Evidence of delayed nigrostriatal dysfunction in corticobasal syndrome: A SPECT follow-up study

ObjectiveTo demonstrate that degeneration of substantia nigra neurons may occur at later stages of disease in some patients with corticobasal syndrome (CBS) who evidenced preserved nigrostriatal pathway at a baseline FP-CIT SPECT study.BackgroundCurrent pathological criteria for the definite diagnosis of corticobasal degeneration consider substantia nigra cell loss as a mandatory finding. However, dopamine transporter SPECT imaging performed in a large cohort of CBS patients showed about 10% of normal scans.MethodsWe describe 4 patients with clinical diagnosis of CBS and normal FP-CIT SPECT at baseline whose tracer uptake resulted pathological at 1-year follow-up scan. Clinical assessment has been performed at the time of SPECT scan. A semi-quantitative approach was performed for striatal FP-CIT binding values.ResultsBaseline SPECT scans have been performed after 2.3 ± 1.5 years from onset. All CBS patients presented asymmetric rigid-akinetic parkinsonism (mean Hoehn-Yahr stage 2.5; UPDRS motor score 18) with poor levodopa response and ideo-motor limb apraxia. At follow-up, neurological examination revealed some additional features, including limb dystonia, language impairment, postural instability, ocular gaze impairment, alien limb. All patients showed pathological FP-CIT uptake at the SPECT performed 10–15 months apart from the baseline scan.ConclusionsOur longitudinal FP-CIT SPECT findings support in vivo the hypothesis that substantia nigra neuronal loss may occur at later stages in some patients with CBS, despite early extrapyramidal symptoms.     

Substantia nigra echogenicity is correlated with nigrostriatal impairment in Machado-Joseph disease

BackgroundSeveral studies have demonstrated increased substantia nigra (SN) echogenicity in Parkinson's disease (PD) and Machado-Joseph disease (MJD). Pathological substrate of PD is characterized by dopaminergic nigrostriatal cell loss, also found in MJD. Also, SN hyperechogenicity might be associated with nigrostriatal dysfunction in PD, when comparing dopamine transporter binding with SN echogenicity. The present study aimed to correlate the SN echogenic size and striatal dopamine transporter density in MJD patients.MethodsWe performed TCS in 30 subjects and SPECT with [^99mTc]-TRODAT-1 in 18 subjects with MJD. Fifteen healthy subjects matched for age and gender formed a control group. TCS and [^99mTc]-TRODAT-1 SPECT findings from both MJD patients and control subjects were compared.ResultsThere were no differences regarding age (p = 0.358) or gender (p = 0.566) between groups (MJD versus control group). Mean DAT binding potentials and SN echogenicity were significantly different between groups. There was a significant negative correlation with regard to the SN echogenic size and the ipsilateral striatal TRODAT-1 uptake: the higher the SN echogenicity, the lower the DAT uptake in the ipsilateral cerebral hemisphere.ConclusionIncrease in SN echogenic size likely correlates with presynaptic dopaminergic nigrostriatal dysfunction in MJD, suggesting a concurrent in vivo pathophysiological mechanism.     

Olfactory dysfunction in pure autonomic failure: Implications for the pathogenesis of Lewy body diseases

BackgroundPure autonomic failure (PAF) and Parkinson disease (PD) both are Lewy body diseases, and both entail substantia nigra dopaminergic, locus ceruleus noradrenergic, and cardiac sympathetic denervation. Multiple system atrophy (MSA) is a non-Lewy body disease in which alpha-synuclein accumulates in glial cells, with central catecholamine deficiency but preserved cardiac sympathetic innervation in most patients. PD is associated with more severe and consistent olfactory dysfunction than in MSA; whether PAF entails olfactory dysfunction has been unknown. In this study we assessed olfactory function in PAF in comparison with the two other synucleinopathies and whether olfactory dysfunction correlates with neuroimaging evidence of cardiac noradrenergic or nigrostriatal dopaminergic denervation.MethodThe University of Pennsylvania Smell Identification Test (UPSIT) was administered to 8 patients with PAF, 23 with PD, and 20 with MSA. 6-[¹⁸F]Fluorodopamine positron emission tomographic (PET) scanning was used to indicate cardiac noradrenergic innervation and the putamen:occipital cortex (PUT:OCC) and substantia nigra (SN):OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity to indicate nigrostriatal dopaminergic innervation.ResultsThe PAF group had a low mean UPSIT score (22 ± 3), similar to that in PD (20 ± 2) and lower than in MSA (31 ± 2, p = 0.004). Individual UPSIT scores correlated positively with cardiac 6-[¹⁸F]fluorodopamine-derived radioactivity (r = 0.63 in the septum, p < 0.0001; r = 0.64 in the free wall, p < 0.0001) but not with PUT:OCC or SN:OCC ratios of 6-[¹⁸F]fluorodopa-derived radioactivity.DiscussionIn synucleinopathies, olfactory dysfunction is related to Lewy body pathology and cardiac sympathetic denervation, independently of parkinsonism or striatal dopamine deficiency.     

Subclinical nigrostriatal dopaminergic denervation in the cerebellar subtype of multiple system atrophy (MSA-C)

Nigrostriatal involvement is considered an additional feature in the new consensus criteria for the diagnosis of the cerebellar variant of multiple system atrophy (MSA-C). However, so far, only a few studies, which include a relative small number of patients, give support to this criterion. Our objective was to assess nigrostriatal dopaminergic innervation in patients with MSA-C without parkinsonism by use of dopamine transporter single photon emission computed tomography (DAT SPECT). Thirteen patients that fulfilled criteria for possible or probable MSA-C and presented no parkinsonian signs, and 12 age-matched healthy controls underwent (¹²³I-2-β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane ([¹²³I]FP-CIT) SPECT. Patients were also evaluated through the Unified Multiple System Atrophy Rating Scale (UMSARS) and brain magnetic resonance imaging (MRI). The mean duration of the cerebellar syndrome was 3.8 ± 1.7 years. DAT SPECT showed a significant decrease of striatal [¹²³I]FP-CIT uptake ratios in patients (p < 0.001). Radiotracer uptake reduction was 21% in the entire striatum, 19% in putamen, and 24% in caudate nuclei. Striatal binding ratios were within the normal range in 3 patients. We did not find correlation between striatal uptake and disease duration, age of patients, UMSARS-II score, and pontine diameter. [¹²³I]FP-CIT SPECT shows that most but not all MSA-C patients without parkinsonism have subclinical nigrostriatal dopaminergic denervation which is not related to disease duration, cerebellar dysfunction, or pontine atrophy.     

Diabetes is associated with postural instability and gait difficulty in Parkinson disease

BackgroundComorbid diabetes may be associated with more severe motor impairment in Parkinson disease. In normal elderly individuals, diabetes is associated with parkinsonian features, including gait difficulty and rigidity, though not tremor. Whether diabetes contributes to increased motor dysfunction in Parkinson disease by exacerbating nigrostriatal dopaminergic denervation or through intensification of extranigral pathology is unknown.MethodsWe performed a case–control study (n = 39) involving 13 Parkinson disease subjects (age 66.4yrs ± 5.5; duration of disease 6.9yrs ± 4.4) with diabetes and 26 age, gender, and duration-of-disease-matched Parkinson disease controls without diabetes. All subjects underwent [¹¹C]dihydrotetrabenazine vesicular monoamine transporter type-2 positron emission tomography imaging to assess striatal dihydrotetrabenazine distribution volume ratio and Unified Parkinson disease rating scale motor examination to determine rigidity, bradykinesia, tremor, and postural instability and gait difficulty subscores. Magnetic resonance imaging scans were analyzed to assess leukoaraiosis burden.ResultsAfter controlling for nigrostriatal dopaminergic denervation, Parkinson disease subjects with diabetes displayed greater postural instability and gait difficulty subscores (t = 3.81, p = 0.0005). There were no differences in bradykinesia, rigidity, or tremor subscores between cases and controls. The association between diabetes and postural instability and gait difficulty persisted after controlling for comorbid hypertension and body mass index. Leukoaraiosis, distal vibratory sense, and levodopa dose equivalents did not differ significantly between cases and controls.ConclusionsDiabetes may contribute to postural instability and gait difficulty in Parkinson disease through mechanisms other than nigrostriatal dopaminergic denervation.     

Clinical features and nigrostriatal dysfunction in patients with combined postural and resting tremors

BackgroundThe characteristics of clinical features and nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors have been less clearly reported.MethodsThe present study examined 43 patients with a visible persistent bilateral postural tremor and a unilateral/bilateral resting tremor involving the hands and forearms. The patients had experienced tremors for more than 3 years, with no evidence of Parkinson's disease or other parkinsonian disorders. Visual and quantitative analyses of [¹⁸F] N-(3-fluoropropyl)-2beta-carbon ethoxy-3beta-(4-iodophenyl) nortropane (FP-CIT) PET in 36 patients were performed. Seventeen age-matched normal controls were also studied.ResultsOn visual analysis, 28 patients (78%) showed normal [¹⁸F] FP-CIT uptake and eight (22%) showed significantly reduced uptake, suggesting nigrostriatal dopaminergic neuronal degeneration. The reduced [¹⁸F] FP-CIT uptake was significantly associated with earlier age-at-onset of tremor and asymmetric presentation of resting tremor. On quantitative analysis, there were statistically significant differences in the [¹⁸F] FP-CIT uptake ratio in the posterior putamen between patients with reduced uptake (2.37 ± 1.83) and patients with normal uptake (6.39 ± 1.35) (P < 0.001). However, posterior putamen uptake levels in patients with normal [¹⁸F] FP-CIT uptake on visual analysis were similar to those in normal controls (7.22 ± 1.29) (P = 0.291).ConclusionThe nigrostriatal dopaminergic dysfunction in patients with combined postural and resting tremors may be associated with earlier age-at-onset of tremor and asymmetric pattern of resting tremor, which might help to correctly diagnose patients with mixed tremors.     

Marked N-acetylaspartate and choline metabolite changes in Parkinson's disease patients with mild cognitive impairment

BackgroundThe mild cognitive impairment in Parkinson's disease (PD-MCI) has received increasing attention, of which the diagnosis is challenging. To analyze the possible biomarkers for the early diagnosis, we investigated the metabolite changes in different brain regions of PD-MCI patients as well as appropriate controls by proton magnetic resonance spectroscopy (MRS).MethodsThe metabolism in the occipital lobe, posterior cingulate, substantia nigra and basal ganglia was studied in 66 PD-MCI patients, 70 cognitively normal PD patients (PD-CN) and 74 healthy controls.ResultsThe N-acetylaspartate to creatine (NAA/Cr) ratio in the occipital lobe in PD-MCI patients was lower than that in healthy controls (P < 0.05). In contrast, the choline to creatine ratio in the posterior cingulate was higher in PD-MCI patients than in controls or PD-CN patients (both P < 0.05). No significant metabolite difference in the substantia nigra and basal ganglia was found. Furthermore, the decreases of the ratios of NAA/Cr in the occipital lobe were associated with PD-CN (P < 0.05) and PD-MCI (P < 0.0001) while the increase in the ratio of Cho/Cr in the posterior cingulate was associated with PD-MCI (P ≤ 0.01).ConclusionThe metabolite changes in the occipital lobe and posterior cingulate occur in the early cognitive impairment phase of PD patients. Such variations can be used as the marker for the detection of PD-MCI.     

“Parkinson-dementia” diseases: A comparison by double tracer SPECT studies

We performed 123I-FP-CIT/SPECT and ECD/SPECT in 30 patients with Parkinson's disease with dementia (PDD) and 30 patients with dementia with Lewy bodies (DLB) to evaluate whether presynaptic nigro-striatal function and/or cerebral perfusional pattern is different in these diseases. The striatal uptake of DAT tracer was statistically significantly lower in PDD and DLB with respect to control data (p < 0.0005), however no significant difference was found between PDD and DLB. Patients with PDD and DLB showed a significant reduction of rCBF (p < 0.001) in parieto-occipital and frontal areas, with respect to controls, but the comparison between the two groups did not result in any significant difference by SPM analysis. Finally no correlation was found between any regional perfusional changes and nigro-striatal dysfunction. We conclude that neither studies with 123I-FP-CIT nor ECD/SPECT were able to discriminate between DLB and PDD in vivo.     

BDNF levels and nigrostriatal degeneration in “drug naïve” Parkinson's disease patients. An “in vivo” study using I-123-FP-CIT SPECT

IntroductionParkinson's Disease (PD) is a common neurodegenerative disorder, characterized by a progressive loss of dopaminergic neurons and whose cause remains unclear. Brain-Derived Neurotrophic factor (BDNF) is a protein involved in dopaminergic cells survival. Previous studies have shown decreased serum BDNF levels in PD patients.Aim and objectivesThe aim of the study was to evaluate serum BDNF levels in a group of recently diagnosed non-medicated PD patients and its relationship with the nigrostriatal system degeneration using I-123-FP-CIT.Methods30 recently diagnosed, unmedicated PD patients were included in this study. Serum BDNF levels were measured twice using a sandwich enzyme linked immunoabsorbent assay and compared with levels of 27 unrelated Caucasian healthy adults.A I-123-FP-CIT SPECT was performed in all PD Patients in order to assess the association between serum BDNF levels and I-123-FP CIT uptake in several brain areas using a volumetric semi-automatic method.ResultsPD patients showed lower serum BDNF levels (Median = 49.61, IQ range: 43.55 to 61.82) than the controls (Median = 68.82, IQ range: 51.87 to 88.14) (U = 211.00, z = -3.10, p = 0.002). BDNF levels in PD patients correlated with both caudate (Spearman r = 0.58, p = 0.001 for ispilateral and r 0.55, p = 0.002 for contralateral) and putamen (Spearman r = 0.68, p < 0.001 for ipsilateral and r = 0.80, p < 0.001 for contralateral) I-123-FP-CIT uptake ratios.ConclusionsSerum BDNF levels were lower in recently diagnosed, untreated PD patients compared to controls. These lower levels were significantly correlated with the I-123-FP-CIT uptake ratios.     

Correlation of striatal dopamine transporter imaging with post mortem substantia nigra cell counts

Dopamine transporter imaging is widely used for the differential diagnosis of parkinsonism. Only limited data are available on the relationship between striatal dopamine transporter binding and dopaminergic cell loss in the substantia nigra (SN). We analyzed postmortem SN cell counts in patients who had previously undergone dopamine transporter single‐photon emission computed tomography (SPECT). Pathological diagnoses included Parkinson's disease (n = 1), dementia with Lewy bodies (n = 2), multiple system atrophy (n = 1), corticobasal degeneration (n = 2), atypical parkinsonism with multiple pathological conditions (n = 1), Alzheimer's disease (n = 1), and Creutzfeldt‐Jakob disease (n = 1). [¹²³I]β‐CIT SPECT had been performed in all subjects using a standardized protocol on the same triple‐head gamma camera. The density of neuromelanin‐containing and tyrosine hydroxylase–positive substantia nigra neurons/mm² was evaluated in paraffin‐embedded tissue sections by morphometric methods. Mean disease duration at the time of dopamine transporter imaging was 2.3 years, and the mean interval from imaging to death was 29.3 months (range, 4‐68 months). Visual analysis of dopamine transporter images showed reduced striatal uptake in all seven patients with neurodegenerative parkinsonism, but not in Alzheimer's and Creutzfeldt‐Jakob disease cases. Averaged [(right+left)/2] striatal uptake was highly correlated with averaged SN cell counts (r_s = 0.98, P < 0.0005 for neuromelanin‐ and r_s = 0.96, P < 0.0005 for tyrosine hydroxylase–positive cells). Similar strong correlations were found in separate analyses for the right and left sides. Striatal dopamine transporter binding highly correlated with postmortem SN cell counts, confirming the validity of dopamine transporter imaging as an excellent in vivo marker of nigrostriatal dopaminergic degeneration. © 2014 International Parkinson and Movement Disorder Society     

Different iron deposition patterns in hemodialysis patients with and without restless legs syndrome: a quantitative susceptibility mapping study

ObjectiveBrain iron deposition in hemodialysis (HD) patients increases over time. Iron deficiency in gray matter nuclei has been reported to lead to idiopathic restless legs syndrome (RLS) symptoms. Regardless of unpleasant RLS sensations, the patterns of iron deposition between hemodialysis patients with RLS (HD-RLS) and hemodialysis patients without RLS (HD-nRLS) are still unclear. To evaluate the differences in iron deposition patterns between HD-RLS and HD-nRLS patients, we utilized quantitative susceptibility mapping (QSM).MethodsIn sum, 24 HD-RLS patients, 25 HD-nRLS patients and 30 age- and sex-matched healthy controls (HCs) were enrolled. The QSM was used to assess susceptibility values of the regions of interest (ROIs), including the caudate nucleus (CN), putamen (PUT), globus pallidus (GP), thalamus (THA), substantia nigra (SN), red nucleus (RN) and dentate nucleus (DN).ResultsHD duration was significantly longer in HD-RLS patients than in HD-nRLS patients (P < 0.05). The susceptibility of HD-RLS and HD-nRLS patients in PUT was higher than that in HCs (P < 0.05), illustrating elevated iron content in the nucleus. Compared with HD-nRLS patients, HD-RLS patients demonstrated reduced susceptibility in CN and PUT (both P < 0.05). Compared with HCs, HD-RLS patients displayed decreased susceptibility in DN (P < 0.05).ConclusionsDifferent iron deposition patterns between HD-RLS and HD-nRLS patients in PUT and DN, which further support disturbed sensory processing in RLS, may be involved in RLS pathogenesis in HD patients.     

Late-onset Huntington's disease: Diagnostic and prognostic considerations

ObjectiveTo address diagnostic and prognostic issues in patients with late-onset Huntington's disease (HD).MethodsWe analyzed a cohort of 41 late-onset (≥60 years) HD patients and compared them to 39 late-onset patients referred for HD testing that were negative for the HD-expansion and to 290 usual-onset (20–59 years) HD patients. Disease severity was assessed by the Total Functional Capacity Scale.ResultsLate-onset HD comprised 11.5% of our HD cohort. In total, 70.7% of late-onset HD patients had positive family history compared to 15.4% of late-onset expansion-negative patients (p < 0.001). Clinical features at onset or presentation could not usefully distinguish between late-onset expansion-positive and negative patients, excepting hemichorea, which was absent from the HD group (p = 0.024). Chorea was the first clinical feature in 53.7% and a presenting feature in 90.2% of late-onset HD. The mutation hit rate for late-onset patients was 51.3%, lower than in usual-onset patients (p = 0.04). Frequencies of chorea, cognitive impairment and psychiatric manifestations at onset or presentation were not significantly different between late-onset and usual-onset HD patients. Gait unsteadiness however was more common at presentation in late-onset HD (p = 0.007). Late-onset HD patients reached a severe stage of illness on average 2.8 years earlier than usual-onset HD patients (p = 0.046).ConclusionsA positive family history suggestive of HD, although absent in a third of patients, remains a helpful clue in diagnosing late-onset HD. Prognosis of late-onset HD in terms of Total Functional Capacity appears no better and shows a trend of being somewhat less favorable compared to usual-onset HD.     

Brain MR imaging changes in patients with hepatic schistosomiasis japonicum without liver dysfunction

BackgroundThe hyperintense signal on T1-weighted magnetic resonance (MR) images in the globus pallidus and substantia nigra of the brain can be found in patients with liver cirrhosis. The abnormality has been considered resulting from the manganese (Mn) deposition caused by liver failure and portal-systemic shunting. However, similar finding may also be found in hepatic schistosomiasis patients, who lack the biochemical evidence of liver dysfunction.ObjectivesTo describe the brain MR imaging findings in patients with hepatic schistosomiasis japonicum (HSJ) without liver dysfunction.MethodsBrain MR and CT images of 18 patients with HSJ without liver dysfunction and 9 healthy volunteers were reviewed by two radiologists in consensus. The signal index (SI) in globus pallidus was obtained on T1-weighted images. Whole blood Mn, serum iron, serum calcium, and other laboratory tests of liver function were investigated.ResultsSymmetric hyperintense signal in the globus pallidus and substantia nigra was observed in 15 of 18 HSJ patients (83.3%) and in none of controls on T1 weighted imaging. No abnormal CT findings were seen in both groups. Blood Mn level in patients was significantly higher than controls (p < 0.05). Significant correlations were demonstrated between blood Mn and SI (p < 0.05). No significantly abnormal results of serum iron, serum calcium and other laboratory tests were shown (p > 0.05).ConclusionThe portal-systemic shunting leading to Mn deposition may be the main cause of the basal ganglia hyperintense signal on T1-weighted MR imaging, which is a frequent finding in patients with HSJ without liver dysfunction.     

Cognitive‐nigrostriatal relationships in de novo,drug‐naïve Parkinson's disease patients: A [I‐123]FP‐CIT SPECT study

To unveil cognitive‐nigrostriatal correlations in Parkinson's disease (PD), 30 de novo, drug‐naïve PD patients and 15 patients with essential tremor (Controls, CTR) underwent a neuropsychological (NPS) battery and brain SPECT with [I‐123]Ioflupane, as a biomarker of nigrostriatal function. Automatic extraction of uptake at caudate and putamen level was conducted through the BasGan software, also allowing partial volume effect correction. Because of the multicollinearity among neuropsychological tests and among SPECT variables, factor analysis was applied to 16 neuropsychological scores; moreover, the four SPECT variables were merged into a mean SPECT value (mSPECT). Factor analysis identified four NPS factors: a dys‐executive (NPS‐EX), a visuospatial (NPS‐VS), a verbal memory (NPS‐VM), and a “mixed” (NPD‐MIX) factor. In PD group, there were inverse correlations between UPDRS‐III score and both NPS‐VS (P < 0.01) and mSPECT (P < 0.05), and a direct correlation between mSPECT and NPS‐EX (P < 0.05). Post hoc analysis showed a direct correlation between NPS‐EX and caudate uptake in both hemispheres (P < 0.05). Moreover, inverse correlations were found between UPDRS‐III and, respectively, putamen uptake in the less affected hemisphere (P < 0.01), and putamen and caudate uptake in the more affected hemisphere (P < 0.05). In CTR, no correlation was found between mSPECT and either NPS or GDS values. Nigro‐caudate function affects executive capabilities in PD but not in CTR, which appears to be unrelated to the disease motor severity at its onset. Instead, PD motor severity is related to nigro‐putaminal impairment and visuospatial dysfunction. The role of these data as predictive features of cognitive decline and eventually dementia remains to be established in longitudinal studies. © 2010 Movement Disorder Society     

Rest tremor correlates with reduced contralateral striatal dopamine transporter binding in Parkinson's disease

IntroductionIn vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor.Methods23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3–10Hz and to calculate the tremor stability index (TSI).ResultsSpearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions.ConclusionThese data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.     

Adults with a history of illicit amphetamine use exhibit abnormal substantia nigra morphology and parkinsonism

IntroductionThe sonographic appearance of the substantia nigra is abnormally bright and enlarged (hyperechogenic) in young adults with a history of illicit stimulant use. The abnormality is a risk factor for Parkinson's disease. The aim of the current study was to identify the type of illicit stimulant drug associated with substantia nigra hyperechogenicity and to determine if individuals with a history of illicit stimulant use exhibit clinical signs of parkinsonism. We hypothesised that use of amphetamines (primarily methamphetamine) is associated with substantia nigra hyperechogenicity and clinical signs of parkinsonism.MethodsThe area of echogenic signal in the substantia nigra was measured in abstinent human amphetamine users (n = 27; 33 ± 8 years) and in three control groups comprising a) ‘ecstasy’ users (n = 19; 23 ± 3 years), b) cannabis users (n = 30; 26 ± 8 years), and c) non-drug users (n = 37; 25 ± 7 years). A subset of subjects (n = 55) also underwent a neurological examination comprising the third and fifth part of the Unified Parkinson's Disease Rating Scale.ResultsArea of substantia nigra echogenicity was significantly larger in the amphetamine group (0.276 ± 0.080 cm²) than in the control groups (0.200 ± 0.075, 0.190 ± 0.049, 0.191 ± 0.055 cm², respectively; P < 0.002). The score on the clinical rating scale was also significantly higher in the amphetamine group (8.4 ± 8.1) than in pooled controls (3.3 ± 2.8; P = 0.002).ConclusionIllicit use of amphetamines is associated with abnormal substantia nigra morphology and subtle clinical signs of parkinsonism. The results support epidemiological findings linking use of amphetamines, particularly methamphetamine, with increased risk of developing Parkinson's disease later in life.     

Modulation effect of substantia nigra iron deposition and functional connectivity on putamen glucose metabolism in Parkinson's disease

Neurodegeneration of the substantia nigra affects putamen activity in Parkinson''s disease (PD), yet in vivo evidence of how the substantia nigra modulates putamen glucose metabolism in humans is missing. We aimed to investigate how substantia nigra modulates the putamen glucose metabolism using a cross‐sectional design. Resting‐state fMRI, susceptibility‐weighted imaging, and [¹⁸F]‐fluorodeoxyglucose‐PET (FDG‐PET) data were acquired. Forty‐two PD patients and 25 healthy controls (HCs) were recruited for simultaneous PET/MRI scanning. The main measurements of the current study were R2* images representing iron deposition (28 PD and 25 HCs), standardized uptake value ratio (SUVr) images representing FDG‐uptake (33 PD and 25 HCs), and resting state functional connectivity maps from resting state fMRI (34 PD and 25 HCs). An interaction term based on the general linear model was used to investigate the joint modulation effect of nigral iron deposition and nigral‐putamen functional connectivity on putamen FDG‐uptake. Compared with HCs, we found increased iron deposition in the substantia nigra (p = .007), increased FDG‐uptake in the putamen (left: P _FWE < 0.001; right: P _FWE < 0.001), and decreased functional connectivity between the substantia nigra and the anterior putamen (left P _FWE < 0.001, right: P _FWE = 0.007). We then identified significant interaction effect of nigral iron deposition and nigral‐putamen connectivity on FDG‐uptake in the putamen (p = .004). The current study demonstrated joint modulation effect of the substantia nigra iron deposition and nigral‐putamen functional connectivity on putamen glucose metabolic distribution, thereby revealing in vivo pathological mechanism of nigrostriatal neurodegeneration of PD.     

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.

     

Non-dopaminergic nigrostriatal pathway

The nigrostriatal projection was studied with a retrograde tracing method (Evans blue, EB) combined with a technique for dopamine histofluorescence. The study, realized in control rats and in animals with 6-hydroxydopamine-induced lesions of the dopaminergic pathway, yielded the following results.

(1) In 3 control rats injected with 0.2 μl of a 10% solution of EB in thecenter of the caudate-putamen 1 mm anterior to the globus pallidus, 96% of all substantia nigra neurons retrogradely labelled with the dye contained dopamine fluorescence. The remaining ones (average 350 per brain) were devoid of dopamine fluorescence and predominantly found in the posterior 75% of the substantia nuigra. These last cells were confined to the upper-half of the pars reticulata.

(2) In a series of 6 animals, the cytotoxic agent 6-hydroxydopamine was injected in various locations in the vicinity of either the substantia nigra ir the nigrostriatal tract 12–15 days prior to the injections of 0.2 μl of EB in the same striatal locations as in the controls. Despite a reduction of up to 85% in the number of dopaminergic cell bodies, the substantia nigra of these rats contained the same average number of EB-labelled neurons devoid of dopamine fluorescence.

(3) Eight rats received smaller injections (0.1 μl) of EB in various striatal sites and in tqo further cases such injections were placed in the globus pallidus to determine more accurately the anatomical location of the dopamine-negative nigral neurons retrogradely labelled with the dye. Following the striatal injections, these cells were found mostly in the upper-half of the pars reticulata and were arranged in longitudinally oriented clusters whose mediolateral location depended on the striatal injection site.

Following the pallidal injections, retrogradely labelled neruons devoid of dopamine fluorescence were found in greater numbers and were located in all areas of the pars reticulata. The possibility of retrograde labelling of some nigrothalamic neurons was not entirely ruled out in these two cases.

(4) Finally 6 rats received 0.1 μl injections of EB in various parts of the parietal cortex. In these cases the substantia nigra did not contain any EB-positivedopamine-negative neurons.

These results are interpreted as evidence in support of the existence of a topographically organized non-dopaminergic nigrostriatal projection.

Does rapid eye movement sleep behavior disorder exist in psychiatric populations? A clinical and polysomnographic case–control study

ObjectivesRapid eye movement (REM) sleep behavior disorder (RBD) has been increasingly reported in patients with psychiatric disorders (pRBD). Although a close association with the usage of psychotropics has been postulated, it remains elusive whether psychotropics are the only causative factor of RBD symptoms in psychiatric populations. Moreover, there is limited literature documenting and quantifying the clinical and polysomnographic features in this population.MethodsA case–control study comparing the clinical and polysomnographic features of 31 pRBD patients with: (1) Age-, sex-, and psychiatric diagnoses-matched controls; and (2) Typical idiopathic RBD (tRBD) patients.ResultsDespite being prescribed with similar psychotropics, pRBD patients had more dream-enacting behaviors (p < 0.01), sleep-related injuries (p < 0.01), and nightmares (p < 0.01) than the psychiatric controls. pRBD patients were younger with more females, but they had comparable sleep-related injuries to tRBD. Both tRBD and pRBD had more REM-related muscle activity than controls (p < 0.01) and the effect remained significant after adjusting for age, gender, and use of antidepressants.ConclusionsOur study suggests that pRBD had comparable clinical features and consequences to those of tRBD. The occurrence of RBD symptoms in these patients may be related to a constellation of factors, including individual predisposition, depressive illness, antidepressants, and other clinical factors. Given the association of RBD and neurodegeneration in tRBD, further prospective follow-up of these patients is warranted.