J. A. Helpern

Increased iron‐related MRI contrast in the substantia nigra in Parkinson's disease

Article abstract—Elevated iron levels in the substantia nigra (SN) of the brain in Parkinsons disease (PD) may mediate lipid peroxidative reactions, promoting SN neuronal death. To assess SN iron accumulation in living PD patients and its relation to motor performance, we measured, in 13 nondemented PD patients and 10 normal control subjects, simple reaction time (SRT) and simple movement time (SMT), followed by head MRI in a 3-tesla system. We measured T2 and T2* in the right and left SN of all subjects and calculated R2‘, the relaxation rate due to local magnetic field in-homogeneities, from these values. Asymmetries of 1/T2 (R2), l/T2* (R2*), or R2’ versus asymmetries of SRT and SMT were assessed in eight PD subjects who had not taken anti-PD medication(s1 for 12 hours. The average of right and lef ϵ SN values for R2 was lower, and R2* and R2‘ were higher, in PD patients than in controls (R2, p = 0.046; R2*, p = 0.001; R2’, p < 0.001). R2‘ best predicted group differences. The asymmetry of SRT performance was highly correlated with asymmetries of SN R2* (0.91; p = 0.001) and R2’ (0.72; p = 0.03). These results strongly suggest that the increases in iron levels seen postmortem in the SN in PD are reflected in increased iron-related MRI contrast at 3 tesla in living PD patients. Correlations with motor performance in PD suggest that the clinical severity of PD may be related to SN iron accumulation.

Magnetic resonance imaging assessment of evolving focal cerebral ischemia. Comparison with histopathology in rats.

Background and Purpose This study was performed to document the progression of ischemic brain damage after middle cerebral artery occlusion in the rat using magnetic resonance imaging and histopathologic methods. Methods Cerebral ischemia was induced through permanent tandem occlusion of ipsilateral middle cerebral and common carotid arteries. The evolution of magnetic resonance imaging and histopathologic parameter changes was studied, both short term (1.5 to 8 hours) and long term (24 to 168 hours), in five specific brain regions within the middle cerebral artery territory. Results Significant changes in proton nuclear magnetic resonance spin-lattice and spin-spin relaxation times and the “apparent” diffusion coefficient of water could be detected within hours after the onset of permanent focal cerebral ischemia, whereas significant alterations in proton spin-density ratios were not apparent until approximately 48 hours. Histological changes were evident within 12 hours, with a significant loss of neurons seen in the most severely damaged regions at 7 days. Diffusion-weighted imaging was the most sensitive technique for visualizing acute ischemic alterations. The water diffusion coefficient was the only magnetic resonance imaging parameter studied to indicate significant alterations within the first 4 hours after arterial occlusion in all five brain regions. Conclusions The degree of change for a particular magnetic resonance imaging parameter appeared to be related to the location and extent of neuronal injury, with the most dramatic changes occurring within the areas displaying the most severe histological damage. These results indicate that complete specification of all brain regions affected by ischemic brain injury may require a combination of imaging strategies applied over a period of days and suggest the possibility of using magnetic resonance imaging to distinguish between permanent and reversible cell damage.

Preliminary observations on brain energy metabolism in migraine studied by in vivo phosphorus 31 NMR spectroscopy.

We measured brain energy phosphate metabolism and intracellular pH (pH1) in a cross-sectional study of migraine patients by in vivo phosphorus 31 NMR spectroscopy. During a migraine attack the ratio ATP/total phosphate signal (mole % ATP) was preserved, but there waa a decrease in mole % phosphocreatine (PCr) and an increase in mole % inorganic phosphate (Pi) resulting in a decrease of the PCr/Pi ratio, an index of brain phosphorylation potential. This was found in chic but not common migraine. Mole % Pi waa also increased in combined brain regions between attacks. There waa no alteration in brain pH1 during or between attacks. Energy phosphate metabolism but not pH1 appears disordered during a migraine attack.

Effect of mild hyperthermia on recovery of metabolic function after global cerebral ischemia in cats.

We investigated the effect of mild whole-body hyperthermia before and after 16 minutes of global cerebral ischemia on metabolic recovery during recirculation in cats using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Hyperthermia (temperature 40.6 +/- 0.2 degrees C) was induced greater than or equal to 1 hour before ischemia and was maintained during 1.5-2 hours of recirculation in nine cats; four cats were subjected to hyperthermia without cerebral ischemia, six to hyperthermia during recirculation (after return of intracellular pH to preischemic values), and 14 to normothermic ischemia and recirculation. Our data indicate that preischemic hyperthermia results in an intracellular cerebral pH during recirculation significantly lower than that in normothermic cats. In hyperthermic cats beta-ATP and phosphocreatine (PCr) concentrations and the ratio of PCr to inorganic phosphate failed to return to preischemic levels during recirculation in contrast to normothermic cats. Hyperthermia without ischemia and hyperthermia during recirculation had no significant effect on intracellular pH. Thus, preischemic hyperthermia has a detrimental effect on metabolic recovery after transient global cerebral ischemia.

Global cerebral ischemia and intracellular pH during hyperglycemia and hypoglycemia in cats.

In 27 cats treated to vary arterial serum glucose concentrations, we measured cerebral high-energy phosphate metabolite concentration and intracellular pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy during transient global cerebral ischemia and reperfusion. Hypoglycemia was induced with 4 units/kg i.v. insulin in six cats before ischemia; hyperglycemia was induced with 1.5 g/kg i.v. glucose in six cats before and in six cats during ischemia. Nine untreated cats subjected to ischemia without manipulation of blood glucose concentration served as controls. During ischemia, intracellular pH fell to similar levels in the control and both hyperglycemic groups. During reperfusion, the hyperglycemic before ischemia group initially exhibited a severe further decline in intracellular pH (p less than 0.003); this further decline was not observed in the control or the hyperglycemic during ischemia groups. Intracellular acidosis was attenuated both during ischemia and early after reperfusion in the hypoglycemic before ischemia group. In all groups, cerebral high-energy phosphate metabolite concentrations were depleted during ischemia and then recovered to the same degree during reperfusion. Our data suggest that brain glucose stores before ischemia determine the severity and time course of intracellular acidosis during ischemia and reperfusion.

Acute elevation and recovery of intracellular [Mg2+] following human focal cerebral ischemia

We used 31P magnetic resonance spectroscopy (MRS) to investigate changes in brain intracellular [Mg2+] following human focal cerebral ischemia. Mean brain pMg (where pMg = -log[Mg2+]) was significantly lower in the ischemic focus of all stroke patients (pMg = 3.34 ± 0.28, n = 45, p < 0.01) when compared with normal controls (pMg = 3.50 ± 0.08, n = 25). Ischemic brain pMg was also significantly reduced when the pH of the stroke region was acidotic (pH < 6.90, pMg = 3.07 ± 0.44, n = 11, p < 0.01) and when the phosphocreatine index (PCrI = PCr/[PCr + Pi (inorganic phosphate)]) was reduced (PCrI < 0.47, pMg = 3.12 ± 0.42, n = 13, p < 0.01). Mean brain pMg was significantly reduced at days 0 to 1 (acute) poststroke (pMg = 3.32 ± 0.28, n = 26, p < 0.01) and at days 2 to 3 (subacute) poststroke (pMg = 3.38 ± 0.28, n = 21, p = 0.03). There was also a significant (p < 0.01) correlation between decreased pMg and increased relative signal intensity of Pi (normalized by total phosphate signal, Pi/TP) for all stroke groups studied. During the temporal evolution of stroke, pH returned to normal levels by days 2 to 3, and pMg returned to normal by days 4 to 10 (subacute). PCrI and Pi/TP returned toward normal levels after 10 days (chronic), at a time when ischemic brain pH had become significantly alkalotic (pH = 7.10 ± 0.24, n = 15, p < 0.01). Elevation of ischemic brain [Mg2+] is temporally linked to the acidotic phase of human stroke as well as the breakdown of energy metabolism. These acute changes in [Mg2+] may contribute to, or be a marker for, cellular injury.

Chronic cerebral intracellular alkalosis following forebrain ischemic insult in rats.

We measured cerebral intracellular pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy during 1 week after forebrain ischemia or sham operation in eight and seven rats, respectively. Mean maximum pH was significantly higher (p less than 0.003) in the ischemic group than in the sham-operated group (7.34 +/- 0.03 and 7.19 +/- 0.02, respectively). The difference between mean maximum pH and baseline pH (7.08 +/- 0.01 in each group) was significantly greater (p less than 0.02) in the ischemic group than in the sham-operated group. In the ischemic group, alkalosis occurred primarily after 48-72 hours of recirculation. We speculate that brain tissue alkalosis occurring chronically after ischemia is associated with delayed ischemic neuronal death.

Nuclear magnetic resonance spectroscopy study of human brain after cardiac resuscitation.

We used 31P nuclear magnetic resonance spectroscopy to study the cerebral metabolic function of eight patients with severe postischemic anoxic encephalopathy secondary to cardiac arrest. Spectroscopy was performed at 18 +/- 13 and 64 +/- 20 hours after resuscitation. Glasgow Coma Scale scores at the time of initial and repeat spectroscopy were 3.6 +/- 1.2 and 3.5 +/- 1.2, respectively. In those patients whose spectra were of adequate quality to monitor pH, all demonstrated tissue alkalosis in at least one brain region. The mean brain pH at initial spectroscopy was 7.14 +/- 0.09 and was significantly alkalotic when compared with age- and sex-matched normal controls (pH = 6.98 +/- 0.04, p less than 0.0001). Five of the eight patients showed at least one region of persistent alkalosis at repeat spectroscopy, whereas one patient demonstrated severe acidosis with a pH of 6.42. Spectra demonstrated marked metabolic heterogeneity, ranging from normal in appearance to complete obliteration of all high-energy phosphates with only inorganic phosphate remaining.

Reduction of hyperthermic ischemic acidosis by a conditioning event in cats.

We investigated the effects of multiple episodes of cerebral ischemia on intracellular brain pH using in vivo phosphorus-31 nuclear magnetic resonance spectroscopy. Four cats were subjected to two 16-minute episodes of complete global cerebral ischemia 6 hours apart; the second episode occurred under hyperthermic conditions (mean +/- SD body temperature 40.8 +/- 0.4 degrees C). Intracellular pH in these four cats was compared with that in nine cats subjected to a single 16-minute episode of complete global cerebral ischemia under hyperthermic conditions (mean +/- SD body temperature 40.6 +/- 0.2 degrees C). Intracellular pH during hyperthermic recirculation was significantly (p less than 0.03) greater in cats subjected to a previous ischemic event than that in cats subjected to only a single hyperthermic ischemic event. We speculate that the induction of heat shock proteins by an initial ischemic event may protect brain tissue from further ischemic insult.

1H magnetic resonance imaging of normal brain tissue response to photodynamic therapy

1H Magnetic resonance imaging (MRI) was used to study the effects of photodynamic therapy (PDT) on normal rat brain (n = 5) using T1-, T2-, diffusion-, and proton density (rho)-weighted images. Rats received intraperitoneal injections of 12.5 mg/kg of Photofrin II, and 48 hours later the dural area over the frontal cortex was treated with 35 J/cm2 of light (632 +/- 1 nm). The T1-, T2-, and diffusion-weighted images revealed an evolving high contrast region of brain that corresponded to the PDT-treated area. Lesioned brain exhibited significant increases in T1 and T2 relaxation times at 1 day (P less than 0.01) and 3 days (T1, P = 0.018; T2, P less than 0.01) after treatment, compared with the contralateral equivalent volume of nonlesioned brain. Water proton diffusion coefficient (DW) in the lesioned area decreased at 1 day (P = 0.026) and increased at 3 days (P = 0.012) compared with nonlesioned brain. An increase in the proton density ratio (rho D/rho O) from PDT (rho D) versus nonlesioned side (rho O) was found 3 days after PDT treatment (P = 0.03). The data indicate that the biophysical parameters obtained from magnetic resonance imaging scans, T1, T2, DW, and proton density, can be used to monitor changes in an evolving photochemically induced lesion.