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Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson's disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4-5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration., Competing Interests: Competing interests The authors declare no competing interests related to this article. B.A.G. provides consulting services for Natera, Inc. D.J.S. has received consultancy honoraria in the past 3 years from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. P.S. reports personal fees from Bial, AbbVie, and Boston Scientific. G.G. owns stocks in Koios Care (https://www.koios.care/) and has received consultancy fees from Abbvie Belgium, Zambon Belgium, and EG Belgium (Stada group). He also received an Honorarium from Abbvie Belgium, Zambon Belgium, and EG Belgium. J.W. has received Honoraria from the Movement Disorders Society. K.P. owns stocks in Amprion and Curasen. She has also received honoraria from invited scientific presentations to universities and professional societies not exceeding $5000/yr and provides consulting services to Curasen. J.K. has received Honoraria from Ipsen and Merz. Y.D.v.d.W. has received a speaker’s fee for postdoctoral training organized by Medilex and AbbVie., (© 2024. The Author(s).)

Background: Increasing evidence points to a pathophysiological role for the cerebellum in Parkinson's disease (PD). However, regional cerebellar changes associated with motor and non-motor functioning remain to be elucidated., Objective: To quantify cross-sectional regional cerebellar lobule volumes using three dimensional T1-weighted anatomical brain magnetic resonance imaging from the global ENIGMA-PD working group., Methods: Cerebellar parcellation was performed using a deep learning-based approach from 2487 people with PD and 1212 age and sex-matched controls across 22 sites. Linear mixed effects models compared total and regional cerebellar volume in people with PD at each Hoehn and Yahr (HY) disease stage, to an age- and sex- matched control group. Associations with motor symptom severity and Montreal Cognitive Assessment scores were investigated., Results: Overall, people with PD had a regionally smaller posterior lobe (d max  = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (d max  = 0.28) in people with PD in HY stage 1 compared to controls. In contrast, smaller bilateral lobule VII volume in the posterior lobe was observed in HY stages 3, 4, and 5 (d max  = -0.76), which was incrementally lower with higher disease stage. Within PD, cognitively impaired individuals had lower total cerebellar volume compared to cognitively normal individuals (d = -0.17)., Conclusions: We provide evidence of a dissociation between anterior "motor" lobe and posterior "non-motor" lobe cerebellar regions in PD. Whereas less severe stages of the disease are associated with larger motor lobe regions, more severe stages of the disease are marked by smaller non-motor regions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

COVID-19 was declared a pandemic in March 2020. The knowledge of COVID-19 pathophysiology soon provided a strong rationale for the early use of both anti-inflammatory and antithrombotic drugs; however, its evidence was slowly and partially incorporated into institutional guidelines. The unmet needs of COVID-19 outpatients were taken care of by networks of physicians and researchers. We analyse the characteristics, management and outcomes in COVID-19 outpatients who were taken care of by physicians within the IppocrateOrg Association. In this observational retrospective study, volunteering doctors provided data on 392 COVID-19 patients. The mean age of patients was 48.5 years (range: 0.5-97), and patients were taken care of in COVID-19 stage 0 (15.6%), stage 1 (50.0%), stage 2a (28.8%) and stage 2b (5.6%). Many patients were overweight (26%) or obese (11.5%), with chronic comorbidities (34.9%), mainly cardiovascular (23%) and metabolic (13.3%). The most frequently prescribed drugs included: vitamins and supplements (98.7%), aspirin (66.1%), antibiotics (62%), glucocorticoids (41.8%), hydroxychloroquine (29.6%), enoxaparin (28.6%), colchicine (8.9%), oxygen therapy (6.9%), and ivermectin (2.8%). Hospitalization occurred in 5.8% of cases, mainly in stage 2b (27.3%). A total of 390 patients (99.6%) recovered; one patient was lost at follow up, and one patient died after hospitalization. This is the first real-world study describing the behaviours of physicians caring for COVID-19 outpatients, and the outcomes of COVID-19 early treatment. The lethality in this cohort was 0.2%, while overall, and over the same period, the COVID-19 lethality in Italy was over 3%. The drug use described in this study appears effective and safe. The present evidence should be carefully considered by physicians and political decision makers.

Background: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated., Objective: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging., Methods: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score., Results: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (d max  = -0.20, d min  = -0.09). The bilateral putamen (d left  = -0.14, d right  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures., Conclusions: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: PINK1 mutations are likely to affect mitochondrial function. The objective of this study was to study brain mitochondrial function in patients with early-onset Parkinson's disease, with or without PINK1 mutations., Methods: We investigated brain intracellular pH, mitochondrial activity, and energetics with functional magnetic resonance spectroscopy in patients with early-onset Parkinson's disease with PINK1 mutations (n = 10), early-onset Parkinson's disease without PINK1 mutations (n = 10), and healthy sex- and age-matched subjects (n = 20). We measured peak areas of phosphocreatine and beta adenosine triphosphate., Results: The EOPD- group had normal PCr + βATP contents at rest (P = NS) and under activation (P = NS), but reduced contents during recovery (P < 0.001). The EOPD+ group had abnormal PCr + βATP contents at rest (P < 0.001) and during activation (P < 0.001); during recovery, the contents only partially recovered (P < 0.001). Brain intracellular pH alterations were more severe with EOPD+ than with EOPD-., Conclusions: Brain mitochondrial impairments were similar in early-onset Parkinson's disease without PINK1 mutations and late-onset Parkinson's disease. However, mitochondrial impairments were more severe in early-onset Parkinson's disease with PINK1 mutations. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) is associated with brain mitochondrial dysfunction. High-energy phosphates (HEPs), which rely on mitochondrial functioning, may be considered potential biomarkers for PD. Phosphorus magnetic resonance spectroscopy ( 31 P-MRS) is a suitable tool to explore in vivo cerebral energetics. We considered 10 31 P-MRS studies in order to highlight the main findings about brain energetic compounds in patients affected by idiopathic PD and genetic PD. The studies investigated several brain areas such as frontal lobes, occipital lobes, temporoparietal cortex, visual cortex, midbrain, and basal ganglia. Resting-state studies reported contrasting results showing decreased as well as normal or increased HEPs levels in PD patients. Functional studies revealed abnormal PCr + βATP levels in PD subjects during the recovery phase and abnormal values at rest, during activation and recovery in one PD subject with PINK1 gene mutation suggesting that mitochondrial machinery is more impaired in PD patients with PINK1 gene mutation. PD is characterized by energetics impairment both in idiopathic PD as well as in genetic PD, suggesting that mitochondrial dysfunction underlies the disease. Studies are still sparse and sometimes contrasting, maybe due to different methodological approaches. Further studies are needed to better assess the role of mitochondria in the PD development.

Quantifying global international mobility patterns can improve migration governance. Despite decades of calls by the international community to improve international migration statistics, the availability of timely and disaggregated data about long-term and short-term migration at the global level is still very limited. In this study, we investigate the feasibility of using non-traditional data sources to fill existing gaps in migration statistics. To this end, we use anonymised and publicly available data provided by Facebook's advertising platform. Facebook's advertising platform classifies its users as "lived in country X" if they previously lived in country X, and now live in a different country. Drawing on statistics about Facebook Network users (Facebook, Instagram, Messenger, and the Audience Network) who have lived abroad and applying a sample bias correction method, we estimate the number of Facebook Network (FN) "migrants" in 119 countries of residence and in two time periods by age, gender, and country of previous residence. The correction method estimates the probability of a person being a FN user based on age, sex, and country of current and previous residence. We further estimate the correlation between FN-derived migration estimates and reference official migration statistics. By comparing FN-derived migration estimates in two different time periods, January-February and August-September 2018, we successfully capture the increase in Venezuelan migrants in Colombia and Spain in 2018. FN-derived migration estimates cannot replace official migration statistics, as they are not representative, and the exact methods the FN uses for classifying its users are not known, and might change over time. However, after carefully assessing the validity of the FN-derived estimates by comparing them with data from reliable sources, we conclude that these estimates can be used for trend analysis and early-warning purposes., Competing Interests: The authors have declared that no competing interests exist.

This paper reconsiders the role of mitochondria in aging and in Parkinson's Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD., Competing Interests: The authors declare no conflict of interest.

Background and Aims: Non-alcoholic fatty liver disease is recognized not only as part of the metabolic syndrome but also as an independent predictor of cardiovascular disease., Methods: In this study, NMR spectroscopy method, together with perfusion techniques, was used to detect subclinical brain vascular damage in subjects with NAFLD without overt atherosclerosis risk factors (i.e. hypertension, diabetes, hypercholesterolemia, obesity)., Results: The results suggest that subjects with histologically proven NAFLD have a reduced cerebral perfusion (CBFr) confined to limited brain areas, i.e., left semioval center and posterior cingulate cortex. No statistically significant differences in CBFr values were found, dividing the NAFLD cohort into subgroups, considering NAS score, presence/absence of NASH/fibrosis, and degree of steatosis., Conclusions: Our data suggest that NAFLD per se may be involved in cerebral atherosclerotic disease. It will be interesting to draw longitudinal studies to determine whether these changes could evolve in more serious cerebral injury., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We discuss here an uncommon condition of neurogenic hypotension in the context of immunoglobulin light chain (amyloid light-chain) amyloidosis. The most serious feature was autonomic nervous system impairment, mainly characterized by severe refractory orthostatic hypotension, which became progressively invalidating, forcing the patient to bed. Moreover, since the systemic involvement of the disease, the patient presented also diarrhea, dysphagia, asthenia, peripheral edema because of gastrointestinal, and kidney dysfunction. Eventually, the massive myocardial depression and infiltration led to a fatal outcome., Competing Interests: There are no conflicts of interest.

Background: Posterior Cortical Atrophy (PCA) is a neurodegenerative disease characterized by a progressive decline in selective cognitive functions anatomically referred to occipital, parietal and temporal brain regions, whose diagnosis is rather challenging for clinicians. The aim of this study was to assess, using quantitative Magnetic Resonance Imaging techniques, the pattern of regional grey matter loss and metabolism in individuals with PCA to improve pathophysiological comprehension and diagnostic confidence., Methods: We enrolled 5 patients with PCA and 5 matched controls who all underwent magnetic resonance imaging (MRI) and spectroscopy (MRS). Patients also underwent neuropsychological and cerebrospinal fluid (CSF) assessments. MRI data were used for unbiased assessment of regional grey matter loss in PCA patients compared to controls. MRS data were obtained from a set of brain regions, including the occipital lobe and the centrum semiovale bilaterally, and the posterior and anterior cingulate., Results: VBM analysis documented the presence of focal brain atrophy in the occipital lobes and in the posterior parietal and temporal lobes bilaterally but more pronounced on the right hemisphere. MRS revealed, in the occipital lobes and in the posterior cingulate cortex of PCA patients, reduced levels of N-Acetyl Aspartate (NAA, a marker of neurodegeneration) and increased levels of Myo-Inositol (Ins, a glial marker), with no hemispheric lateralization., Conclusion: The bilateral but asymmetric pattern of regional grey matter loss is consistent with patients' clinical and neuropsychological features and with previous literature. The MRS findings reveal different stages of neurodegeneration (neuronal loss; gliosis), which coexist and likely precede the occurrence of brain tissue loss, and might represent early biomarkers. In conclusion, this study indicates the potential usefulness of a multi-parametric MRI approach for an early diagnosis and staging of patients with PCA.

Purpose: Temperature plays a fundamental role for the proper functioning of the brain. However, there are only fragmentary data on brain temperature (T(br)) and its regulation under different physiological conditions., Methods: We studied T(br) in the visual cortex of 20 normal subjects serially with a wide temporal window under different states including rest, activation and recovery by a visual stimulation-Magnetic Resonance Spectroscopy Thermometry combined approach. We also studied T(br) in a control region, the centrum semiovale, under the same conditions., Results: Visual cortex mean baseline T(br) was higher than mean body temperature (37.38 vs 36.60, P<0.001). During activation Tbr remained unchanged at first and then showed a small decrease (-0.20 C°) around the baseline value. After the end of activation T(br) increased consistently (+0.60 C°) and then returned to baseline values after some minutes. Centrum semiovale T(br) remained unchanged through rest, visual stimulation and recovery., Conclusion: These findings have several implications, among them that neuronal firing itself is not a major source of heat release in the brain and that there is an aftermath of brain activation that lasts minutes before returning to baseline conditions.

In vivo brain metabolomics in Parkinson's disease is still in its infancy. This chapter will review brain metabolomics in the human brain as studied noninvasively by magnetic resonance spectroscopy. Although preliminary, the results shed some light on the pathophysiology of Parkinson's disease., (© 2015 Elsevier Inc. All rights reserved.)

We sought to study brain temperature in patients with mitochondrial diseases in different functional states compared with healthy participants. Brain temperature and mitochondrial function were monitored in the visual cortex and the centrum semiovale at rest and during and after visual stimulation in seven individuals with mitochondrial diseases (n=5 with mitochondrial DNA mutations and n=2 with nuclear DNA mutations) and in 14 age- and sex-matched healthy control participants using a combined approach of visual stimulation, proton magnetic resonance spectroscopy (MRS), and phosphorus MRS. Brain temperature in control participants exhibited small changes during visual stimulation and a consistent increase, together with an increase in high-energy phosphate content, after visual stimulation. Brain temperature was persistently lower in individuals with mitochondrial diseases than in healthy participants at rest, during activation, and during recovery, without significant changes from one state to another and with a decrease in the high-energy phosphate content. The lowest brain temperature was observed in the patient with the most deranged mitochondrial function. In patients with mitochondrial diseases, the brain is hypothermic because of malfunctioning oxidative phosphorylation. Neuronal activity is reduced at rest, during physiologic brain stimulation, and after stimulation.

Mutations in the PINK1 gene are associated with early onset autosomal recessive parkinsonism (EOP), which is characterized by a phenotypic presentation that, although variable, generally overlaps with that of idiopathic Parkinson Disease (PD). The clinical features and brain metabolomics of a patient who was compound heterozygous for the novel association of PINK1 A168P/W437X mutations have been extensively characterized. Apart from a few typical EOP findings, the clinical features and SPECT mostly overlapped with typical idiopathic PD. Brain metabolomics, as examined by magnetic resonance spectroscopy and PET, were clearly distinguishable., (2012 Elsevier B.V. All rights reserved)

Unlabelled: INTRODUCTION, PATIENTS AND METHODS: We measured brain temperature in a case of central hyperthermia., Results: Brain temperature was increased except for hypothalamus that was colder., Conclusion: We suppose that central hyperthermia is driven by cold hypothalamus.

Vanishing white matter (VWM; OMIM # 603896) is one of the most prevalent inherited childhood leukoencephalopathies. It has, however, become evident that VWM has a wider clinical spectrum, with age at onset inversely related to clinical severity. Many affected women experience a combination of leukoencephalopathy and primary amenorrhea or premature ovarian failure, a condition named ovarioleukodystrophy. Mutations in any of the genes encoding the 5 subunits of the Eukaryotic Initiation Factor 2B gene (EIF2B1, 2, 3, 4, and 5) can independently cause VWM.(1).

This review article presents a summary of recent efforts to understand brain temperature and its regulation under different conditions. Brain temperature has a crucial influence on brain processes. Its regulation is the outcome of the balance of core and arterial blood temperatures, cerebral blood flow, brain metabolism, functional conditions, and external temperature. However, the relationship between these factors is not fully understood and several uncertainties remain. There are no satisfactory normative data on temperatures throughout the brain, but new technologies promise to fill this gap. Brain temperature changes with brain functional activation and under pathological conditions in ways that are not understood. A full understanding of brain temperature control is mandatory to optimize attempts at brain cooling during clinical conditions such as stroke and head injury.

The maintenance of a stable temperature is of the utmost importance for the proper functioning of the brain. Brain temperature is tightly linked to mitochondrial energetics. Although Parkinson's disease is characterized by mitochondrial dysfunction, no data are available on brain temperature. We measured the temperature in the visual cortex and in the centrum semiovale at rest by proton magnetic resonance spectroscopy in patients with Parkinson's disease and in age-matched and sex-matched control participants. We report evidence of increased temperature in the visual cortex and, to a minor extent, in the centrum semiovale of patients with Parkinson's disease. The increase in brain temperature is best explained by an energy loss along the oxidative phosphorylation/respiratory chain.

Objective: The objective of the study was to determine the feasibility of detecting fetal brain lactate, a marker of fetal metabolic acidemia, using a noninvasive technique, proton magnetic resonance spectroscopy ((1)H MRS), in intrauterine growth-restricted (IUGR) fetuses., Study Design: In vivo human fetal brain lactate detection was determined by (1)H MRS in 5 fetuses with IUGR. Oxygenation and acid-base balance data were obtained at birth., Results: (1)H MRS analysis showed the presence of a lactate peak in the brain of the most severely affected IUGR fetus, with abnormal umbilical artery Doppler and fetal heart rate tracing. This finding was consistent with the low oxygen content and high lactic acid concentration observed in umbilical blood obtained at delivery., Conclusion: (1)H MRS allows the noninvasive detection of cerebral lactate in IUGR fetuses. Lactate detected by (1)H MRS may represent a possible marker of in utero cerebral injury or underperfusion., (Crown Copyright © 2011. Published by Mosby, Inc. All rights reserved.)

Magnetic resonance spectroscopy represents an invaluable tool for the in vivo study of brain development at the chemistry level. Whereas magnetic resonance spectroscopy has received wide attention in pediatric and adult settings, only a few studies were performed on the human fetal brain. They revealed changes occurring throughout gestation in the levels of the main metabolites detected by proton magnetic resonance spectroscopy (N-acetylaspartate, choline, myo-inositol, creatine, and glutamate), providing a reference for the normal metabolic brain development. Throughout the third trimester of gestation, N-acetylaspartate gradually increases, whereas choline undergoes a slow reduction during the process of myelination. Less clear are the modifications in creatine, myo-inositol, and glutamate levels. Under conditions of fetal distress, the meaning of lactate detection is unclear, and further studies are needed. Another field for investigation involves the possibility of early detection of glutamate levels in fetuses at risk for hypoxic-ischemic encephalopathy, because the role of glutamate excitotoxicity in this context is well-established. Because metabolic modifications may precede functional or morphologic changes in the central nervous system, magnetic resonance spectroscopy may likely serve as a powerful, noninvasive tool for the early diagnosis and prognosis of different pathologic conditions.

Background: The axonal forms of Charcot-Marie-Tooth (CMT2) disease are a clinically and genetically heterogeneous group of disorders. Mitofusin 2 gene (MFN2) mutations are the most common cause of CMT2. Complex phenotypes have been described in association with MFN2 gene mutations, including CMT2 with pyramidal features (hereditary motor and sensory neuropathy [HSMN V]) and CMT2 with optic atrophy (HMSN VI)., Objective: To report on the clinical, neurophysiologic, and neuropathologic features of an Italian family with a novel MFN2 gene mutation and investigate brain functional parameters using magnetic resonance spectroscopy (MRS)., Methods: Three family members, a father and his two sons, were affected by peripheral neuropathy, cognitive impairment, and poor nocturnal vision (also optic neuropathy in one case). A member of this family also showed spastic paraparesis. The MFN2 gene sequence was analyzed. A sural nerve biopsy as well as brain (1)H-MRS and (31)P-MRS were evaluated in two patients., Results: Affected family members carried a novel MFN2 missense mutation, namely R104W, located within the critical GTPase domain of the protein which affects a highly conserved amino acid position. Sural nerve biopsies showed a normal mitochondrial network, particularly at the nodes of Ranvier, upon electron microscopy examination. A significant defect of high energy phosphates (HEPs) in the visual cortex was observed at rest by (31)P-MRS in the adult proband, while his son showed a defective recovery of HEPs after stimulation of the visual cortex., Conclusion: Cognitive impairment may be another feature of the MFN2-related phenotype. The widespread peripheral and CNS involvement, as well as the neurosensorial defects, underline the similarities among MFN2-related and primary mitochondrial disorders.

Brain content of myoinositol (mI) has been shown to be altered in several neuropsychiatric conditions. Likewise, various forms of electric currents have been applied to the human brain for therapeutic purposes in neuropsychiatric diseases. In this study we aimed to depict the effects of low-power transcranial direct current stimulation (tDCS) on brain mI by proton magnetic resonance spectroscopy ((1)H-MRS). We studied two groups of five healthy subjects by (1)H-MRS: the first group was studied before and after both anodal and sham (placebo) tDCS over the right frontal lobe, and the second group was studied at the same intervals without undergoing either sham or anodal tDCS. Anodal tDCS induced a significant increase of mI content at 30 min after stimulation offset (141.5 +/- 16.7%, P < 0.001) below the stimulating electrode but not in distant regions, such as the visual cortex, whereas sham tDCS failed to induce changes in mI. Neither N-acetyl-aspartate (NAA) nor the other metabolite contents changed after anodal or sham stimulation. (1)H-MRS represents a powerful tool to follow the regional effects of tDCS on brain mI and, possibly, on the related phosphoinositide system., ((c) 2008 Wiley-Liss, Inc.)

Purpose: To develop a method for the non-invasive detection and quantification of eyelid movements during spontaneous blinking., Methods: Spontaneous eyelid movements were monitored using an optoelectronic motion analyzer with passive markers in a younger group aged 20-30 years (13 men, 12 women) and in an older group over 50 years (10 men and nine women). Blink rate, eyelid displacement as a percentage of maximum excursion, and maximum eyelid velocity in closing and opening were calculated., Results: Spontaneous blink rate was significantly larger in women than in men (19 vs 11 blinks per minute); older women blinked more frequently than younger women. On average, young men closed the eyes completely (or almost completely) 44% of times, whereas the eyelid closure of young and older women was more frequently between 51 and 75% of the maximum excursion. Older men rarely closed completely and showed a similar frequency of blinks with up to 25%, 50% and 75% of maximum excursion. During eyelid closure and opening, the maximum velocity reduced with age: older subjects moved their eyelids approximately 80-70% slower than younger subjects. In all subjects, closing was performed 40-47% faster than opening; women moved faster than men. Eyelid displacement was greater in young than in older subjects., Conclusions: The method used in this study allowed the non-invasive detection of eyelid movements during spontaneous blinking, providing a set of descriptive and kinematic data. The method could also be used to assess blink characteristics in patients with movement disorders, without invasive or time-consuming procedures.

We tested the hypothesis that parkin polymorphisms (SNPs) and environmental exposure (EE) interact to reduce the age of onset of idiopathic Parkinson disease (PD). We prospectively and consecutively enrolled a total of 81 Italian PD patients. The diagnosis of PD was based on the UK Parkinson's Disease Society's brain bank criteria. Twenty-one patients with a positive family history for PD or tremor were excluded from the study. We collected information about medical history and EE. PARK1, PARK2 genes and PARK8 (exon 41) were screened. We detected one parkin mutation in a single patient and three parkin polymorphisms in a total of 25 patients; no alpha synuclein mutations, no common mutations of LRKK2 gene were found. The mutation-positive patient has been excluded from the study. The cohort of the remaining 59 patients has been divided into four subgroups, according to the presence/absence of parkin polymorphisms and the presence/absence of environmental factors-exposure. The age of onset of PD was significantly lower in patients with both SNPs and EE as compared to patients without (62.18+/-9.5 years versus 71.62+/-8 years, p=0.024; -13%). Patients with either SNPs or EE had an intermediate age of onset. The association of parkin polymorphisms and environmental exposure has a strong effect in lowering the age of onset of PD; the effect of environmental exposure or parkin polymorphisms alone seems to influence modestly the age of onset of PD. Individuals with environmental/occupational exposure should be screened for the presence of parkin SNPs.

This paper looks at the use of magnetic resonance spectroscopy (MRS) for diagnostic and research purposes in Parkinson's disease and parkinsonian syndromes. The review considers both proton MRS (1H MRS) and phosphorus MRS (31 P MRS) studies. MRS is useful for diagnostic purposes, helping to differentiate Parkinson's disease from other parkinsonian syndromes. Even more usefully, MRS can be used for non invasive in vivo human research.

Several patients with Parkinson' s disease (PD) reveal an history of chronic exposure to hydrocarbon-solvents. Chronic exposure to hydrocarbon-solvents has been proposed as a risk factor for more severe forms of PD with earlier onset of symptoms and reduced response to dopaminergic therapy. A direct correlation between disease severity and exposure degree has been previously shown. Seven exposed PD patients (two with low degree exposure and five with high degree exposure), 10 unexposed PD patients matched for sex, age and Hoehn and Yahr scale (=3 in the "on" phase), and 10 unexposed PD patients matched for sex, age and l-dopa daily intake instead of disease severity (Hoehn and Yahr scale=3.5 in the "on" phase) were studied. Twenty normal subjects without previous exposure to hydrocarbon-solvents and matched for age and sex with HPD patients were studied for comparison. The purpose of the study was to assess neuronal degeneration in the striatum of exposed vs unexposed PD patients. The authors investigated whether neuronal damage/loss was detectable in the lentiform nucleus measuring N-acetylaspartate (NAA) levels by 1-H MRS. Multiple single voxel MRS water-suppressed spectra were obtained also from the white matter and the occipital lobe. NAA was normal in the lentiform nucleus of patients with low exposure as well as in patients with no exposure whereas it was decreased in PD patients with high degree exposure. White matter and occipital lobe NAA content was normal both in exposed and unexposed PD patients. Clinical expression is more severe in PD patients with previous high degree solvent exposure because of the associated post-synaptic damage of the nigro-striatal pathway.

In spite of several evidences for a mitochondrial impairment in Parkinson's disease (PD), so far it has not been possible to show in vivo mitochondrial dysfunction in the human brain of PD patients. The authors used the high temporal and spatial resolution 31 phosphorus magnetic resonance spectroscopy (31P MRS) technique, which they have previously developed in normal subjects and in patients with mitochondrial diseases to study mitochondrial function by observing high-energy phosphates (HEPs) and intracellular pH (pH) in the visual cortex of 20 patients with PD and 20 normal subjects at rest, during, and after visual activation. In normal subjects, HEPs remained unchanged during activation, but rose significantly (by 16%) during recovery, and pH increased during visual activation with a slow return to rest values. In PD patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 36%) in the recovery period; pH did not reveal a homogeneous pattern with a wide spread of values. Energy unbalance under increased oxidative metabolism requirements, that is, the postactivation phase, discloses a mitochondrial dysfunction that is present in the brain of patients with PD even in the absence of overt clinical manifestations, as in the visual cortex. This is in agreement with our previous findings in patients with mitochondrial disease without clinical central nervous system (CNS) involvement. The heterogeneity of the physicochemical environment (i.e., pH) suggests various degrees of subclinical brain involvement in PD. The combined use of MRS and brain activation is fundamental for the study of brain energetics in patients with PD and may prove an important tool for diagnostic purposes and, possibly, to monitor therapeutic interventions.

It remains unclear whether brain energetics is disturbed in patients with mitochondrial disease without clinical central nervous system involvement (MDW). The authors used the high temporal and spatial resolution phosphorus magnetic resonance spectroscopy (31P MRS) technique that they developed to study high energy phosphates (HEPs) and intracellular pH (pH) in the visual cortex of 9 normal subjects and 5 MDW patients with single mtDNA deletion at rest, during, and after visual activation. In normal subjects, HEPs remained unchanged during activation but rose significantly (by 17%) during recovery, and pH increased during visual activation with a slow return to rest values. In MDW patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 22%) in the recovery period; pH did not reveal a homogeneous pattern. In the brain of patients with MDW, energy balance remains normal until oxidative metabolism is intensively stressed, as during a postactivation phase. The heterogeneity of the physicochemical environment (that is, pH) suggests various degrees of subclinical brain involvement. The combined use of MRS and brain activation is fundamental for the study of brain energetics and may prove an important diagnostic tool in patients with MDW.

No direct information on brain energetics and energy-related compounds in the first seconds of physiological activation has been reported to date. In this study visual cortex high energy phosphate changes were monitored in 11 normal subjects during 3.5 s activation and the following 23.5 s by a simple 31P magnetic resonance spectroscopic method. An intraactivation decrease of phosphocreatine (PCr) was observed in all subjects, with changes in pH in three, one of them also presenting a change in adenosine triphosphate (ATP). In the subgroup of eight subjects without changes in pH, the mean rate of mean PCr decrease (D(PCr)) was 7.24 +/- 0.78%/s, and the postactivation mean rate of mean PCr recovery was <1/2 D(PCr). Short phasic neural activity requires a large amount of energy, i.e., at least three times basal consumption, in agreement with theoretical calculations. Additional energy demands in the visual cortex are several times those measured by positron emission tomography during prolonged stimulation studies, implying that mean energy requirements decrease with increases in duration of stimulation. During short activation, the vascular responses as detected by brain-mapping techniques (BMT) are preceded by an important reduction of the intracellular high-energy phosphate content, which returns to resting values during an interval that corresponds to the poststimulation return of BMT signals to baseline.

N-acetylaspartate (NAA) has previously been proposed as a neuronal marker. 1H magnetic resonance spectroscopy (MRS) is able to detect NAA in brain, and decreases of NAA have been documented after brain injury. The reason for this decrease is not fully understood and neuron loss damage and "dysfunction" have all been proposed. It is hypothesized that acute central nervous system (CNS) deafferentation causes a trans-synaptic NAA decrease and that high resolution 1H MRS is able to detect such a decrease. To test this hypothesis, an experimental model was used in which axonal lesions were obtained by stretch injury in guinea pig right optic nerve (95-99% crossed fibers). The trans-synaptic concentration of NAA, total creatine (Cr), and the NAA/Cr ratio in lateral geniculate bodies (LGB) and superior colliculi (SC) sample extracts were measured 72 h later by high resolution 1H MRS. In the left LGB/SC, which is where right optic nerve fibers project, reductions of NAA and NAA/Cr were found whereas Cr levels were normal. NAA, NAA/Cr, and Cr values were all normal in the right LGB/SC. Histology and EM findings revealed no abnormalities. At 7 days, left LGB/SC NAA and NAA/Cr values were in the normal range. It was concluded that 1) acute deafferentation in the CNS causes a trans-synaptic decrease of NAA levels that can be detected by 1H MRS and 2) NAA decrease may be due to changes of NAA metabolism caused by functional neuronal inactivity rather than neuronal loss, injury or "dysfunction." 1H MRS is a potential tool for the study of functional effect of CNS lesions in vivo.

It has been suggested that brain acidosis may follow head trauma, and therapies aimed at correcting acidosis have been proposed. Direct measurements of intracellular pH, however, have thus far not been possible in clinical situations. We have studied the intracellular brain pH in 22 patients after head injury (mean Glasgow Coma Score 6.1). Patients were investigated by a combined approach of phosphorus 31 magnetic resonance spectroscopy and magnetic resonance imaging (overall examination time 50-75 min) at a mean time of 11 days after injury (36 hours to 24 days). 31P spectra were obtained in 11 patients on assisted ventilation and in 11 patients on spontaneous ventilation. These spectra were analyzed to yield the pH in the regions studied in all the patients. All pH values were in the normal or alkalotic range when compared with 6 age-matched normal controls. No differences were found between patients on assisted ventilation and patients on spontaneous ventilation. When analyzed as a group, the brain pH in the focal lesions appeared to increase in the first days, to reach a peak in the alkalotic range in the second week, and to return toward normal within 3 weeks from acute injury. Our results suggest that there is no evidence of posttraumatic intracellular brain acidosis in recent human head injury, and therefore, therapies aimed at alkalinizing brain cells need to be reconsidered.

We studied the relation of serum glucose level measured in the first 12 hours of symptoms to the clinical findings, results of computed tomography (CT), and patterns of cerebral metabolism in 39 patients who had acute ischemic cerebral infarction. Structural damage was assessed by CT. Metabolic disruption was assessed using 18F-fluorodeoxyglucose and positron emission tomography (PET). Median initial serum glucose concentration was 155 mg/dl (6.7 mM). Clinical recovery was significantly poorer in patients with initial serum glucose levels higher than the median (p less than 0.05, chi square). PET tended to show normal results or minor abnormalities in patients with initial glucose levels less than the median, as opposed to lobar or multilobe abnormalities in patients with levels that were higher than the median (p less than 0.05, Kendall's Tau b). The severity of hypometabolism in the ischemic region, expressed as the percent asymmetry of local cerebral glucose metabolism between homologous brain regions, was greater in patients with initial glycemia concentrations higher than the median (p less than 0.001, t test). Relationships of serum glucose level with metabolic derangement and structural damage, but not outcome, held true in patients without a history of diabetes mellitus.

We studied the radioisotope iodine-123-iodoamphetamine ([123I]IMP) and its performance in single-photon emission computed tomographic (SPECT) studies of cerebral blood flow (CBF). In seven normal volunteers, IMP/SPECT CBF measurements were calculated using a two-compartment model and were compared with the results of CBF measurements utilizing (O15)-H2O and positron emission tomography (PET). Calculated mean PET CBF was 57.6 ml/100 g/min while the SPECT CBF value was 47.3 ml/100 g/min. The response of IMP/SPECT CBF to alterations in arterial PaCO2 was studied in hypo-, eu- and hypercarbic subjects. SPECT CBF values showed a reactivity of 1.03 ml/100 g/min per mmHg PaCO2 change. These results show that the IMP/SPECT CBF technique may be used for quantitative imaging of CBF in man. They provide further support for IMP as a CBF tracer.

We studied brain cortical radioactive tracer activity in a consecutive series of nine patients with acute hemispheric ischemic stroke at their first cerebral ischemic stroke at their first cerebral ischemic episode. Results from N,N,N'-trimethyl-N'- (2-hydroxy-3-methyl-5-[123-I]-iodobenzyl)-1,3 propanediamine-2HCl (four patients) and technetium Tc 99m hexamethylpropyleneamine oxime (five patients) single photon emission computed tomographic studies were compared with x-ray computed tomography (CT) and clinical findings within the first 48 hours, on day 10, and on day 30 after the clinical ictus. Cortical hypoactivity agreeing with the clinical findings was found on all initial scans but not in the follow-up studies. Cortical activity on the affected side in patients with stroke was significantly lower when compared with cortical activity in sex- and age-matched controls (n = 21). Computed tomography (with contrast) was less sensitive in detecting the ischemic lesions. These studies demonstrate that in the acute phase of stroke there is a single photon emission computed tomographic cortical disturbance that agrees with clinical findings, even when computed tomography scan infarction is limited to subcortical structures.