Abnormal brain temperature in early‐onset Parkinson's disease

MR spectroscopy (MRS) measures brain temperature in vivo and allows noninvasive measurement of the temperature of specific brain areas. Brain temperature depends on the net balance of the heat released by mitochondrial oxidative phosphorylation and the heat removed by cerebral blood flow. Most of the genetic mutations associated with earlyonset Parkinson’s disease (EOPD) impair the mitochondrial machinery. Brain temperature can impair many functions of dopaminergic neurons and may play a large role in the development of PD. Accordingly, the aim of this study was to investigate whether brain temperature is altered in EOPD. We studied brain temperature in 5 consecutive patients with EOPD, 3 men and 2 women, with a mean age of 41 6 6 years. All patients were genotyped and 2 patients showed mutations (1 in PLA2G6 and 1 in PINK1). The clinical and genetic characteristics are reported in Table 1. Ten healthy subjects matched for age and sex were also included in the study and comprised 6 men and 4 women with a mean age of 43 6 7 years. The body temperature of all participants was assessed. Brain temperature was assessed by MRS (1.5T Siemens AVANTO; Siemens Healthcare GmbH, Erlangen, Germany) in the visual cortex, posterior cingulate, hypothalamus, centrum semiovale, and lenticulate nucleus. The brain temperature calculations were based on measurement of the difference between the water resonance frequency and the N-acetyl aspartate (NAA) methyl resonance frequency. The absolute values of brain temperature (expressed as Celsius degrees) were calculated according to the equation T85228.2–72.23(dH2O-dNAA) (2) Mean body temperature did not differ significantly (P> 0.05) between patients (36.70 6 0.48 8C) and healthy subjects (36.50 6 0.84 8C). However, there were substantial increases in brain temperature in patients compared to healthy subjects. Significant brain temperature differences were observed in the hypothalamus (38.50 6 0.20 vs. 37.01 6 0.60 8C; P< 0.05), posterior cingulate gyrus (37.60 6 0.20 vs. 36.70 6 0.40 8C; P< 0.05), centrum semiovale (38.00 6 0.60 vs. 36.60 6 0.60 8C; P< 0.05), and lenticulate nucleus (38.80 6 0.80 vs. 37.40 6 0.60 8C; P< 0.05). There was a tendency toward a warmer brain temperature in the visual cortex in the patient group, but this was not statistically significant (37.20 6 0.20 vs. 36.80 6 0.40 8C; not significant). The reason for brain temperature increase remains unclear. The increase in the hypothalamus temperature should have induced a hypothalamic response restoring physiological conditions (i.e., reducing the temperature). However, in the present study, the hypothalamus failed to control brain temperature. An uncoupling of oxidative phosphorylation would explain increased brain temperature, given that this would lead to an increase of the heat released by mitochondria. Indeed, mutations in PINK1 and PLA2G6 uncouple oxidative phosphorylation. Inhibition of dopamine reuptake alters the heat loss mechanisms. The typical dopaminergic deafferentation of Parkinson’s disease may play a critical role in increasing brain temperature. Conversely, levodopa/dopaminergic drugs intake should decrease brain temperature because they increase cerebral blood flow. Brain temperature affects passive membrane properties, neuronal action potential, protein conformation, and assembly and alters protein expression. The mitochondrial and plasma membranes are the most temperaturesensitive cellular elements. Hyperthermia damages neurons. Together, such alterations are likely to contribute to neurodegeneration, such as that found in EOPD. Lowering brain temperature might be considered as a potential therapeutic target to prevent neurodegeneration in EOPD. -----------------------------------------------------------*Correspondence to: Dr. Mario Rango, Department of Neuroscience and Mental Health, IRCCS C a Granda-Ospedale Maggiore Policlinico Foundation, University of Milano, Via Francesco Sforza, 35, 20122, Milan, Italy; E-mail: mariocristia@yahoo.it