Neurodegenerative diseases are a common cause of morbidity and cognitive impairment in older adults. Most clinicians who care for the elderly are not trained to diagnose these conditions, perhaps other than typical Alzheimer's disease (AD). Each of these disorders has varied epidemiology, clinical symptomatology, laboratory and neuroimaging features, neuropathology, and management. Thus, it is important that clinicians be able to differentiate and diagnose these conditions accurately. This review summarizes and highlights clinical aspects of several of the most commonly encountered neurodegenerative diseases, including AD, frontotemporal dementia (FTD) and its variants, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Parkinson's disease (PD), dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and Huntington's disease (HD). For each condition, we provide a brief overview of the epidemiology, defining clinical symptoms and diagnostic criteria, relevant imaging and laboratory features, genetics, pathology, treatments, and differential diagnosis.

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Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases

Despite its being one of the most commonly observed neurological disorders, neuropathological studies of essential tremor (ET) are rare. There have been surprisingly few autopsy studies and even fewer case-control comparisons. The primary objective was to describe and quantify the pathological changes in 33 ET and 21 control brains. A secondary objective was to correlate clinical and pathological features. We examined autopsy tissue from the Essential Tremor Centralized Brain Repository. Eight (24.2%) of the 33 ET brains had Lewy bodies in the brainstem, mainly in the locus ceruleus. However, the majority of ET brains (25/33, 75.8%) had no Lewy bodies, but had pathological changes in the cerebellum. The mean number of Purkinje cells per 100× field was reduced in ET cases without Lewy bodies (6.6 ± 2.4 versus 9.6 ± 3.4, P < 0.01), and there were ∼7× more Purkinje cell torpedoes per section (12.6 ± 7.9 versus 1.7 ± 1.4, P < 0.001) compared to controls. ET cases without Lewy bodies also had degeneration of the dentate nucleus (two cases). Other findings in ET cases were Purkinje cell heterotopias and dendrite swellings. Lewy body ET cases were older than ET cases without Lewy bodies. Several trends were observed in ET cases without Lewy bodies, including a younger age of onset of tremor and higher proportions with gait difficulty and family history of ET. The pathological changes of ET seem to be heterogeneous and degenerative. The majority have cerebellar changes without Lewy bodies; a smaller proportion has brainstem Lewy bodies. The clinical differences between cases with versus without Lewy bodies require additional study.

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Neuropathological changes in essential tremor: 33 cases compared with 21 controls

Tremor is defined as rhythmic oscillatory activity of body parts. Four physiological basic mechanisms for such oscillatory activity have been described: mechanical oscillations; oscillations based on reflexes; oscillations due to central neuronal pacemakers; and oscillations because of disturbed feedforward or feedback loops. New methodological approaches with animal models, positron emission tomography, and mathematical analysis of electromyographic and electroencephalographic signals have provided new insights into the mechanisms underlying specific forms of tremor. Physiological tremor is due to mechanical and central components. Psychogenic tremor is considered to depend on a clonus mechanism and is thus believed to be mediated by reflex mechanisms. Symptomatic palatal tremor is most likely due to rhythmic activity of the inferior olive, and there is much evidence that essential tremor is also generated within the olivocerebellar circuits. Orthostatic tremor is likely to originate in hitherto unidentified brainstem nuclei. Rest tremor of Parkinson's disease is probably generated in the basal ganglia loop, and dystonic tremor may also originate within the basal ganglia. Cerebellar tremor is at least in part caused by a disturbance of the cerebellar feedforward control of voluntary movements, and Holmes' tremor is due to the combination of the mechanisms producing parkinsonian and cerebellar tremor. Neuropathic tremor is believed to be caused by abnormally functioning reflex pathways and a wide variety of causes underlies toxic and drug-induced tremors. The understanding of the pathophysiology of tremor has made significant progress but many hypotheses are not yet based on sufficient data. Modern neurology needs to develop and test such hypotheses, because this is the only way to develop rational medical and surgical therapies.

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The pathophysiology of tremor

The oxygen-15 water bolus positron emission tomography (PET) method was used to image regional brain activity in 4 patients with chronic post-traumatic neuropathic pain confined to one lower limb and in 1 patient with post-herpetic neuralgia. In comparison to 13 normal subjects, scans of the patients disclosed a statistically significant decrease in thalamic activity contralateral to the symptomatic side. Examination of the right/left ratio for all the subjects showed that the values for the patients fell at the extremes of the normal range, according to the side of the affected body part. These initial observations suggest that functional alterations in thalamic pain processing circuits may be an important component of chronic neuropathic pain.

Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain.

The cerebellum is assumed to play a major role in the pathophysiology of essential tremor (ET). As intention tremor is considered one of the classical features of cerebellar disease, we have assessed a large group of patients with ET for the semiology of the tremor and have performed objective quantitative analysis of a grasping movement in patients with ET, cerebellar disease and a normal control group. We found 25% of the patients to have a moderate or severe kinetic tremor with clear-cut features of a classical intention tremor. Another 33% of the patients had a mild intentional component of their kinetic tremor. Patients with intention tremor (ET(IT)) did not differ from those with predominant postural tremor (ET(PT)) with respect to alcohol sensitivity of the tremor and the frequency of a family history. ET(IT) patients were older and more often showed head and trunk involvement. The onset of this intention tremor has been assessed retrospectively. It was found to begin at a randomly distributed time interval after the onset of the postural tremor, but older patients had a shorter time to development of intention tremor. Quantitative accelerometry of postural tremor showed similar tremor frequencies in both patient groups, but ET(IT) patients had a slightly larger tremor amplitude. Quantitative analysis of a grasping movement using an infrared-camera system was performed in two subgroups of the patients with ET(PT) and ET(IT) and control groups with cerebellar disease or normal subjects. The intention tremor could be quantified objectively as an increased amplitude of curvature during the deceleration and target phase of the movement. The amplitude measurements of intention tremor were clearly abnormal and of comparable magnitude for ET(PT) and cerebellar disease. Additionally, the patients with ET(IT) had a significantly slowed grasping movement during the deceleration and target period. Hypermetria was significantly increased for the patients with ET(IT) and cerebellar disease. We conclude that intention tremor is a feature of ET. ET(IT) patients have abnormalities of their upper limb function compatible with cerebellar disease. This suggests that patients with more advanced ET show abnormalities of cerebellar functions.

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Essential tremor and cerebellar dysfunction Clinical and kinematic analysis of intention tremor

Glucose metabolism in the brain of patients with essential tremor

We analyzed local cerebral metabolic rates of glucose (LCMRglu) in 20 regions from 22 patients with complex partial seizures, who were taking neither phenytoin nor phenobarbital and who had normal CTs. Results were compared with data from 19 normal controls. Ten patients had left temporal, eight right temporal, and four bitemporal or generalized EEG discharges. There were no significant differences between patient and control values in any of 20 regions of interest. LCMRglu was depressed at the site of the epileptic focus: L/R ratio was 0.85 +/- 0.12 (p less than 0.003 compared with control), 0.92 +/- 0.08 (p less than 0.05), and 0.84 +/- 0.1 (p less than 0.001), respectively, in mesial, superior, and inferior temporal regions for patients with left temporal foci; 1.7 +/- 0.96 (p less than 0.04), 1.1 +/- 0.1 (NS), and 1.15 +/- 0.04 (p less than 0.001) for patients with right temporal foci. Patients with left temporal EEG foci had significantly lower values than patients with right temporal foci in left superior frontal and thalamic as well as left temporal regions, while patients with right-sided EEG foci had depressed LCMRglu (compared with patients with left temporal EEG foci) restricted to right mesial temporal lobe. The patients with left temporal foci tended to have longer seizure histories (22.7 +/- 5.4 versus 11 +/- 5.6 years; p less than 0.001). There was an inverse correlation between length of seizure history and mean LCMRglu (r = 0.38; 0.1 greater than p greater than 0.05). Our study suggests that LCMRglu is not depressed in regions beyond the epileptic focus when patients are not taking drugs known to decrease cerebral glucose metabolism.

Patterns of cerebral glucose metabolism in patients with partial seizures

Hypertrophic degeneration of the inferior olivary nuclei is the pathologic substrate for palatal myoclonus, but the physiologic correlate of this finding is uncertain. Using the 2-[ 18 F]fluoro-2-deoxy-d-glucose and PET method, we determined the local cerebral metabolic rate of glucose utilization in seven patients with palatal myoclonus (following stroke or infection, or idiopathic), one patient with oculopalatal myoclonus (following a stroke affecting the brainstem), and nine normal subjects. The metabolism of glucose in the medulla of the patients with palatal myoclonus was significantly greater than that of the normal subjects. This may well have been due to increased metabolism of the inferior olivary nuclei. Glucose metabolism in the medulla of the patient with oculopalatal myoclonus was normal. These findings suggest that the inferior olivary nuclei, or a region of the brainstem encompassing the inferior olivary nuclei, are hypermetabolic in palatal myoclonus and may be the generators of the involuntary movements in palatal myoclonus.

Increased glucose metabolism in the medulla of patients with palatal myoclonus.

Two brothers with neuroacanthocytosis had [18F]-2-fluoro-2-deoxyglucose PET scans showing marked glucose hypometabolism of the caudate and putamen. MRIs showed no evidence of atrophy or modification of signal intensity in these structures. Decreased glucose utilization of the striatum can underlie hyperkinetic movement disorders of various etiologies.

Regional brain glucose metabolism in neuroacanthocytosis

We studied 45 patients who had autonomic failure with computed tomography, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose to characterize the neuroimaging features of multiple system atrophy and pure autonomic failure and determine the utility of these techniques in distinguishing multiple system atrophy from pure autonomic failure. There were 30 patients with multiple system atrophy and 15 with pure autonomic failure. In the multiple system atrophy group, eight patients had mainly cerebellar signs, seven extrapyramidal and 15 had combinations of cerebellar and extrapyramidal signs. Cerebellar atrophy on computerized tomography and magnetic resonance imaging, signal hypointensity in the posterolateral putamen on magnetic resonance imaging and a generalized reduction in glucose utilization rate with positron emission tomography with [18F]fluorodeoxyglucose, were the main findings and were seen only in the patients with multiple system atrophy. Decreased glucose utilization (hypometabolism) was most prominent in the cerebellum, brainstem, striatum and frontal and motor cortices. These results indicate clear differences, using neuroimaging studies, between multiple system atrophy and pure autonomic failure.

Computed tomography, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose in multiple system atrophy and pure autonomic failure.

Richard M. Dubinsky

Papers

Glucose metabolism in the brain of patients with essential tremor

Patterns of cerebral glucose metabolism in patients with partial seizures

Increased glucose metabolism in the medulla of patients with palatal myoclonus.

Regional brain glucose metabolism in neuroacanthocytosis

Computed tomography, magnetic resonance imaging and positron emission tomography with [18F]fluorodeoxyglucose in multiple system atrophy and pure autonomic failure.