Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always.

OBJECTIVE: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD. METHODS: We reviewed clinical data from all patients with autopsy data seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2019. All patients with a diagnosis of PD based on neuropathology were included. We used logistic regression and multivariate analysis of covariance (MANCOVA) to investigate the relationship between neuropathology and dementia. RESULTS: A total of 165 patients with PD met inclusion criteria. Among these, 128 had clinical dementia. Those with dementia had greater mean ages of motor onset and death but equivalent mean disease duration. The delay between motor symptom onset and dementia was 1 year or less in 14 individuals, meeting research diagnostic criteria for possible or probable dementia with Lewy bodies (DLB). Braak Lewy body stage was associated with diagnosis of dementia, whereas severities of Alzheimer's disease neuropathologic change (ADNC) and small vessel pathology did not. Pathology of individuals diagnosed with DLB did not differ significantly from that of other patients with PD with dementia. Six percent of individuals with PD and dementia did not have neocortical Lewy bodies; and 68% of the individuals with PD but without dementia did have neocortical Lewy bodies. INTERPRETATION: Neocortical Lewy bodies almost always accompany dementia in PD; however, they also appear in most PD patients without dementia. In some cases, dementia may occur in patients with PD without neocortical Lewy bodies, ADNC, or small vessel disease. Thus, other factors not directly related to these classic neuropathologic features may contribute to PD dementia. ANN NEUROL 2023;93:184-195.

Is Levodopa Response a Valid Indicator of Parkinson's Disease?

BACKGROUND: The clinical diagnosis of Parkinson's disease (PD) requires the presence of parkinsonism and supportive criteria that include a clear and dramatic beneficial response to dopaminergic therapy. Our aim was to test the diagnostic criterion of dopaminergic response by evaluating its association with pathologically confirmed diagnoses in a large population of parkinsonian patients. METHODS: We reviewed clinical data maintained in an electronic medical record from all patients with autopsy data who had been seen in the Movement Disorders Center at Washington University, St. Louis, between 1996 and 2018. All patients with parkinsonism who underwent postmortem neuropathologic examination were included in this analysis. RESULTS: There were 257 unique parkinsonian patients with autopsy-based diagnoses who had received dopaminergic therapy. Marked or moderate response to dopaminergic therapy occurred in 91.2% (166/182) of those with autopsy-confirmed PD, 52.0% (13/25) of those with autopsy-confirmed multiple systems atrophy, 44.4% (8/18) of those with autopsy-confirmed progressive supranuclear palsy, and 1 (1/8) with autopsy-confirmed corticobasal degeneration. Other diagnoses were responsible for the remaining 24 individuals, 9 of whom had a moderate response to dopaminergic therapy. CONCLUSION: A substantial response to dopaminergic therapy is frequent but not universal in PD. An absent response does not exclude PD. In other neurodegenerative disorders associated with parkinsonism, a prominent response may also be evident, but this occurs less frequently than in PD. © 2020 International Parkinson and Movement Disorder Society.

Parkinson Disease: The Relationship Between Non-motor Symptoms and Motor Phenotype.

BACKGROUND: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine-responsive axial signs would correlate with NMS severity. METHODS: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. RESULTS: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. CONCLUSIONS: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.

Pedunculopontine Nucleus Dysconnectivity Correlates With Gait Impairment in Parkinson's Disease: An Exploratory Study.

Background: Gait impairment is a debilitating and progressive feature of Parkinson's disease (PD). Increasing evidence suggests that gait control is partly mediated by cholinergic signaling from the pedunculopontine nucleus (PPN). Objective: We investigated whether PPN structural connectivity correlated with quantitative gait measures in PD. Methods: Twenty PD patients and 15 controls underwent diffusion tensor imaging to quantify structural connectivity of the PPN. Whole brain analysis using tract-based spatial statistics and probabilistic tractography were performed using the PPN as a seed region of interest for cortical and subcortical target structures. Gait metrics were recorded in subjects' medication ON and OFF states, and were used to determine if specific features of gait dysfunction in PD were related to PPN structural connectivity. Results: Tract-based spatial statistics revealed reduced structural connectivity involving the corpus callosum and right superior corona radiata, but did not correlate with gait measures. Abnormalities in PPN structural connectivity in PD were lateralized to the right hemisphere, with pathways involving the right caudate nucleus, amygdala, pre-supplementary motor area, and primary somatosensory cortex. Altered connectivity of the right PPN-caudate nucleus was associated with worsened cadence, stride time, and velocity while in the ON state; altered connectivity of the right PPN-amygdala was associated with reduced stride length in the OFF state. Conclusion: Our exploratory analysis detects a potential correlation between gait dysfunction in PD and a characteristic pattern of connectivity deficits in the PPN network involving the right caudate nucleus and amygdala, which may be investigated in future larger studies.

Ventricular dilatation and brain atrophy in patients with Parkinson's disease with incipient dementia.

Age-related ventricular enlargement is accelerated in Alzheimer's disease, but its relationship to cognitive decline in Parkinson's disease is less clear, even though dementia is common in Parkinson's disease. Our goals were to determine if greater enlargement of the ventricles and gray or white matter atrophy occurred in Parkinson's disease patients developing cognitive decline. Older nondemented patients with Parkinson's disease (33) and age- and sex-matched controls (39) were recruited and prospectively assessed for the development of significant cognitive decline over 36 months. Magnetic resonance imaging was obtained every 18 months, and ventricular volume and total brain gray and white matter volumes were measured using reliable segmentation of T1-weighted volumetric scans. Subjects with incidental intracranial abnormalities, an atypical course, and stroke as well as dropouts were excluded from a cohort of 52 patients and 50 controls. Among 33 patients and 39 controls, 10 patients and 3 controls developed significant cognitive impairment or dementia. Ventricular change and Parkinson's disease status were significantly associated with dementia. Ventricular change was significantly correlated with change in Mini-Mental Status Examination in the Parkinson's disease with dementia group (r = 0.87, P = .001). Gray matter atrophy was greater in Parkinson's disease with dementia, with similar change over time in both Parkinson's disease and Parkinson's disease with dementia. White matter volumes were not significantly different between Parkinson's disease and Parkinson's disease with dementia; however, the decrease over time might be greater in Parkinson's disease with dementia. Ventricular dilatation occurs early in the course of significant cognitive decline in patients with Parkinson's disease, possibly reflecting both cortical gray and white matter loss.

Subcortical microstructural diffusion changes correlate with gait impairment in Parkinson's disease.

BACKGROUND: Gait impairments are common in Parkinson's Disease (PD) and are likely caused by degeneration in multiple brain circuits, including the basal ganglia, thalamus and mesencephalic locomotion centers (MLC). Diffusion tensor imaging (DTI) assesses fractional anisotropy (FA) and mean diffusivity (MD) that reflect the integrity of neuronal microstructure. We hypothesized that DTI changes in motor circuits correlate with gait changes in PD. OBJECTIVE: We aimed to identify microstructural changes of brain locomotion control centers in PD via DTI and their correlations with clinical and quantitative measures of gait. METHODS: Twenty-one PD patients reporting gait impairment and 15 controls were recruited. Quantitative gait and clinical tests were recorded in PD subjects' medication ON and OFF states. Region of Interest (ROI) analysis of the thalamus, basal ganglia and MLC was performed using ExploreDTI. Correlations between FA/MD with clinical gait parameters were examined. RESULTS: Microstructural changes were seen in the thalamus, caudate and MLC in the PD compared to the control group. Thalamic microstructural changes significantly correlated with gait parameters in the pace domain including the Timed Up and Go in the ON state. Caudate changes correlated with cadence and stride time in the OFF state. CONCLUSIONS: Our pilot study suggests that PD is associated with a characteristic regional pattern of microstructural degradation in the thalamus, caudate and MLC. The DTI changes may represent subcortical locomotion network failure. Overall, DTI ROI analyses might provide a useful tool for assessing PD for functional status and specific motor domains, such as gait, and potentially could serve as an imaging marker.

Dihydrotetrabenazine positron emission tomography imaging in early, untreated Parkinson's disease.

OBJECTIVE: To determine the sensitivity of positron emission tomography with 11C-labeled dihydrotetrabenazine (DTBZ) to the nigrostriatal changes associated with early, untreated Parkinson's disease (PD), and to determine the correlation between any regionally reduced DTBZ binding and the major motor features of PD. METHODS: Untreated patients with early PD (n = 27) and age-matched control subjects (n = 33) underwent DTBZ/positron emission tomography scanning to measure binding to the presynaptic type 2 vesicular monoamine transporter site in dopaminergic neurons in basal ganglia regions. Clinical symptoms were rated with the Unified Parkinson's Disease Rating Scale. RESULTS: Mean striatal DTBZ binding values in the patient group were decreased as compared with control subjects (p < 0.001) in all regions examined. The difference between patients and control subjects was most marked in the midputamen, where only one patient had DTBZ binding within 3 standard deviations of the control mean. Bradykinesia and rigidity scores correlated with DTBZ binding in the contralateral midputamen region, particularly for the clinically least affected limbs. Tremor scores showed no significant correlation. INTERPRETATION: Reduced striatal binding of DTBZ is associated with early PD. Tremor appears to be only partially related to presynaptic dopaminergic function and may have a mechanism differing from that of symptoms such as bradykinesia. The method appears to be most sensitive in mildly affected individuals with a possible "floor" effect that may limit the degree of additional change occurring once more severe clinical symptoms are evident.

Temporal lobe changes in early, untreated Parkinson's disease.

The purpose of this study was to determine if focal cortical abnormalities may occur in early Parkinson's disease (PD). We studied 26 untreated patients with early PD and 14 healthy control subjects, with cognitive screening and magnetic resonance imaging (MRI). Voxel-based morphometry was used to assess for the presence of localized cortical grey matter (GM) and/or subcortical white matter (WM) changes. Patient and control groups showed no differences in age or gender distribution. Females had a greater GM% than males (P = 0.001). Comparison of patients and controls revealed no difference in local GM volumes. In PD, however, there was decreased WM volume in the anterior right fusiform gyrus and superior temporal gyrus. There were no correlations between the California Verbal Learning Test long delay free recall, Judgment of Line Orientation, Trail Making A or B and either the GM or WM localized volumes. These results suggest that right anterior temporal lobe changes occur in untreated patients with PD. The earliest changes may occur in subcortical white matter rather than temporal cortex.

Voxel-based morphometry reveals extra-nigral atrophy patterns associated with dopamine refractory cognitive and motor impairment in parkinsonism.

OBJECTIVES: To determine overall patterns of brain atrophy associated with memory, executive function (EF) and dopamine non-responsive motor measures in older parkinsonian patients. DESIGN: Forty-three older PD patients (>or=65 years) and matched controls underwent a neurological examination (Unified Parkinson's Disease Rating Scale, separated into dopamine responsive and dopamine non-responsive signs) and neuropsychological testing (memory: California Verbal Learning Test (CVLT)) and a composite of index of executive function (EF): Stroop Interference, Trail Making Test Part B, and digit ordering. All underwent volumetric MRI scans analyzed using voxel-based morphometry (VBM). Group comparisons, and the correlations between MRI gray and white matter volume and motor and cognitive measures were controlled for age, sex and intracranial volume. Cerebellar volume was independently measured using a validated extraction method. RESULTS: Patients and controls were matched for demographics and global cognitive measures. VBM indicated significant gray matter (GM) atrophy in the cerebellum in PD and was confirmed independently. Poor memory was associated with GM atrophy in the left (uncus, middle temporal and fusiform gyri) and right temporal lobes and left putamen. Dopamine non-responsive motor signs and EF were associated with caudate atrophy. EF was also associated with GM atrophy in the middle temporal gyri, the left precuneus and cerebellum. CONCLUSIONS: Cortical and striatal atrophy were associated with dopamine non-responsive motor signs and cognitive impairment and provide a morphologic correlate for progression of PD. Cerebellar atrophy was found in older PD patients.

Intact presupplementary motor area function in early, untreated Parkinson's disease.

Although motor symptoms of Parkinson's disease (PD) are initially responsive to dopamine replacement therapy, nonresponsive features develop over time, suggesting that impaired dopaminergic function alone may not be wholly responsible for all the motor features of the disease. Previous studies suggest impaired function in the presupplementary motor area (pre-SMA) in PD. Our objective was to determine whether pre-SMA abnormalities are present in untreated patients with early disease. We measured N-acetyl aspartate (NAA)/creatine (Cr) and choline (Cho)/Cr ratios in pre-SMA in 26 untreated patients with early PD (disease duration 3.0 +/- 2.0 yr) and 15 control subjects with single voxel magnetic resonance spectroscopy. Neither NAA/Cr nor Cho/Cr ratios differed significantly between groups. These observations suggest that, although pre-SMA function is impaired in moderately advanced PD, it is relatively spared in early disease. We suggest that pre-SMA dysfunction is in part responsible for the dopamine nonresponsive features associated with disease progression.

Early, untreated Parkinson's disease patients show reaction time variability.

While Parkinson's disease (PD) is associated with motor slowing, less attention has been paid to variability in performance on motor and cognitive tasks. To examine reaction time latencies and intraindividual variability in untreated patients with PD compared to healthy controls. Twenty-nine (19 men/10 women) patients with untreated PD and 16 controls (8 men/8 women) were examined using measures of simple reaction time (SRT) and choice reaction time (CRT) in addition to cognitive measures of executive function (Trail Making Test; adaptive digit ordering). Latencies and intraindividual variability were compared between groups. Partial correlation coefficients, adjusting for age, sex and education were used to examine the relationship between RT measures and motor or cognitive measures. Patients and controls did not differ with respect to age or sex distribution. Education and cognitive status differed between groups, but no subject was demented or clinically depressed. After adjusting for age, sex and education, significant group differences were found in latencies (2-choice RT and 8-choice RT) and intraindividual variability scores (all CRT conditions). Latencies did not differ significantly after adjusting for finger tapping rate. In the PD group neither the motor nor the executive measures correlated significantly with any of the reaction time measures. We conclude that CRT intraindividual variability and latencies are increased in untreated PD.

MR spectroscopy in neurodegenerative disease.

Unlike traditional, tracer-based methods of molecular imaging, magnetic resonance spectroscopy (MRS) is based on the behavior of specific nuclei within a magnetic field and the general principle that the resonant frequency depends on the nucleus' immediate chemical environment. Most clinical MRS research has concentrated on the metabolites visible with proton spectroscopy and measured in specified tissue volumes in the brain. This methodology has been applied in various neurodegenerative disorders, most frequently utilizing measures of N-acetylaspartate as a neuronal marker. At short echo times, additional compounds can be quantified, including myo-inositol, a putative marker for neuroglia, the excitatory neurotransmitter glutamate and its metabolic counterpart glutamine, and the inhibitory neurotransmitter gamma-aminobutyric acid. 31P-MRS can be used to study high-energy phosphate metabolites, providing an in vivo assessment of tissue bioenergetic status. This review discusses the application of these techniques to patients with neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis.

Is brain lactate increased in Huntington's disease?

Impaired brain energy metabolism with increased regional brain lactate may play a role in the pathogenesis of Huntington's disease (HD). Magnetic resonance spectroscopy (MRS) has provided conflicting evidence, however, regarding metabolic changes. Our objective was to evaluate the potential contribution of CSF lactate to the changes observed with MRS in HD. We performed single voxel MRS at 3 T in 23 patients with HD and 28 age-matched control subjects using a method to segment voxels into grey matter, white matter, and CSF, and to extrapolate regional lactate content to a hypothetical voxel containing 100% brain in order to control for differences in CSF lactate. Lactate/creatine and lactate/N-acetyl aspartate (Lac/NAA) ratios were significantly increased in parieto-occipital (p<0.05) and cerebellar (p<0.01) voxels in HD patients. After extrapolating group Lac/NAA results to a theoretical voxel containing 100% brain, this ratio was greater in the HD group than the control group, suggesting possibly increased lactate in this predicted voxel, although the difference between groups did not reach statistical significance. These results suggest an increase in brain lactate content in manifest HD, in a regionally non-specific fashion, although the possibility of a CSF contribution to this increase cannot be ruled out. Regardless, this supports the possibility of impaired mitochondrial function resulting in abnormal brain energy metabolism in HD.

Detection of cerebral degeneration in amyotrophic lateral sclerosis using high-field magnetic resonance spectroscopy.

BACKGROUND: Clinical assessment is insensitive to the degree of cerebral involvement in amyotrophic lateral sclerosis (ALS). Regional brain concentrations N-acetylaspartylglutamate (NAA) plus myo-inositol (Ins), as measured by magnetic resonance spectroscopy, are respectively decreased and increased, suggesting that these compounds may provide a biomarker of the degree of cerebral involvement in ALS. OBJECTIVE: To test the hypothesis that the NAA/Ins ratio may provide an index of cerebral involvement in patients with ALS. DESIGN: High-field (3.0-T) magnetic resonance spectroscopy was performed to determine the NAA/creatine plus phosphocreatine (NAA/Cr), NAA/choline (NAA/Cho), Ins/Cr, and NAA/Ins ratios in the motor cortex. PARTICIPANTS: Seventeen patients with ALS and 15 healthy control subjects were studied. RESULTS: In patients with ALS, the greatest abnormality was a 22% decrease in NAA/Ins (71% sensitivity and 93% specificity, P = .001); Ins/Cr was increased 18% (88% sensitivity and 53% specificity, P = .04), NAA/Cr was decreased 10% (88% sensitivity and 47% specificity, P = .04), and NAA/Cho was decreased 14% (53% sensitivity and 87% specificity, P = .047). Correlation of the ALS Functional Rating Scale with NAA/Ins approached statistical significance (R = 0.43, P = .07). CONCLUSION: The NAA/Ins ratio may provide a meaningful biomarker in ALS given its optimal sensitivity and specificity profile.

Valvular heart disease in pergolide-treated Parkinson's disease.

BACKGROUND: A 61-year-old woman with Parkinson's disease, receiving pergolide 1.75 mg four times daily, was admitted with progressive dyspnea. METHODS: Investigations revealed mitral and aortic regurgitation. She underwent surgical mitral replacement and aortic repair, but had a post-operative course characterized by repeated bouts of congestive heart failure. RESULTS: Severe tricuspid valve (TV) regurgitation developed within one month after the TV was reported on echocardiography to be relatively normal. Subsequent discontinuation of pergolide was associated with symptomatic improvement. CONCLUSIONS: This case illustrates the severity and rapidity with which cardiac valvular abnormalities can develop in patients receiving pergolide.

Freezing of gait in early Parkinson's disease: Nigral iron content estimated from magnetic resonance imaging.

PURPOSE: Freezing of gait is a major source of disability associated with the progression of Parkinson's disease (PD). Our objective was to determine whether evolving changes in nigral iron content in association with declining motor function in early PD differentiates subjects who develop freezing from those who do not. METHODS: A cohort of previously untreated individuals with early PD (n=19) was followed for 36 months clinically and with MRI. The cohort was divided into two groups based on the development of freezing during follow-up. A multiple gradient echo MRI sequence provided an index of basal ganglia iron content. RESULTS: There were significant baseline differences between those who developed freezing (n=7) and those who did not (n=12) in Unified Parkinson's Disease Rating Scale motor scores, time to complete a 14 m walk and timed up and go. There was a significant correlation between the measured change in transverse relaxation in the lateral substantia nigra pars compacta and the change in motor score from baseline to 36 months (p=0.002). The freezing group showed a greater change in motor score and iron content than did the non-freezing group. CONCLUSIONS: Individuals destined to develop freezing early in PD have more motor impairment at baseline, more rapid deterioration in motor function, and pars compacta changes suggestive of increased iron content in comparison to those who do not.

Dopamine transporter imaging as a diagnostic tool for parkinsonism and related disorders in clinical practice.

BACKGROUND: Accurate diagnosis of Parkinson disease (PD) and other degenerative parkinsonian syndromes is important for management and prognostic purposes. Diagnosis can be challenging in early disease and in atypical cases. METHODS: We reviewed the literature on the application of dopamine transporter single-photon emission computed tomography (DAT-SPECT) in degenerative parkinsonism and related disorders as a diagnostic tool. RESULTS: The use of DAT-SPECT shows some utility in the early diagnosis of PD and differentiation from other non-degenerative parkinsonian disorders (i.e. essential tremor, dystonic tremor, drug-induced and in most cases of psychogenic parkinsonism), since it can accurately detect the presynaptic dopaminergic deficit. The test has been shown to have high sensitivity/specificity by multiple studies. DAT imaging may also have some prognostic value for disease progression. However, it has limited value in differentiating among degenerative causes of parkinsonism. DAT imaging has some limitations. In most studies, true test accuracy is unknown since the gold standard is clinical diagnosis by a movement disorders neurologist. Therefore, the sensitivity of the test cannot exceed that of the clinical diagnosis. In addition, false negative scans occur and highlight the need for clinical follow-up. CONCLUSION: Clinical assessment remains the most important aspect in evaluating these patients. DAT-SPECT is a sensitive modality to detect nigrostriatal degeneration. In spite of increasing data using this technique, however, more long-term clinical studies are required to determine how DAT-SPECT scan can guide decision-making.

Longitudinal midbrain changes in early Parkinson's disease: iron content estimated from R2*/MRI.

OBJECTIVE: To determine whether, in patients with early Parkinson's disease (PD), longitudinal changes in midbrain iron content are associated with declining motor function over a period of three years. METHODS: Nineteen untreated subjects with early PD and 13 age- and sex-matched controls were followed clinically for 36 months. MRI with a 3 T magnet was performed at baseline, 18 months and 36 months with a multiple gradient echo sequence designed for rapid single-scan mapping of the proton transverse relaxation rate R2*. R2* was calculated for midbrain and forebrain basal ganglia regions. RESULTS: A difference in R2* between patients and controls was observed at baseline (p = 0.035) but not at 18 or 36 months in the lateral substantia nigra pars compacta (SNc). Linear regression indicated significant correlations between the change in R2* in the lateral SNc and the change score in UPDRS III (p = 0.008) and the PDQ-39 -mobility sub-score (p = 0.03) from baseline to 36 months. R2* tended to increase in those with more advanced disease and to decrease in those with milder disease. CONCLUSIONS: High field MRI demonstrates lateral SNc abnormalities that progress over 3 years in early PD consistent with increased iron content in those with more advanced disease, corresponding to the known distribution of neuronal loss occurring in this disorder, and correlating with motor symptomatology. Larger and longer investigations with more precise mapping of iron-containing midbrain structures are needed to fully evaluate the potential of R2* as a biomarker of disease progression in PD.

Reduction in metabolite transverse relaxation times in amyotrophic lateral sclerosis.

BACKGROUND: Proton magnetic resonance spectroscopy (1H MRS) is used frequently to evaluate normal and pathological states in brain. MRS results are often reported as ratios of peak areas from spectra acquired at a single echo time, primarily for the peaks arising from N-acetyl groups (NA), creatine/phosphocreatine (t-Cr), and choline (Cho). Peak areas, however, are affected not only by metabolite concentration, but also by transverse relaxation times (T(2)). While the ratio approach appears to be valid in normal brain, pathology may affect T(2), thereby leading to misinterpretation of the apparent changes in metabolite ratios. The objective of the present study was to determine if any T(2) changes might affect the apparent metabolite ratio measures, which we have previously reported as being abnormal in amyotrophic lateral sclerosis (ALS). METHODS: 1H MRS data were acquired from the brainstems of ALS and control subjects, for a range of TE times, to calculate T(2) times for each of NA, t-Cr, and Cho. Metabolite ratios were measured experimentally at TE=120 ms and calculated for TE=0 ms, based on measured T(2) values. RESULTS: The T(2)'s for the ALS vs. control group were NA=272+/-10 ms vs. 351+/-58 ms (p<0.01), t-Cr=132+/-17 vs. 184+/-42 ms (p<0.02), and Cho=223+/-55 vs. 245+/-50 ms (p>0.05). The effect of these T(2) changes on metabolite ratios showed both the NA/t-Cr (ALS=0.98+/-0.13, Control=1.44+/-0.10, p<0001) and Cho/t-Cr (ALS=1.01+/-0.12, Control=1.34+/-0.24, p<0.001) ratios to differ significantly between groups. CONCLUSION: This study confirms the presence of significant abnormalities in metabolite concentration in ALS brainstem and the importance of evaluating the effects of metabolite T(2) values when making ratio measurements in disease states.