Parkinson Disease: Galasko D

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.

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.

Granholm E, Morris S, Galasko D, Shults C, Rogers E, Vukov B. · VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. · Int J Psychophysiol. · Pubmed #12568941 No free full text.

Abstract: Diagnostic tests for Alzheimer's disease (AD) involving tropicamide blockade of cholinergic oculomotor functions were examined in AD patients (n=15), Parkinson's disease (PD) patients (n=15), and non-clinical control (NC) participants (n=15). Pupillographic methods were used to measure pupil diameter and pupillary light reflexes after double-blind ocular administration of dilute tropicamide (0.01%) in one eye and saline in the other eye. Changes in pupil size were measured in bright background light and near-darkness. Tropicamide increased pupil diameter to a similar extent in all three groups in light and darkness. Tropicamide also reduced the amplitude and latency of the pupillary light reflex to a similar extent for all three groups. Tropicamide pupillary response tests, therefore, were not sensitive or specific diagnostic tests for AD. Peak constriction amplitude of the pupillary light reflex was significantly reduced in both eyes in AD and PD groups relative to non-clinical controls, but AD and PD groups did not differ significantly. The pupillary light reflex test, therefore, was sensitive to AD, but lacked adequate specificity. Finally, peak constriction amplitude correlated significantly with dementia severity and donepezil treatment may have partially normalized pupillary light reflex abnormalities in AD patients. The pupillary light reflex test, therefore, may index central cholinergic dysfunction associated with disease progression and improvement in cholinergic function associated with pharmacologic treatment response in AD.

Snyder LR, Cruz-Aguado R, Sadilek M, Galasko D, Shaw CA, Montine TJ. · Department of Chemistry, Box 351700, University of Washington, Seattle, WA 98195-1700, USA. · Neurology. · Pubmed #19365059 No free full text.

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Galasko D. · Univ. of California San Diego, USA. · Rinsho Shinkeigaku. · Pubmed #18210848 No free full text.

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Nakashima-Yasuda H, Uryu K, Robinson J, Xie SX, Hurtig H, Duda JE, Arnold SE, Siderowf A, Grossman M, Leverenz JB, Woltjer R, Lopez OL, Hamilton R, Tsuang DW, Galasko D, Masliah E, Kaye J, Clark CM, Montine TJ, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP/Maloney 3rd Floor, Philadelphia, PA 19104-4283, USA. · Acta Neuropathol. · Pubmed #17653732 No free full text.

Abstract: Here, we investigated if TAR-DNA-binding protein-43 (TDP-43), the disease protein in frontotemporal lobar degeneration and ubiquitin inclusions with or without motor neuron disease as well as amyotrophic lateral sclerosis, also formed inclusions in Lewy body (LB) disorders including Parkinson's disease (PD) without or with dementia (PDD), and dementia with LBs (DLB) alone or in association with Alzheimer's disease (AD). Immunohistochemical analyses of TDP-43 in clinically well characterized and pathologically confirmed cases of DLB + AD, PD and PDD demonstrated TDP-43 pathology in the following percentage of cases: DLB + AD = 25/80 (31.3%); PD = 5/69 (7.2%); PDD = 4/21 (19%), while DLB and normal controls exhibited no (0/10, 0%) and one cases (1/33, 3%) presenting TDP-43 pathology, respectively. Significant differences in the prevalence of TDP-43 lesions were noted between disease versus normal brains (P < 0.001) as well as demented versus non-demented brains (P < 0.001). Statistical analyses revealed a positive relationship between TDP-43 lesions and several clinical and pathological parameters in these disorders suggesting the TDP-43 pathology may have co-morbid effects in LB diseases. This study expands the concept of TDP-43 proteinopathies by implicating TDP-43 lesions in mechanisms of neurodegeneration in LB disorders.

Kaye JA, Moore MM, Galasko D, Craig UK, Adonay R, Silbert LC. · Departments of Neurology, Oregon Health and Science University, Portland, OR 97239, USA. · Neurology. · Pubmed #17620553 No free full text.

Abstract: We sought to determine if Chamorro individuals with a family history of Guam dementia (GD) or Parkinson dementia complex (PDC) exhibit presymptomatic brain MRI changes. Sixty-six Chamorro subjects had neurocognitive assessment and volumetric MRI. MRI brain volumes differed between diagnostic groups (GD, PDC, control) and according to family history. Chamorros with a family history of PDC or dementia may have increased brain atrophy, suggesting a hereditary susceptibility to neurodegenerative disorders.

Winton MJ, Joyce S, Zhukareva V, Practico D, Perl DP, Galasko D, Craig U, Trojanowski JQ, Lee VM. · The Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA. · Acta Neuropathol. · Pubmed #16609851 No free full text.

Abstract: Guam parkinsonism-dementia complex (PDC) is a neurodegenerative tauopathy in ethnic Chamorro residents of the Mariana Islands that manifests clinically with parkinsonism as well as dementia and is characterized neuropathologically by prominent cortical neuron loss in association with extensive telencephalic neurofibrillary tau pathology. To further characterize cortical gray and white matter tau, alpha-synuclein and lipid peroxidation pathologies in Guam PDC, we examined the brains of 17 Chamorro PDC and control subjects using biochemical and immunohistological techniques. We observed insoluble tau pathology in both gray and white matter of PDC and Guam control cases, with frontal and temporal lobes being most severely affected. Using phosphorylation dependent anti-tau antibodies, abundant tau inclusions were detected by immunohistochemistry in both neuronal and glial cells of the neocortex, while less alpha-synuclein pathology was observed in more limited brain regions. Further, in sharp contrast to Alzheimer's disease (AD), levels of the lipid peroxidation product 8, 12-iso-iPF(2alpha)-VI isoprostane were not elevated in Guam PDC brains relative to controls. Thus, although the tau pathologies of Guam PDC share similarities with AD, the composite Guam PDC neuropathology profile of tau, alpha-synuclein and 8, 12-iso-iPF(2alpha)-VI isoprostane reported here more closely resembles that seen in other tauopathies including frontotemporal dementias (FTDs), which may imply that Guam PDC and FTD tauopathies share underlying mechanisms of neurodegeneration.

Janvin CC, Larsen JP, Salmon DP, Galasko D, Hugdahl K, Aarsland D. · Stavanger University Hospital, Section of Geriatric Psychiatry, Stavanger, Norway. · Mov Disord. · Pubmed #16211595 No free full text.

Abstract: We describe the pattern of cognitive profiles within a community-based sample of patients with Parkinson's disease (PD) and dementia (PDD) using cluster analyses, and compare the results with data from patients with Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Fifty patients with PDD and 39 with AD from Stavanger, Norway, and 62 patients with DLB from San Diego, CA, USA were diagnosed by either standardized clinical procedures or criteria (all PDD and all AD cases) or necropsy (all DLB cases). Four subgroups were identified: two subgroups with a subcortical cognitive profile (one with mild and one with moderate dementia severity), one subgroup with global impairment and severe dementia, and one subgroup with a cortical cognitive profile and moderate dementia. Of the patients with PDD and with DLB, 56% and 55%, respectively, had a subcortical cognitive profile, compared with only 33% of the AD patients. Conversely, 30% of the patients with PDD and 26% of those with DLB had a cortical cognitive profile, compared with 67% of the patients with AD. These findings suggest that in some patients with PDD, frontosubcortical changes are the main contributing factor to dementia, whereas in other patients, cortical and hippocampal changes are more important.

Montine TJ, Li K, Perl DP, Galasko D. · Department of Pathology, University of Washington, Seattle, WA 98104, USA. · Neurology. · Pubmed #16157919 No free full text.

Abstract: High levels of beta-methylamino-l-alanine (BMAA), a putative neurotoxin, have been reported in brain samples from Chamorros and patients with Alzheimer disease (AD) from western Canada. The authors assayed free BMAA in the brains of five control subjects and five patients with AD from the US Pacific Northwest as well as Chamorros with and without Parkinson-dementia complex. In contrast to others, they detected no free BMAA in any of these samples.

Aarsland D, Litvan I, Salmon D, Galasko D, Wentzel-Larsen T, Larsen JP. · Section of Geriatric Psychiatry, Psychiatric Clinic, Central Hospital of Rogaland, Stavanger, and School of Medicine, University of Bergen, Norway. · J Neurol Neurosurg Psychiatry. · Pubmed #12933921 links to  free full text

Abstract: BACKGROUND: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown. OBJECTIVES: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease). DESIGN: Survey of cognitive features. SETTING: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA. PATIENTS: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education. MAIN OUTCOME MEASURES: Dementia rating scale subscores corrected for age. RESULTS: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001). CONCLUSIONS: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.

Plato CC, Garruto RM, Galasko D, Craig UK, Plato M, Gamst A, Torres JM, Wiederholt W. · Department of Neurosciences, University of California San Diego School of Medicine, La Jolla 92093-0624, USA. · Am J Epidemiol. · Pubmed #12522022 links to  free full text

Abstract: In the 1950s, the incidence of amyotrophic lateral sclerosis (ALS, or Lytico) and parkinsonism-dementia complex (PDC, or Bodig) on the island of Guam was much higher than anywhere else in the world. From the late 1960s to the early 1980s, the incidence of both disorders has decreased. The objective of the present study was to ascertain whether the decreasing incidence continued until the end of the century (1999). The average annual incidence of ALS and PDC was calculated for each 5-year period from 1940 to 1999, utilizing registration records of all ALS and PDC cases on Guam during that period. The results of this study confirmed that the incidence of ALS declined steadily during the past 40 years. The incidence of PDC also declined until the late 1980s but, unlike ALS, showed a slight increase from 1980 to 1999. The rapid decrease in incidence is not likely to be due to genetic factors. Instead, it is most likely to be the results of radical socioeconomic, ethnographic, and ecologic changes brought about by the rapid westernization of Guam.

Plato CC, Galasko D, Garruto RM, Plato M, Gamst A, Craig UK, Torres JM, Wiederholt W. · Department of Neurosciences, University of California San Diego School of Medicine, La Jolla 92093-0624, USA. · Neurology. · Pubmed #11889241 No free full text.

Abstract: BACKGROUND: It was noticed in the mid-1950s that the incidence of ALS and parkinsonism--dementia complex (PDC) were much higher on Guam than anywhere else in the world. In 1958, a registry of patients and controls was established to ascertain the familial and genetic aspects of these diseases. Patients and individually matched controls and their relatives were registered from 1958 to 1963. The registry was updated and analyzed in 1998 through 1999. OBJECTIVE: To ascertain whether first-degree relatives of patients had a higher risk for developing ALS or PDC than relatives of controls. Methods: During the period of 1958 to 1963, 126 new patients and 126 individually matched controls and their respective first-degree relatives and spouses were evaluated neurologically and registered. Forty years later, the number of new cases among the patient and control relatives were compared to an expected number of new cases based on the age- and sex-specific incidence of ALS and PDC in the population at large. RESULTS: From 1958 to 1999, there were 102 new ALS or PDC cases among relatives of patients and 33 among relatives of controls. These values were compared with the derived expected values. There were more observed than expected new cases among patients' relatives, and less observed cases than expected among the controls' relatives. CONCLUSIONS: Relatives of patients with ALS or PDC have significantly higher risks for developing the disease than the Guamanian population, whereas relatives of controls have significantly lower risks.

Galasko D, Salmon DP, Craig UK, Thal LJ, Schellenberg G, Wiederholt W. · Department of Neurosciences, University of California, San Diego, USA. · Neurology. · Pubmed #11781411 No free full text.

Abstract: BACKGROUND: In the 1950s, high-incidence ALS and Parkinson-dementia complex (PDC) were identified among Chamorros, the native inhabitants of Guam. Brains of patients with these syndromes showed widespread neurofibrillary tangles. Although ALS and PDC were reported to have dramatically declined in the 1980s, new cases are still encountered. Late-life dementia has received little study among Chamorros. METHODS: From 1997 to 2000, the authors evaluated newly referred and previously identified patients. They screened first-degree relatives of previous registries, and subjects aged 60 or older. Subjects who scored below a cognitive test cutoff or had symptoms or signs consistent with parkinsonism or ALS underwent psychometric testing, assessment by a neurologist, and laboratory studies as appropriate. Consensus diagnoses were made. RESULTS: The authors identified 194 Chamorros with ALS (n = 10), PD (n = 11), PDC (n = 90), or late-life dementia (n = 83). Mean ages at onset were 55 for ALS, 68 for PDC, 63 for PD, and 74 for dementia. Late-life dementia was more common in women, and met criteria for probable or possible AD. The APOE-epsilon 4 allele frequency was uniformly low regardless of neurologic diagnosis. CONCLUSIONS: The rapid decline of high-incidence ALS on Guam over the past 40 years suggests the contribution of a modifiable environmental factor. PDC remains relatively common, with an unchanged clinical picture apart from later age at onset. Dementia among elderly Chamorros (termed "Mariana dementia") resembles AD. Autopsy studies will clarify whether this dementia is related to AD pathology or represents a late-life neurofibrillary tangle syndrome more closely allied to PDC.

Masliah E, Alford M, Galasko D, Salmon D, Hansen LA, Good PF, Perl DP, Thal L. · Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA. · Neuroreport. · Pubmed #11742207 No free full text.

Abstract: Patients with parkinsonism-dementia complex (PDC) of Guam showed moderate loss of choline acetyl transferase activity in the midfrontal and inferior parietal cortex, and severe loss in the superior temporal cortex. This deficit was similar to that seen in Alzheimer's disease and less severe than Lewy body disease. Thus, cholinergic deficits in the neocortex might contribute to some of the cognitive alterations in PDC of Guam.

Galasko D, Salmon D, Craig UK, Wiederholt W. · Department of Neurosciences, University of California, San Diego, San Diego, California, USA. · Ann N Y Acad Sci. · Pubmed #11193140 No free full text.

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