Dysosmia and dysgeusia presenting as depression

Disorders of taste and smell are underrecognized and often misdiagnosed. Two cases are described in which patients mistakenly thought to suffer from depression actually had unnoticed drug-induced dysosmia and dysgeusia. Also reviewed are psychiatric, neurologic, and medical disorders and drugs that cause abnormalities of taste and smell, and some behavioral aspects of food aversions. Three groups, all of whom may superficially appear depressed, must be distinguished from each other: 1) patients with dysosmia or dysgeusia, 2) patients with primary neuropsychiatric illness with olfactory or gustatory hallucinations, and 3) patients with conditioned taste aversions.     

Fibrin/fibrinogen degradation products in cerebrospinal fluid of patients admitted to a psychiatric unit

Paired cerebrospinal fluid (CSF) and serum samples collected from 81 of 241 patients admitted to a district psychiatric hospital during a six month period were assayed for fibrin/fibrinogen degradation products (FDP) using a haemagglutination inhibition technique. FDP were found in all serum samples. Fifteen patients (18·5%) had FDP in the CSF (range 0·7-3·75 μg/ml.) and of these 13 (87%) had associated CSF protein abnormalities and 9 (60%) were hypertensive. Mean serum FDP values were the same (4·4 μg/ml.) in patients with and without FDP in the CSF. Three patients had raised serum FDP concentrations but no FDP in the CSF. The evidence suggests that the presence of FDP in CSF indicates recent central nervous system damage. In this series the most common cause was vascular disease.     

Antiplatelet pretreatment does not increase hematoma volume in experimental intracerebral hemorrhage

While oral anticoagulants are associated with greater hematoma expansion and higher mortality rates in patients with intracerebral hemorrhage (ICH), there is ongoing discussion whether pretreatment with antiplatelet drugs also worsens prognosis. Using an experimental model of ICH, we investigated the effects of antiplatelet pretreatment on hematoma volume and functional outcome. CD-1 mice were treated with acetyl-salicylic acid (ASA, 60 mg/kg per 24 hours), clopidogrel (22.5 mg/kg per 24 hours), or both (ASA+clopidogrel) through drinking water for 3 days (n=20 per group). Thereafter, platelet aggregation was found to be significantly reduced. Untreated mice and mice pretreated with warfarin served as controls. A stereotactic injection of collagenase into the right striatum was used to induce ICH. Twenty-four hours after ICH induction, hematoma volume was measured to be 15.0±4.4 μL in controls, 14.1±5.3 μL in ASA mice, 16.8±5.1 μL in clopidogrel mice, and 16.4±5.1 μL in ASA+clopidogrel animals. These differences were not statistically significant. However, mice pretreated with warfarin revealed largely increased hematoma volumes (25.0±7.4 μL versus controls, P=0.001). Neurologic outcome was not different between antiplatelet-pretreated animals and untreated controls. Our results suggest that plasmatic coagulation rather than platelet function is the most critical element for preventing hematoma expansion in acute ICH. Future therapeutic strategies may take these findings into account.     

Neurochemical and BOLD responses during neuronal activation measured in the human visual cortex at 7 Tesla

Several laboratories have consistently reported small concentration changes in lactate, glutamate, aspartate, and glucose in the human cortex during prolonged stimuli. However, whether such changes correlate with blood oxygenation level–dependent functional magnetic resonance imaging (BOLD-fMRI) signals have not been determined. The present study aimed at characterizing the relationship between metabolite concentrations and BOLD-fMRI signals during a block-designed paradigm of visual stimulation. Functional magnetic resonance spectroscopy (fMRS) and fMRI data were acquired from 12 volunteers. A short echo-time semi-LASER localization sequence optimized for 7 Tesla was used to achieve full signal-intensity MRS data. The group analysis confirmed that during stimulation lactate and glutamate increased by 0.26±0.06 μmol/g (~30%) and 0.28±0.03 μmol/g (~3%), respectively, while aspartate and glucose decreased by 0.20±0.04 μmol/g (~5%) and 0.19±0.03 μmol/g (~16%), respectively. The single-subject analysis revealed that BOLD-fMRI signals were positively correlated with glutamate and lactate concentration changes. The results show a linear relationship between metabolic and BOLD responses in the presence of strong excitatory sensory inputs, and support the notion that increased functional energy demands are sustained by oxidative metabolism. In addition, BOLD signals were inversely correlated with baseline γ-aminobutyric acid concentration. Finally, we discussed the critical importance of taking into account linewidth effects on metabolite quantification in fMRS paradigms.     

α-MSH: A potential neuroprotective and immunomodulatory agent for the treatment of stroke

Alpha-melanocyte-stimulating hormone (MSH) is a neuropeptide with profound immunomodulatory properties; we evaluated the effects of α-MSH on stroke outcome and its ability to modulate the postischemic immune response. In Lewis rats subjected to 3 hours of middle cerebral artery occlusion (MCAO), plasma concentrations of α-MSH rapidly decreased and returned to baseline over the course of days. Exogenous administration of α-MSH (100 or 500 μg/kg) improved 24 hour outcome in animals subjected to 2 hours MCAO; α-MSH 500 μg/kg also decreased infarct volume at this time point. Both doses of α-MSH were ineffective in improving outcome or decreasing infarct volume in animals subjected to 3 hours MCAO. The splenocyte response to phytohemagglutin in animals treated with α-MSH was attenuated at 24 hours after MCAO. At 1 month after MCAO, treatment with α-MSH 500 μg/kg at the time of stoke was associated with a decrease in TH1 response to myelin basic protein (MBP) in animals subjected to 2 hours MCAO, although treatment was not associated with improved outcome at this time point. Given the early benefits of α-MSH treatment and its effect on immunologic outcome, further studies to evaluate the utility of α-MSH for the treatment of cerebral ischemia are warranted.     

Calibrated MRI to evaluate cerebral hemodynamics in patients with an internal carotid artery occlusion

The purpose of this study was to assess whether calibrated magnetic resonance imaging (MRI) can identify regional variances in cerebral hemodynamics caused by vascular disease. For this, arterial spin labeling (ASL)/blood oxygen level-dependent (BOLD) MRI was performed in 11 patients (65±7 years) and 14 controls (66±4 years). Cerebral blood flow (CBF), ASL cerebrovascular reactivity (CVR), BOLD CVR, oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) were evaluated. The CBF was 34±5 and 36±11 mL/100 g per minute in the ipsilateral middle cerebral artery (MCA) territory of the patients and the controls. Arterial spin labeling CVR was 44±20 and 53±10% per 10 mm Hg ▵EtCO₂ in patients and controls. The BOLD CVR was lower in the patients compared with the controls (1.3±0.8 versus 2.2±0.4% per 10 mm Hg ▵EtCO₂, P<0.01). The OEF was 41±8% and 38±6%, and the CMRO₂ was 116±39 and 111±40 μmol/100 g per minute in the patients and the controls. The BOLD CVR was lower in the ipsilateral than in the contralateral MCA territory of the patients (1.2±0.6 versus 1.6±0.5% per 10 mmHg ▵EtCO₂, P<0.01). Analysis was hampered in three patients due to delayed arrival time. Thus, regional hemodynamic impairment was identified with calibrated MRI. Delayed arrival artifacts limited the interpretation of the images in some patients.     

Translational insights into traumatic brain injury occurring during dabigatran or warfarin anticoagulation

To date, only limited data are available on the effects of pretreatment with novel oral anticoagulants in the event of traumatic brain injury (TBI). We determined intracerebral hemorrhage volume and functional outcome in a standardized TBI model in mice treated with warfarin or dabigatran. Additionally, we investigated whether excess concentrations of dabigatran could increase bleeding and whether this was preventable by using prothrombin complex concentrate (PCC). C57 mice were treated orally with warfarin or dabigatran; sham-treated mice served as controls. Effective anticoagulation was verified by measurement of international normalized ratio and diluted thrombin time, and TBI was induced by controlled cortical impact (CCI). Twenty-four hours after CCI, intracerebral hemorrhage volume was larger in warfarin-pretreated mice than in controls (10.1±4.9 vs 4.1±1.7 μL; analysis of variance post hoc P=0.001), but no difference was found between controls and dabigatran-pretreated mice (5.3±1.5 μL). PCC applied 30 minutes after CCI did not reliably reduce intracerebral hemorrhage induced by excess dabigatran concentration compared with saline (10.4±11.2 vs 8.7±7.1 μL). Our data suggest pathophysiological differences in TBI occurring during warfarin and dabigatran anticoagulation. The reduced hemorrhage formation under dabigatran therapy could present a safety advantage compared with warfarin. An excess dabigatran concentration, however, can increase hemorrhage.     

Optogenetic Control of Serotonin and Dopamine Release in Drosophila Larvae

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Myopathy with mitochondrial inclusion bodies: histological and metabolic studies

Apparently new information about a metabolic abnormality has been obtained by measuring biochemical and respiratory responses to controlled exercise in a patient with abnormal mitochondria in muscle fibres. A male patient (49 years old) presented with bilateral ptosis of 15 to 20 years' duration and weakness for one to two years. Biopsies from the deltoid and triceps muscles were subjected to histological, histochemical, and electron microscopical examination. Routine histology showed only minor changes; 2-5% of muscle fibres had pale borders in which there were aggregates of mitochondria and 1-5% of fibres showed atrophy. Histochemical examination showed increased activity of succinic dehydrogenase in mitochondria and lactate dehydrogenase in cytoplasm. Electron microscopy showed crystalline inclusions in many subsarcolemmal mitochondria. Metabolites were studied during and after exercise on an ergometer and revealed remarkable differences from normal. Blood lactate rose to 12·5 μmol/ml and pyruvate to 0·39 μmol/ml compared with up to 4·0 and 0·16 μmol/ml respectively in controls exercising to a comparable percentage of capacity. Concentrations of ketone-bodies and free fatty acids fell during and after exercise, while they rose in the controls. These observations imply a major mitochondrial defect which causes dramatic biochemical changes in fuel supply in blood during exercise. The changes suggest that fat metabolism was accelerated (in this patient) and was related to a block of carbohydrate utilization as fuel.     

Protein therapy using heme-oxygenase-1 fused to a polyarginine transduction domain attenuates cerebral vasospasm after experimental subarachnoid hemorrhage

A sequence of 11 consecutive arginine residues (11R) is one of the best protein transduction domains for introducing proteins into cell membranes. Heme-oxygenase-1 (HO-1) is involved in heme catabolism and reduces the contractile effect of hemoglobin after subarachnoid hemorrhage (SAH). Therefore, we constructed 11R-fused HO-1 protein to achieve successful transduction of the protein into the cerebral arteries and examined the therapeutic effect of the 11R-HO-1 protein for cerebral vasospasm (CV) after SAH. We injected the 11R-HO-1 protein into the cisterna magna of male rats and, several hours after the injection, performed immunofluorescence staining and western blotting analysis of the rat basilar arteries (BAs) to determine transduction efficacy. We also assessed intraarterial HO-1 activity as cGMP (cyclic guanosine 3′, 5′-cyclic monophosphate) accumulation in SAH and determined whether protein transduction of 11R-HO-1 quantified the therapeutic effect in a rat double-hemorrhage model of SAH. The BAs expressed significantly more HO-1 in the group injected with 11R-HO-1 (3.56±0.54 (11R-HO-1) versus control (saline)), and transduction of 11R-HO-1 resulted in higher activity (>3.25-fold) in rat BAs with SAH. Moreover, the results of the rat double-hemorrhage model showed that the 11R-HO-1 protein significantly attenuated CV after SAH (317.59±23.48 μm (11R-HO-1) versus 270.08±14.66 μm (11R-fused enhanced green fluorescent protein), 252.05±13.95 μm (saline), P<0.01).     

Assessment of metabolic fluxes in the mouse brain in vivo using 1H-[13C] NMR spectroscopy at 14.1 Tesla

¹³C magnetic resonance spectroscopy (MRS) combined with the administration of ¹³C labeled substrates uniquely allows to measure metabolic fluxes in vivo in the brain of humans and rats. The extension to mouse models may provide exclusive prospect for the investigation of models of human diseases. In the present study, the short-echo-time (TE) full-sensitivity ¹H-[¹³C] MRS sequence combined with high magnetic field (14.1 T) and infusion of [U-¹³C₆] glucose was used to enhance the experimental sensitivity in vivo in the mouse brain and the ¹³C turnover curves of glutamate C4, glutamine C4, glutamate+glutamine C3, aspartate C2, lactate C3, alanine C3, γ-aminobutyric acid C2, C3 and C4 were obtained. A one-compartment model was used to fit ¹³C turnover curves and resulted in values of metabolic fluxes including the tricarboxylic acid (TCA) cycle flux V_TCA (1.05±0.04 μmol/g per minute), the exchange flux between 2-oxoglutarate and glutamate V_x (0.48±0.02 μmol/g per minute), the glutamate-glutamine exchange rate V_gln (0.20±0.02 μmol/g per minute), the pyruvate dilution factor K_dil (0.82±0.01), and the ratio for the lactate conversion rate and the alanine conversion rate V_Lac/V_Ala (10±2). This study opens the prospect of studying transgenic mouse models of brain pathologies.     

Jugular venous and arterial concentrations of serum S-100B protein in patients with severe head injury: a pilot study

The objective of this study was to analyse the temporal courseof the jugular venous-arterial gradient of S-100B protein after severehead injury and the correlation between the absoluteconcentrations of serum S-100B protein and outcome, CTfindings, and clinical variables.
Fifteen patients were included in this pilot study. Allpatients were treated according to a standard therapy protocol targeted to maintain cerebral perfusion pressure. The serum concentration ofS-100 protein was measured daily for five consecutive days after injuryby a monoclonal two site immunoluminometric assay. Nine patients showedfavourable and six unfavourable outcome after 6 months with a mortalityrate of 33% (five patients). The mean gradient between jugular venousand arterial blood was 8.2% (p<0.05). Patients showing anunfavourable outcome had significantly higher jugular venous orarterial S-100 values compared with those with a favourable outcome(jugular venous S-100B 2.78 µg/l v 1.22 µg/l, p<0.05;arterial S-100B 2.48 µg/l v 1.19 µg/l, p<0.05). Allpatients with an initial or secondary increase in S-100B value of >2µg/l were found to have an unfavourable outcome. S-100B was found to be an independent predictor of outcome after severe head injury. Thepersisting increase of S-100B for three to five days even in patientswith favourable outcome and no signs of secondary insults might reflectcontinuing damage to the blood-brain barrier or ongoing glial cell death.

     

Kaitocephalin Antagonism of Glutamate Receptors Expressed in Xenopus Oocytes

d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)/kainic acid (kainate, KA) receptors. Nevertheless, the effects of kaitocephalin on the function of these receptors were unknown. In this work, we report some pharmacological properties of synthetic (−)-kaitocephalin on rat brain glutamate receptors expressed in Xenopus laevis oocytes and on the homomeric AMPA-type GluR3 and KA-type GluR6 receptors. Kaitocephalin was found to be a more potent antagonist of NMDA receptors (IC₅₀ = 75 ± 9 nM) than of AMPA receptors from cerebral cortex (IC₅₀ = 242 ± 37 nM) and from homomeric GluR3 subunits (IC₅₀ = 502 ± 55 nM). Moreover, kaitocephalin is a weak antagonist of the KA-type receptor GluR6 (IC₅₀ ∼ 100 μM) and of metabotropic (IC₅₀ > 100 μM) glutamate receptors expressed by rat brain mRNA.     

Amyloid‐β protein and MicroRNA‐384 in NCAM‐Labeled exosomes from peripheral blood are potential diagnostic markers for Alzheimer's disease

ObjectiveWe aimed to establish a method to determine whether amyloid‐β (Aβ) protein and miR‐384 in peripheral blood neural cell adhesion molecule (NCAM)/ATP‐binding cassette transporter A1 (ABCA1) dual‐labeled exosomes may serve as diagnostic markers for the diagnosis of Alzheimer''s disease (AD).MethodsThis was a multicenter study using a two‐stage design. The subjects included 45 subjective cognitive decline (SCD) patients, 50 amnesic mild cognitive impairment (aMCI) patients, 40 AD patients, and 30 controls in the discovery stage. The results were validated in the verification stage in 47 SCD patients, 45 aMCI patients, 45 AD patients, and 30 controls. NCAM single‐labeled and NCAM/ABCA1 double‐labeled exosomes in the peripheral blood were captured and detected by immunoassay.ResultsThe Aβ42, Aβ_42/40, Tau, P‐T181‐tau, and miR‐384 levels in NCAM single‐labeled and NCAM/ABCA1 double‐labeled exosomes of the aMCI and AD groups were significantly higher than those of the SCD, control, and vascular dementia (VaD) groups (all p < 0.05). The Aβ42 and miR‐384 levels in NCAM/ABCA1 dual‐labeled exosomes of the aMCI and AD groups were higher than those of the control and VaD groups (all p < 0.05). The exosomal Aβ42, Aβ_42/40, Tau, P‐T181‐tau, and miR‐384 levels in peripheral blood were correlated with those in cerebrospinal fluid (all p < 0.05).ConclusionThis study, for the first time, established a method that sorts specific surface marker exosomes using a two‐step immune capture technology. The plasma NCAM/ABCA1 dual‐labeled exosomal Aβ_42/40 and miR‐384 had potential advantages in the diagnosis of SCD.     

An in vitro study of the effects of methylprednisolone on lesioned and uninjured mammalian spinal neurons

Cultured spinal neurons were subjected to dendrite amputation 100 μm from the perikaryon and treated with methylprednisolone (MP). Survival was significantly increased by 30 μg/ml MP but not by 10, 20 or 60 μg/ml. Survival was reduced by 100 μg/ml MP. These results suggest: (1) MP protects neurons subjected to physical trauma, and (2) the effective dose range is very narrow. These findings may have implications for MP's observed bimodal effects in spinal cord injury.     

Glutamatergic and GABAergic TCA cycle and neurotransmitter cycling fluxes in different regions of mouse brain

The ¹³C nuclear magnetic resonance (NMR) studies together with the infusion of ¹³C-labeled substrates in rats and humans have provided important insight into brain energy metabolism. In the present study, we have extended a three-compartment metabolic model in mouse to investigate glutamatergic and GABAergic tricarboxylic acid (TCA) cycle and neurotransmitter cycle fluxes across different regions of the brain. The ¹³C turnover of amino acids from [1,6-¹³C₂]glucose was monitored ex vivo using ¹H-[¹³C]-NMR spectroscopy. The astroglial glutamate pool size, one of the important parameters of the model, was estimated by a short infusion of [2-¹³C]acetate. The ratio V_cyc/V_TCA was calculated from the steady-state acetate experiment. The ¹³C turnover curves of [4-¹³C]/[3-¹³C]glutamate, [4-¹³C]glutamine, [2-¹³C]/[3-¹³C]GABA, and [3-¹³C]aspartate from [1,6-¹³C₂]glucose were analyzed using a three-compartment metabolic model to estimate the rates of the TCA cycle and neurotransmitter cycle associated with glutamatergic and GABAergic neurons. The glutamatergic TCA cycle rate was found to be highest in the cerebral cortex (0.91±0.05 μmol/g per minute) and least in the hippocampal region (0.64±0.07 μmol/g per minute) of the mouse brain. In contrast, the GABAergic TCA cycle flux was found to be highest in the thalamus–hypothalamus (0.28±0.01 μmol/g per minute) and least in the cerebral cortex (0.24±0.02 μmol/g per minute). These findings indicate that the energetics of excitatory and inhibitory function is distinct across the mouse brain.     

Cognitive inflexibility in Japanese adolescents and adults with autism spectrum disorders

AIM: To investigate executive function in Japanese adolescents and adults with autism spectrum disorders(ASD) compared to Japanese controls.METHODS: Thirty-three individuals with ASD and 33 controls participated. The ASD and control groups' demographic variables were matched for gender(male/female: 20/13 vs 20/13), age(26.1 ± 11.5 vs 26.8 ± 9.6), years of education(13.2 ± 2.9 vs 14.2 ± 1.9), full-scale intelligence quotient(IQ)(103.0 ± 16.7 vs 103.7 ± 14.7), performance IQ(96.2 ± 16.1 vs 97.8 ± 15.0), and verbal IQ(107.9 ± 16.3 vs 107.7 ± 14.4). Participants performed the Wisconsin Card Sorting Test(WCST), which assesses the executive processes involved in problem solving and cognitive flexibility, and the Continuous Performance Test(CPT), which assesses attention and impulsivity. Symptoms were assessed by the Autism-Spectrum Quotient Japanese version(AQ-J). First, we compared the scores of the WCST between the groups using a Mann-Whitney U-test and conducted an analysis of covariance for the variables with the scores of category archives and CPT scores as covariates. Second, we analyzed the correlation between the scores of the WCST and the AQ-J in the ASD group using Pearson's r.RESULTS: The total errors(TE) and the percentages of perseverative errors of the Milner type(%PEM) and Nelson type(%PEN) among the TE in the ASD group were significantly worse compared with the control group(ASD vs Control, respectively: TE: 16.0 ± 6.2 vs 12.6 ± 3.5, P = 0.012; %PEM: 11.7 ± 10.7 vs 6.6 ± 8.9, P = 0.037; %PEN: 20.1 ± 14.5 vs 8.7 ± 10.4, P = 0.0011). In contrast, no significant difference was observed between the two groups in the scores of categories achieved on the WCST or the CPT. An analysis of covariance revealed significant differences between the groups in the %PEN scores(P = 0.0062) but not in the TE or the %PEM scores. These results suggest that Japanese adolescents and adults with ASD have cognitive inflexibility. Furthermore, our results suggest that Japanese adolescents and adults with ASD may have difficulties using negative feedback because perseverative errors of the Nelson type indicate persistence in choosing the incorrect reaction. By contrast, there was no significant correlation between the WCST and AQ-J scores.CONCLUSION: We confirmed the presence of cognitive inflexibility in Japanese adolescents and adults with ASD. Our results also indicated that subjects with ASD may not use negative feedback effectively.     

Acetylsalicylic acid,but not clopidogrel,inhibits therapeutically induced cerebral arteriogenesis in the hypoperfused rat brain

This study investigated the effects of acetylsalicylic acid (ASA) and clopidogrel, standardly used in the secondary prevention of vascular occlusions, on cerebral arteriogenesis in vivo and in vitro. Cerebral hypoperfusion was induced by three-vessel occlusion (3-VO) in rats, which subsequently received vehicle, ASA (6.34 mg/kg), or clopidogrel (10 mg/kg). Granulocyte colony-stimulating factor (G-CSF), which enhanced monocyte migration in an additional cell culture model, augmented cerebrovascular arteriogenesis in subgroups (40 μg/kg). Cerebrovascular reactivity and vessel diameters were assessed at 7 and 21 days. Cerebrovascular reserve capacity was completely abolished after 3-VO and remained severely compromised after 7 (−14±14%) and 21 (−5±11%) days in the ASA groups in comparison with controls (4±5% and 10±10%) and clopidogrel (4±13% and 10±8%). It was still significantly decreased when ASA was combined with G-CSF (1±4%) compared with G-CSF alone (20±8%). Posterior cerebral artery diameters confirmed these data. Monocyte migration into the vessel wall, improved by G-CSF, was significantly reduced by ASA. Acetylsalicylic acid, but not clopidogrel, inhibits therapeutically augmented cerebral arteriogenesis.     

Triple Therapy with Prednisolone,Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load,Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

Considering that there is no effective treatment for human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis, this study aimed to assess the impact of triple combination therapy—interferon-α, valproic acid, and prednisolone—on clinical outcomes, main HTLV-1 viral factors, and host anti-HTLV-1 antibody response. HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μg pegylated interferon once a week, 10–20 mg/kg/day sodium valproate, and 5 mg/day prednisolone for 25 weeks using a TaqMan real-time polymerase chain reaction assay. Furthermore, anti-HTLV-1 titer, Osame Motor Disability Score, Ashworth spasticity scale, and urinary symptoms (through standard questionnaire and clinical monitoring) were assessed in patients before and after the treatment. HTLV-1 PVL and HBZ expression significantly decreased after the treatment [PVL from 1443 ± 282 to 660 ± 137 copies/10⁴ peripheral blood mononuclear cells (p = 0.01); and HBZ from 8.0 ± 1.5 to 3.0 ± 0.66 (p < 0.01)]. Tax mRNA expression decreased after the treatment from 2.26 ± 0.45 to 1.44 ± 0.64, but this reduction was not statistically significant (p = 0.10). Furthermore, anti-HTLV-1 titer reduced dramatically after the treatment, from 3123 ± 395 to 815 ± 239 (p < 0.01). Clinical signs and symptoms, according to Osame Motor Disability Score and Ashworth score, improved significantly (both p < 0.01). Urinary symptoms and sensory disturbances with lower back pain were reduced, though not to a statistically significant degree. Although signs and symptoms of spasticity were improved, frequent urination and urinary incontinence were not significantly affected by the triple therapy. The results provide new insight into the complicated conditions underlying HTLV-1-associated diseases.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0369-3) contains supplementary material, which is available to authorized users.Key Words: HTLV-1 proviral load, HAM/TSP, Tax, HBZ, combination therapy, clinical symptoms