Parkinson Disease: Dickson DW

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Dickson DW, Farrer MJ. · No affiliation provided · Ann Neurol. · Pubmed #16315283 No free full text.

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Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B. · Department of Neurology, Behavioral Neurology and Movement Disorders Unit, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. · Mov Disord. · Pubmed #17542011 links to  free full text

Abstract: Dementia has been increasingly more recognized to be a common feature in patients with Parkinson's disease (PD), especially in old age. Specific criteria for the clinical diagnosis of dementia associated with PD (PD-D), however, have been lacking. A Task Force, organized by the Movement Disorder Study, was charged with the development of clinical diagnostic criteria for PD-D. The Task Force members were assigned to sub-committees and performed a systematic review of the literature, based on pre-defined selection criteria, in order to identify the epidemiological, clinical, auxillary, and pathological features of PD-D. Clinical diagnostic criteria were then developed based on these findings and group consensus. The incidence of dementia in PD is increased up to six times, point-prevelance is close to 30%, older age and akinetic-rigid form are associated with higher risk. PD-D is characterized by impairment in attention, memory, executive and visuo-spatial functions, behavioral symptoms such as affective changes, hallucinations, and apathy are frequent. There are no specific ancillary investigations for the diagnosis; the main pathological correlate is Lewy body-type degeneration in cerebral cortex and limbic structures. Based on the characteristic features associated with this condition, clinical diagnostic criteria for probable and possible PD-D are proposed.

Litvan I, Chesselet MF, Gasser T, Di Monte DA, Parker D, Hagg T, Hardy J, Jenner P, Myers RH, Price D, Hallett M, Langston WJ, Lang AE, Halliday G, Rocca W, Duyckaerts C, Dickson DW, Ben-Shlomo Y, Goetz CG, Melamed E. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17483689 No free full text.

Abstract: We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors. Although there is extensive new information on the etiology and pathogenesis of PD, which may advance its treatment, new syntheses of this information are needed. The second part of this two-part, state-of-the-art review by leaders in PD research critically examines the research field to identify areas for which new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part II are genetics, animal models, and oxidative stress.

Litvan I, Halliday G, Hallett M, Goetz CG, Rocca W, Duyckaerts C, Ben-Shlomo Y, Dickson DW, Lang AE, Chesselet MF, Langston WJ, Di Monte DA, Gasser T, Hagg T, Hardy J, Jenner P, Melamed E, Myers RH, Parker D, Price DL. · University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. · J Neuropathol Exp Neurol. · Pubmed #17413315 No free full text.

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Lippa CF, Duda JE, Grossman M, Hurtig HI, Aarsland D, Boeve BF, Brooks DJ, Dickson DW, Dubois B, Emre M, Fahn S, Farmer JM, Galasko D, Galvin JE, Goetz CG, Growdon JH, Gwinn-Hardy KA, Hardy J, Heutink P, Iwatsubo T, Kosaka K, Lee VM, Leverenz JB, Masliah E, McKeith IG, Nussbaum RL, Olanow CW, Ravina BM, Singleton AB, Tanner CM, Trojanowski JQ, Wszolek ZK, Anonymous00243. · Department of Neurology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. · Neurology. · Pubmed #17353469 No free full text.

Abstract: For more than a decade, researchers have refined criteria for the diagnosis of dementia with Lewy bodies (DLB) and at the same time have recognized that cognitive impairment and dementia occur commonly in patients with Parkinson disease (PD). This article addresses the relationship between DLB, PD, and PD with dementia (PDD). The authors agreed to endorse "Lewy body disorders" as the umbrella term for PD, PDD, and DLB, to promote the continued practical use of these three clinical terms, and to encourage efforts at drug discovery that target the mechanisms of neurodegeneration shared by these disorders of alpha-synuclein metabolism. We concluded that the differing temporal sequence of symptoms and clinical features of PDD and DLB justify distinguishing these disorders. However, a single Lewy body disorder model was deemed more useful for studying disease pathogenesis because abnormal neuronal alpha-synuclein inclusions are the defining pathologic process common to both PDD and DLB. There was consensus that improved understanding of the pathobiology of alpha-synuclein should be a major focus of efforts to develop new disease-modifying therapies for these disorders. The group agreed on four important priorities: 1) continued communication between experts who specialize in PDD or DLB; 2) initiation of prospective validation studies with autopsy confirmation of DLB and PDD; 3) development of practical biomarkers for alpha-synuclein pathologies; 4) accelerated efforts to find more effective treatments for these diseases.

Dächsel JC, Lincoln SJ, Gonzalez J, Ross OA, Dickson DW, Farrer MJ. · No affiliation provided · Mov Disord. · Pubmed #17094104 No free full text.

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Whaley NR, Uitti RJ, Dickson DW, Farrer MJ, Wszolek ZK. · Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA. · J Neural Transm Suppl. · Pubmed #17017533 No free full text.

Abstract: The etiology for Parkinson's disease (PD) remains unknown. Genetic causes have been identified with several distinct mutations. Recently, 9 mutations involving a novel gene, leucine-rich repeat kinase 2 (LRRK2), have been identified as the cause of autosomal dominant PD in kindreds, with some of them previously linked to the PARK8 locus on chromosome 12. LRRK2 mutations are relatively common genetic causes of familial and sporadic PD. In addition, these mutations have been identified in diverse populations. The clinical and pathologic features of LRRK2-associated PD are indistinguishable from idiopathic PD; however, considerable clinical and pathologic variability exists even among kindreds. This short review highlights the clinical and pathologic features in LRRK2-associated parkinsonism.

Eriksen JL, Dawson TM, Dickson DW, Petrucelli L. · Department of Neurogenetics, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Neuron. · Pubmed #14642269 No free full text.

Abstract: Previous reports on Parkinson's disease indicate that genetic mutations in alpha-synuclein result in the aberrant accumulation of this protein, causing toxic gain of function leading to the development of Parkinson's. A recent report on the Iowan kindred, an extended pedigree with an autosomal dominant form of this disease, provides new mechanistic insight into Parkinson's disease by showing that an elevation in wild-type alpha-synuclein protein is sufficient to develop the early-onset form of the disorder. This review discusses how insights gained from these studies of alpha-synuclein may direct future research into Parkinson's disease.

Dickson DW. · Department of Pathology, Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA. · J Geriatr Psychiatry Neurol. · Pubmed #12489917 No free full text.

Abstract: The pathologic substrate of the clinical syndrome of dementia with Lewy bodies (DLB) remains to be determined. Only a few prospective clinicopathologic studies have been reported. In those reports, most cases of DLB had neocortical or limbic Lewy bodies and Alzheimer-type pathology below threshold for diagnosis of Alzheimer's disease. These results are in accord with recent retrospective clinicopathologic studies of dementia occurring in Parkinson's disease, in which cortical Lewy bodies, rather than concurrent Alzheimer's disease, are increasingly recognized as the pathologic substrate of dementia. Additional clinicopathologic studies are warranted to address the role of other Lewy-related pathology, most notably Lewy neurites, in the cognitive impairment of DLB.

Vilariño-Güell C, Wider C, Soto-Ortolaza AI, Cobb SA, Kachergus JM, Keeling BH, Dachsel JC, Hulihan MM, Dickson DW, Wszolek ZK, Uitti RJ, Graff-Radford NR, Boeve BF, Josephs KA, Miller B, Boylan KB, Gwinn K, Adler CH, Aasly JO, Hentati F, Destée A, Krygowska-Wajs A, Chartier-Harlin MC, Ross OA, Rademakers R, Farrer MJ. · Molecular Genetics Laboratory and Core, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Neurology. · Pubmed #19506225 No free full text.

Abstract: OBJECTIVE: Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration. METHODS: In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS. RESULTS: This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk. CONCLUSIONS: This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.

Vilariño-Güell C, Soto AI, Lincoln SJ, Ben Yahmed S, Kefi M, Heckman MG, Hulihan MM, Chai H, Diehl NN, Amouri R, Rajput A, Mash DC, Dickson DW, Middleton LT, Gibson RA, Hentati F, Farrer MJ. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA. · Hum Mutat. · Pubmed #19085912 No free full text.

Abstract: Recessively inherited mutations in ATP13A2 result in Kufor-Rakeb syndrome (KRS), whereas genetic variability and elevated ATP13A2 expression have been implicated in Parkinson disease (PD). Given this background, ATP13A2 was comprehensively assessed to support or refute its contribution to PD. Sequencing of ATP13A2 exons and intron-exon boundaries was performed in 89 probands with familial parkinsonism from Tunisia. The segregation of mutations with parkinsonism was subsequently assessed within pedigrees. The frequency of genetic variants and evidence for association was also examined in 240 patients with nonfamilial PD and 372 healthy controls. ATP13A2 mRNA expression was also quantified in brain tissues from 38 patients with nonfamilial PD and 38 healthy subjects from the United States. Sequencing analysis revealed 37 new variants; seven missense, six silent, and 24 that were noncoding. However, no single ATP13A2 mutation segregated with familial parkinsonism in either a dominant or recessive manner. Four markers showed marginal association with nonfamilial PD, prior to correction for multiple testing. ATP13A2 mRNA expression was marginally decreased in PD brains compared with tissue from control subjects. In conclusion, neither ATP13A2 genetic variability nor quantitative gene expression in brain appears to contribute to familial parkinsonism or nonfamilial PD.

DelleDonne A, Klos KJ, Fujishiro H, Ahmed Z, Parisi JE, Josephs KA, Frigerio R, Burnett M, Wszolek ZK, Uitti RJ, Ahlskog JE, Dickson DW. · Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. · Arch Neurol. · Pubmed #18695057 links to  free full text

Abstract: BACKGROUND: The significance of Lewy bodies detected at autopsy in the brains of clinically normal individuals is uncertain but may represent preclinical Parkinson disease (PD). OBJECTIVE: To determine whether diminished striatal dopaminergic innervation and nigral cell loss are present in incidental Lewy body disease (iLBD), as one might expect if it is a forerunner of PD. DESIGN: Case-control study. SETTING: Medical records and archival brain tissue were obtained from a tertiary medical center for further study. PARTICIPANTS: Brains from clinically healthy individuals older than 60 years with alpha-synuclein-immunoreactive Lewy bodies (iLBD; n = 12) were compared with those from clinically healthy individuals with no alpha-synuclein pathologic findings (n = 31) and patients with PD (n = 25). MAIN OUTCOME MEASURES: Striatal dopaminergic integrity assessed in sections of putamen by immunofluorescence for tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT2), neuronal loss score in the substantia nigra, and distribution of Lewy bodies according to PD stage. RESULTS: Among the participants with iLBD, decreased striatal dopaminergic immunoreactivity was documented for both TH (33%) and VMAT2 (42%), compared with the pathologically normal subjects; as expected, the reductions were even greater in PD (73% decrease for TH and 96% decrease for VMAT2). Substantia nigra neuronal loss inversely correlated with both striatal TH (r = -0.84) and VMAT2 (r = -0.77). In addition, PD stage inversely correlated with both striatal VMAT2 (r = -0.85) and TH (r = -0.85). CONCLUSIONS: The results indicate that iLBD has nigrostriatal pathological features that are intermediate between those in pathologically normal persons and those with PD. The findings suggest that iLBD probably represents presymptomatic PD, rather than nonspecific, age-related alpha-synuclein pathological changes.

Fujishiro H, Frigerio R, Burnett M, Klos KJ, Josephs KA, Delledonne A, Parisi JE, Ahlskog JE, Dickson DW. · Department of Pathology (Neuropathology), Mayo Clinic, Jacksonville, Florida, USA. · Mov Disord. · Pubmed #18442129 No free full text.

Abstract: Attention has been drawn to cardiac sympathetic denervation in Parkinson's disease (PD) based on clinical studies using [123I] metaiodobenzylguanidine scintigraphy; however, the histologic correlates and time course of cardiac sympathetic denervation are poorly understood. To address these issues, we used tyrosine hydroxylase (TH) immunohistochemistry to detect cardiac sympathetic nerve fibers in the epicardium of 4 normal controls, 11 cases with incidental Lewy bodies (iLBs), and 14 cases of PD. Cardiac sympathetic innervation was significantly less in PD than in normal controls and cases with iLBs (P < 0.05). There was also a decrease in TH-immunoreactive fibers in iLB cases compared to normal controls (P < 0.01). TH-immunoreactive fibers correlated with the PD stage (r = -0.75, P < 0.001), as well as with Hoehn & Yahr clinical stage (r = -0.61, P < 0.001), and disease duration (r = -0.63, P < 0.001). Immunohistochemistry for alpha-synuclein showed neurites in epicardium in PD and iLB cases, but not in normal controls. The density of alpha-synuclein neurites correlated with Braak PD stage (r = 0.38, P < 0.05), Hoehn & Yahr clinical stage (r = 0.44, P < 0.05), and disease duration (r = 0.42, P < 0.05). This study demonstrates that cardiac sympathetic degeneration and alpha-synuclein pathology is present in presymptomatic phase of PD, and that both increase with disease duration and severity.

Markopoulou K, Dickson DW, McComb RD, Wszolek ZK, Katechalidou L, Avery L, Stansbury MS, Chase BA. · Department of Neurology, University of Thessaly Medical School, Papakyriazi 22, Larissa, 41222, Greece. · Acta Neuropathol. · Pubmed #18389263 No free full text.

Abstract: Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T alpha-synuclein heterozygotes from Family H, a multigenerational alpha-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T alpha-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.

Tsuboi Y, Uchikado H, Dickson DW. · Fifth Department of Internal Medicine, Fukuoka University, Fukuoka, Japan. · Parkinsonism Relat Disord. · Pubmed #18267239 No free full text.

Abstract: Dementia is relatively common in Parkinson's Disease (PD). When dementia occurs in the setting of PD, it is referred to as Parkinson's disease dementia (PDD), which is distinguished from the clinical syndrome in which dementia precedes extrapyramidal features, dementia with Lewy bodies (DLB). In this report, the neuropathology of PDD and DLB is reviewed and preliminary findings are reported on striatal pathology in 28 brains, including 7 PD, 7 PDD and 14 DLB. Sections of putamen immunostained for a-synuclein and investigated with image analysis show that striatal pathology is common and that both cortical and striatal a-synuclein pathology is greater in PDD and DLB than PD. Most cases of PDD and DLB have Alzheimer-type pathology, particularly amyloid plaques, which may act in an additive or synergistic manner with a-synuclein pathology. There are few pathologic differences between PDD and DLB, despite differences in their clinical course.

Dickson DW, Fujishiro H, DelleDonne A, Menke J, Ahmed Z, Klos KJ, Josephs KA, Frigerio R, Burnett M, Parisi JE, Ahlskog JE. · Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Acta Neuropathol. · Pubmed #18264713 No free full text.

Abstract: 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.

Dickson DW. · Department of Pathology, Mayo Clinic College of Medicine, Jacksonville, FL, USA. · Am J Pathol. · Pubmed #17200178 links to  free full text

This publication has no abstract.

Woodruff BK, Graff-Radford NR, Ferman TJ, Dickson DW, DeLucia MW, Crook JE, Arvanitakis Z, Brassler S, Waters C, Barker W, Duara R. · Department of Neurology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, Arizona 85259, USA. · Neurology. · Pubmed #16801670 No free full text.

Abstract: Genetic factors are important in Alzheimer disease (AD) and Parkinson disease but have not been well characterized in Lewy body dementia (LBD). The authors obtained family history in patients from an autopsy series of AD and LBD and in living healthy controls. A family history of dementia was more common in both LBD and AD compared with controls, suggesting that genetic factors are as important in LBD as they are in AD.

Uchikado H, DelleDonne A, Ahmed Z, Dickson DW. · Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, USA. · J Neuropathol Exp Neurol. · Pubmed #16691119 No free full text.

Abstract: Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy characterized by Parkinsonism, vertical gaze palsy, and early falls. Lewy bodies (LBs) are detected in approximately 10% of PSP cases, but there is little information on the relationship of LBs to tau pathology. We determined the frequency of LBs in a large series of autopsy-confirmed cases of PSP and studied the density and distribution of LBs, including Parkinson disease stage, in cases with LBs (PSP/LBD). PSP/LBD was compared with pure LB disease (LBD), including assessment of neuronal loss in key brainstem nuclei. Immunohistochemistry for alpha-synuclein revealed LBs in 31 of 290 PSP cases (11%). One case had multiple system atrophy in addition to PSP and was excluded from further study along with 2 PSP/LBD cases with concurrent Alzheimer disease. The 29 cases of PSP/LBD were compared with 30 cases of PSP and 24 cases of LBD. The age, sex, brain weight, Braak neurofibrillary tangle (NFT) stage, as well as counts of NFTs and senile plaques were not different among PSP, LBD, and PSP/LBD, but disease duration was longer in LBD. The Parkinson disease stage was similar, but the density of LBs in most subcortical nuclei tended to be greater in LBD than in PSP/LBD. In contrast, substantia nigra neuronal loss was greater in PSP/LBD than both PSP and LBD. Double immunostaining demonstrated alpha-synuclein and tau in different neurons with few exceptions. The findings suggest that LBs in PSP are similar in distribution to those in LBD and independent of tau pathology. The greater density of LBs in LBD compared with PSP/LBD may be the result of longer disease duration in LBD, whereas greater neuronal loss in the substantia nigra in PSP/LBD may be the result of vulnerability of this brain region to both disease processes.

Klos KJ, Josephs KA, Parisi JE, Dickson DW. · Department of Neurology, Movement Disorder Division, Mayo Clinic, Rochester, Minnesota, USA. · Mov Disord. · Pubmed #16035099 No free full text.

Abstract: We report on two cases of sporadic idiopathic Parkinson's disease with motor neuron disease co-occurring in the same individuals. Pathological analysis revealed the presence of Lewy bodies in brainstem nuclei and basal forebrain consistent with Lewy body disease (LBD), as well as motor neuron degeneration and argyrophilic grain disease. We compared our two cases to all previously published pathological cases of combined LBD and motor neuron degeneration.

Tsuboi Y, Dickson DW. · Fifth Department of Internal Medicine, Fukuoka University, Japan. · Parkinsonism Relat Disord. · Pubmed #15885629 No free full text.

Abstract: The relationship of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is debated. In DLB, dementia antedates Parkinsonism; in PDD, Parkinsonism antedates dementia. Other than presenting features, diagnostic measures fail to distinguish DLB from PDD. There are few or no pathologic differences between DLB and PDD. In most cases cortical Lewy bodies (LBs) are widespread and there is coexistent Alzheimer type pathology, insufficient to diagnose Alzheimer's disease. Given the predominance of Parkinsonism in PDD, neuronal loss in the substantia nigra is more severe in PDD than DLB. Further clinicopathologic studies are needed to define other pathologic differences between DLB and PDD and to explore the role of neuritic, basal forebrain and striatal pathology in these clinical syndromes.

Uitti RJ, Calne DB, Dickson DW, Wszolek ZK. · Department of Neurology and the Section of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · Parkinsonism Relat Disord. · Pubmed #15542004 No free full text.

Abstract: Genetically-derived neurodegenerative disorders offer a rare opportunity to test validity of neuropathological criteria for diagnosis. Implications regarding an autosomal dominant neurodegenerative disorder (PARK 8) in which four different neuropathological diagnoses were found at autopsy are discussed. We suggest that just as there is currently no clinical 'gold standard' for Parkinson's disease, there is no pathological 'gold standard.' We conclude that in certain circumstances genetic studies may provide definitive arbitration of validity of clinical and pathological diagnostic criteria.

Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimprich A, Müller-Myhsok B, Farrer MJ, Gasser T, Calne DB, Dickson DW. · Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA. · Neurology. · Pubmed #15136696 No free full text.

Abstract: Since the original 1995 report of a parkinsonian kindred, four individuals have been affected (mean age at onset, 65 years). All four had cardinal signs of Parkinson disease (PD) and good response to levodopa. Four autopsies showed neuronal loss and gliosis in the substantia nigra. Lewy bodies (LB) limited to brainstem nuclei were detected in one case, diffuse LB in the second, neurofibrillary tangles (NFT) without LB in the third, and neither NFT nor LB in the fourth. Genetic studies suggested linkage to the PARK8 locus on chromosome 12.

Ishizawa T, Mattila P, Davies P, Wang D, Dickson DW. · Department of Pathology (Neuropathology), Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. · J Neuropathol Exp Neurol. · Pubmed #12722831 No free full text.

Abstract: The major protein constituent of Lewy bodies (LBs), the pathological hallmark of Parkinson disease and dementia with Lewy bodies, is considered to be alpha-synuclein, but other proteins, in particular the microtubule-associated protein tau, have been implicated in the pathogenesis of LBs. Tau is the major structural component of neurofibrillary tangles (NFTs). Both direct immunochemical studies of partially purified LBs and indirect immunohistochemical studies have suggested that LBs may contain tau, but most of these studies were based upon a single tau antibody, and immunologic cross-reactivity was not completely excluded. To gain insight into the relation between tau and alpha-synuclein in LBs, double immunostaining was performed in Lewy body cases with a rabbit polyclonal antibody to alpha-synuclein and a panel of monoclonal antibodies to phospho- and nonphospho-tau epitopes (Alz50, CP9, CP13, PG5, TG3, PHFI) that spanned the length of the tau molecule. Tau-immunoreactive LBs were present in the medulla in 80% of the cases, irrespective of Braak stage. All tau antibodies recognized at least some LBs, arguing against nonspecific antibody cross-reactivity. In most lesions the tau immunostaining was present at the periphery of the LB. The phospho-tau antibody, TG3, detected more LBs than any of the other tau antibodies. The proportion of LBs with tau immunoreactivity was greatest in neurons vulnerable to NETs, such as those in the locus ceruleus and basal nucleus of Meynert, and least in neurons resistant to NFTs, such as the dorsal motor nucleus of the vagus in the medulla. The present results suggest that tau may coaggregate with alpha-synuclein in LBs, especially in neuronal populations vulnerable to both NFTs and LBs.