.

INTRODUCTION: Traditionally visual hallucinations have been divided into simple and complex. Complex hallucinations due to disorder of the brainstem have been described, and this process referred to as peduncular hallucinosis. CLINICAL CASE: A 74 year old woman with a history of endometrial carcinoma with metastases to bones and lungs, was admitted for progressive ataxia and paraesthesias of the left half of her body. During her admission to hospital she had complex visual hallucinations of cartoon animals, animals, people and geometrical figures. The patient herself realized that they were hallucinations. On cerebral computerized tomography there was a space occupying lesion in the pons-midbrain region of the brainstem. In the clinical context of this particular patient, it was considered to probably be a metastasis from the carcinoma of the endometrium. CONCLUSIONS: Apart from its theoretical interest, peduncular hallucinosis has well defined stereotyped characteristics, and recognition of these may be useful in topographical diagnosis of the lesion.

[Spanish version of the Autonomic Symptom Profile test]. / Versión española del test perfil de síntomas autonómicos.

INTRODUCTION: The Autonomic Symptom Profile (ASP) is a self-administered questionnaire that has been validated in English to assess autonomic symptoms and to differentiate between patients and healthy subjects according to said symptoms. Our group has studied its application in Spanish. SUBJECTS AND METHODS: After translating the English version into Spanish and then back-translating it, the reliability and validity of criteria in the Spanish version of the ASP test were evaluated in a sample of 50 subjects (27 controls and 23 patients). All the patients with symptoms of autonomic dysfunction were studied by means of the Ewing and Clarke battery. RESULTS: The reliability of the Spanish version of the ASP was high and an interclass correlation coefficient of 0.93 was obtained. A score of 47 or over in the test yields a sensitivity of 73.9% and a specificity of 100% for the detection of autonomic dysfunction. Furthermore, the score in the Spanish version of the ASP test showed statistically significant differences between the group of patients and the control group. CONCLUSIONS: The Spanish version of the ASP is reliable and makes it possible to distinguish between patients with autonomic dysfunction and control subjects. As far as we are aware, this is the first test to evaluate the symptoms of the autonomic nervous system in a global manner and in Spanish.

[Two years' experience in a specific autonomic nervous system service]. / Experiencia de dos años en una consulta específica de sistema nervioso autónomo.

INTRODUCTION: Despite the high incidence and prevalence of pathologies affecting the autonomic nervous system (ANS), this part of neurology has received very little specific attention in clinical care in our country. AIM: To present the experience we have gained over a two-year period in an ANS-specific service. PATIENTS AND METHODS: Our patients were referred to the ANS service by other colleagues, most of whom were neurologists, between April 2006 and April 2008, after proposing a set of eligibility and exclusion criteria. Clinical history, examination and general analysis were performed for all patients. The following tests were also carried out on an individualised basis: Ewing-Clarke test, the Spanish version of the autonomic symptom profile test, tilt table test, holter heart monitor, urodynamic study and reflex sympathetic test, among other complementary studies. RESULTS: Thirty-four first visits and 62 successive visits were registered. The most frequent diagnoses were neurologically mediated syncopes and diabetic autonomic neuropathies, but other less prevalent conditions were also diagnosed. The most cost-effective complementary tests were the Ewing-Clarke test and the autonomic symptom profile test. Apart from benzodiazepines, the most commonly prescribed pharmacological treatments were paroxetine and pyridostigmine. CONCLUSIONS: As expected, neurologically mediated syncopes and diabetic neuropathies with an autonomic component are the most frequent pathologies in an ANS service. Nevertheless, their diagnosis and individualised treatment, together with that of other less prevalent autonomic pathologies, may require specific attention. To our knowledge, this is the first service of its kind in our country.

[Methods to evaluate cognitive disorders in animal models]. / Métodos de evaluación de trastornos cognitivos en modelos animales.

INTRODUCTION: The increasing prevalence of cognitive dysfunction and dementia associated, among others, to population aging in developed countries has grown a great interest in the study of the etiopathogenesis of cognitive deficit and the likely pharmacological targets which improve intellectual function or alter the neurodegeneration underlying these symptoms. DEVELOPMENT AND CONCLUSIONS: An essential tool for that purpose is the use of animal models of human-related pathologies which clinically develop with cognitive impairment and dementia. In this review we will analyse the animal models of these disorders and, specially, the main tests that, by means of the observational evolution of the experimental animal, allow assessing its cognitive functions and its modification by experimental treatments that are wanted to investigate for its eventual introduction into clinics.

[Pyridostigmine in the treatment of primary orthostatic hypotension]. / Tratamiento de la hipotensión ortostática primaria con piridostigmina.

INTRODUCTION: Primary orthostatic hypotension (POH) is an uncommon condition. It is defined as a fall in blood pressure of at least 20 mmHg systolic or 10 mmHg diastolic within three minutes of standing up without any other neurological or general illness. It has recently been reported that pyridostigmine is useful in neurogenic orthostatic hypotension. OBJECTIVE: To know the utility of pyridostigmine in POH. CASE REPORT: Since she was a teenager, a 77 woman has suffered dizziness, nausea, blurred vision and generalized weakness that appeared a few minutes after standing up and improved when sitting or lying down. Neurological examination was normal for her age. Blood pressure control showed systolic and diastolic decreases of 37 mmHg. She improved with fludrocortisone, however, this had to be discontinued due to a supine hypertension and peripheral edemas. Low doses of pyridostigmine treatment were initiated, having similar results in blood pressure control and independence level as fludrocortisone, but with fewer side effects. DISCUSSION: Acetylcholinesterase inhibition by pyridostigmine seems to enhance ganglionic sympathetic transmission and consequently leads to an increase in peripheral resistances that resulted in blood pressure, above all in the upright position. CONCLUSION: Pyridostigmine seems to be as useful as fludrocortisone in the POH treatment and has less side effects. This new strategy may be an alternative or a complement in the treatment of the illness.