Cerebellar Volume and Disease Staging in Parkinson's Disease: An ENIGMA-PD Study.

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 (dmax = -0.15). HY stage-specific analyses revealed a larger anterior lobule V bilaterally (dmax = 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 (dmax = -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.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

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 (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -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.

Brain mitochondrial impairment in early-onset Parkinson's disease with or without PINK1 mutation.

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 + ßATP contents at rest (P = NS) and under activation (P = NS), but reduced contents during recovery (P < 0.001). The EOPD+ group had abnormal PCr + ßATP 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.

In Vivo Mitochondrial Function in Idiopathic and Genetic Parkinson's Disease.

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 (31P-MRS) is a suitable tool to explore in vivo cerebral energetics. We considered 10 31P-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 + ßATP 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.

Brain Mitochondria, Aging, and Parkinson's Disease.

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.

Subclinical cerebrovascular disease in NAFLD without overt risk factors for atherosclerosis.

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.

Progressively invalidating orthostatic hypotension: A common symptom for a challenging diagnosis.

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.

Usefulness of Multi-Parametric MRI for the Investigation of Posterior Cortical Atrophy.

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.

Parkinson's disease: in vivo brain metabolomics by MRS.

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.

Post-Activation Brain Warming: A 1-H MRS Thermometry Study.

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.

The brain is hypothermic in patients with mitochondrial diseases.

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.

A 66-year-old patient with vanishing white matter disease due to the p.Ala87Val EIF2B3 mutation.

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).

Central hyperthermia, brain hyperthermia and low hypothalamus temperature.

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.

Brain temperature: what do we know?

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.

Increased brain temperature in Parkinson's disease.

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.

Lactate detection in the brain of growth-restricted fetuses with magnetic resonance spectroscopy.

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.

Human fetal brain chemistry as detected by proton magnetic resonance spectroscopy.

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.

Spontaneous blinking in healthy persons: an optoelectronic study of eyelid motion.

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.