Expanding the spectrum of VAC14 related pediatric-onset neurological disease; striatonigral degeneration with brainstem involvement.

VAC14 related childhood-onset striatonigral degeneration was first defined in 2016 in two unrelated children with sudden onset neurological disease and regression of developmental milestones. Up to now, 11 cases have been reported. VAC14 is a component of a trimolecular complex that tightly regulates the level of phosphatidylinositol 3,5-bisphosphate (PI (3, 5)P2) and PI (3, 5)P2 is critical for the survival of neural cells. Pathogenic VAC14 variants result in striatonigral degeneration chacterised by prominent vacuolation of neurons in basal ganglia. Here, we present a patient with a homozygous pathogenic VAC14 variant, whose symptoms started at an early age and who had both basal ganglia and brain stem involvement. Our case is one of the youngest patients in literature and involvement of the brain stem is defined for the first time in VAC14 related neurological disease.

MRI biomarkers of motor and non-motor symptoms in Parkinson's disease.

Parkinson's disease is a heterogeneous disorder with both motor and non-motor symptoms that contribute to functional impairment. To develop effective, disease modifying treatments for these symptoms, biomarkers are necessary to detect neuropathological changes early in the disease course and monitor changes over time. Advances in MRI scan sequences and analytical techniques present numerous promising metrics to detect changes within the nigrostriatal system, implicated in the cardinal motor symptoms of the disease, and detect broader dysfunction involved in the non-motor symptoms, such as cognitive impairment. There is emerging evidence that iron sensitive, neuromelanin sensitive, diffusion sensitive, and resting state functional magnetic imaging measures can capture changes within the nigrostriatal system. Iron, neuromelanin, and diffusion sensitive measures demonstrate high specificity and sensitivity in distinguishing Parkinson's disease relative to controls, with inconsistent results differentiating Parkinson's disease relative to atypical parkinsonian disorders. They may also serve as useful monitoring biomarkers, with each possibly detecting different aspects of the disease course (early nigrosome changes versus broader substantia nigra changes). Investigations of non-motor symptoms, such as cognitive impairment, require careful consideration of the nature of cognitive deficits to characterize regional and network specific impairment. While the early, executive dysfunction observed is consistent with nigrostriatal degeneration, the memory and visuospatial impairments, the harbingers of a dementia process reflect dopaminergic independent dysfunction involving broader regions of the brain.

Bilateral striatal necrosis due to homoplasmic mitochondrial 3697G>A mutation presents with incomplete penetrance and sex bias.

BACKGROUND: Heteroplasmic mitochondrial 3697G>A mutation has been associated with leber hereditary optic neuropathy (LHON), mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and LHON/MELAS overlap syndrome. However, homoplasmic m.3697G>A mutation was only found in a family with Leigh syndrome, and the phenotype and pathogenicity of this homoplasmic mutation still need to be investigated in new patients. METHODS: The clinical interviews were conducted in 12 individuals from a multiple-generation inherited family. Mutations were screened through exome next-generation sequencing and subsequently confirmed by PCR-restriction fragment length polymorphism. Mitochondrial complex activities and ATP production rate were measured by biochemical analysis. RESULTS: The male offspring with bilateral striatal necrosis (BSN) were characterized by severe spastic dystonia and complete penetrance, while the female offspring presented with mild symptom and low penetrance. All offspring carried homoplasmic mutation of NC_012920.1: m.3697G>A, p.(Gly131Ser). Biochemical analysis revealed an isolated defect of complex I, but the magnitude of the defect was higher in the male patients than that in the female ones. The ATP production rate also exhibited a similar pattern. However, no possible modifier genes on the X chromosome were identified. CONCLUSION: Homoplasmic m.3697G>A mutation could be associated with BSN, which expanded the clinical spectrum of m.3697G>A. Our preliminary investigations had not found the underlying modifiers to support the double hit hypothesis, while the high level of estrogens in the female patients might exert a potential compensatory effect on mutant cell metabolism.

Bilateral striatal necrosis caused by a founder mitochondrial 14459G>A mutation in two independent Japanese families.

Bilateral striatal necrosis (BSN) has many causes and is characterized by unique clinical and neuroradiological features. Herein, we report a clinical and genetic analysis of three BSN cases from two independent Japanese families harboring a mitochondrial DNA (mtDNA) 14459G>A mutation located in a coding region of the NADH dehydrogenase subunit 6 gene. In the first family, two male siblings from non-consanguineous parents exhibited similar phenotypes, with infantile-onset generalized dystonia. A third sporadic case involved a male patient with a comparatively milder phenotype characterized by juvenile-onset mild truncal ataxia and parkinsonism. Cerebral magnetic resonance imaging of these cases revealed abnormal signal intensities along the bilateral putaminal area and enlarged lateral ventricle anterior horns caused by caudate nuclear atrophy, particularly in the sibling pair. The sibling-pair cases shared a homoplasmic 14459G>A mutation, and the sporadic case showed heteroplasmy of the same mutation. Additionally, all three cases harbored the 14605A>G single nucleotide polymorphism, which was previously reported as a rare synonymous variation (4.3%) in a Japanese population. Plasmid sequencing revealed a genetic linkage of these two DNA substitutions, suggesting that the three patients shared a genetic founder. Although our mtDNA analysis was only accessible using leukocytes, clinical severity might be associated with homoplasmy or heteroplasmy. In summary, it is important to evaluate potential mtDNA defects in BSN cases, regardless of familial occurrence.

Cardiac sympathetic impairment parallels nigrostriatal degeneration in Probable Dementia with Lewy Bodies.

AIM: Dementia with Lewy Bodies (DLB) must be distinguished from other types of dementia because of important differences in patient management and outcome. Both reduction in cardiac 123I-metaiodobenzilguanidine (MIBG) uptake and decreased 123I-FP-CIT binding in basal ganglia have been described in DLB. The aim of this study was to assess the relationship between cardiac sympathetic activity and nigrostriatal degeneration in patients with probable DLB. METHODS: Twenty-eight patients (15 males; mean age 77 years, range 64-88 years) with clinical international criteria of probable DLB were included in the study. All patients underwent a cardiac MIBG scintigraphy and a FP-CIT SPECT. Global cardiac MIBG uptake was semiquantified by means of heart-to-mediastinum ratio (HMR) (normal >1.56). FP-CIT binding in basal ganglia was calculated and compared with an age-matched control group. The relation between cardiac MIBG uptake and FP-CIT uptake in basal ganglia, and the relationship of these two techniques with distinctive symptoms of DLB, features of past medical history and data from the neuropsychological examination were assessed. RESULTS: Cardiac MIBG uptake was decreased in 23 of 28 patients (HMR=1.32, range 0.95-1.85). The FP-CIT binding in basal ganglia was significantly lower than in control group (2.01±0.5 vs 2.62±0.2, P<0.05). All patients with reduced cardiac HMR showed decreased FP-CIT binding in basal ganglia. There was a positive correlation between the HMR and specific binding ratio of striatum (P<0.01). A high correlation between FP-CIT SPECT and the presence of parkinsonism also was found. No correlation between cardiac MIBG uptake and demographic, clinical or neuropsychological data was found. CONCLUSION: In probable DLB cardiac MIBG uptake and FP-CIT binding in basal ganglia are reduced. The positive correlation between both measures suggests that cardiac sympathetic degeneration and nigrostriatal degeneration parallel similarly in patients with probable DLB.

Grooved pegboard test as a biomarker of nigrostriatal denervation in Parkinson's disease.

Recent pharmacotherapy trials in Parkinson's disease (PD) using dopaminergic neuroimaging as outcome parameter failed to show significant relationships between imaging and clinical results. One possible explanation is that there is a non-linear relationship between striatal denervation and motor performance reflecting a statistical "floor" effect in the imaging data with advanced disease. Both the motor manifestations and the striatal dopamine denervation of idiopathic PD, however, are typically asymmetric and more meaningful associations may be found by comparing data from the least denervated striatum with motor performance in the corresponding body side. PD patients (n=28) underwent [11C]beta-CFT dopamine transporter (DAT) positron emission tomography (PET) and grooved pegboard testing. Voxel-based analysis of DAT PET and bimanual pegboard scores demonstrated significant correlation clusters within the bilateral striata (P<0.001). However, findings were most prominent in the least denervated striatum. There was a significant inverse correlation between pegboard scores of the least affected arm and DAT binding of the least denervated striatum (Rs=-0.69, P<0.0001) but no significant correlation between pegboard scores of the clinically most affected arm and DAT binding of the most denervated striatum (Rs=-0.15, ns). These data indicate that the robustness of the grooved pegboard test as a biomarker for nigrostriatal denervation in PD mainly reflects the relationship between test performance of the clinically least affected limb and the least denervated striatum. These findings indicate that there is both a statistical "floor" and "ceiling" effect for the most affected striatal and body sides that must be considered when employing imaging as an outcome measure in clinical trials in PD.

Striatal dopamine transporter in dementia with Lewy bodies and Parkinson disease: a comparison.

OBJECTIVE: To study the nigrostriatal pathways in 21 patients with dementia with Lewy bodies (DLB), 19 drug naive Parkinson disease (PD) patients, and 16 controls using a dopaminergic presynaptic ligand [123I]-2beta-carbometoxy-3beta-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) and SPECT in order to assess similarities or differences between DLB and PD. METHODS: A SPECT scan was carried out 3 to 4 hours after administration of 185 MBq (IV) of FP-CIT. Using occipital cortex as a radioactivity uptake reference, ratios for the caudate nuclei and the anterior and posterior putamina of both hemispheres were calculated. From the FP-CIT binding measurements, asymmetry indices and caudate:putamen ratios were derived. RESULTS: The DLB and PD groups had lower FP-CIT binding in all striatal areas than controls (analysis of variance: p < 0.001 in all measures). DLB patients also had significantly lower binding in the caudate nucleus than the PD patients. There was greater asymmetry of uptake in the posterior putamina of PD patients than DLB patients (p < 0.04) and controls (p < 0.01). The mean caudate:putamen ratio for the DLB group was not significantly different from that of the controls, while the mean caudate:putamen ratio of the PD group was higher than that of the control group (p < 0.001) and the DLB group (p < 0.001). CONCLUSION: This study showed differences between PD and DLB in the pattern of striatal dopaminergic dysfunction. DLB patients do not have the characteristic selective degeneration of ventrolateral nigral neurons seen in PD. This could explain some of the clinical differences between DLB and PD.

[Statistic rCBF study of extrapyramidal disorders].

We studied regional cerebral blood flow (rCBF) in 16 patients with Parkinson's disease (PD), 2 patients with dementia with Lewy bodies (DLB), 2 patients with progressive supranuclear palsy (PSP), 2 patients with striatonigral degeneration, and 16 normal volunteers, using Three-dimensional stereotactic surface projections (3 D-SSP). Decreased rCBF in PD patients was shown in the posterior parietal and occipital cortex. Decreased rCBF in DLB was shown in the frontal, parietal and occipital cortex with relative sparing of the sensorimotor cortex. Decreased rCBF in PSP was shown in the frontal cortex. Decreased rCBF in SND was shown in the frontal cortex and cerebellum. Statistic rCBF analysis using 3 D-SSP was a useful measure for the early differential diagnosis of extrapyramidal disorders.

Striatal dopamine transporter function in dementia with Lewy bodies and Parkinson's disease.

The aim of this study was to compare parkinsonian features and loss of striatal dopamine transporter (DAT) function in patients with dementia with Lewy bodies (DLB) and Parkinson's disease (PD), matched for age and disease duration. Twenty patients with DLB. 24 PD patients and 10 matched controls were examined with SPET using a dual-head camera and the dopamine-transporter ligand 123I-beta-CIT (148 MBq). Moreover, in a subgroup of patients (16 DLB and 20 PD patients), subscores of the Unified Parkinson's Disease Rating Scale (UPDRS)-motor examination (ME) subscale were obtained during "practical off", i.e. 12 h following withdrawal of antiparkinsonian therapy. Compared with controls, striatal/cerebellar (S/C) ratios of DAT binding were significantly reduced in both DLB and PD, deficits being more marked in DLB patients (controls 7.2 +/- 1.2, DLB 3.3 +/- 1, PD 4.2 +/- 1.4; means +/- SD). The side-to-side differences in the S/C ratios were lower in the DLB group and the controls than in PD patients (0.4 +/- 0.4. 0.2 +/- 0.2 and 0.6 +/- 0.3, respectively, P<0.05). The total UPDRS-ME scores during practical-off were significantly higher in the DLB than in the PD group (41.2 +/- 12.7 vs 26.6 +/- 15.3, P<0.01). The side-to-side differences of the summed UPDRS extremity subscores were smaller in the DLB than in the PD group (2.2 +/- 2.3 vs 7.4 +/- 3.9, P<0.0001). Our findings suggest that parkinsonism evolves largely symmetrically and progresses more rapidly with more severe loss of striatal dopamine transporter function in DLB compared to PD. Whether these findings are helpful in the differential diagnosis of DLB and PD needs to be examined in further studies.

Tremor is associated with PET measures of nigrostriatal dopamine function in MPTP-lesioned monkeys.

Unilateral intracarotid artery (ICA) MPTP infusion, along with sequential systemic doses of MPTP, produces near complete degeneration of the nigrostriatal pathway on the side of infusion (ipsilateral) and variable levels of damage in the contralateral hemisphere accompanied by varying levels of parkinsonism (overlesioned hemiparkinsonian model). Positron emission tomography and the dopamine (DA) metabolism tracer [(18)F]6-fluoro-l-m-tyrosine (FMT) were used to evaluate the relationship between DA metabolism and clinical features of parkinsonism in 14 overlesioned hemiparkinsonian monkeys. Monkeys were rated on a parkinsonian scale that included ratings of bradykinesia, fine motor skills (FMS), and rest tremor. Because the monkeys tended to show more severe clinical signs on the side of the body contralateral to ICA MPTP infusion, we calculated asymmetry scores for each of the clinical features as well as for FMT uptake (K(i)) in the caudate and putamen. Tremor asymmetry was associated with FMT uptake asymmetry in the putamen. No such relationship was observed for FMS or bradykinesia. The overall severity of tremor (mild, moderate/severe) was associated with FMT uptake in the caudate and putamen. Postmortem biochemical analysis for a subset of monkeys showed that the monkeys with moderate/severe tremor had significantly lower DA levels in both caudate and putamen than those with mild tremor. In addition, K(i) values were significantly correlated with DA levels in both caudate and putamen. These findings support the idea that nigrostriatal degeneration contributes to rest tremor.