Gender differences in cholinergic and dopaminergic deficits in Parkinson disease

As Parkinson disease (PD) may affect men and women differentially, we investigated gender differences in regional projection system integrity in 148 PD subjects (36 women, 112 men) using monoaminergic [¹¹C]dihydrotetrabenazine and acetylcholinesterase [¹¹C]PMP positron emission tomography. After controlling for age, disease duration, and Hoehn and Yahr score, men showed 5.9 % greater caudate dopaminergic denervation (p = 0.0018) and 5.8 % greater neocortical cholinergic denervation (p = 0.0097). No significant gender differences were seen in putaminal dopaminergic or thalamic cholinergic denervation.     

Heterogeneity of cholinergic denervation in Parkinson's disease without dementia

Parkinson's disease (PD) is a multisystem neurodegenerative disorder. Heterogeneous clinical features may reflect heterogeneous changes in different brain regions. In contrast to the pronounced nigrostriatal denervation characteristic of PD, cholinergic changes are less marked. We investigated cholinergic innervation activity in PD subjects relative to normal subjects. Nondemented PD subjects (n=101, age 65.3±7.2 years) and normal subjects (n=29, age 66.8±10.9 years) underwent clinical assessment and [(11)C]methyl-4-piperidinyl propionate acetylcholinesterase and [(11)C]dihydrotetrabenazine monoaminergic positron emission tomography (PET) imaging. Cholinergic projection changes were heterogeneous for 65 out of 101 PD subjects who had neocortical and thalamic acetylcholinesterase activity within the normal range. The remainder had combined neocortical and thalamic (13/101), isolated neocortical (18/101), or isolated thalamic (5/101) acetylcholinesterase activity below the normal range. The low neocortical acetylcholinesterase activity subgroup had significantly lower global cognitive performance compared with the normal range subgroup (F=7.64, P=0.0069) with an independent effect for nigrostriatal denervation (F=7.60, P=0.0074). The low thalamic acetylcholinesterase activity subgroup did not differ from the normal thalamic acetylcholinesterase activity subgroup in cognitive performance or motor impairments except for a history of falls (P=0.0023). Cholinergic denervation is heterogeneous with reduced neocortical and/or thalamic acetylcholinesterase activity in 36% of nondemented PD subjects with corresponding clinical phenotypic variation. Results also show independent cognitive effects for both cholinergic and dopaminergic system changes in nondemented PD subjects.     

Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

Neuroimaging and clinical predictors of fatigue in Parkinson disease

BackgroundFatigue is disabling in Parkinson disease. It is often associated with other non-motor symptoms, but little is known about its underlying pathophysiology.ObjectiveTo investigate neuroimaging (using dopaminergic and cholinergic PET) and clinical factors associated with fatigue severity in PD.Methods133 PD subjects (96M/37F) completed the Fatigue Severity Scale, Movement Disorders Society-Sponsored Revision of the Unified PD Rating Scale (MDS-UPDRS), Hoehn-Yahr staging, validated scales for depression, anxiety, apathy, sleep, and cognition, and underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [¹¹C]dihydrotetrabenazine (DTBZ) monoaminergic PET imaging. We explored contributions to PD fatigue using separate regression models based either on neuroimaging parameters or clinicometric scales.ResultsIn a neuroimaging regression model, neither striatal DTBZ uptake nor AChE PMP uptake were predictors of fatigue in PD. In a post-hoc neuroimaging regression model, stratifying the total cohort into mild vs. moderate-to-severe PD, striatal DTBZ uptake was a significant predictor of fatigue in mild but not moderate-to-severe PD. In a clinicometric regression model, higher Beck Depression Inventory-somatic subscore, higher levodopa dose equivalents and younger age were all significant predictors of fatigue in PD, but the MDS-UPDRS non-motor experiences of daily living score was the best predictor overall.ConclusionsCholinergic uptake was not a predictor of fatigue in PD, but nigrostriatal dopaminergic denervation predicted fatigue in mild disease. Total non-motor symptom burden, somatic affective symptoms, levodopa dose equivalents, and younger age were independent clinical predictors of fatigue.     

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.     

β‐amyloid and postural instability and gait difficulty in Parkinson's disease at risk for dementia

Although motor impairments in Parkinson's disease (PD) are attributed to nigrostriatal dopaminergic denervation, postural instability and gait difficulty (PIGD) features are less responsive to dopaminergic medications. PIGD features are a risk factor also for the development of dementia in PD (PDD). These observations suggest that nondopaminergic mechanisms may contribute to axial motor impairments. The aim was to perform a correlative PET study to examine the relationship between neocortical β‐amyloid deposition ([¹¹C]‐Pittsburgh Compound B), nigrostriatal dopaminergic denervation ([¹¹C]‐dihydrotetrabenazine), and PIGD feature severity in PD patients at risk for dementia. This was a cross‐sectional study of 44 PD patients (11 female and 33 male; 69.5 ± 6.6 years of age; 7.0 ± 4.8 years motor disease duration; mean H & Y stage: 2.7 ± 0.5) who underwent PET, motor feature severity assessment using the Movement Disorder Society revised UPDRS, and the Dementia Rating Scale (DRS). Linear regression (R²_adj = 0.147; F_4,39 = 2.85; P = 0.036) showed that increased PIGD feature severity was associated with increased neocortical [¹¹C]‐Pittsburgh Compound B binding (β = 0.346; t₃₉ = 2.13; P = 0.039) while controlling for striatal [¹¹C]‐dihydrotetrabenazine binding, age, and DRS total score. Increased neocortical β‐amyloid deposition, even at low‐range levels, is associated with higher PIGD feature severity in PD patients at risk for dementia. This finding may explain why the PIGD motor phenotype is a risk factor for the development of PDD. © 2012 Movement Disorder Society     

Extra‐nigral pathological conditions are common in Parkinson's disease with freezing of gait: An in vivo positron emission tomography study

Cholinergic denervation has been associated with falls and slower gait speed and β‐amyloid deposition with greater severity of axial motor impairments in Parkinson disease (PD). However, little is known about the association between the presence of extra‐nigral pathological conditions and freezing of gait (FoG). Patients with PD (n = 143; age, 65.5 ± 7.4 years, Hoehn and Yahr stage, 2.4 ± 0.6; Montreal Cognitive Assessment score, 25.9 ± 2.6) underwent [¹¹C]methyl‐4‐piperidinyl propionate acetylcholinesterase and [¹¹C]dihydrotetrabenazine dopaminergic PET imaging, and clinical, including FoG, assessment in the dopaminergic “off” state. A subset of subjects (n = 61) underwent [¹¹C]Pittsburgh compound‐B β‐amyloid positron emission tomography (PET) imaging. Normative data were used to dichotomize abnormal β‐amyloid uptake or cholinergic deficits. Freezing of gait was present in 20 patients (14.0%). Freezers had longer duration of disease (P = 0.009), more severe motor disease (P < 0.0001), and lower striatal dopaminergic activity (P = 0.013) compared with non‐freezers. Freezing of gait was more common in patients with diminished neocortical cholinergic innervation (23.9%, χ² = 5.56, P = 0.018), but not in the thalamic cholinergic denervation group (17.4%, χ² = 0.26, P = 0.61). Subgroup analysis showed higher frequency of FoG with increased neocortical β‐amyloid deposition (30.4%, Fisher Exact test: P = 0.032). Frequency of FoG was lowest with absence of both pathological conditions (4.8%), intermediate in subjects with single extra‐nigral pathological condition (14.3%), and highest with combined neocortical cholinopathy and amyloidopathy (41.7%; Cochran‐Armitage trend test, Z = 2.63, P = 0.015). Within the group of freezers, 90% had at least one of the two extra‐nigral pathological conditions studied. Extra‐nigral pathological conditions, in particular the combined presence of cortical cholinopathy and amyloidopathy, are common in PD with FoG and may contribute to its pathophysiology. © 2014 International Parkinson and Movement Disorder Society     

Abnormal MoCA and normal range MMSE scores in Parkinson disease without dementia: Cognitive and neurochemical correlates

BackgroundThe Montreal Cognitive Assessment (MoCA) is increasingly being used as a cognitive screening test in Parkinson disease (PD). The MoCA's popularity likely reflects its ability to detect executive dysfunction, a relative deficiency of the Mini-Mental State Examination (MMSE).ObjectiveTo compare neurochemical and neuropsychological functions in non-demented PD patients with mild cognitive impairment (PD-MCI) and without, as defined by MoCA (PD-MCI = MoCA<26).MethodsNon-demented PD subjects underwent combined MoCA and MMSE, detailed cognitive testing and [¹¹C]methyl-4-piperidinyl propionate acetylcholinesterase and [¹¹C]dihydrotetrabenazine monoaminergic PET imaging.ResultsEighteen subjects met MoCA PD-MCI criteria but had MMSE scores in the normal range, compared to 29 subjects with normal MoCA and MMSE scores. The MoCA-defined PD-MCI group had reduced performance in global cognition (t = 2.91, P = 0.0056), most significantly in executive function (t = 3.18, P = 0.002), as well as significant reduction in dorsal caudate nucleus dopaminergic innervation (t = 2.72, P = 0.009) compared to the PD without MCI group. Both MoCA and MMSE had poor diagnostic accuracy for PD-MCI (65.3%) when using the Level 2 Movement Disorder Society Task Force definition.ConclusionPD subjects with normal range MMSE but abnormal MoCA scores had evidence of caudate nucleus dopaminergic denervation and mild cognitive changes, predominantly in executive function. The MoCA may be able to preferentially detect executive dysfunction compared to the MMSE, but the MoCA has limited diagnostic accuracy for PD-MCI, and should not be used alone to make this diagnosis.     

The cholinergic system and Parkinson disease

Although Parkinson disease (PD) is viewed traditionally as a motor syndrome secondary to nigrostriatal dopaminergic denervation, recent studies emphasize non-motor features. Non-motor comorbidities, such as cognitive impairment, are likely the result of an intricate interplay of multi-system degenerations and neurotransmitter deficiencies extending beyond the loss of dopaminergic nigral neurons. The pathological hallmark of parkinsonian dementia is the presence of extra-nigral Lewy bodies that can be accompanied by other pathologies, such as senile plaques. Lewy first identified the eponymous Lewy body in neurons of the nucleus basalis of Meynert (nbM), the source of cholinergic innervation of the cerebral cortex. Although cholinergic denervation is recognized as a pathological hallmark of Alzheimer disease (AD), in vivo neuroimaging studies reveal loss of cerebral cholinergic markers in parkinsonian dementia similar to or more severe than in prototypical AD. Imaging studies agree with post-mortem evidence suggesting that basal forebrain cholinergic system degeneration appears early in PD and worsens coincident with the appearance of dementia. Early cholinergic denervation in PD without dementia appears to be heterogeneous and may make specific contributions to the PD clinical phenotype. Apart from well-known cognitive and behavioral deficits, central, in particular limbic, cholinergic denervation may be associated with progressive deficits of odor identification in PD. Recent evidence indicates also that subcortical cholinergic denervation, probably due to degeneration of brainstem pedunculopontine nucleus neurons, may relate to the presence of dopamine non-responsive gait and balance impairments, including falls, in PD.     

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.     

Altered sensorimotor cortex noradrenergic function in idiopathic REM sleep behaviour disorder – A PET study

IntroductionNoradrenergic denervation is thought to aggravate motor dysfunction in Parkinson's disease (PD). In a previous PET study with the norepinephrine transporter (NART) ligand ¹¹C-MeNER, we detected reduced NART binding in primary sensorimotor cortex (M1S1) of PD patients. Idiopathic rapid-eye-movement sleep behaviour disorder (iRBD) is a phenotype of prodromal PD. Using ¹¹C-MeNER PET, we investigated whether iRBD patients showed similar NART binding reductions in M1S1 cortex as PD patients. Additionally, we investigated whether ¹¹C-MeNER binding and loss of nigrostriatal dopamine storage capacity measured with ¹⁸F-DOPA PET were correlated.Methods17 iRBD patients, 16 PD patients with (PD^RBD+) and 14 without RBD (PD^RBD−), and 25 control subjects underwent ¹¹C-MeNER PET. iRBD patients also had ¹⁸F-DOPA PET. Volume-of-interest analyses and voxel-level statistical parametric mapping were performed.ResultsPartial-volume corrected ¹¹C-MeNER binding potential (BP^ND) values in M1S1 differed across the groups (P = 0.022) with the iRBD and PD^RBD+ groups showing significant reductions (controls vs. iRBD P = 0.007; control vs. PD^RBD+ P = 0.008). Voxel-wise comparisons confirmed reductions of M1S1 ¹¹C-MeNER binding in PD and iRBD patients. Significant correlation was seen between putaminal ¹⁸F-DOPA uptake and thalamic ¹¹C-MeNER binding in iRBD patients (r² = 0.343, P = 0.013).ConclusionsThis study found altered noradrenergic neurotransmission in the M1S1 cortex of iRBD patients. The observed reduction of M1S1 ¹¹C-MeNER binding in iRBD may represent noradrenergic terminal degeneration or physiological down-regulation of NARTs in this prodromal phenotype of PD. The correlation between thalamic ¹¹C-MeNER binding and putaminal ¹⁸F-DOPA binding suggests that these neurotransmitter systems degenerate in parallel in the iRBD phenotype of prodromal PD.     

Rhinorrhea: A common nondopaminergic feature of Parkinson's disease

We compared the frequency of rhinorrhea between 34 Parkinson's disease (PD) subjects and 15 normal controls (NC) and explored relationships between rhinorrhea and clinical functions, and degree of nigrostriatal dopaminergic denervation using [¹¹C]dihydrotetrabenazine (DTBZ) brain positron emission tomography imaging. Sixty‐eight percent (23 of 34) of PD subjects reported rhinorrhea of any cause compared with 27% (4 of 15) of NC (χ² = 7.07, P = 0.008). Rhinorrhea frequency remained higher in the PD group after excluding possible rhinitic etiologies: 35% (12 of 34) of PD versus 7% (1 of 15) of NC (χ² = 4.38, P = 0.04). There were no differences in demographics, nigrostriatal dopaminergic denervation, and clinical motor or nonmotor variables between PD subjects with and without rhinorrhea, except that more PD subjects with rhinorrhea complained of lightheadedness (52% vs. 9%, χ² = 5.85, P = 0.02). Rhinorrhea is a common nondopaminergic feature of PD, unrelated to olfactory or motor deficits. Further investigations are needed to determine if rhinorrhea correlates with sympathetic denervation or other autonomic symptoms in PD. © 2010 Movement Disorder Society     

Thalamic volume and related visual recognition are associated with freezing of gait in non-demented patients with Parkinson's disease

BackgroundThe pathophysiology of freezing of gait (FOG) in non-demented Parkinson's disease (PD) patients remains poorly understood. Recent studies have suggested that neurochemical alterations in the cholinergic systems play a role in the development of FOG. Here, we evaluated the association between subcortical cholinergic structures and FOG in patients with non-demented PD.MethodsWe recruited 46 non-demented patients with PD, categorized into PD with (n = 16) and without FOG (n = 30) groups. We performed neuropsychological test, region-of-interest-based volumetric analysis of the substantia innominata (SI) and automatic analysis of subcortical brain structures using a computerized segmentation procedure.ResultsThe comprehensive neuropsychological assessment showed that PD patients with FOG had lower cognitive performance in the frontal executive and visual-related functions compared with those without freezing of gait. The normalized SI volume did not differ significantly between the two groups (1.65 ± 0.18 vs. 1.68 ± 0.31). The automatic analysis of subcortical structures revealed that the thalamic volumes were significantly reduced in PD patients with FOG compared with those without FOG after adjusting for age, sex, disease duration, the Unified PD Rating Scale scores and total intracranial volume (left: 6.71 vs. 7.16 cm³, p = 0.029, right: 6.47 vs. 6.91 cm³, p = 0.026). Multiple linear regression analysis revealed that thalamic volume showed significant positive correlations with visual recognition memory (left: β = 0.441, p = 0.037, right: β = 0.498, p = 0.04).ConclusionsThese data suggest that thalamic volume and related visual recognition, rather than the cortical cholinergic system arising from the SI, may be a major contributor to the development of freezing of gait in non-demented patients with PD.     

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.     

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.     

Nigrostriatal dopaminergic function in subjects with isolated action tremor

BackgroundIsolated action tremor (IAT) is the hallmark clinical feature of essential tremor (ET), but it may also be a prominent feature of some individuals with Parkinson’s disease (PD) suggesting a pathogenic relationship between these two disorders.ObjectivesWe investigated the integrity of the striatal presynaptic dopaminergic system in subjects presenting IAT to improve the diagnostic accuracy and to explore any putative relationships between ET and PD.MethodsThe striatal dopaminergic system was examined by means of dopamine transporter imaging using ¹²³I-(fluoropropyl)-2ß-carbomethoxy-3ß-(4-iodophenyl) nortropane ([123I]-FP-CIT) single-photon emission tomography (DAT-SPECT) in a clinical series of individuals with IAT, excluding those with associated resting tremor and bradykinesia.ResultsAmong 167 incidental individuals with IAT eligible for DAT-SPECT (Male/Female = 58.9/41.1%; Age = 67.8 ± 14.3 years), reduced striatal uptake was observed in 114 out of 167 (68.3%), whereas normal striatal binding was observed in the remaining 53 subjects (31.7%). Onset of tremor after 50 years and asymmetrical distribution of tremor were predictive variables of nigrostriatal denervation, whereas gender, family history and the presence of intentional, cephalic or voice tremors were not associated with nigrostriatal denervation.ConclusionsOur findings suggest that IAT is a frequent presenting symptom in a subset of individuals with PD, often misdiagnosed as ET, and that DAT-SPECT can help differentiate between these two disorders. Current diagnostic criteria for ET should be revised to include asymmetry and late-onset tremor as predictors of nigrostriatal denervation.     

Self-regulatory practices of drivers with Parkinson's disease: Accuracy of patient reports

BackgroundStudies suggest that drivers with Parkinson's disease (PD) are more likely than controls to restrict their exposure and avoid challenging situations possibly to compensate for declining abilities; however it is questionable whether patient reports should be taken at face value. To address this issue, this study examined agreement between self-reported and actual driving practices in drivers with and without PD.MethodsTwo electronic devices (one with GPS) were installed in the vehicles of 26 drivers with PD (mean age 71.5 ± 6.8, 77% men) and 20 controls (mean age 70.6 ± 7.9, 80% men) for two weeks. Participants completed a questionnaire on usual driving patterns, scales on Situational Driving Frequency (SDF) and Avoidance (SDA), the MoCA and an interview.ResultsSelf-estimates of distance driven (km) over the two weeks were inaccurate in both groups; however the tendency to under-estimate was more pronounced in PD drivers. Drivers with PD reported more self-restrictions (higher SDA scores, p < .01; lower SDF scores, p < .05), yet drove more at night, in bad weather, in rush hour and on highways than they reported. Drivers with PD had significantly lower MoCA scores overall (p < .01) and on the memory subtest (p < .05), however, MoCA scores were not correlated with self-reported restrictions, or actual driving distance in either group.ConclusionsThese findings indicate that patient reports of driving behavior should not be taken at face value by researchers or clinicians. Patients with PD may be more likely than drivers in general to have problems with recall and possibly less awareness of their driving practices.     

REM sleep behavior disorder in early Parkinson’s disease predicts the rapid dopaminergic denervation

ObjectiveTo test the hypothesis that REM sleep behavior disorder (RBD) in early Parkinson's disease (PD) predicts rapid progression of dopaminergic denervation.Methods123I-FP-CIT single photon emission computed tomography (SPECT) scans were performed sequentially at baseline, 1 year, 2 years, and 4 years in 416 de novo patients with PD. RBD screening questionnaire scores >5 at baseline placed the participant in the likely-RBD group. Temporal changes in the specific binding ratio (SBR; caudate, putamen. sum of both, striatum) were compared between the likely-RBD and the non-likely-RBD groups for more or less affected striatum with a repeated measure ANOVA.ResultsLikely-RBD was reported in 37.7% of the drug-naïve PD patients at baseline. The likely-RBD and non-likely-RBD groups did not have significant differences in the baseline clinical features including gender, age, disease duration, UPDRS motor score, and striatal SBR. Striatal SBR decreased significantly over four years in both groups (P < .001). In the analysis of a more affected striatum, striatal SBR decreased significantly faster in the likely-RBD group than in the non-likely-RBD group (P < .05 for all), whereas it was not statistically significant for the less affected striatum. The mean striatal SBR value (mean value of both striata), especially the caudate SBR, indicated greater acceleration of denervation in the likely-RBD group than in the non-likely-RBD group over time (P < .05).ConclusionLikely-RBD in PD predicts accelerating dopaminergic denervation, thereby implicating it as a marker for a poor prognosis or distinctive subtype in PD.     

Association between dopaminergic dysfunction and anxiety in de novo Parkinson's disease

ObjectivesTo explore the relationships between nigrostriatal dysfunction and neuropsychiatric symptoms (including anxiety, depression and apathy) in a large cohort of newly diagnosed, drug-naïve Parkinson disease (PD) patients compared to a cohort of healthy controls (HC).MethodsThis is a cross-sectional analysis of the Parkinson's Progression Markers Initiative (PPMI) cohort at baseline, including 405 PD patients and 187 HC. Nigrostriatal degeneration was evaluated by means of SPECT DAT scan. Relationships between neuropsychiatric symptoms and DAT uptakes were analysed by means of stepwise multiple regression analysis.ResultsIn the PD group, lower DAT uptake in the right caudate was associated with higher STAI trait subscore (β = −2.939, 95%CI: −4.634 to −1.254, p = 0.001). Depression and apathy scores were not related with DAT uptakes. No associations were found in the HC group.ConclusionsOur cross-sectional analysis of the PPMI data shows that lower caudate DAT uptake is associated with higher level of anxiety. The data strengthens the relationship between dopaminergic dysfunction and neuropsychiatric symptoms in early PD.