Parkinson's disease dementia: what's in a Lewy body?

This brief review deals with pathological aspects of dementia associated with Parkinson's disease (PDD). PDD has been variably linked with cortical Lewy body topography and density. alpha-Synuclein and Alzheimer-type pathology frequently co-exist, suggesting that a combination of pathology related to protein dysmetabolism, possibly with synergistic protein-protein interaction, underpins the cognitive impairment in PDD. Dementia may therefore ensue when a "toxic threshold" is reached, irrespective of the combination of pathologies involved in reaching that threshold. The nature of this putative protein-protein interaction needs to be further elucidated, and also whether there are specific clinical correlates of the pathological substrate. Serum and cerebrospinal fluid proteins or imaging techniques may be useful in future as biomarkers to identify the relative contribution of Lewy-related and Alzheimer-type pathology in a given case of PDD and to inform the rational use of drugs that can reduce alpha-synuclein aggregation and beta-amyloid production.     

Diffuse type of Lewy body disease: progressive dementia with abundant cortical Lewy bodies and senile changes of varying degree--a new disease?

The term Lewy body disease (LBD) was proposed earlier to describe a disease classified into three types (A, B, and C) according to the distributional pattern of Lewy bodies in the CNS. Group A (diffuse type of LBD) shows clinical symptoms of "dementia-parkinsonism syndrome". The most remarkable pathologic feature is the widespread appearance of numerous Lewy bodies not only in the brain stem and diencephalon (as in group C), but also in the cerebral cortex and basal ganglia, which is complicated by senile changes of various degrees. Group B is the transitional type between groups A and C. Group C (brain stem type of LBD) is identical with idiopathic Parkinson's disease. In this paper, 12 of our cases with diffuse type LBD were studied clinicopathologically and compared with eight similar cases in the literature. The neuropathologic substrate of progressive dementia in this disease is also discussed. LBD is a clinicopathologic entity; the diffuse type of LBD, a special form of this disease, presents mainly a presenile dementia.     

D-2-Hydroxyglutaric aciduria: Biochemical marker or clinical disease entity?

D -2-Hydroxyglutaric aciduria has been observed in patients with extremely variable clinical symptoms, creating doubt about the existence of a disease entity related to the biochemical finding. An international survey of patients with D -2-hydroxyglutaric aciduria was initiated to solve this issue. The clinical history, neuroimaging, and biochemical findings of 17 patients were studied. Ten of the patients had a severe early-infantile-onset encephalopathy characterized by epilepsy, hypotonia, cerebral visual failure, and little development. Five of these patients had a cardiomyopathy. In neuroimaging, all patients had a mild ventriculomegaly, often enlarged frontal subarachnoid spaces and subdural effusions, and always signs of delayed cerebral maturation. In all patients who underwent neuroimaging before 6 months, subependymal cysts over the head or corpus of the caudate nucleus were noted. Seven patients had a much milder and variable clinical picture, most often characterized by mental retardation, hypotonia, and macrocephaly, but sometimes no related clinical problems. Neuroimaging findings in 3 patients variably showed delayed cerebral maturation, ventriculomegaly, or subependymal cysts. Biochemical findings included elevations of D -2-hydroxyglutaric acid in urine, plasma, and cerebrospinal fluid in both groups. Cerebrospinal fluid γ-aminobutyric acid was elevated in almost all patients investigated. Urinary citric acid cycle intermediates were variably elevated. The conclusion of the study is that D -2-hydroxyglutaric aciduria is a distinct neurometabolic disorder with at least two phenotypes. Ann Neurol 1999;45:111–119     

Lewy body pathology in Alzheimer’s disease

Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.     

Unipolar mania: a distinct clinical entity?

Of the 241 lithium clinic patients at the New York State Psychiatric Institute with bipolar I affective disorder, 38 (15.7%) had never been hospitalized or somatically treated for depression. These "unipolar manic" patients had a significantly lower incidence of rapid cycling and suicide attempts than other bipolar I patients. No differences were found, however, in risk of illness in first-degree relatives. Lithium was an effective prophylactic agent in these patients. Some patients originally classified as "unipolar manic" were found to have depressive episodes with additional information and clinical observation. "Unipolar mania" appears to be a subgroup of bipolar I illness, but there are no data to support the hypothesis that it is a separate entity.     

Ophthalmoplegic Guillain-Barré syndrome: An independent entity or a transitional spectrum?

Ophthalmoplegia can occur in both Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with typical limb involvement. However, ophthalmoplegic GBS (OGBS) has been poorly defined. We aimed to characterize OGBS and clarify the pathophysiological implications across the overall GBS spectrum. Twenty GBS and seven MFS patients from three university based teaching hospitals in Korea were enrolled and analyzed. Six GBS patients who were classified as OGBS commonly also had facial diplegia (50%) and bulbar palsy (50%), while only a small portion of non-ophthalmoplegic GBS (NOGBS) patients had facial diplegia (21%). None of the patients had bulbar palsy in the NOGBS or MFS groups. The most frequent anti-ganglioside antibody in OGBS was the IgG anti-GT1a antibody (50%). The IgG anti-GM1 antibody was found mainly in NOGBS (57%) with high concordance with the pure motor type classification on electrophysiology. IgG anti-GQ1b antibody was positive uniquely in MFS (100%), although some patients were also positive for anti-GT1a antibody (71%). OGBS had distinct clinical features, including bulbar palsy, as well as ophthalmoplegia and limb weakness for both GBS and MFS. Relevant immunological factors were anti-GT1a antibody. Whether OGBS is an independent entity or a transitional spectrum remains to be established and further study will be needed.     

Is Alzheimer’s disease a homogeneous disease entity?

The epidemic proportions of dementia in old age are a cause of great concern for the medical profession and the society at large. It is customary to consider Alzheimer’s disease (AD) as the most common cause of dementia, and vascular dementia (VaD) as being the second. This dichotomous view of a primary neurodegenerative disease as opposed to a disorder where extrinsic factors cause brain damage led to separate lines of research in these two entities. New biomarkers, particularly the introduction of modern neuroimaging and cerebrospinal fluid changes, have, in recent years, helped to identify anatomical and chemical changes of VaD and of AD. Nevertheless, there is a substantial difference between the two entities. While it is clear that VaD is a heterogeneous entity, AD is supposed to be a single disorder. Nobody attempts to use CADASIL as a template to develops treatment for sporadic VaD. On the other hand, early-onset AD is used to develop therapy for sporadic AD. This paper will discuss the problems relating to this false concept and its consequences.     

Diffuse pachygyria with cerebellar hypoplasia: a milder form of microlissencephaly or a new genetic syndrome?

We report on 2 families with diffuse pachygyria and cerebellar hypoplasia, who presented hypotonia, ataxia, seizures, and developmental delay since infancy. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed decreased gyral formation in the cerebral cortex and marked hypoplasia in the cerebellum. Cerebellar hypoplasia is often associated with type 2 lissencephaly; however, our cases showed no polymicrogyria, and their clinical findings were quite mild compared with those of microlissencephaly. Their characteristic phenotype suggested a new genetic syndrome, which was possibly inherited as an autosomal recessive trait.     

Is fibromyalgia a distinct clinical syndrome?

The validity of the fibromyalgia syndrome (FMS) as a distinct clinical entity has been challenged for several reasons. Many skeptics express concern about the subjective nature of chronic pain, the subjectivity of the tender point (TeP) examination, the lack of a gold standard laboratory test, and the absence of a clear pathogenic mechanism by which to define FMS. Another expressed concern has been the relative nature of the pain-distress relationship in the rheumatology clinic. The apparently continuous relationship between TePs and somatic distress across a variety of clinical disorders is said to argue against FMS as a separate clinical disorder. The most aggressive challenges of the FMS concept have been from legal defenses of insurance carriers motivated by economic concerns. Other forms of critique have presented as psychiatric dogma, uninformed posturing, suspicion of malingering, ignorance of nociceptive physiology, and occasionally have resulted from honest misunderstanding. It is not likely that a few paragraphs of data and logic will cause an unbeliever to change an ingrained opinion. Therefore, this review describes the clinical manifestations of FMS, responds to some of the theoretic arguments against it, and discusses some possible pathophysiologic mechanisms by which FMS may develop and persist as a unique syndrome.     

Is subcortical vascular dementia a clinical entity for clinical drug trials?

Several therapeutic trials have been performed for vascular dementia, with drugs differing in type and mechanism of action. The results have been almost invariably inconclusive. Given the current notion that there are different subtypes of vascular dementia according to pathophysiological mechanisms, it is reasonable to suspect that one of the main causes of the disappointing results was that the study samples included patients not fitting with the rationale of selective treatments. Testing this hypothesis is difficult because characterization of patients in relation to different subtypes of vascular dementia is not available for most studies. However, attempts are ongoing to reclassify patients entered in some trials for post hoc subgroup analyses with some preliminary interesting results. We propose that (1) specific subtypes of vascular dementia should be the target in any single trial using a treatment with a proper rationale; and (2) subcortical vascular dementia, caused by small vessel disease leading to lacunar infarcts and subcortical white matter changes, represents a clinically and radiologically well-defined entity to be considered for future trials designed specifically for testing adequate drugs.     

Controversy: is Parkinson's disease a single disease entity? Yes

Parkinson's disease (PD) is a common, and in principle, sporadic, neurodegenerative disorder that occurs in adults. Pathological studies have revealed that in PD, nerve cell loss and Lewy bodies (LB) are distributed widely in the nervous system. Moreover, molecular pathology has made remarkable advances over the last several years, after the identification of alpha-synuclein gene abnormality in familial PD. Extensive pathological findings support the idea that PD is a single disease entity and that there are no cases of PD in which neurodegeneration occurs only in the substantia nigra and in which there are no LBs.     

Evidence that incidental Lewy body disease is pre-symptomatic Parkinson’s disease

Lewy bodies, the histologic hallmark of Parkinson’s disease (PD), are detected in the brains of about 10% of clinically normal people over the age of 60 years. When Lewy bodies are found in normal individuals, the process is sometimes referred to as incidental Lewy body disease (iLBD). The distribution of Lewy bodies in iLBD is similar to the distribution in PD, but neuronal populations vulnerable to Lewy bodies do not show significant neuronal loss in iLBD. It remains unknown if Lewy bodies in this setting represent pre-symptomatic PD or an age-related change unrelated to PD. To address this question we identified cases of iLBD and used a marker for dopaminergic and noradrenergic neurons, tyrosine hydroxylase (TH), to determine if there were changes similar to those found in PD. TH immunoreactivity in the striatum and the epicardial nerve fibers was decreased in iLBD compared to normal controls, but not to the same extent as in PD. The findings suggest that iLBD is preclinical PD and that the lack of symptoms is due to subthreshold pathology.     

Are Parkinson's disease with dementia and dementia with Lewy bodies the same entity?

The diagnosis of Parkinson's disease with dementia (PDD) or dementia with Lewy bodies (DLB) is based on an arbitary distinction between the time of onset of motor and cognitive symptoms. These syndromes share many neurobiological similarities, but there are also differences. Deposition of beta-amyloid protein is more marked and more closely related to cognitive impairment in DLB than PDD, possibly contributing to dementia at onset. The relatively more severe executive impairment in DLB than PDD may relate to the loss of frontohippocampal projections in DLB. Visual hallucinations and delusions associate with more abundant Lewy body pathology in temporal cortex in DLB. The differential involvement of pathology in the striatum may account for the differences in parkinsonism. Longitudinal studies with neuropathological and neurochemical evaluations will be essential to enable more robust comparisons and determine pathological substrates contributing to the differences in cognitive, motor, and psychiatric symptoms.