Biomarkers: Parkinson disease with dementia and dementia with Lewy bodies

Dementia is a common feature in Parkinson disease (PD), the time of onset determining how patients are classified. Those patients where dementia develops prior to parkinsonism or during the first year of disease are designated as having dementia with Lewy bodies (DLB). In those where dementia develops over a year after the onset of motor signs, the condition is known as Parkinson's disease with dementia (PDD).While this seems at first sight to be a definitive way to distinguish these conditions, reality is rather different. The overlap between them is considerable, and there is much uncertainty associated with patients who have both motor symptoms and early cognitive impairment. The diagnosis is still based on medical history and clinical evaluation. It is not even certain that they can be accurately distinguished at autopsy. For this reason, the data concerning these entities have been reviewed, to examine various markers employed or measured in clinical, neuropathological, neuroimaging, and biochemical investigations. The concept of PDD and DLB being separate conditions is comparatively new, and the most promising tools with which to separate them at present are cerebrospinal fluid (CSF) markers and positron emission tomography (PET) scanning that indicate increased amyloid-β burden in DLB compared to PDD. However as yet there are no markers that unequivocally distinguish between PDD and DLB.     

Relationship between Parkinson disease with dementia and dementia with Lewy bodies

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are considered Lewy body diseases (LBDs). To clarify the relation between PD with dementia (PDD) and DLB, 30 patients with LBD were divided into pathological subtypes according to the consensus guidelines for DLB. Patients with PDD showed neocortical and limbic type of LBD as well as patients with DLB. Dementia had not been noted in 2 patients with neocortical type. Our results indicate that PDD and DLB share a common pathological substrate and that the pathological subtypes of LBD show considerable overlap in clinical manifestations.     

L-dopa responsiveness in dementia with Lewy bodies, Parkinson disease with and without dementia

The authors analyzed whether nondemented (PD) and demented Parkinson patients (PDD) and patients with dementia with Lewy bodies (DLB) respond similarly in the levodopa test (LDT). Percentage of motor improvement was similar in the three groups; the proportion of patients with 10% and more improvement was greater in PD than in PDD and DLB. Positive LDT was predictive for favorable response in chronic levodopa treatment, but also some nonresponsive demented patients profited from chronic levodopa therapy.     

Involvement of the cerebellum in Parkinson disease and dementia with Lewy bodies

Brains from patients with Parkinson disease or dementia with Lewy bodies show aggregation of alpha‐synuclein in precerebellar brainstem structures. Furthermore, patients exhibit resting tremor, unstable gait, and impaired balance, which may be associated with cerebellar dysfunction. Therefore, we screened the cerebella of 12 patients with alpha‐synucleinopathies for neuropathological changes. Cerebellar nuclei and neighboring white matter displayed numerous aggregates, whereas lobules were mildly affected. Cerebellar aggregation pathology may suggest a prionlike spread originating from affected precerebellar structures, and the high homogeneity between patients with dementia with Lewy bodies and Parkinson disease shows that both diseases likely belong to the same neuropathological spectrum. Ann Neurol 2017;81:898–903     

Gastrointestinal function in dementia with Lewy bodies: a comparison with Parkinson disease

Clinical Autonomic Research - To investigate gastrointestinal function in dementia with Lewy bodies and Parkinson disease. We examined gastric emptying and colonic transit time in 19 dementia with...     

Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are alpha-synucleinopathies

Parkinson's disease is neuropathologically defined by the presence of intracytoplasmic Lewy bodies and Lewy neurites. Similar filamentous inclusions are also present in dementia with Lewy bodies, a common late-life dementia, which is clinically similar to Alzheimer's disease. Lewy bodies and Lewy neurites are made of abnormal filamentous material containing alpha-synuclein. Glial cytoplasmic inclusions in multiple system atrophy also contain alpha-synuclein. Using recombinant alpha-synuclein, we have produced synthetic filaments indistinguishable from those present in the intracellular inclusions of Parkinson's disease, dementia with Lewy bodies and multiple system atrophy. Taken together, these findings indicate that Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are alpha-synucleinopathies.     

Visual hallucinations and altered visual information processing in Parkinson disease and dementia with Lewy bodies

Visual hallucinations (VHs) are common in dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), while auditory hallucinations are rare. To neurophysiologically investigate the pathophysiology of VHs in these disorders, we studied event‐related potentials (ERPs) of DLB, PDD, and Alzheimer's disease (AD) patients. We compared visual and auditory ERP latencies among PDD patients with and without VHs (PDD‐H: 11, PDD‐N: 6), DLB patients (24), and AD patients (21). To elicit visual and auditory ERPs, a facial discrimination paradigm and a conventional auditory odd‐ball paradigm, respectively, were used. The mean visual P3 latencies in the PDD‐H and DLB groups were significantly longer than that in the AD group, while the mean auditory P3 latencies in all four patient groups were comparable. The mean visual P2 latencies in the PDD‐N, PDD‐H, and DLB groups were significantly longer than that in the control group. Our findings suggest that visual cognitive functions are selectively impaired in hallucinatory patients with DLB and PDD. VHs may be associated in part with predominant visual cognitive impairments attributable to PDD and DLB pathologies. Our findings also suggest that the impairments occur at the early stage of facial information processing. © 2010 Movement Disorder Society     

Lewy body dementia and Parkinson’s disease with dementia

Journal of Neurology - Parkinson’s disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders...     

Autonomic failure as the initial presentation of Parkinson disease and dementia with Lewy bodies

The authors report the clinical and postmortem neuropathologic findings of two patients, one with Parkinson disease (PD) and one with dementia with Lewy bodies (DLB), both of whom initially sought treatment for isolated autonomic failure. These cases suggest that neurodegeneration in PD and DLB may begin outside the CNS in autonomic postganglionic neurons, a finding with potential diagnostic and therapeutic implications.     

Parkinson's disease, dementia with Lewy bodies, multiple system atrophy and alpha-synuclein]

Lewy bodies (LBs) are hallmark lesions of degenerating neurons in the brains of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). DLB is the second most common neurodegenerative dementia after Alzheimer's disease, which is characterized clinically by fluctuating cognitive impairments, visual hallucinations and parkinsonism, and pathologically by the appearance of cortical LBs. To characterize the components of LBs, we have developed a purification procedure for LBs from cortices of patients with DLB using sucrose density separation followed by fluorescence-activated particle sorting. We then raised monoclonal antibodies (mAbs) to purified LBs, and obtained a mAb (LB509) that intensely immunolabeled LBs and specifically reacted with a approximately 18kDa brain protein, which was identified as alpha-synuclein. LB509 as well as other antibodies to alpha-synuclein, but not to beta-synuclein, immunostained brainstem and cortical LBs in sporadic PD and DLB brains. Recently, a point mutation in alpha-synuclein gene was identified in some autosomal-deminantly inherited familial PD pedigrees. Moreover, glial cytoplasmic inclusions in the brains of patients with multiple system atrophy (MSA) were shown to be alpha-synuclein positive. Taken together, our data strongly implicate alpha-synuclein in the formation of LBs and the selective neuronal degeneration in PD, DLB and MSA.     

Alpha-synuclein in familial Alzheimer disease: epitope mapping parallels dementia with Lewy bodies and Parkinson disease.

BACKGROUND: Alpha-synuclein is a major component of Lewy bodies (LBs) in Parkinson disease and dementia with LBs and of glial cytoplasmic inclusions in multiple system atrophy. However, epitope mapping for alpha-synuclein is distinctive in different neurodegenerative diseases. The reasons for this are poorly understood but may reflect fundamental differences in disease mechanisms. OBJECTIVE: To investigate the alpha-synuclein epitope mapping properties of LBs in familial Alzheimer disease. DESIGN AND SETTING: We compared LBs in familial Alzheimer disease with those in synucleinopathies by probing 6 brains of persons with familial Alzheimer disease using a panel of antibodies to epitopes spanning the alpha-synuclein protein. Results were compared with data from brains of persons with Parkinson disease, dementia with LBs, and multiple system atrophy. RESULTS: The brains of persons with familial Alzheimer disease showed consistent staining of LBs with all antibodies, similar to Parkinson disease and dementia with LBs but different from alpha-synuclein aggregates that occurred in multiple system atrophy. CONCLUSIONS: These data suggest that the epitope profiles of alpha-synuclein in LBs are similar, regardless of whether the biological trigger is related to synuclein or a different genetic pathway. These findings support the hypothesis that the mechanism of alpha-synuclein aggregation is the same within cell types but distinctive between cell types.     

Medial temporal lobe atrophy on MRI in dementia with Lewy bodies

OBJECTIVE: To investigate whether medial temporal lobe atrophy (MTA) on MRI is less frequent in dementia with Lewy bodies (DLB) compared with AD and vascular dementia (VaD), and to determine the diagnostic utility of MTA in the differential diagnosis of dementia. METHOD: Coronal T1-weighted 1.0-T MR images were acquired in patients with DLB (consensus criteria; n = 26; mean age, 75.9 years), AD (National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association; n = 28; mean age, 77.4 years), VaD (National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences; n = 24; mean age, 76.9 years), and normal control subjects (n = 26; mean age, 76.2 years). Cognitive function was assessed using the Cambridge Cognitive Examination (CAMCOG), and MTA was rated visually using a standardized scale. RESULTS: MTA was more frequent and severe in all dementia groups compared with control subjects (AD, 100%; VaD, 88%; DLB, 62%; control subjects, 4%; p < 0.001). Comparing dementia groups, MTA scores were significantly lower in DLB than AD (p = 0.002), with a trend toward less atrophy in DLB compared with VaD (p = 0.07). The absence of MTA had a specificity of 100% and 88% for separating DLB from AD and VaD respectively, and a sensitivity of 38%. In patients with DLB, MTA increased with age (r = 0.58, p = 0.002), and in all dementia patients MTA correlated with memory impairment (combined memory score, r = -0.34, p = 0.003) but not total CAMCOG score or other subscales. CONCLUSION: Patients with DLB have significantly greater MTA than control subjects but significantly less than those with AD. The authors confirmed that the presence of MTA is useful in detecting AD but less useful in differentiating between dementias. However, in the differentiation of DLB from AD and VaD, the absence of MTA is highly suggestive of a diagnosis of DLB.     

Clinical trials in Parkinson's disease dementia and dementia with Lewy bodies

Parkinson's disease with dementia (PDD) and dementia with Lewy bodies (DLB) are pathological overlapping and important causes of dementia for which clinical trials are in their infancy. Cholinesterase inhibitors may be of benefit in DLB and PDD, as suggested by placebo-controlled clinical trials of rivastigmine and donepezil. The anti-psychotic agent clozapine has been of benefit in PD and PDD, but other agents, such as quetiapine, require adequate assessment. Barriers to trials include pathological overlap that can lead to inaccuracies in clinical diagnosis, unavailability of a consensus definition for PDD, unanswered questions regarding natural history and the paucity of validated outcome measures. Motor impairment must be considered in patients with PDD and DLB; conversely, cognitive impairment should be assessed in trials targeting motor impairment in advanced PD. Potential targets for treatment include onset of dementia, cognitive impairment, behavioral impairment, functional decline, falls, nursing home placement, mortality, quality of life and economic impact. Biomarkers including neuroimaging and cerebrospinal fluid markers are not currently established. At present PDD and DLB are distinct entities by definition. Future studies, including clinical trials and biomarker studies, will help to further define the clinical and therapeutic implications of this distinction.     

White matter changes in dementia with Lewy bodies and Alzheimer's disease: a tractography-based study

Dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) are different types of dementia. However, their clinical symptoms partially overlap and differential diagnosis is occasionally difficult. There is need for additional diagnostic criteria to reliably differentiate between these two conditions. Meanwhile, several imaging studies have showed inconsistent results between DLB and AD. The aim of this study was to use a tractography-based analysis to elucidate white matter alterations in subjects with DLB compared to those with AD and to controls. An understanding of the white matter connectivity differences between AD, DLB and controls will be helpful for differential diagnosis and an understanding of the pathophysiology. Twenty-six subjects with DLB, 26 with AD and 26 controls underwent magnetic resonance diffusion tensor imaging and neuropsychological assessment. Diffusion tensors were computed and fiber-tract maps were created using “dTV II” software. We measured mean fractional anisotropy (FA) values along the uncinate fasciculus (UNC), the inferior occipitofrontal fasciculus (IOFF) and the inferior longitudinal fasciculus (ILF). Both subjects with DLB and AD had lower FA values for the bilateral UNC than controls. Subjects with DLB exhibited significantly lower FA values on both sides of the IOFF and the left side of the ILF than those of controls. Although there were no significant differences between subjects with DLB and AD for any measurements, those with DLB exhibited lower FA values especially in visual-related white matter. These different changes in white matter tracts among groups could be helpful for differential diagnosis and an understanding of the pathophysiology.