Mary Heumann

REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA

Objective: To explore the neurochemical basis of REM sleep behavior disorder (RBD) in multiple-system atrophy (MSA). Methods: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of REM atonia loss by the percentage of REM sleep with tonically increased electromyographic (EMG) activity and the percentage of REM sleep with phasic EMG bursts. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was employed to measure the density of striatal monoaminergic terminals and SPECT with (−)-5-[123I]iodobenzovesamicol ([123I]IBVM) to measure the density of thalamic cholinergic terminals. Data in the patient group were compared with data from 15 normal control subjects scanned with [11C]DTBZ and 12 with [123I]IBVM. Results: Age and gender distributions were similar in patient and normal control groups. The MSA subjects showed decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) and decreased [123I]IBVM binding in the thalamus (p < 0.001). Moreover, in the MSA group, striatal [11C]DTBZ binding was inversely correlated with the severity of REM atonia loss (p = 0.003). Thalamic [123I]IBVM binding, however, was not correlated to the severity of REM atonia loss. Conclusion: Decreased nigrostriatal dopaminergic projections may contribute to RBD in MSA.

Differentiation of Alzheimer's disease from dementia with Lewy bodies utilizing positron emission tomography with [18F]fluorodeoxyglucose and neuropsychological testing

We compared the relative utility of neuropsychological testing and positron emission tomography (PET) with [18F]fluorodeoxyglucose ([18F]FDG) in differentiating Alzheimers disease (AD) from dementia with Lewy bodies (DLB). We studied 25 patients with AD, 20 with DLB, and 19 normal elderly controls. There was no difference between patient groups for MMSE, confrontational naming, or verbal learning. The DLB group was significantly more impaired than the AD group for verbal fluency, and the AD group was significantly more impaired than the DLB group for verbal delayed recall. The DLB group had greater difficulty than the AD group on a visual discrimination task that does not require motor functioning, but the difference did not reach significance. Family ratings of motor functioning suggested significantly greater impairment in DLB patients than in AD patients. PET studies revealed significantly lower local cerebral metabolic rates for glucose (lCMRglc) for visual cortex (Brodmann areas 17, 18, and 19) in the DLB than the AD group, but no differences for other regions commonly affected in AD, including posterior cingulate, superior parietal lobe, lateral temporal lobe, and the prefrontal region. Motor ratings were significantly correlated with lCMRglc in all areas of cerebral cortex, including Brodmann areas 17, 18, and 19. The results demonstrate a similar profile of cerebral hypometabolism in the two patient groups except in the visual cortex, where the DLB group shows markedly lower lCMRglc than the AD group. Neuropsychological testing also differentiates the groups, and family ratings of motor functioning are as robust as PET in these later stages of the disorders.

Obstructive sleep apnea is related to a thalamic cholinergic deficit in MSA

Objective: To explore the neurochemical basis of obstructive sleep apnea (OSA) in multiple-system atrophy (MSA). Methods: In 13 patients with probable MSA, nocturnal, laboratory-based polysomnography was used to rate the severity of OSA using the apnea–hypopnea index during sleep. SPECT with (−)-5-[123I]iodobenzovesamicol ([123I]IBVM) was utilized to measure the density of thalamic cholinergic terminals, which project from the brainstem pedunculopontine and laterodorsal tegmental nuclei. PET with (+)-[11C]dihydrotetrabenazine ([11C]DTBZ) was also used to measure the density of striatal monoaminergic terminals, which project from the brainstem. Findings in the patient group were compared with data from 12 normal control subjects scanned utilizing [123I]IBVM and 15 normal control subjects utilizing [11C]DTBZ. Results: Age and gender distributions were similar in patient and control groups. The MSA subjects showed decreased [123I]IBVM binding in the thalamus (p < 0.001) and decreased mean [11C]DTBZ binding in the striatum (p < 0.0001) in comparison with the control subjects. In the MSA group, thalamic [123I]IBVM binding was inversely correlated with the severity of OSA (p = 0.011). Striatal [11C]DTBZ binding was not correlated with the severity of OSA (p = 0.19). Conclusion: Decreased pontine cholinergic projections may contribute to OSA in MSA.

Evolution of sporadic olivopontocerebellar atrophy into multiple system atrophy

Objective: To determine the percentage of sporadic olivopontocerebellar atrophy (sOPCA) patients who later develop multiple system atrophy (MSA). Methods: Observations of the course of 51 sOPCA patients 20 years of age or older initially evaluated in an ataxia clinic over 14 years and followed at 3- to 6-month intervals for 3 months to 10 years (median 2.5 years, interquartile range 5 months to 4 years). Results: Seventeen patients evolved to develop MSA, whereas the remaining 34 manifested only progressively worsening cerebellar ataxia. The features of the MSA cases included autonomic failure and parkinsonism in 10 patients, autonomic failure without parkinsonism in six, and parkinsonism without autonomic failure in one. Using survival analysis methods, the authors estimated that 24% of subjects in this population will evolve to MSA within 5 years of the onset of sOPCA symptoms (95% CI 10% to 36%). An older age at onset of symptoms and a shorter time from onset of symptoms to first presentation in a neurology specialty clinic were both highly predictive of evolution to MSA. Six of the 17 patients who evolved to MSA died 4 months to 5 years after they had met diagnostic criteria for MSA. The estimated median survival time from time of transition was 3.5 years. In contrast, death occurred in only one of the 34 patients with sOPCA who did not evolve to MSA. Autopsy examination of all six patients with MSA who died confirmed the diagnosis. Conclusions: Approximately one-fourth of sporadic olivopontocerebellar atrophy patients will evolve to multiple system atrophy within 5 years, and this transition carries a poor prognosis for survival. Older age at onset of ataxia and earlier presentation in a neurologic specialty clinic predicted transition to MSA.

Effects of abstinence and relapse upon neuropsychological function and cerebral glucose metabolism in severe chronic alcoholism

Prolonged excessive consumption of alcohol has been associated with a variety of cognitive disorders accompanied by neuropathological and neurochemical abnormalities of the brain, particularly in the frontal lobes. Studies with positron emission tomography (PET) have shown decreased local cerebral metabolic rates for glucose (lCMRglc) in frontal regions, with correlated abnormalities on neuropsychological tests sensitive to executive functioning. This investigation was designed as a pilot study to examine the effects of abstinence and relapse in patients with severe chronic alcoholism studied longitudinally with PET and with neuropsychological evaluation to assess both general and executive functioning. Six patients, including 4 who remained relatively abstinent and 2 who relapsed following their initial evaluation, were studied twice, with inter-evaluation intervals ranging from 10 to 32 months. The patients who remained abstinent or who had minimal alcohol use showed partial recovery of lCMRglc in two of three divisions of the frontal lobes and improvement on neuropsychological tests of general cognitive and executive functioning, whereas the patients who relapsed had further declines in these areas. These results, although based upon a relatively small number of subjects, provide preliminary support for at least partial recovery of metabolic and cognitive functioning in individual patients who abstain from alcohol.

Striatal monoamine terminals in Lewy body dementia and Alzheimer's disease

We used positron emission tomography (PET) with (+)‐[11C]dihydrotetrabenazine ([+]‐[11C]DTBZ) to examine striatal monoaminergic presynaptic terminal density in 20 patients with dementia with Lewy bodies (DLB), 25 with Alzheimers disease (AD), and 19 normal elderly controls. Six DLB patients developed parkinsonism at least 1 year before dementia (DLB/PD) and 14 developed dementia before parkinsonism or at about the same time (DLB/AD). Striatal mean binding potential was decreased by 62 to 77% in the DLB/PD group and 45 to 67% in the DLB/AD compared to AD and control. Binding was lower in the DLB/PD group than the DLB/AD, but the differences reached only marginal significance in the caudate nucleus. No differences were found between AD and control groups though a few AD patients had binding values below the range of the controls. Subsequent neuropathological examination in one AD patient revealed both AD and DLB changes despite the absence of clinical parkinsonism. Both DLB groups had an anterior to posterior binding deficit gradient relative to controls, largest in posterior putamen, smaller in anterior putamen, smallest in caudate nucleus. The DLB/AD group showed significant binding asymmetry only in posterior putamen. We conclude that PET with (+)‐[11C]DTBZ differentiates DLB from AD, and decreased binding in AD may indicate subclinical DLB pathology in addition to AD pathology. Ann Neurol 2004

PET measures of benzodiazepine receptors in progressive supranuclear palsy

Objective: To evaluate the integrity of neurons containing benzodiazepine receptors in metabolically affected regions of the brain in patients with clinically diagnosed progressive supranuclear palsy (PSP). Methods: The cerebral distribution of [11C]flumazenil (FMZ), a ligand that binds to the gamma-aminobutyric acid A (GABAA) receptor, and [18F]fluorodeoxyglucose (FDG), a measure of local cerebral glucose metabolism, was determined with PET in 12 patients with PSP and 10 normal control subjects. Tracer kinetic analysis was applied to quantify data and analysis was performed using three-dimensional stereotactic surface projections and stereotactically determined volumes of interest. Results: There was a global reduction in FMZ binding of 13%, with a reduction in the anterior cingulate gyrus of 20% (p = 0.004), where glucose metabolic rates also showed the greatest reduction. Conclusions: PSP causes loss of benzodiazepine receptors in the cerebral cortex. Consistent with postmortem studies, the authors did not find significant changes in FMZ binding in subcortical nuclei that exhibit the most pathologic change. This study suggests that both loss of intrinsic neurons containing benzodiazepine receptors and deafferentation of the cerebral cortex from distant brain regions contribute to cerebral cortical hypometabolism in PSP.

Decreased striatal monoaminergic terminals in multiple system atrophy detected with positron emission tomography

We examined the density of striatal presynaptic monoaminergic terminals, using a ligand for the type 2 vesicular monoamine transporter, (+)‐[11C]dihydrotetrabenazine, with positron emission tomography in 7 normal control subjects, 8 multiple system atrophy (MSA) patients with predominantly parkinsonian features (MSA‐P), 8 MSA patients with principally cerebellar dysfunction (MSA‐C), and 6 sporadic olivopontocerebellar atrophy (sOPCA) patients. The findings were correlated with the results of neurological evaluations and magnetic resonance imaging studies. Specific binding was significantly reduced in the putamen of all patient groups in the order MSA‐P < MSA‐C < sOPCA, compared with controls. Mean blood‐to‐brain ligand transport (K1) was significantly decreased in the putamen of all patient groups and in the cerebellar hemispheres of MSA‐C and sOPCA but not MSA‐P groups, compared with controls. Significant negative correlations were found between striatal binding and the intensity of parkinsonian features and between cerebellar K1 and the intensity of cerebellar dysfunction. The results suggest fundamental differences between MSA‐P and MSA‐C groups reflecting differential severity of degeneration of nigrostriatal and cerebellar systems in these two forms of MSA. The findings also show that some sOPCA patients have subclinical nigrostriatal dysfunction and are at risk of developing MSA with disease progression. Ann Neurol 1999;45:769–777

17 – Neurodegenerative Disorders of the Cerebellum

This chapter discusses the important diagnostic information about cerebellar neurodegenerative disorders. The neurodegenerative disorders of the central nervous system are characterized by the progressive degeneration and subsequent loss of neurons accompanied by reactive gliosis, degeneration of fibers from the deteriorating neurons, and clinical symptoms reflecting the locations of the lost neurons. These disorders occur sporadically, usually without known cause or from genetic disease with either dominant or recessive inheritance. Many neurodegenerative disorders affect the cerebellum and its pathways, resulting in progressive deterioration of cerebellar function manifested by increasing unsteadiness of gait. An autosomal recessive neurodegenerative disorder, Friedreichs Ataxia, or FA in short, is one of the most common of the hereditary ataxias. FA was thought to begin in childhood or early adolescence, at times in late adolescence and only rarely above age 20. In these “typical” patients, the disorder begins with progressive ataxia of the legs followed by the arms and then progresses to cause leg weakness, leading to paraplegia, ataxic dysarthria, decreased peripheral sensation to all modalities with particularly severe involvement of vibration sense and position sense, areflexia, and bilateral extensor plantar reflexes. FA patients have an increased prevalence of impaired glucose tolerance and diabetes mellitus in comparison with the general population.