Dopamine transporter imaging with [123I]-β-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson's disease

OBJECTIVES—The mostcommon neurological manifestations in Wilson's disease areparkinsonism and dystonia. These are assumed to be due to striatalinjury, which has been repeatedly demonstrated by pathology and CT orMRI. The substantia nigra has not been shown to be damaged inpathological studies. However, there have been clinical and imagingstudies suggesting presynaptic nigrostriatal injury.(1r)-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) is aspecific ligand that binds to the dopamine transporter (DAT), and canexamine the integrity of dopaminergic nerve terminals. Evidence forpresynaptic nigrostriatal dopaminergic damage in Wilson's disease wassearched for using [¹²³I]-β-CIT SPECT.
METHODS—Six patientswith Wilson's disease were studied, together with 15 healthy normalcontrols, and six patients with Parkinson's disease. After injectionof [¹²³I]-β-CIT, SPECT studies were done at 18 hours.Specific striatal/occipital binding ratio (S/O ratio) was calculated as(striatal binding−occipital binding)/occipital binding.
RESULTS—The specificS/O ratios were 6.22 (1.32) (mean (SD)) in normal volunteers, 3.78 (0.65) in Parkinson's disease, and 3.60 (0.49) in Wilson's disease.
CONCLUSION—There wassevere loss of the DAT in the striatum suggesting significant damage inpresynaptic nigrostriatal dopaminergic nerve terminals. Therefore, apresynaptic lesion may contribute to neurological manifestations inWilson's disease.

     

Presynaptic dopaminergic function in patients with restless legs syndrome: Are there common features with early Parkinson's disease?

The cause of restless legs syndrome (RLS) is unknown, but an involvement of the dopaminergic system and a possible relation to Parkinson's disease (PD) is suggested by the positive response to dopaminergic treatment. We imaged the striatal dopamine transporter with [(123)I] N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(chloro-phenyl) tropane ([(123)I]IPT) and single-photon emission computed tomography (SPECT) in 28 RLS patients, and compared the results with transporter binding in 29 patients with early PD and 23 age-matched controls. No difference in IPT binding was found between RLS patients and controls. IPT binding was correlated significantly with age in RLS patients and controls, whereas there was no relation with the duration of symptoms or severity of RLS. PD patients presented significant lower presynaptic IPT binding ipsi- and contralateral to the affected body side compared with RLS patients or controls. We found no common characteristics between RLS patients and patients with early PD detectable by dopamine transporter SPECT. Our results do not strengthen an identical pathophysiologic pathway between RLS and PD on the level of nigrostriatal presynaptic terminal function.     

Apolipoprotein E ε4 allele decreases functional connectivity in Alzheimer's disease as measured by EEG coherence

OBJECTIVES—The ε4 allele of apolipoprotein E(APOE) represents a major biological risk factor for late onsetAlzheimer's disease. However, it is still not known whether the APOEgenotype affects the progression of the disease, assessed by differentfunctional methods.
METHODS—The study sample included 41 patientswith probable Alzheimer's disease. Subjects had similar severity ofdisease, age of onset, and duration of illness, and were subcategorisedaccording to their APOE genotypes: 17 with no ε4 allele, 14 with oneε4 allele, and 10 with two ε4 alleles. The control group consisted of 18 healthy subjects comparable with the patients in age and education. Analysed quantitive EEG (qEEG) variables were the ratio ofalpha and theta absolute power and EEG coherence in alpha frequency band, representing major cortical association pathways.
RESULTS—There was pronounced EEG slowing in allthree patient subgroups compared with the controls for the alpha/thetaratio, but there was no significant difference across the patientsubgroups. Patients homozygous for the APOE ε4 allele had reducedright and left temporoparietal, right temporofrontal, and leftoccipitoparietal coherence. Patients without and with one ε4 alleleshowed an overlap between the control group and group with two ε4alleles in coherence measures.
CONCLUSIONS—APOE ε4 does not influence EEGslowing, an index which reflects severity of the disease in patientswith Alzheimer's disease, but seems to be associated with selectivedecreases in functional connectivity as assessed by EEG coherence. Thisfinding might be of clinical importance when considering differentpathogenetic mechanisms.

     

Apolipoprotein E genotype in familial Parkinson's disease

APOE genotypes were compared in 57 cases of familialParkinson's disease, 46 cases of sporadic Parkinson's disease, and387controls. The frequency of the APOE allele ε4 was similar inpatients with Parkinson's disease and controls, but the APOE alleleε2, thought to be protective for dementia, was significantly more frequent in patients with sporadic Parkinson's disease than in controls. This is the first study of Parkinson's disease to include familial cases. It confirms the absence of association between the APOEallele ε4 and this disease.

     

Major decrease in the volume of the entorhinal cortex in patients with Alzheimer's disease carrying the apolipoprotein E ε4 allele

OBJECTIVE—Recentevidence indicates that the apolipoprotein E (ApoE) ε4 allele is arisk factor for developing Alzheimer's disease. It has also beenproposed that it is associated with increased counts of amyloid plaquesand neurofibrillary tangles that in turn are neuropathologicalhallmarks initially appearing in the medial temporal lobe structures inAlzheimer's disease. In this study, the effect of the ApoE ε4 alleleon the volume of the entorhinal cortex was evaluated in vivo.
METHODS—The volume ofthe entorhinal cortex was measured on MR images using a recentlydesigned histology based protocol in 16 patients with Alzheimer'sdisease with ApoE ε4 (mean age 70.4 (SD 9.9)), 11 patients withAlzheimer's disease without ApoE ε4 (mean age 69.1 (SD7.1)), and in31 healthy age and sex matched normal controls (72.2 (SD 3.9)). Thepatients met the NINCDS-ADRDA criteria for probable Alzheimer'sdisease and were in mild to moderate stages of the disease. MRI wasperformed with a 1.5 Tesla Magnetom and a 3D technique permitting thereconstruction of 2.0 mm thick contiguous slices perpendicular to theaxis of the anterior-posterior commissure.
RESULTS—The patientswith Alzheimer's disease without the ApoE ε4 allele had atrophy inthe entorhinal cortex, the volume was reduced by 27 % compared withcontrol subjects. However, the most prominent shrinkage (45%) in theentorhinal cortex was seen in patients with Alzheimer's disease withthe ApoE ε4 allele (p=0.0001). The effect of ε4 on the entorhinalcortex volume was especially prominent in female patients withAlzheimer's disease compared to male patients with Alzheimer'sdisease (p=0.014). Additionally, patients with the ApoE ε4 allele hadinferior performance in verbal and visual memory functions than thosewithout the allele
CONCLUSIONS—VolumetricMRI measurements disclose that ApoE ε4 is associated with the degreeof atrophy in the entorhinal cortex in early Alzheimer's disease, thiseffect being especially prominent in female patients with Alzheimer's disease.

     

The role of the α-synuclein gene mutation in patients with sporadic Parkinson's disease in the United Kingdom

Parkinson's disease is a common neurodegenerative disorder ofunknown aetiology. A pathogenic point mutation within the α-synuclein gene has recently been identified in one Italian-American kindred andthree families of Greek origin with parkinsonism. DNA from 70 patientswith Parkinson's disease was screened for this G209A mutation. Nosamples were positive for the mutation, suggesting that it is notrelevant for most patients with sporadic idiopathic Parkinson's disease.

     

Striatal dopamine transporter binding assessed by [I-123]IPT and single photon emission computed tomography in patients with early Parkinson's disease: implications for a preclinical diagnosis

BACKGROUND: Specific binding to dopamine transporters may serve as a tool to detect early loss of nigrostriatal dopaminergic neurons in patients with Parkinson's disease. OBJECTIVE: To determine striatal dopamine transporter binding using the cocaine analogue [I-123]N-(3-iodopropen-2-yl)-2beta-carbomethoxy-3beta-(4-chl orophenyl) tropane ([I-123]IPT) and single photon emission computed tomography. PATIENTS AND METHODS: We studied 9 control subjects (mean age, 58 years; range, 41-69 years) and 28 patients with early Parkinson's disease (Hoehn and Yahr stages I [n = 14] and II [n = 14] [symptom duration, <5 years]; mean age, 55.5 years; range, 36-71 years). Single photon emission computed tomography was performed 90 minutes after injection of 120 to 150 MBq of radioactive [I-123]IPT. RESULTS: Specific striatal [I-123] IPT binding (mean +/- SD) was significantly reduced in patients with early Parkinson's disease (ipsilateral striatum: 4.09+/-0.97; range, 2.46-6.40; contralateral striatum: 3.32+/-0.76; range, 1.80-5.13) compared with controls (left striatum: 7.28+/-0.94; range, 5.78-8.81; right striatum: 7.41+/-1.28; range, 5.58-9.44). IPT binding ratios (mean +/- SD) were significantly lower in patients with Hoehn and Yahr stage II (ipsilateral striatum: 3.47+/-0.75; contralateral striatum: 2.96+/-0.73) compared with those with Hoehn and Yahr stage I (ipsilateral striatum: 4.72+/-0.75; contralateral striatum: 3.69+/-0.61) (P<.001). The ipsilateral striatum of patients with Hoehn and Yahr stage I showed a significant mean+/-SD reduction of IPT binding (ipsilateral striatum: 4.72+/-0.75) compared with either right or left striatum of controls (P<.001). Only in 1 patient was IPT binding to the ipsilateral striatum (ratio, 6.40) higher than the lowest value observed in the striatum of a control subject (ratio, 5.58). CONCLUSIONS: Use of [I-123] IPT and single photon emission computed tomography demonstrates a reduction of dopamine transporter binding in patients with early Parkinson's disease. Significantly reduced IPT binding already observed in the ipsilateral striatum of patients with Hoehn and Yahr stage I demonstrates the potential of this method to detect preclinical disease.     

Circulating transforming growth factor beta 1 (TGF-β1) in Guillain-Barré syndrome: decreased concentrations in the early course and increase with motor function

OBJECTIVE—To delineate the possible implication ofthe immunosuppressive cytokine transforming growth factor beta 1 (TGF-β1) in the pathogenesis of Guillain-Barré syndrome.Guillain-Barré syndrome is a disorder that may implicate cytokines inits pathogenesis. TGF-β1 is a potent anti-inflammatory cytokineoccasionally shown to be regulated in the course of demyelinating disorders.
METHODS—The study measured circulatingproinflammatory and anti-inflammatory cytokines from the progressingphase to early recovery in patients with Guillain-Barré syndrome.Plasma concentrations of TNF-α, IL-1β, IL-2, IL-4,IL-6, IL-10, and TGF-β1 were prospectively evaluated in 15 patientswith Guillain-Barré syndrome every three days for the first 15 daysafter admission to hospital, and in 15 controls with non-inflammatoryneurological diseases.
RESULTS—Concentrations of TGF-β1 inplasma were decreased in 13/15 patients (87 %) at day 1, remained low during progression and the plateau of paralysis (days1-10), and then progressively increased up to controlconcentrations during early recovery (days 12-15). Concentrations of plasma TGF-β1 correlated positivelywith motor function, the lowest values being found in the most disabledpatients. Concentrations of plasma TGF-β1 were decreased before anytreatment, and during treatment by either plasma exchange orintravenous immunoglobulins, plasma exchange being associated with amore pronounced decrease in TGF-β1 at day 7. Circulating TNF-αconcentrations were raised, as previously reported, when othercytokines were either randomly increased (IL-2, IL-6), or undetectable(IL-1, IL-4, IL-7, IL-10).
CONCLUSIONS—Down regulation of TGF-β1 in theearly course of Guillain-Barré syndrome could participate in neural inflammation.

     

The EAAT2 (GLT-1) gene in motor neuron disease: absence of mutations in amyotrophic lateral sclerosis and a point mutation in patients with hereditary spastic paraplegia

OBJECTIVES—To investigate if sequence alterationsof the excitatory amino acid transporter gene EAAT2 (GLT-1) may be acontributory factor to the pathogenesis of motor system degeneration.EAAT2 serves as a candidate gene as its reduced expression was reportedin patients with amyotrophic lateral sclerosis (ALS). Furthermore, neurolathyrism, a motor neuron disease clinically related to hereditary spastic paraplegia (HSP), has been associated with an exogenous excitotoxin.
METHODS—Sequence alterations were screened for inthe coding region of EAAT2 in 55 patients with ALS and one family withautosomal dominant HSP (AD-HSP).
RESULTS—In ALS, no sequence alteration in theEAAT2 gene have been found. Interestingly, a heterozygous A79G mutationof the EAAT2 gene was detected in two of seven affected patients withAD-HSP in the same kindred. The absence of cosegregation with thefamilial disease showed that the detected variant was not the cause of disease. The A79G sequence variant was not found in 55 patients withALS or in 50 non-neurological controls.
CONCLUSION—The allelic variant of the EAAT2 genein conjunction with the primary gene defect may be a modifying factorfor the highly variable AD-HSP phenotype.

     

Striatal presynaptic monoaminergic vesicles are not increased in Tourette's syndrome.

BACKGROUND: Abnormal function of striatal dopaminergic synapses is suggested to underlie Tourette's syndrome (TS). OBJECTIVE: To determine dorsal striatal dopaminergic innervation in TS. Prior in vitro and in vivo studies of dopamine reuptake transporter binding sites suggest increased striatal dopaminergic innervation in TS. METHODS: We used in vivo measures of striatal vesicular monoamine transporter type-2 (VMAT2) binding to quantify striatal dopaminergic innervation in TS. Eight TS patients (mean age 30+/-9 years) and 22 age-comparable normal controls (age 34+/-8 years) underwent PET imaging with the VMAT2 ligand (+)-alpha-[11C]dihydrotetrabenazine (DTBZ). Compartmental modeling was used to quantify blood-to-brain ligand transport and VMAT2 binding site density from the tissue-to-plasma distribution volume (DV) during continuous (+)-alpha-[11C]DTBZ infusion. DTBZ DV in dorsal striatal regions was expressed relative to the occipital cortex to estimate relative specific VMAT2 binding (binding potential). RESULTS: We found no significant differences in VMAT2 binding potential between patients and controls in the caudate nucleus, anterior putamen, or posterior putamen. There were no significant differences in striatal VMAT2 binding between patients with (n = 5) or without (n = 3) features of obsessive-compulsive disorder. CONCLUSIONS: There is no evidence for increased binding to the VMAT2 in TS striatum and that dorsal striatal dopaminergic innervation density is normal in TS. The previously reported changes in dopamine transporter binding sites may reflect medication effect and/or altered synaptic activity or regulation of dopamine transporter expression in nigrostriatal neurons.     

Prevalence of Alzheimer plaques in AIDS

OBJECTIVES—Bothgenetic and environmental risk factors for Alzheimer's disease havebeen identified. The best established environmental risk factor, headtrauma, is thought to act through the triggering of an inflammatoryresponse. Another stimulus to an inflammatory response in the brain isAIDS. Whether there is an increased prevalence of β/A4 amyloiddeposits in the form of argyrophilic plaques in the brains of patientswith AIDS has therefore been investigated.
METHODS—The prevalenceof argyrophilic amyloid plaques in the cerebral cortex of frontal andtemporal lobes was compared in 97 cases of AIDS dying at ages 30-69years with that in 125 age matched, non-HIV infected controls.
RESULTS—In the controlgroup, and in AIDS, the prevalence of plaques increased with age(p=0.005 and 0.048 respectively). There was a significantly greaterprevalence of argyrophilic plaques in the AIDS group as a whole (29%)(p< 0.004) and in those in the fourth decade (18%) (p<0.014) than incontrol subjects (13% and 0% respectively).
CONCLUSION—There is apredisposition to argyrophilic plaque formation in the brain in AIDS.The findings support the view that a stimulus to an inflammatoryresponse in the brain favours argyrophilic plaque formation. Theclinical relevance of our findings is, as yet, unclear.

     

A self report measure of affective lability

OBJECTIVES—The development and validation of theCenter for Neurologic Study- Lability Scale (CNS-LS), the first selfreport measure of affective lability in patients with amyotrophiclateral sclerosis (ALS).
METHODS—Potential questionnaire items wereidentified through interviews with patients and families and expertreview. Potential items, as well as measures of affect intensity,affective lability in psychopathology, and depression were administeredto 99 patients with ALS for item selection and the examination offactor structure and construct validity. Test-retest reliability wasexamined using an additional sample of 31 patients with ALS, andcriterion related validity was examined by comparing CNS-LS scores withphysicians' diagnoses of affective lability in a sample of 77 patientswith ALS.
RESULTS—A seven item questionnaire emerged,composed of two subscales measuring labile laughter (four items) andlabile tearfulness (three items). The CNS-LS showed a pattern ofassociations with affect intensity, affective lability inpsychopathology, and depression consistent with a scale measuringaffective lability. The CNS-LS also showed good test-retest reliabilityand internal consistency, and successfully predicted physicians'diagnoses of affective lability. An auxiliary subscale measuring labilefrustration, anger, and impatience also emerged.
CONCLUSIONS—The CNS-LS is a short, easilyadministered, and psychometrically sound measure of affective labilityfor use with patients with ALS. It has potential applications as both aclinical screening device and a research tool. The need for futureresearch into the relation of depression as well as labile frustration,anger, and impatience to the syndrome of affective lability inneurological disorders is discussed.

     

The prevalence of apoE-ε4 in Alzheimer's disease is age dependent

The ε4 allele of apolipoprotein E is a risk factor forAlzheimer's disease. However, other yet unidentified factors might beinvolved. It has been suggested that the ε4 allele might be relatively less relevant in Alzheimer's disease with onset before age60 and after age 80. The aim was to evaluate the association of theε4 allele with Alzheimer's disease across a wide range of ages atonset. 156 patients with age at onset between 46 and 89 and 120 cognitively unimpared subjects aged 53 to 89 as controls were studied.Age at onset in the cases and age in the controls were stratified intosix groups (60 and younger, 60 to 64, 65to 69, 70 to 74, 75 to 79, and80 and older). Multivariable sex adjusted probit regression analysiswas used to model ε4 prevalences in cases and controls across age.The sex adjusted relation of ε4 with age in controls was slightlynegative with prevalence of 0.16 in the youngest and 0.09 in the oldestage groups. The sex adjusted relation in cases with Alzheimer'sdisease had a bell shaped curve with prevalence of 0.23 in the youngestage group, rising to 0.54 and 0.51 in the age groups 65 to 69 and 70 to74, and decreasing to 0.12 in the oldest age group. It is concludedthat the relation of the ε4 allele with Alzheimer's disease is agedependent, indicating that other risk factors might be relevant in theyounger and older ages.

     

Decreased β-phenylethylamine in CSF in Parkinson's disease

OBJECTIVE—To determine the concentrations ofβ-phenylethylamine (PEA) in CSF in patients with Parkinson'sdisease, and to evaluate the relation between concentration of PEA inCSF and severity of Parkinson's disease.
METHODS—Using gas chromatography-chemicalionisation mass spectrometry, CSF concentrations of PEA were measuredin 23 patients with Parkinson's disease (mean age, 64.0 (SD 8.2)years), of whom three were at Hoehn and Yahr stage II, 11 were at stageIII, and nine were at stage IV. Comparison was made with eight patientswith neuropathy (mean age, 57.0 (SD 19.2) years) and 12 controlswithout neurological disease (mean age, 57.6 (SD 4.8) years).
RESULTS—Concentrations of PEA in CSF inParkinson's disease were significantly lower (mean 205 (SD 131) pg/ml)than in patients with peripheral neuropathy (433 (SD 254) pg/ml) andcontrols (387 (SD 194) pg/ml). The concentrations of PEA in CSFcorrelated negatively with Hoehn and Yahr stage (P<0.01).
CONCLUSIONS—There are decreased CSF concentrationsof PEA in patients with Parkinson's disease.

     

Dopaminergic stimulation in unilateral neglect

OBJECTIVE—To explorethe hypothesis that dopaminergic circuits play a part in the premotorcomponents of the unilateral neglect syndrome, the effects of acutedopaminergic stimulation in patients with neglect were studied.
METHODS—Two tasks wereevaluated before and after subcutaneous administration of apomorphineand placebo: a circle crossing test and a test of target exploration (amodified version of the bell test), performed both in perceptual(counting) and in perceptual-motor (pointing) conditions.
SUBJECTS—Four patientswith left neglect.
RESULTS—Afterdopaminergic stimulation, a significant improvement was found comparedwith placebo administration and baseline evaluation, in the performanceof the two tests. Three of the patients had a more marked improvementin the perceptual-motor condition (pointing) of the task than theperceptual condition (counting).
CONCLUSIONS—Thefindings suggest that dopaminergic neuronal networks may mediate, indifferent ways, both perceptive and premotor components of theunilateral neglect syndrome.

     

Presenilin 1 intronic polymorphism is not associated with Alzheimer type neuropathological changes or sporadic Alzheimer's disease

BACKGROUND—A genetic association between thepresenilin 1 (PS-1) intronic polymorphism and sporadic Alzheimer'sdisease has been a matter of controversy. Recent findings havesuggested that the PS-1 polymorphism is not associated withAlzheimer's disease or amyloid β-protein (Aβ) deposition in brainsfrom patients with Alzheimer's disease.
OBJECTIVES—To elucidate the influence of the PS-1polymorphism on Alzheimer type neuropathological changes and thedevelopment of Alzheimer's disease, the relation between the PS-1polymorphism and quantitative severity of Alzheimer typeneuropathological changes in the brains from patients with Alzheimer'sdisease and non-demented subjects was studied.
METHODS—The PS-1 and apolipoprotein E(ApoE) genotypes, were examined, together with the densities of thesenile plaques, senile plaques with dystrophic neurites, andneurofibrillary tangles in the brains from 36 postmortem confirmedpatients with sporadic Alzheimer's disease and 86 non-dementedsubjects. Association of the PS-1 polymorphism with sporadicAlzheimer's disease and ages at onset and duration of illness inAlzheimer's disease was also examined.
RESULTS—The PS-1 polymorphism was not associatedwith the senile plaques, senile plaques with dystrophic neurites, orneurofibrillary tangles in Alzheimer's disease or non-dementedsubjects. There was no association of the PS-1 intronic polymorphismwith Alzheimer's disease, ages at onset, or durations of illness inAlzheimer's disease. The results remained non-significant even whenthe PS-1 genotype groups were divided into the subgroups withdifferent ApoE ε4 status.
CONCLUSIONS—The PS-1 intronic polymorphismdoes not itself have a direct causal role in the formation of Alzheimertype neuropathological changes or in the development of sporadicAlzheimer's disease.

     

Delayed recovery of nerve conduction and vibratory sensibility after ischaemic block in patients with diabetes mellitus

OBJECTIVES—To determine if the recovery of nervefunction after ischaemic block is impaired in patients with diabetesmellitus relative to healthy controls.
METHODS—Median nerve impulse conduction andvibratory thresholds in the same innervation territory were studied inpatients with diabetes mellitus (n = 16) and age matched controls (n = 10) during and after 30 minutes of cuffing of the forearm.
RESULTS—Cuffing caused a 50% reduction of thecompound nerve action potential (CNAP) after 21.9 (SEM 1.6) minutes inpatients with diabetes mellitus and after 10.6 (0.7) minutes incontrols. After release of the cuff the half life for CNAP recovery was5.13 (0.45) minutes in patients with diabetes mellitus and <1 minutein controls. At seven minutes after release of the cuff CNAP was fullyrestored in the controls whereas in patients with diabetes mellitusCNAP had only reached 75.1 (4.1)% of its original amplitude. After onset of ischaemia it took 14.6 (1.9) minutes in patients with diabetesmellitus before the vibratory threshold was doubled, whereas this took5.8 (0.8) minutes in controls. After release of the cuff half time forrecovery of vibratory threshold was 8.8 (1.0) minutes in patients withdiabetes mellitus and 2.6 (0.3) minutes in controls. Ten minutes afterthe cuff was released the threshold was still raised (2.0 (0.3)-fold)in the diabetes mellitus group, whereas it was normalised in controls.Among patients with diabetes mellitus the impaired recovery correlatedwith older age, higher HbA1c, and signs of neuropathy, but not withblood glucose.
CONCLUSION—After ischaemia there is a delayedrecovery of nerve conduction and the vibratory sensibility in patientswith diabetes mellitus. Impaired recovery after ischaemic insults maycontribute to the high frequency of entrapment neuropathy in patientswith diabetes mellitus.

     

Monoamine Oxidase-B Inhibition Facilitates α-Synuclein Secretion In Vitro and Delays Its Aggregation in rAAV-Based Rat Models of Parkinson's Disease

Cell-to-cell transmission of α-synuclein (α-syn) pathology is considered to underlie the spread of neurodegeneration in Parkinson''s disease (PD). Previous studies have demonstrated that α-syn is secreted under physiological conditions in neuronal cell lines and primary neurons. However, the molecular mechanisms that regulate extracellular α-syn secretion remain unclear. In this study, we found that inhibition of monoamine oxidase-B (MAO-B) enzymatic activity facilitated α-syn secretion in human neuroblastoma SH-SY5Y cells. Both inhibition of MAO-B by selegiline or rasagiline and siRNA-mediated knock-down of MAO-B facilitated α-syn secretion. However, TVP-1022, the S-isomer of rasagiline that is 1000 times less active, failed to facilitate α-syn secretion. Additionally, the MAO-B inhibition-induced increase in α-syn secretion was unaffected by brefeldin A, which inhibits endoplasmic reticulum (ER)/Golgi transport, but was blocked by probenecid and glyburide, which inhibit ATP-binding cassette (ABC) transporter function. MAO-B inhibition preferentially facilitated the secretion of detergent-insoluble α-syn protein and decreased its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Moreover, in a rat model (male Sprague Dawley rats) generated by injecting recombinant adeno-associated virus (rAAV)-A53T α-syn, subcutaneous administration of selegiline delayed the striatal formation of Ser129-phosphorylated α-syn aggregates, and mitigated loss of nigrostriatal dopaminergic neurons. Selegiline also delayed α-syn aggregation and dopaminergic neuronal loss in a cell-to-cell transmission rat model (male Sprague Dawley rats) generated by injecting rAAV-wild-type α-syn and externally inoculating α-syn fibrils into the striatum. These findings suggest that MAO-B inhibition modulates the intracellular clearance of detergent-insoluble α-syn via the ABC transporter-mediated non-classical secretion pathway, and temporarily suppresses the formation and transmission of α-syn aggregates.SIGNIFICANCE STATEMENT The identification of a neuroprotective agent that slows or stops the progression of motor impairments is required to treat Parkinson''s disease (PD). The process of α-synuclein (α-syn) aggregation is thought to underlie neurodegeneration in PD. Here, we demonstrated that pharmacological inhibition or knock-down of monoamine oxidase-B (MAO-B) in SH-SY5Y cells facilitated α-syn secretion via a non-classical pathway involving an ATP-binding cassette (ABC) transporter. MAO-B inhibition preferentially facilitated secretion of detergent-insoluble α-syn protein and reduced its intracellular accumulation under chloroquine-induced lysosomal dysfunction. Additionally, MAO-B inhibition by selegiline protected A53T α-syn-induced nigrostriatal dopaminergic neuronal loss and suppressed the formation and cell-to-cell transmission of α-syn aggregates in rat models. We therefore propose a new function of MAO-B inhibition that modulates α-syn secretion and aggregation.     

Cerebrospinal fluid transthyretin: aging and late onset Alzheimer's disease

The deposition of insoluble β-amyloid protein fibrils isprobably the central event in the pathogenesis of Alzheimer's disease. Cerebrospinal fluid inhibits this fibril formation, likely by theintervention of one or several proteins binding to soluble β-amyloidprotein. In vitro, transthyretin (TTR), a CSF protein, impedes amyloidfibrillogenesis. Lowered concentrations of CSFTTR couldtherefore be associated with Alzheimer's disease. Concentrations ofTTR in CSF samples from 149 consecutive patients wereassayed, using a kinetic nephelemetric method. These concentrationswere correlated positively with age, but were significantly lower in patients with Alzheimer's disease. These data raise the possibility that amyloid fibril formation could be promoted in patients with lateonset Alzheimer's disease by the lack of sufficient concentrations of TTR.

     

Spinocerebellar ataxia type 6: genotype and phenotype in German kindreds

OBJECTIVE—Spinocerebellar ataxia type 6 (SCA6) isan autosomal dominant cerebellar ataxia (ADCA) of which the mutationcausing the disease has recently been characterised as an expanded CAGtrinucleotide repeat in the gene coding for theα_1A-subunit of the voltage dependent calcium channel. Theaim was to further characterise the SCA6 phenotype
METHODS—The SCA6 mutation was investigated in 69 German families with ADCA and 61 patients with idiopathic sporadiccerebellar ataxia and the CAG repeat length of the expanded allele wascorrelated with the disease phenotype.
RESULTS—Expanded alleles were found in nine of 69 families as well as in four patients with sporadic disease. Diseaseonset ranged from 30 to 71 years of age and was significantlylater than in other forms of ADCA. Age at onset correlated inverselywith repeat length. The SCA6 phenotype comprises predominantlycerebellar signs in concordance with isolated cerebellar atrophy onMRI. Non-cerebellar systems were only mildly affected with external ophthalmoplegia, spasticity, peripheral neuropathy, and parkinsonism. Neither these clinical signs nor progression rate correlated with CAGrepeat length.
CONCLUSIONS—This study provides the first detailedcharacterisation of the SCA6 phenotype. Clinical features apart fromcerebellar signs were highly variable in patients with SCA6. Bycomparison with SCA1, SCA2, and SCA3 no clinical orelectrophysiological finding was specific for SCA6. Therefore, themolecular defect cannot be predicted from clinical investigations. InGermany, SCA6 accounts for about 13% of families with ADCA. However,up to 30% of SCA6 kindreds may be misdiagnosed clinically as sporadicdisease due to late manifestation in apparently healthy parents.Genetic testing is therefore recommended for the SCA6 mutation also inpatients with putative sporadic ataxia.