Cerebrospinal fluid biomarkers for Parkinson's disease - a systematic review.

Diagnosis of Parkinson's disease (PD) relies on clinical history and physical examination, but misdiagnosis is common in early stages. Identification of biomarkers for PD may allow early and more precise diagnosis and monitoring of dopamine replacement strategies and disease modifying treatments. Developments in analytical chemistry allow the detection of large numbers of molecules in plasma or cerebrospinal fluid, associated with the pathophysiology or pathogenesis of PD. This systematic review includes cerebrospinal fluid biomarker studies focusing on different disease pathways: oxidative stress, neuroinflammation, lysosomal dysfunction and proteins involved in PD and other neurodegenerative disorders, focusing on four clinical domains: their ability to (1) distinguish PD from healthy subjects and other neurodegenerative disorders as well as their relation to (2) disease duration after initial diagnosis, (3) severity of disease (motor symptoms) and (4) cognitive dysfunction. Oligomeric alpha-synuclein might be helpful in the separation of PD from controls. Through metabolomics, changes in purine and tryptophan metabolism have been discovered in patients with PD. Neurofilament light chain (NfL) has a significant role in distinguishing PD from other neurodegenerative diseases. Several oxidative stress markers are related to disease severity, with the antioxidant urate also having a prognostic value in terms of disease severity. Increased levels of amyloid and tau-proteins correlate with cognitive decline and may have prognostic value for cognitive deficits in PD. In the future, larger longitudinal studies, corroborating previous research on viable biomarker candidates or using metabolomics identifying a vast amount of potential biomarkers, could be a good approach.

Genetic analysis of the isolated Faroe Islands reveals SORCS3 as a potential multiple sclerosis risk gene.

BACKGROUND: In search of the missing heritability in multiple sclerosis (MS), additional approaches adding to the genetic discoveries of large genome-wide association studies are warranted. OBJECTIVE: The objective of this research paper is to search for rare genetic MS risk variants in the genetically homogenous population of the isolated Faroe Islands. METHODS: Twenty-nine Faroese MS cases and 28 controls were genotyped with the HumanOmniExpressExome-chip. The individuals make up 1596 pair-combinations in which we searched for identical-by-descent shared segments using the PLINK-program. RESULTS: A segment spanning 63 SNPs with excess case-case-pair sharing was identified (0.00173 < p > 0.00212). A haplotype consisting of 42 of the 63 identified SNPs which spanned the entire the Sortilin-related vacuolar protein sorting 10 domain containing receptor 3 (SORCS3) gene had a carrier frequency of 0.34 in cases but was not present in any controls (p = 0.0008). CONCLUSION: This study revealed an oversharing in case-case-pairs of a segment spanning 63 SNPs and the entire SORCS3. While not previously associated with MS, SORCS3 appears to be important in neuronal plasticity through its binding of neurotrophin factors and involvement in glutamate homeostasis. Although additional work is needed to scrutinise the genetic effect of the SORCS3-covering haplotype, this study suggests that SORCS3 may also be important in MS pathogenesis.

High inbreeding in the Faroe Islands does not appear to constitute a risk factor for multiple sclerosis.

BACKGROUND: Large population-based genome-wide association studies have identified several multiple sclerosis (MS) genetic risk variants, but the existing missing heritability warrants different strategies. Isolated populations offer an alternative way of searching for rare genetic variants and evaluating the possible role of consanguinity in the development of MS. Studies of consanguinity and MS risk have yielded conflicting results. OBJECTIVES: In this study we investigated the role of consanguinity on MS risk in the relatively isolated Faroe Islands, which have a presumed high level of inbreeding. METHODS: A total of 29 cases and 28 matched controls were genotyped and assessed for inbreeding coefficients, number of runs of homozygosity (ROH) at different lengths and observed number of homozygotes as measures of relatedness. Parametric and non-parametric statistical models were applied. RESULTS: Both cases and controls exhibited considerable relatedness demonstrated by very high inbreeding coefficients, large number of observed homozygotes and many long ROH. However, apart from the number of ROH ≥ 2.5 mega base pairs, no significant differences between the two groups were observed. CONCLUSIONS: Overall, no significant difference between cases and controls were found, indicating that consanguinity in itself does not appear to be an important risk factor for MS in the population of the Faroe Islands.

Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase.

Recent reports have shown heterozygosity for some twenty different mutations in the CuZn-superoxide dismutase (CuZn-SOD) gene in familial amyotrophic lateral sclerosis (FALS), and analysed samples from patients have shown decreased enzymic activity. Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland. The erythrocyte CuZn-SOD activity is essentially normal. Our findings suggest that this CuZn-SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp90Ala mutation is less detrimental than previously reported mutations.

Multiple sclerosis in a family on the Faroe Islands.

BACKGROUND: John Kurtzke has proposed that multiple sclerosis (MS) on the Faroe Islands occurred as a result of the spread of a transmittable agent brought to the country during World War II. AIM: Kurtzke's theory has been opposed earlier and in this study, we present a family from the Faroe Islands containing a total of 14 family members with MS which show further inconsistencies with the theory. The present study is to our knowledge, the first description of familial incidences of MS on the Faroe Islands. METHODS: Medical histories were gathered from 12 family members and 6 of the 8 living MS cases were human leukocyte antigen (HLA)-typed. RESULTS: Seven family members had primary progressive MS (PPMS), while five had relapsing remitting MS. The HLA-DR15 allele was carried by the three cases with the most aggressive form of MS and they shared a common haplotypes. The HLA types carried by the remaining cases varied. CONCLUSION: This research questions Kurtzke's theory as three of the cases do not conform to the epidemic cohorts described. Furthermore, there appears to be a higher than usual prevalence of PPMS. The high degree of heterogeneity of the HLA types carried indicates that HLA alleles do not independently explain the risk of developing MS.

Non-steroidal anti-inflammatory drugs in the treatment of migraine.

NSAIDs can be used in both the acute and prophylactic treatment of migraine with and without aura. It is a safe therapeutic alternative fore young healthy patients, but should be used with caution in the elderly. NSAIDs do not influence blood pressure and can be used in combination with most other migraine agents. The selective COX-2 inhibitors are an interesting therapeutic possbility for the future.

Illness behavior in the acute phase of motor disability in neurological disease and in conversion disorder: a comparative study.

Sixty patients with a sudden onset of motor disability were assessed for illness behavior and depression. In 30 of the patients, etiology was attributed to a definite structural lesion. The remaining 30 patients were diagnosed as having conversion disorder. The Illness Behaviour Questionnaire (IBQ) and the Hamilton Rating Depression Scale (HRDS) were used as instruments for assessment. The mean HRDS score was significantly higher in the conversion group, indicating a higher degree of affective disease in these patients. According to the results of the IBQ, the patients with conversion disorder showed a higher degree of irritability, disease conviction, and phobic preoccupation, and also, to a greater extent, rejected psychological explanations for their symptoms. Denial was high in both patient groups, coexisting with affective symptoms in the conversion patients but not in the neurological patients. Although valuable information could be extracted from the IBQ, it was not found to be a reliable instrument for distinguishing between psychogenic and organic causes of motor disability.

[Psychogenic paralysis. A prospective study]. / Psykogene lammelser. Et prospektivt studium.

INTRODUCTION: Patients with motor conversion disorder are frequently seen in neurological departments. Long term prognosis is usually considered to be good, although earlier research has been somewhat unsystematic and mostly retrospective. This study follows a well investigated sample of patients for two to five years and attempts to identify predictors associated with prognosis. MATERIAL AND METHODS: Thirty patients with a recent onset of motor conversion disorder were assessed for key psychiatric and demographic variables. They were reassessed two to five years later. RESULTS: Nineteen patients had recovered completely and eight patients had improved, while only three patients were unchanged or worse. Contrary to other follow-up studies none of the patients received a rediagnosis of neurological disease. The presence of a personality disorder, concomitant somatic disease, and low DSM-IV axis V score proved to be associated with poor outcome. DISCUSSION: The results of this study stresses the need for careful and well-conducted neurological and psychiatric assessments in patients with psychogenic paralyses, bearing in mind the substantial possibility for coinciding illnesses. If this is ensured, it appears that the risk of subsequent neurological rediagnosis is negligible.

[Amyotrophic lateral sclerosis and superoxide dismutase--a review]. / Amyotrofisk lateralsklerose og superoxiddismutase--en oversigt.

The recent observation that mutations in cytosolic CuZn-superoxide dismutase (CuZn-SOD) are associated with amyotrophic lateral sclerosis (ALS) suggests that the disease arises from a perturbation of the homeostasis of free radicals resulting in neuronal degeneration by reactive oxygen species. The stability is altered in these mutant molecules, but without necessarily reducing the specific activity of the CuZn-SOD molecule. Substantial evidence argues that the disease arises not from the loss of CuZn-SOD function, but rather from an adverse or novel property of the mutant enzyme molecule. The mechanism for this acquired adverse function is, as yet, completely unknown. SOD research is an important step for a better understanding of the pathogenesis of ALS.

[Clinical, radiological, histopathological and genetic findings in a Danish "CADASIL" family]. / Kliniske, radiologiske, histopatologiske samt genetiske fund i en dansk "CADASIL"-familie.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare adult-onset inherited arterial disease with a distinctive neuropathological phenotype. Owing to its recent identification and variable mode of presentation, the disease is often misdiagnosed. The CADASIL gene is Notch 3 and has been mapped on chromosome 19q12 in several unrelated families. Knowledge of the phenotypic range of CADASIL, however, remains incomplete. Clinical, pathological radiological, and genetic findings in the first known Danish CADASIL pedigree are presented. Genetic testing confirmed a Notch 3 mutation. The mutation consisted of the substitution of a nucleotide at position 475 leading to the replacement of amino acid arginine for cysteine at position 133 in the third EGF motif.

Motor conversion disorder. A prospective 2- to 5-year follow-up study.

In this prospective study, 30 patients with motor conversion disorder were assessed for key psychiatric and demographic variables. At reassessment 2 to 5 years later, 19 patients had completely recovered and 8 patients had improved, whereas only 3 were unchanged or worse. Contrary to other follow-up studies, none of the patients received a rediagnosis of neurological disease. The presence of a personality disorder and overall personality pathology, particularly within cluster C, the presence of a concomitant somatic disease, low DSM-IV Axis V score, and high score on the Becks Hopelessness Scale proved to be associated with poor outcome.

Childhood experiences and personality traits in patients with motor conversion symptoms.

A total of 30 patients with newly diagnosed motor conversion disorder were consecutively investigated by means of a Swedish self-rating inventory designed to assess perceived parental rearing practices (EMBU), and the Karolinska Scale of Personality (KSP). DSM Axis I and II psychopathology was assessed using a Structured Clinical Interview (SCID), and comparisons were made with 30 age- and sex-matched in-patients with motor symptoms due to a neurological disorder. Depression, the presence of a personality disorder and also poor schooling proved to be significantly associated with motor conversion disorder. The index patients perceived a high degree of parental rejection as well as low levels of affection and emotional warmth during childhood, but contrary to most previous studies, childhood physical and/or sexual abuse was not found to be associated with motor conversion disorder.

[Multiple sclerosis--the great imitator!]. / Multipel skleros--det finns imitatörer!

Multiple sclerosis (MS) is traditionally a clinical diagnosis based on relapsing and remitting multifocal CNS symptoms. In recent years new diagnostic tools such as cerebrospinal fluid analysis, magnetic resonance imaging and evoked potential testing have been developed. This article reviews diagnostic difficulties and discusses other medical conditions that can be mistaken for MS due to similar clinical, laboratory or radiological findings.

Clinical characteristics of patients with motor disability due to conversion disorder: a prospective control group study.

OBJECTIVES: Previous studies have suggested associations between conversion and many different clinical characteristics. This study investigates these findings in a prospective design including a control group. METHODS: Thirty consecutive patients with a recent onset of motor disability due to a conversion disorder were compared with a control group of patients with corresponding motor symptoms due to a definite organic lesion. Both groups had a similar duration of symptoms and a comparable age and sex profile and were assessed on a prospective basis. Background information about previous somatic and psychiatric disease was collected and all patients were assessed by means of a structured clinical interview linked to the diagnostic system DSM III-R, the Hamilton rating depression scale, and a special life events inventory. RESULTS: The conversion group had a higher degree of psychopathology with 33% of the patients fulfilling the criteria for psychiatric syndromes according to DSM-III-R axis I, whereas 50% had axis II personality disorders compared with 10% and 17% respectively in the control group. Conversion patients also had significantly higher scores according to the Hamilton rating depression scale. Although patients with known neurological disease were not included in the conversion group, a concomitant somatic disorder was found in 33% of the patients and 50% complained of benign pain. The educational background in conversion patients was poor with only 13% having dropped out of high school compared with 67% in the control group. Self reported global assessment of functioning according to the axis V on DSM IV was significantly lower in conversion patients, who also registered significantly more negative life events before the onset of symptoms than controls. Logistic regression analysis showed that low education, presence of a personality disorder, and high Hamilton depression score were significantly associated with conversion disorder. CONCLUSION: The importance of several previously reported predisposing and precipitating factors in conversion disorder is confirmed. The results support the notion that conversion should be treated as a symptom rather than a diagnosis and that efforts should be made in diagnosing and treating possible underlying somatic and psychiatric conditions.

Familial clustering of multiple sclerosis in a northern Swedish rural district.

A small rural district in the most northerly province of Sweden was found to have a very high occurrence of multiple sclerosis. A total of 12 patients with multiple sclerosis among 4744 inhabitants were identified (five females, seven males), corresponding to a prevalence of 253/100,000. Many of the patients were related and a further 21 cases with multiple sclerosis (14 females, seven males), mostly living in the neighbouring area, have family ties to the district. A genealogical investigation showed that 22 of the 33 patients identified had ties of kinship and thus, to our knowledge, the largest aggregation of multiple sclerosis in a family is presented.

Autoimmunity and ALS: studies on antibodies to acetylcholinesterase in sera.

The involvement of the immune system in the pathogenesis of amyotrophic lateral sclerosis is controversial. It has been suggested that ALS patients develop specific antibodies against acetylcholinesterase (AChE) and that these antibodies by retrograde axonal transport may be the cause of death of the spinal motor neurons. It has also been argued that these antibodies elicit hemolysis of erythrocytes. However, using recombinant human AChE as antigen in ELISA and Western blot analysis, we have been unable to find any evidence for the existence of specific AChE antibodies in ALS patients.

Autosomal recessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for Asp90Ala CuZn-superoxide dismutase mutation. A clinical and genealogical study of 36 patients.

We describe 36 patients (six were apparently sporadic cases and 30 were cases from nine families) with amyotrophic lateral sclerosis (ALS) characterized by a distinct phenotype associated with homozygosity for an Asp90Ala mutation in the CuZn-superoxide dismutase gene. The presenting motor manifestation in all patients was paresis in the legs, with slow progression to the upper extremities and finally to the bulbar muscles. The age of ALS onset varied from 20 to 94 years, with a mean of 44 years. Mean survival time was 13 years for the 11 deceased patients. However, this is probably biased and untypical (low) when compared with the disease duration in the surviving patients, and when considering other medical complications in the deceased patients. The rate of progression was highly variable, even within families. All patients showed signs of involvement of both upper and lower motor neurons. Other neurological features included painful muscle spasms and paraesthesiae in the lower extremities. Two-thirds of patients experienced difficulty with micturition. Electrophysiological studies confirmed the slow progression and spatial distribution of clinical symptoms in the peripheral motor system. Furthermore, [corrected] potentials evoked by transcranial magnetic stimulation (MEP) were compared with those evoked by cervical or lumbosacral electrical stimulation and often revealed marked slowing of transmission in central motor pathways. In Sweden and Finland ALS patients homozygous for the Asp90Ala mutation constitute a phenotypically characteristic subset of motor neuron disease.