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1.  Fluoxetine Ameliorates Behavioral and Neuropathological Deficits in a Transgenic Model Mouse of α-synucleinopathy 
Experimental neurology  2012;234(2):405-416.
The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson’s disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA.
Fluoxetine, a selective serotonin reuptake inhibitor, has been shown to be protective in toxin-induced models of PD, however its effects in an in vivo transgenic model of α-synucleinopathy remain unclear. In this context, this study examined the effect of fluoxetine in the MBP1-hαsyn tg mice, a model of MSA.
Fluoxetine adminstration ameliorated motor deficits in the MBP1-hαsyn tg mice, with a concomitant decrease in neurodegenerative pathology in the basal ganglia, neocortex and hippocampus. Fluoxetine adminstration also increased levels of the neurotrophic factors, GDNF (glial-derived neurotrophic factor) and BDNF (brain-derived neurotrophic factor) in the MBP1-hαsyn tg mice compared to vehicle-treated tg mice. This fluoxetine-induced increase in GDNF and BDNF protein levels was accompanied by activation of the ERK signaling pathway. The effects of fluoxetine adminstration on myelin and serotonin markers were also examined.
Collectively these results indicate that fluoxetine may represent a novel therapeutic intervention for MSA and other neurodegenerative disorders.
doi:10.1016/j.expneurol.2012.01.008
PMCID: PMC3897235  PMID: 22281106
2.  Manganese exposure induces α-synuclein aggregation in the frontal cortex of non-human primates 
Toxicology letters  2012;217(3):177-183.
Aggregation of α-synuclein (α-syn) in the brain is a defining pathological feature of neurodegenerative disorders classified as synucleinopathies. They include Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Occupational and environmental exposure to manganese (Mn) is associated with a neurological syndrome consisting of psychiatric symptoms, cognitive impairment and parkinsonism. In this study, we examined α-syn immunoreactivity in the frontal cortex of Cynomolgus macaques as part of a multidisciplinary assessment of the neurological effects produced by exposure to moderate levels of Mn. We found increased α-syn-positive cells in the gray matter of Mn-exposed animals, typically observed in pyramidal and medium-sized neurons in deep cortical layers. Some of these neurons displayed loss of Nissl staining with α-syn-positive spherical aggregates. In the white matter we also observed α-syn-positive glial cells and in some cases α-syn-positive neurites. These findings suggest that Mn exposure promotes α-syn aggregation in neuronal and glial cells that may ultimately lead to degeneration in the frontal cortex gray and white matter. To our knowledge, this is the first report of Mn-induced neuronal and glial cell α-syn accumulation and aggregation in the frontal cortex of non-human primates.
doi:10.1016/j.toxlet.2012.12.006
PMCID: PMC3638947  PMID: 23262390
Synucleinopathies; Manganese; Frontal cortex; α-synuclein; Neurotoxicity; Non-human primates
3.  The Role of Glia in Alpha-Synucleinopathies 
Molecular Neurobiology  2012;47(2):575-586.
α-Synuclein (AS)-positive inclusions are the pathological hallmark of Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), all belonging to the category of α-synucleinopathies. α-Synucleinopathies represent progressive neurodegenerative disorders characterised by increasing incidences in the population over the age of 65. The relevance of glial reactivity and dysfunction in α-synucleinopathies is highlighted by numerous experimental evidences. Glial AS inclusion pathology is prominent in oligodendroglia of MSA (glial cytoplasmic inclusions) and is a common finding in astroglial cells of PD and DLB, resulting in specific dysfunctional responses. Involvement of AS-dependent astroglial and microglial activation in neurodegenerative mechanisms, and therefore in disease initiation and progression, has been suggested. The aim of this review is to summarise and discuss the multifaceted responses of glial cells in α-synucleinopathies. The beneficial, as well as detrimental, effects of glial cells on neuronal viability are taken into consideration to draw an integrated picture of glial roles in α-synucleinopathies. Furthermore, an overview on therapeutic approaches outlines the difficulties of translating promising experimental studies into successful clinical trials targeting candidate glial pathomechanisms.
doi:10.1007/s12035-012-8340-3
PMCID: PMC3589649  PMID: 22941028
α-Synuclein; Astroglia; Microglia; Multiple system atrophy; Oligodendroglia; Parkinson’s disease
4.  Dopamine cell loss in the periaqueductal gray in multiple system atrophy and Lewy body dementia 
Neurology  2009;73(2):106-112.
Background:
Experimental studies indicate that dopaminergic neurons in the ventral periaqueductal gray matter (PAG) are involved in maintenance of wakefulness. Excessive daytime sleepiness (EDS) is a common manifestation of multiple system atrophy (MSA) and dementia with Lewy bodies (DLB) but involvement of these neurons has not yet been explored.
Methods:
We sought to determine whether there is loss of dopaminergic neurons in the ventral PAG in MSA and DLB. We studied the midbrain obtained at autopsy from 12 patients (9 male, 3 female, age 61 ± 3) with neuropathologically confirmed MSA, 12 patients (11 male, 1 female, age 79 ± 4) with diagnosis of DLB and limbic or neocortical Lewy body disease, and 12 controls (7 male, 5 female, ages 67 ± 4). Fifty-micron sections were immunostained for tyrosine hydroxylase (TH) or α-synuclein and costained with thionin. Cell counts were performed every 400 μm throughout the ventral PAG using stereologic techniques.
Results:
Compared to the total estimated cell numbers in controls (21,488 ± 8,324 cells), there was marked loss of TH neurons in the ventral PAG in both MSA (11,727 ± 5,984; p < 0.01) and DLB (5,163 ± 1,926; p < 0.001) cases. Cell loss was more marked in DLB than in MSA. There were characteristic α-synuclein inclusions in the ventral PAG in both MSA and DLB.
Conclusions:
There is loss of putative wake-active ventral periaqueductal gray matter dopaminergic neurons in both multiple system atrophy and dementia with Lewy bodies, which may contribute to excessive daytime sleepiness in these conditions.
GLOSSARY
= Alzheimer disease;
= Braak and Braak;
= Consortium to Establish a Registry for Alzheimer's Disease;
= continuous positive airway pressure;
= dementia with Lewy bodies;
= electrocardiogram;
= excessive daytime sleepiness;
= electrooculography;
= Epworth Sleepiness Scale;
= glial cytoplasmic inclusion;
= Lewy body disease;
= multiple system atrophy;
= MSA with predominant parkinsonism;
= MSA with predominant cerebellar involvement;
= obstructive sleep apnea;
= periaqueductal gray matter;
= polysomnogram;
= REM sleep behavior disorder;
= tyrosine hydroxylase.
doi:10.1212/WNL.0b013e3181ad53e7
PMCID: PMC2713188  PMID: 19597132
5.  Cognition in Rapid Eye Movement Sleep Behavior Disorder 
Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by excessive muscle activity and undesirable motor events during REM sleep. RBD occurs in approximately 0.5% of the general population, with a higher prevalence in older men. RBD is a frequent feature of dementia with Lewy bodies (DLB), but is only rarely reported in Alzheimer’s disease. RBD is also a risk factor for α-synuclein-related diseases, such as DLB, Parkinson’s disease (PD), and multiple system atrophy. Therefore, RBD has major implications for the diagnosis and treatment of neurodegenerative disorders and for understanding specific neurodegeneration patterns. Several markers of neurodegeneration have been identified in RBD, including cognitive impairments such as deficits in attention, executive functions, learning capacities, and visuospatial abilities. Approximately 50% of RBD patients present mild cognitive impairment. Moreover, RBD is also associated with cognitive decline in PD.
doi:10.3389/fneur.2012.00082
PMCID: PMC3354332  PMID: 22629254
sleep; cognition; elderly; REM sleep behavior disorder; mild cognitive impairment; Parkinson’s disease; dementia with Lewy bodies
6.  Neuropathology of Dementia with Lewy Bodies in Advanced Age: a comparison with Alzheimer Disease 
Neuroscience letters  2010;485(3):222-227.
Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α–synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70–79, 80–89 and ≥90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80–89 and ≥90 year cases compared to 70–79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70–79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.
doi:10.1016/j.neulet.2010.09.016
PMCID: PMC2987680  PMID: 20849919
Cognition; Neuropsychological assessment
7.  REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century(e–Pub ahead of print)(CME) 
Neurology  2010;75(6):494-499.
Background:
Idiopathic REM sleep behavior disorder (RBD) may be the initial manifestation of synucleinopathies (Parkinson disease [PD], multiple system atrophy [MSA], or dementia with Lewy bodies [DLB]).
Methods:
We used the Mayo medical records linkage system to identify cases presenting from 2002 to 2006 meeting the criteria of idiopathic RBD at onset, plus at least 15 years between RBD and development of other neurodegenerative symptoms. All patients underwent evaluations by specialists in sleep medicine to confirm RBD, and behavioral neurology or movement disorders to confirm the subsequent neurodegenerative syndrome.
Results:
Clinical criteria were met by 27 patients who experienced isolated RBD for at least 15 years before evolving into PD, PD dementia (PDD), DLB, or MSA. The interval between RBD and subsequent neurologic syndrome ranged up to 50 years, with the median interval 25 years. At initial presentation, primary motor symptoms occurred in 13 patients: 9 with PD, 3 with PD and mild cognitive impairment (MCI), and 1 with PDD. Primary cognitive symptoms occurred in 13 patients: 10 with probable DLB and 3 with MCI. One patient presented with primary autonomic symptoms, diagnosed as MSA. At most recent follow-up, 63% of patients progressed to develop dementia (PDD or DLB). Concomitant autonomic dysfunction was confirmed in 74% of all patients.
Conclusions:
These cases illustrate that the α-synuclein pathogenic process may start decades before the first symptoms of PD, DLB, or MSA. A long-duration preclinical phase has important implications for epidemiologic studies and future interventions designed to slow or halt the neurodegenerative process.
GLOSSARY
= dementia with Lewy bodies;
= mild cognitive impairment;
= multiple system atrophy;
= Parkinson disease;
= PD with associated mild cognitive impairment;
= Parkinson disease dementia;
= polysomnogram;
= REM sleep behavior disorder.
doi:10.1212/WNL.0b013e3181ec7fac
PMCID: PMC2918473  PMID: 20668263
8.  Post mortem cerebrospinal fluid α-synuclein levels are raised in multiple system atrophy and distinguish this from the other α-synucleinopathies, Parkinson's disease and Dementia with Lewy bodies 
Neurobiology of Disease  2012;45(1):188-195.
Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p < 0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p < 0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.
doi:10.1016/j.nbd.2011.08.003
PMCID: PMC3657198  PMID: 21856424
Parkinson's disease; Dementia with Lewy Bodies; Multiple system atrophy; Alpha synuclein; Cerebrospinal fluid
9.  Visuospatial Deficits Predict Rate of Cognitive Decline in Autopsy-Verified Dementia with Lewy Bodies 
Neuropsychology  2008;22(6):729-737.
Dementia with Lewy Bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer’s disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict two-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed “pure” AD patients. Generalized Estimating Equations (GEE) revealed a significant interaction such that poor baseline performances on tests of visuospatial skills were strongly associated with a rapid rate of cognitive decline in DLB but not AD (p < .001). No effect of confrontation naming was found. DLB patients with poor visuospatial skills had fewer neurofibrillary tangles and were more likely to experience visual hallucinations than those with better visuospatial skills. These results suggest that the severity of visuospatial deficits in DLB may identify those facing a particularly malignant disease course and may designate individuals whose clinical syndrome is impacted more by Lewy body formation than AD pathology.
doi:10.1037/a0012949
PMCID: PMC2587484  PMID: 18999346
Dementia with Lewy bodies; cognitive decline; visuospatial skills; Alzheimer’s disease
10.  Rivastigmine for the treatment of dementia associated with Parkinson’s disease 
Parkinson’s disease (PD) afflicts millions of people worldwide and leads to cognitive impairment or dementia in the majority of patients over time. Parkinson’s disease dementia (PDD) is characterized by deficits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Cortical cholinergic deficits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.
This review examines current evidence for rivastigmine (a cholinesterase/butyrylcholinesterase inhibitor) treatment in PDD. In addition to its efficacy, we examine the safety profile, side effects, and cost effectiveness of rivastigmine in PDD. Rivastigmine provides modest benefit in PDD and further long-term studies are needed to determine the effectiveness and safety of rivastigmine over time. Tolerability is a problem for many PDD patients treated with rivastigmine. Future studies of rivastigmine in PDD should focus on pragmatic outcomes such as time to need for nursing home placement, pharmacoeconomic outcomes and simultaneous patient/caregiver quality of life assessments.
PMCID: PMC2656320  PMID: 19300613
Parkinson’s disease; dementia; rivastigmine; cholinesterase inhibitor
11.  Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease 
Acta Neuropathologica  2013;125(6):795-813.
In neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood–brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1114-9) contains supplementary material, which is available to authorized users.
doi:10.1007/s00401-013-1114-9
PMCID: PMC3661926  PMID: 23604588
12.  Higher cortical deficits influence attentional processing in dementia with Lewy bodies, relative to patients with dementia of the Alzheimer's type and controls 
Background
Attentional dysfunction is believed to be a prominent and distinguishing neuropsychological feature of dementia with Lewy bodies (DLB); yet, the specific nature of the attentional deficit and factors that can potentially influence attentional processing in DLB have not been fully defined.
Aims
To clarify the nature of the attentional deficit in early‐stage DLB relative to patients with early‐stage dementia of the Alzheimer's type (DAT) and elderly controls, and examine the effect of task complexity and type of cognitive load on attentional processing in DLB.
Methods
Attentional impairment and fluctuating attention were investigated in three groups of subjects—patients with clinical features of early probable DLB (n = 20), a group with early probable DAT (n = 19) and healthy elderly controls (n = 20)—using an experimental computerised reaction time paradigm.
Results
Patients with DLB showed greater attentional impairment and fluctuations in attention relative to patients with DAT and elderly controls. The attentional deficit was generalised in nature but increased in magnitude as greater demands were placed on attentional selectivity. Attentional deficits in DLB were most pronounced under task conditions that required more active recruitment of executive control and visuospatial cognitive processes.
Conclusions
Attentional deficits in DLB are widespread and encompass all aspects of attentional function. Deficits in higher cortical function influence the degree of attentional impairment and fluctuating attention, suggesting that attentional processing in DLB is mediated by interacting cortical and subcortical mechanisms. These findings serve to clarify the nature of the attentional deficit in DLB and have potentially important ramifications for our understanding of the neurocognitive underpinnings of fluctuations.
doi:10.1136/jnnp.2006.090183
PMCID: PMC2077555  PMID: 16772356
13.  Comparison of Clinical Manifestation in Familial Alzheimer's disease and Dementia with Lewy Bodies 
Archives of neurology  2008;65(12):1634-1639.
Background
The clinical delineation of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) remains unclear.
Objective
To compare the neuropsychological profiles of patients with clinically diagnosed Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD).
Methods
We first compared measures of memory, orientation, language, executive, visual perception and visual construction function between persons with DLB and AD in two Caribbean Hispanic cohorts, including a family dataset (DLB =89; AD: n=118) and an epidemiologic dataset (DLB: n=70; AD: n=157). DLB in the family sample was further divided into i) families with two or more affected family members (DLB), or ii) one affected family member (DLB). To determine whether observed differences in cognitive profiles were driven by heritable factors, we then repeated the analyses in the epidemiologic cohort excluding all familial cases. We applied general linear models adjusting for age, sex, education, disease duration, and APOE-ε4 genotype.
Results
Persons with DLB were in both cohorts more severely impaired in orientation, visual construction and non verbal reasoning after controlling for potential confounders. Persons with 2 or more DLB cases per family had the most severe impairment in episodic and semantic memory, followed by those with one DLB case per family, then by those with AD. When familial AD and DLB cases were excluded from the analysis in the epidemiologic cohort, the differences between the AD and DLB groups persisted but were attenuated.
Conclusions
Compared to persons with AD, persons with DLB are more severely impaired in various cognitive domains, particularly orientation, visual perception and visual construction. The difference appears strong in familial rather than sporadic DLB. Whether this divergence in cognitive functions is caused by gene-gene or gene-environmental interactions remains unclear.
doi:10.1001/archneur.65.12.1634
PMCID: PMC2633487  PMID: 19064751
14.  Selective Molecular Alterations in the Autophagy Pathway in Patients with Lewy Body Disease and in Models of α-Synucleinopathy 
PLoS ONE  2010;5(2):e9313.
Background
Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by α-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in α-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in α-synuclein transgenic mice.
Methodology/Principal Findings
By immunoblot analysis, compared to controls and AD, in DLB cases levels of mTor were elevated and Atg7 were reduced. Levels of other components of the autophagy pathway such as Atg5, Atg10, Atg12 and Beclin-1 were not different in DLB compared to controls. In DLB brains, mTor was more abundant in neurons displaying α-synuclein accumulation. These neurons also showed abnormal expression of lysosomal markers such as LC3, and ultrastructural analysis revealed the presence of abundant and abnormal autophagosomes. Similar alterations were observed in the brains of α-synuclein transgenic mice. Intra-cerebral infusion of rapamycin, an inhibitor of mTor, or injection of a lentiviral vector expressing Atg7 resulted in reduced accumulation of α-synuclein in transgenic mice and amelioration of associated neurodegenerative alterations.
Conclusions/Significance
This study supports the notion that defects in the autophagy pathway and more specifically in mTor and Atg7 are associated with neurodegeneration in DLB cases and α-synuclein transgenic models and supports the possibility that modulators of the autophagy pathway might have potential therapeutic effects.
doi:10.1371/journal.pone.0009313
PMCID: PMC2824828  PMID: 20174468
15.  Cerebrospinal Fluid Biomarkers for Dementia with Lewy Bodies 
More than 750,000 of the UK population suffer from some form of cognitive impairment and dementia. Of these, 5–20% will have Dementia with Lewy Bodies (DLB). Clinico-pathological studies have shown that it is the low frequency of DLB clinical core features that makes the DLB diagnosis hardly recognisable during life, and easily misdiagnosed for other forms of dementia. This has an impact on the treatment and long-term care of the affected subjects. Having a biochemical test, based on quantification of a specific DLB biomarker within Cerebrospinal Fluid (CSF) could be an effective diagnostic method to improve the differential diagnosis. Although some of the investigated DLB CSF biomarkers are well within the clinical criteria for sensitivity and specificity (>90%), they all seem to be confounded by the contradictory data for each of the major groups of biomarkers (α-synuclein, tau and amyloid proteins). However, a combination of CSF measures appear to emerge, that may well be able to differentiate DLB from other dementias: α-synuclein reduction in early DLB, a correlation between CSF α-synuclein and Aβ42 measures (characteristic for DLB only), and t-tau and p-tau181 profile (differentiating AD from DLB).
doi:10.4061/2010/536538
PMCID: PMC2965495  PMID: 21048932
16.  Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies 
Background
Levodopa (L‐dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L‐dopa use in patients with parkinsonism and dementia. Therefore, the effect of L‐dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear.
Aim
To ascertain the acute and long‐term effects of L‐dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease.
Method
Baseline cognitive and motor function was assessed off L‐dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard “bedside” measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L‐dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L‐dopa to assess the prolonged effect.
Results
Acute L‐dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L‐dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L‐dopa treatment.
Conclusion
The use of L‐dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.
doi:10.1136/jnnp.2006.098079
PMCID: PMC2077405  PMID: 16952917
17.  Lewy Body Pathology in Normal Elderly Subjects 
Lewy body and Lewy neurite formation are the hallmark neuropathological findings in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), dementia with Lewy bodies (DLB), and other alpha-synucleinopathies. They also have been described in the brains of normal older individuals and referred to as incidental Lewy body disease. The purpose of this study was to determine the prevalence of Lewy bodies and Lewy neurites (Lewy body pathology; LBP) in 139 autopsies from our normal volunteer control group of the University of Kentucky Alzheimer’s Disease Center. All subjects were followed longitudinally and were cognitively normal without any type of movement disorder, neuropsychiatric features, or other CNS findings. Thirty-three out of 139 normal subjects contained LBP in various brain regions. The most common regions involved were the medulla (26%), amygdala (24%), pons (20%), and midbrain (20%). No mean statistical differences were found between those with and without LBP on any demographic or cognitive variable, Braak stage, or neurofibrillary tangle and neuritic plaque quantitation. The high prevalence of LBP in our elderly, well educated group is not clear although it does not appear to be related to aging or the presence of AD pathology. Overall, our findings support the concept that incidental Lewy body disease most likely represents preclinical or presymptomatic PD, PDD or DLB.
doi:10.1097/NEN.0b013e3181ac10a7
PMCID: PMC2704264  PMID: 19535990
Aging; Alpha-synucleinopathies; Lewy bodies; Lewy neurites
18.  Familial Aggregation of Dementia With Lewy Bodies 
Archives of Neurology  2011;68(1):90-93.
Background
Familial aggregation of dementia with Lewy bodies (DLB) remains unclear.
Objectives
To determine the degree of family aggregation of DLB by comparing DLB risk between siblings of probands with clinically diagnosed DLB and siblings of probands with clinically diagnosed Alzheimer disease in a cohort of Caribbean Hispanic families and to explore the degree of aggregation of specific clinical manifestations (ie, cognitive fluctuations, visual hallucinations, and parkinsonism) in DLB.
Design
Familial cohort study.
Setting
Academic research.
Patients
We separately compared risks of possible DLB, probable DLB, and clinical core features of DLB (cognitive fluctuations, visual hallucinations, and parkinsonism) between siblings of probands with clinically diagnosed DLB (n=344) and siblings of probands with clinically diagnosed Alzheimer disease (n=280) in 214 Caribbean Hispanic families with extended neurologic and neuropsychological assessment.
Main Outcome Measures
We applied general estimating equations to adjust for clustering within families. In these models, age and proband disease status were independent variables, and disease status of siblings was the measure of disease risk and the dependent variable.
Results
Compared with siblings of probands having clinically diagnosed Alzheimer disease, siblings of probands having clinically diagnosed DLB had higher risks of probable DLB (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.04–5.04) and visual hallucinations (2.32; 1.16–4.64). They also had increased risks of possible DLB (OR, 1.51; 95% CI, 0.97–2.34) and cognitive fluctuations (1.55; 0.95–2.53).
Conclusions
Dementia with Lewy bodies and core features of DLB aggregate in families. Compared with siblings of probands having clinically diagnosed AD, siblings of probands having clinically diagnosed DLB are at increased risks of DLB and visual hallucinations. These findings are an important step in elucidating the genetic risk factors underlying DLB and in delineating DLB from other neurodegenerative diseases, such as Alzheimer disease.
doi:10.1001/archneurol.2010.319
PMCID: PMC3268781  PMID: 21220678
19.  Time course of symptomatic orthostatic hypotension and urinary incontinence in patients with postmortem confirmed parkinsonian syndromes: a clinicopathological study 
OBJECTIVE—Although both orthostatic hypotension and urinary incontinence have been reported in a number of parkinsonian syndromes, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), differences in the evolution of these features have not been studied systematically in pathologically confirmed cases.
METHODS—77 cases with pathologically confirmed parkinsonian syndromes (PD, n=11; MSA, n=15; DLB, n=14; CBD, n=13; PSP, n=24), collected up to 1994, formed the basis for a multicentre clinicopathological study organised by the NINDS to improve the differential diagnosis of parkinsonian disorders. The present study determined the time course—that is, latency to onset and duration from onset to death, of symptomatic orthostatic hypotension, and urinary incontinence in the NINDS series. Furthermore, the diagnostic validity of a predefined latency to onset within 1 year of disease onset of symptomatic orthostatic hypotension or urinary incontinence was analysed.
RESULTS—Significant group differences for latency, but not duration, of symptomatic orthostatic hypotension and urinary incontinence were found. Latencies to onset of either feature were short in patients with MSA, intermediate in patients with DLB, CBD, and PSP, and long in those with PD. Symptomatic orthostatic hypotension occurring within the first year after disease onset predicted MSA in 75% of cases; early urinary incontinence was less predictive for MSA (56%).
CONCLUSION—Latency to onset, but not duration, of symptomatic orthostatic hypotension or urinary incontinence differentiates PD from other parkinsonian syndromes, particularly MSA.


PMCID: PMC1736638  PMID: 10519868
20.  Comparing hippocampal atrophy in Alzheimer's dementia and Dementia with Lewy Bodies 
Background/Aims
Dementia with Lewy Bodies (DLB) and Alzheimer's disease (AD) are the two most common neurodegenerative dementias. During the early stages, clinical distinction between them is often challenging. Our objective is to compare hippocampal atrophy patterns in mild AD and mild DLB. We hypothesized that DLB subjects have milder hippocampal atrophy relative to AD subjects.
Methods
We analyzed the T1-weighted magnetic resonance imaging data from 113 subjects: 55 AD, 16 DLB and 42 cognitively normal elderly (NC). Using the hippocampal radial distance technique and multiple linear regression, we analyzed the effect of clinical diagnosis on hippocampal radial distance, while adjusting for gender and age. 3D statistical maps were adjusted for multiple comparisons using permutation-based statistics with a threshold of p<0.01.
Results
Compared to NC, AD exhibited significantly greater atrophy in the Cornu Ammonis (CA) 1, CA2-3 and subicular regions bilaterally while DLB showed left-predominant atrophy in the CA1 region and subiculum. AD and DLB directly compared did not reveal statistically significant differences.
Conclusion
Hippocampal atrophy, while present in mildly impaired DLB subjects, is less severe than atrophy seen in mildly impaired AD subjects, when compared to NC. Both groups show predominant atrophy of the CA1 subfield and subiculum.
doi:10.1159/000339727
PMCID: PMC3470878  PMID: 22922563
Alzheimer's disease; Dementia with Lewy Bodies; hippocampus; MRI; atrophy
21.  Brain amyloid and cognition in Lewy body diseases 
Background
Many patients with Parkinson disease (PD) develop dementia (PDD), a syndrome that overlaps clinically and pathologically with dementia with Lewy bodies (DLB); PDD and DLB differ chiefly in the relative timing of dementia and parkinsonism. Brain amyloid deposition is an early feature of DLB and may account in part for its early dementia. We sought to confirm this hypothesis and also to determine whether amyloid accumulation contributes to cognitive impairment and dementia in the broad range of parkinsonian diseases.
Methods
29 cognitively normal PD, 14 PD subjects with mild cognitive impairment (PD-MCI), 18 with DLB, 12 with PDD and 85 healthy control subjects (HCS) underwent standardized neurologic and neuropsychological examinations and PiB imaging with PET. Apolipoprotein (APOE) genotypes were obtained in many patients. PiB retention was expressed as the distribution volume ratio using a cerebellar tissue reference.
Results
PiB retention was significantly higher in DLB than in any of the other diagnostic groups. PiB retention did not differ across PDD, PD-MCI, PD, and HCS. Amyloid burden increased with age and with the presence of the APOEε4 allele in all patient groups. Only in the DLB group was amyloid deposition associated with impaired cognition.
Conclusions
DLB subjects have higher amyloid burden than subjects with PDD, PD-MCI, PD or HCS; amyloid deposits are linked to cognitive impairment only in DLB. Early amyloid deposits in DLB relative to PDD may account for their difference in the timing of dementia and parkinsonism.
doi:10.1002/mds.25048
PMCID: PMC3725259  PMID: 22693110
dementia; Lewy; Parkinson; amyloid; PiB
22.  Prodromal clinical manifestations of neuropathologically confirmed Lewy body disease 
Neurobiology of aging  2008;31(10):1805-1813.
The mild cognitive impairment (MCI) stage of dementia with Lewy bodies (MCI-DLB) has not yet been defined, but is likely to differ in the MCI stage of Alzheimer’s disease (MCI-AD). To determine whether clinical features distinguish MCI-DLB and MCI-AD, 9 cases of neuropathologically confirmed MCI-DLB and 12 cases of MCI-AD were compared. No significant differences were found between MCI-DLB and MCI-AD cases in age at death, gender, ApoE status, education, time followed while clinically normal, or duration of MCI. MCI-DLB and MCI-AD cases differed clinically in the expression of Parkinsonism (P = 0.012), provoked hallucinations or delirium (P = 0.042), or the presence of any of these noncognitive symptoms of DLB (P < 0.0001). Letter fluency (P = 0.007) was significantly lower and Wechsler Logical Memory I (P = 0.019) was significantly higher in MCI-DLB compared to MCI-AD cases. These data demonstrate the feasibility of differentiating underlying pathologic processes responsible for cognitive decline in the preclinical disease state and suggest that further refinement in diagnostic criteria may allow more accurate early detection of prodromal DLB and AD.
doi:10.1016/j.neurobiolaging.2008.09.017
PMCID: PMC2891418  PMID: 19026468
Mild cognitive impairment; Alzheimer’s disease; Dementia with Lewy bodies
23.  The role of 123I-ioflupane SPECT dopamine transporter imaging in the diagnosis and treatment of patients with dementia with Lewy bodies 
The diagnosis of dementia with Lewy bodies (DLB) is difficult if one relies solely on clinical features. Current International Consensus Criteria for DLB have high specificity but a significant percentage of patients might be misdiagnosed. Reasons for clinical uncertainty regard the presence of concomitant motor signs in patients with Alzheimer’s disease as well as the observation that cognitive abnormalities in DLB might develop with memory impairment without significant parkinsonism. This has clinical relevance as DLB patients may be particularly sensitive to antipsychotics and even the effectiveness of atypical neuroleptics such as quetiapine for the treatment of agitation and hallucinations has been questioned by double-blind, placebo-controlled, randomized studies. By contrast, acetyl-cholinesterase inhibitors such as rivastigmine have shown benefit not only on cognitive but also on psychiatric symptoms. Recent evidence shows that striatal dopamine transporter binding of 123I-ioflupane SPECT is reduced in DLB and this is consistent with a significant loss of nigral dopamine neurons in this disorder. Several studies have demonstrated the diagnostic accuracy of 123I-ioflupane in the differential diagnosis of parkinsonism. Given the availability of SPECT, this investigation represents a useful marker to support clinical diagnosis and can help establishing appropriate treatment for this disorder.
PMCID: PMC2654798  PMID: 19300562
dementia with Lewy bodies; 123I-ioflupane-SPECT; dopamine transporter; parkinsonism; Alzheimer’s disease
24.  Prospective Belgian study of neurodegenerative and vascular dementia: APOE genotype effects 
Methods: APOE genotyping was performed in patients with probable Alzheimer's disease (AD) (n=504), frontotemporal dementia (FTD) (n=47), vascular dementia (VaD) (n=152), mixed dementia (n=132), mild cognitive impairment (MCI) (n=44), Parkinson's disease (PD) (n=30), dementia with Lewy bodies (DLB) (n=17), and multisystem atrophy (MSA)/progressive supranuclear palsy (PSP) (n=12).
Results: The APOE allele frequencies of this Belgian control population (ε2: 6.9%; ε3: 76.2%; ε4: 16.9%) did not differ from those reported for other white populations. AD, MCI, and mixed dementia patients had higher APOE ε4 (32.9%, 38.6%, and 28.4% respectively) and lower APOE ε3 (62.2%, 53.4%, and 66.3%) frequencies compared with controls, whereas only AD and mixed dementia patients had lower APOE ε2 frequencies (4.9% and 5.3%). Apart from a borderline significant different distribution of APOE allele frequencies in VaD patients compared with controls, no other differences were detected. The influence of APOE ε4 on clinical features of dementia was limited to lower age at onset in AD patients and a less pronounced negative correlation between age at onset and number of ε4 alleles in MCI and mixed dementia patients.
Conclusions: This study confirmed the risk association between APOE ε4 and AD. The observation that APOE ε4 is associated with mixed dementia reflected the role of AD in the aetiopathogenesis of this condition. Although MCI is an aetiologically heterogeneous syndrome, the increased APOE ε4 frequencies indicated that a large proportion of the MCI patients included in the study might be predisposed to develop AD.
doi:10.1136/jnnp.74.8.1148
PMCID: PMC1738626  PMID: 12876259
25.  Alpha-synuclein aggregation involves a bafilomycin A1-sensitive autophagy pathway 
Autophagy  2012;8(5):754-766.
Synucleinopathies like Parkinson disease and dementia with Lewy bodies (DLB) are characterized by α-synuclein aggregates within neurons (Lewy bodies) and their processes (Lewy neurites). Whereas α-synuclein has been genetically linked to the disease process, the pathological relevance of α-synuclein aggregates is still debated. Impaired degradation is considered to result in aggregation of α-synuclein. In addition to the ubiquitin-proteasome degradation, the autophagy-lysosomal pathway (ALP) is involved in intracellular degradation processes for α-synuclein. Here, we asked if modulation of ALP affects α-synuclein aggregation and toxicity. We have identified an induction of the ALP markers LAMP-2A and LC3-II in human brain tissue from DLB patients, in a transgenic mouse model of synucleinopathy, and in a cell culture model for α-synuclein aggregation. ALP inhibition using bafilomycin A1 (BafA1) significantly potentiates toxicity of aggregated α-synuclein species in transgenic mice and in cell culture. Surprisingly, increased toxicity is paralleled by reduced aggregation in both in vivo and in vitro models. The dichotomy of effects on aggregating and nonaggregating species of α-synuclein was specifically sensitive to BafA1 and could not be reproduced by other ALP inhibitors. The present study expands on the accumulating evidence regarding the function of ALP for α-synuclein degradation by isolating an aggregation specific, BafA1-sensitive, ALP-related pathway. Our data also suggest that protein aggregation may represent a detoxifying event rather than being causal for cellular toxicity.
doi:10.4161/auto.19371
PMCID: PMC3378419  PMID: 22647715
alpha-synuclein; dementia with Lewy bodies (DLB); Lewy body; lysosomal degradation; Parkinson disease (PD); protein aggregation

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