Age at onset in Huntington's disease: replication study on the association of HAP1.

In recent years two association studies investigating the HAP1 T441M (rs4523977) polymorphism as a potential modifying factor of the age at onset (AAO) of Huntington's disease (HD), have been reported. Initially evidence for association was found between the M441 risk allele and the AAO. Subsequently, a second study, although failing to replicate these findings, found evidence for association between the same risk allele and AAO of motor symptoms (mAAO). In the present study, the role of the HAP1 T441M polymorphism as a modifier of the AAO in HD was investigated in a cohort of 298 Greek HD patients. In this cohort the CAG repeat number accounted for 55% of the variance in AAO. No association was found between the HAP1 T441M polymorphism and the AAO of HD.

Asymptomatic elevation of serum creatine kinase leading to the diagnosis of 4q35 facioscapulohumeral muscular dystrophy.

Persistent, asymptomatic (hyperCKemia) may be the prelude to, or the sole manifestation of, a neuromuscular disease. However, the clinical spectrum of facioscapulohumeral muscular dystrophy (FSHD) ranges from asymptomatic individuals with minimal clinical signs to patients who are wheelchair-bound. We describe a patient with persistent, asymptomatic hyperCKemia who received the diagnosis of 4q35 FSHD after a thorough stepwise investigation.

Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration.

BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have been increasingly studied in dementia clinical and differential diagnosis. METHODS: We assessed levels of total tau protein (tauT), tau phosphorylated at threonine 181 (tau P-181), and beta-amyloid1-42 (A beta 42) in 34 patients with frontotemporal lobar degeneration (FTLD), 76 Alzheimer disease (AD) cases, and 93 controls (CTRL). Double sandwich enzyme-linked immunosorbent assays (Innogenetics) were used for measurements. RESULTS: Total tau was significantly increased and A beta 42 decreased in FTLD and AD patients as compared with CTRL. CSF tau P-181 levels were significantly increased only in AD. The tauT/A beta 42 ratio successfully discriminated FTLD from CTRL with a 86.7% specificity and 80.6% sensitivity, whereas the tauT alone was more specific (95.7%) but less sensitive (64.75%). For the discrimination of FTLD from AD, tauT/A beta 42 ratio was better (90.3% sensitivity and 64.5% specificity) compared with the other biomarkers alone or in combination, whereas tau P-181 was less sensitive but more specific (68.4% and 85.7%, respectively). Subtype analysis revealed that the most AD-like profile of biomarkers were observed in FTLD with motor neuron signs, whereas the most non-AD profile were observed in patients with primary progressive aphasia. CONCLUSIONS: Combined analysis of CSF biomarkers may be useful for the best possible antemortem discrimination of FTLD from AD.

An uncommon variant of fibromuscular dysplasia.

Fibromuscular dysplasia is a rare cause of stroke affecting mostly young females. It is characterized by the typical "string of beads" sign located mostly bilaterally in the midcervical portion of the carotid or vertebral arteries. We present the uncommon case of borderzone hemispheric infarction in a man with isolated unilateral fibromuscular dysplasia affecting continuously the distal extracranial and proximal intracranial portion of the left internal carotid artery leading to distal hypoperfusion and ischemia.

Cognitive impairment in different MS subtypes and clinically isolated syndromes.

OBJECTIVE: To investigate the pattern of cognitive impairment in patients with relapsing-remitting (RR), secondary progressive (SP), primary progressive (PP) multiple sclerosis, and patients with clinically isolated syndrome (CIS) suggestive of MS, relative to control participants in the Greek population. METHODS: RR patients (N=75), SP patients (N=29), PP patients (N=23), CIS patients (N=33), and healthy control participants (N=43) were assessed by the Brief Repeatable Battery of Neuropsychological Tests (BRBN). RESULTS: The overall prevalence of cognitive dysfunction in our patients was 52.8% with CIS patients excluded and 47.5% with CIS patients included. All MS patients differed significantly from controls in all BRBN measures. Similar was the pattern of cognitive dysfunction in patients with CIS suggestive of MS, although verbal learning/memory capacity (as measured by the Selective Reminding Test) remained relatively spared. The comparisons between patient groups revealed some differences in the performance mainly in favor of CIS and RRMS patients. These differences largely disappeared after controlling for physical disability (EDSS). CONCLUSION: All MS subtypes patients exhibit a pattern of cognitive impairment running across the studied cognitive domains. The pattern of cognitive dysfunction in patients with CIS is similar with relative sparing of verbal learning.

Superficial siderosis due to a lumbar ependymoma mimicking adult-onset spinocerebellar ataxia.

Superficial siderosis (SS), as a result of chronic subarachnoid haemorrhage and haemosiderin deposition on the leptomeninges and subpial layers of the brain, cerebellum and spinal cord, can cause ataxia, pyramidal tract lesions and hearing deficits. In cases with not pronounced hearing impairment adult-onset spinocerebellar ataxia can be considered as a differential diagnostic alternative. We report a similar case where the diagnosis of SS was established by means of gradient echo MRI sequences 5 years after symptom onset. A bleeding lumbar ependymoma was identified as a source of haemorrhage. Surgical tumor resection stopped any further disease progression. Our report underlines that clinicians should be aware of the clinical features and diagnostic pitfalls of SS. Time of diagnosis and neurosurgical intervention can essentially influence the patients' prognosis.

Cerebrospinal fluid tau protein is increased in neurosyphilis: a discrimination from syphilis without nervous system involvement?

OBJECTIVE: The objective of this study was to investigate the levels of tau protein in neurosyphilis. STUDY DESIGN: Total tau protein in the cerebrospinal fluid of 12 patients with neurosyphilis, 17 with syphilis without nervous system involvement, 14 controls, and 14 patients with Alzheimer disease of comparable age were analyzed. Double-sandwich enzyme-linked immunosorbent assay was used for measurements. RESULTS: Increased levels of cerebrospinal fluid total tau were observed in neurosyphilis (median [25th-75th percentile]: 349 pg/mL [312-429]) and in Alzheimer disease (543 [441-1017]) as compared with the controls (189 [106-220]) and syphilis without nervous system involvement (190 [160-223]). Using a cutoff level of 300 pg/mL, increased tau discriminated cases of neurosyphilis from syphilis without nervous system involvement with a sensitivity and specificity of 83% and 94%, respectively. CONCLUSIONS: These results indicate that increased total tau may be useful in the discrimination of neurosyphilis from syphilis without nervous system involvement.

New mutation of the MPZ gene in a family with the Dejerine-Sottas disease phenotype.

Charcot-Marie-Tooth disease type 1B is associated with mutations in the myelin protein zero gene. In the present study a new myelin protein zero gene mutation (c.89T>C,Ile30Thr) was detected in a family with the Dejerine-Sottas disease phenotype. The results support the hypothesis that severe, early-onset neuropathy may be related to either an alteration of a conserved amino acid or a disruption of the tertiary structure of myelin protein zero.

Thyroid function in patients with Alzheimer disease: implications on response to anticholinesterase treatment.

Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in Alzheimer disease (AD). The aim of the present study was to explore thyroid function in patients with AD before and after acetylcholinesterase inhibition treatment to possibly identify variances in response. Thyroid function tests were evaluated in 28 AD patients and 24 age and sex-matched controls. Nineteen of the patients were reevaluated after (4 mo) treatment with donepezil. Serum thyrotropin (TSH), triiodothyronine (T3), thyroxine (T4), the free fractions (fT3, fT4) and thyroid autoantibodies were determined using standard methods. All subjects were clinically euthyroid. Patients presented with higher fT4 and anti-thyroperoxidase levels, as compared with the controls. Significant reduction in T4, fT3, fT4, and anti-thyroperoxidase levels were observed 4 months after treatment. Responders had higher T4 and fT4, than nonresponders, followed by significant reductions after treatment. The above, within the normal range alterations, may represent a direct effect on hormone release from the thyroid gland and/or increased conversion of T4 to T3 within the brain. Higher T4 and fT4 levels before treatment might predict a favorable response to donepezil treatment.

Impact of the time rate of blood pressure variation on left ventricular mass.

OBJECTIVES: Blood pressure (BP) changes are steeper in hypertensive than in normotensive individuals, whereas an increased rate of BP fluctuations is associated with medial hypertrophy of the carotid arteries. We evaluated the association between the rate of BP variation derived from ambulatory blood pressure monitoring (ABPM) data analysis and left ventricular mass (LVM). METHODS: ABPM and echocardiographic measurements of LVM were performed in 365 normotensive, 185 white-coat hypertensive (WCH) and 448 uncomplicated hypertensive individuals. RESULTS: The daytime and night-time rate of systolic blood pressure (SBP) and diastolic BP variation were significantly higher in hypertensive than in normotensive (P < 0.001) and WCH (P < 0.05) individuals. In the entire study population multiple linear regression models revealed independent determinants of LVM in the following rank order: body mass index (beta + 0.266, P < 0.001), daytime SBP (beta + 0.264, P < 0.001), male sex (beta +0.220, P < 0.001), age (beta + 0.203, P < 0.001), daytime heart rate (HR; beta - 0.191, P < 0.001), daytime rate of SBP variation (beta + 0.167, P < 0.001), and SBP dipping (beta - 0.132, P < 0.001). A 0.1 mmHg/min increase in the daytime rate of SBP variation correlated with an increment of 7.087 g (95% confidence interval 4.775-9.399) in the LVM. The addition of the daytime rate of SBP variation in the multiple regression model for the prediction of LVM significantly increased the adjusted model R [R change 0.024 (2.4%); P for change < 0.001]. CONCLUSION: Steeper BP variations may produce a greater stress on the left ventricular wall and may have an additive role to body habitus, BP and HR levels in the detection of cardiac hypertrophy. Target-organ damage in hypertensive patients, in addition to BP levels, dipping status and BP variability, may also be related to a steeper rate of BP oscillations.

Stroke etiology is associated with symptom onset during sleep.

BACKGROUND AND OBJECTIVES: Almost every fifth stroke occurs during sleep. Data about characteristics and etiology of stroke during sleep are conflicting. We investigated the association of the activity at stroke onset (onset during night sleep vs. onset while awake) with stroke subtypes of different etiology. METHODS: A total of 1448 patients with first-ever stroke with known time of symptom presentation were prospectively evaluated. Statistical comparisons were performed between patients with stroke during sleep and stroke while awake in terms of demographic features, known risk factors, vascular comorbidities, and stroke subtypes. Multiple variable logistic regression analyses were performed to identify predictor variables (including stroke risk factors and stroke subtypes) for stroke during sleep. RESULTS: Stroke during sleep was documented in 264 cases (18.2%). In subjects with stroke during sleep, lacunar infarction was the most prevalent stroke subtype (39%), while in patients with stroke while awake, small-vessel disease was the underlying mechanism significantly (P < .001) less often (13.8%). In contrast, patients with stroke while awake suffered significantly (P < .001) more frequently from intracerebral hemorrhage (18.2%) and cardioembolic stroke (34.9%) when compared with subjects with stroke during sleep (6.4% and 18.9%, respectively). The multiple variable logistic regression model identified the following factors as independent predictors of stroke during sleep: atrial fibrillation (odds ratio: 0.346, 95% confidence interval: 0.237-0.505, P < .001) and intracerebral hemorrhage versus ischemic stroke (odds ratio: 0.238, 95% confidence interval: 0.138-0.410, P < .001). Lacunar infarction was the only ischemic stroke subgroup that was positively associated with stroke during sleep (odds ratio: 2.568, 95% confidence interval: 1.447-4.560, P < .001). CONCLUSIONS: There are significant differences between stroke during sleep and stroke while awake concerning vascular risk profile and stroke etiologic subtypes.

Symptomatic focal mononeuropathies in diabetic patients: increased or not?

The aim of this study was to investigate whether symptomatic mononeuropathies are more frequent in diabetic patients without symptoms of acute or subacute polyneuropathy than in the general population.For this purpose, six hundred and forty two consecutive outpatients with various acute symptomatic mononeuropathies (radial, ulnar or peroneal neuropathy, Bell's palsy or carpal tunnel syndrome) without symptoms of acute or subacute polyneuropathy were studied. The results showed that in 522 patients with symptomatic carpal tunnel syndrome (CTS) and in 38 patients with Bell's palsy, the rate of diabetes was 7.7% and 10.5%, respectively. These rates do not differ significantly from the anticipated frequency of diabetes in the general population. On the other hand, in 18 patients with radial neuropathy at (or distally to) the spiral groove, in 41 patients with ulnar neuropathy and in 23 patients with peroneal neuropathy at the fibular head, the respective rates were 27.8%, 12.2 % and 30.4%. These rates are significantly higher than those anticipated according to the frequency of diabetes in the general population. The findings of the present study indicate that only focal limb neuropathies due to acute external compression are more frequent in diabetic patients.

Aetiopathogenesis and long-term outcome of isolated pontine infarcts.

BACKGROUND AND PURPOSE: Isolated pontine strokes cause characteristic neurological syndromes and have a good short-term prognosis. The aim of this study was to examine the long-term survival, cumulative recurrence rate and clinical handicap of patients with isolated pontine infarcts of different aetiology. METHODS: One hundred consecutive patients with an isolated pontine infarction were identified by imaging studies and evaluated prospectively. After extensive study, cases were classified according to the aetiopathogenetic mechanisms: stroke due to basilar artery branch disease (BABD), small-artery disease (SAD) and large-artery-occlusive disease (LAOD). During a mean follow-up period of 46 months, stroke presentation and initial course, early and long-term mortality, disability and recurrence were evaluated. RESULTS: BABD was the most frequent cause of isolated pontine ischaemia (43%), followed by SAD (34%) and LAOD (21%). Hypertension was the most prominent risk factor, especially among patients with SAD (94.1%). Neurological impairment on admission was more severe in the LAOD group, followed by BABD. After 1 month patients with LAOD had the highest cumulative mortality (14.3%, p = 0.026) and more severe disability (61.1%, p = 0.001). Five-year mortality rate was 20.6%, 14% and 23.8% in the SAD-, BABD- and in LAOD-group respectively (p = 0.776). Cumulative 5-year recurrence rate was 2.3 % for BABD, 14.3 % for LAOD, and 29.4 % for SAD (p = 0.011). CONCLUSIONS: Overall long-term survival of patients with isolated pontine infarcts is good. Initial differences regarding short-term outcome in infarctions of different aetiology resolve with time. Effective secondary prevention among SAD patients may limit stroke recurrence and positively influence long-term prognosis.

Emerin expression in tubular aggregates.

Emerin is an inner nuclear membrane protein that is mutated or not expressed in patients with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD/EMD). Cytoplasmic localization of emerin in cultured cells or tissues has been reported, although this remains a controversial issue. Tubular aggregates (TAs) are pathological structures seen in the sarcoplasm of human skeletal muscle fibers in various disorders. The TAs derive from the sarcoplasmic reticulum (SR) and represent, probably, an adaptive response of the SR to various insults to the muscle fibers. In the present study, we present immunohistochemical evidence of emerin expression in TAs. Muscle biopsies with tubular aggregates from four male, unrelated patients were studied. The percentage of muscle fibers containing TAs varied between 5 and 20%. Routine histochemistry revealed intense reaction of TAs with NADH-TR, AMPDA, and NSE, but not with COX, SDH, myosin ATPase (pH 9.4, 4.3, 4.6), PAS, and Oil red O staining. Immunohistochemical study revealed strong immunostaining of TAs with antibodies against emerin and 7 SERCA2-ATPase. Immunostaining of TAs was also seen with antibodies against heat shock protein and dysferlin, but not with antibodies to lamin A, dystrophin, adhalin, beta, gamma, delta sarcoglycans, and merosin. These results suggest that emerin, an inner nuclear membrane protein, is present at the TAs. The interpretation and significance of this finding is discussed in relation to experimental data suggesting that normal emerin localization at the inner nuclear membrane depends on lamin A and mutations in the N-terminal domain of emerin cause mislocalization of the protein to the sarcoplasmic membranes.