Cognitive impairment in Parkinson's disease and dementia with Lewy bodies

doi:10.1016/j.parkreldis.2015.09.034

Parkinsonism & Related Disorders

Volume 22, Supplement 1, January 2016, Pages S144-S148

https://doi.org/10.1016/j.parkreldis.2015.09.034 Get rights and content

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) share clinical and pathological similarities. The defining features are motor parkinsonism and cognitive impairment, often accompanied by visual hallucinations, fluctuating consciousness, autonomic and sleep disturbances, and a number of other non-motor symptoms. Mild cognitive impairment (MCI) can be identified in 15% of PD patients at time of diagnosis, and may even precede motor symptoms. MCI usually progresses further, and dementia is a common endpoint. Cognitive impairment is usually the initial symptom of DLB, and the disease course is severe. A variety of biomarkers can assist in the diagnosis and prognosis of PD and DLB, including structural and functional imaging, cerebrospinal fluid, and EEG. Compared to the many treatments available for motor symptoms, relatively few systematic studies exist to guide the treatment of cognitive impairment in PD, and even less in DLB. However, there is good evidence for cholinesterase inhibitors in both DLB and PD with dementia, and some indications that memantine is helpful. Emerging evidence suggest that physical exercise and cognitive training are also effective, as are some reports of various brain stimulation techniques. Disease-modifying agents that delay the rate of cognitive decline in PD and DLB are urgently needed.

Introduction

Parkinson's disease (PD), PD dementia (PDD) and dementia with Lewy bodies (DLB) are characterized pathologically by neuronal loss and inclusions containing alpha-synuclein (asyn) in the cell bodies and processes of the surviving neurons, known as Lewy bodies [1]. In addition, diffuse amyloid-beta (abeta) plaques, which are one of the hallmarks of Alzheimer's disease (AD) are also commonly seen, in particular in PDD and DLB. Key features of the three syndromes include: motor parkinsonism and cognitive impairment, often in combination with visual hallucinations, sleep and autonomic disturbances. Accordingly, PD, PDD and DLB are often considered as spectrum disorders, and DLB and PDD combined as Lewy body dementias. Whereas in PD, there is typically a period of pure motor symptoms before significant cognitive decline occurs, the reverse is characteristic of DLB, i.e. cognitive decline followed by parkinsonism, or occurring simultaneously. In some PD patients with early and significant cognitive decline, it can be difficult to decide whether PDD or DLB is the correct diagnosis. Another important distinction is between mild cognitive impairment (MCI) and dementia. Both syndromes are characterized by cognitive impairment, if accompanied by significant decline in the ability to perform activities of daily living (ADL)and the function independently, dementia is diagnosed. Whereas there is an emerging literature in PD-MCI, little is known about the prodromal stage of DLB. In this paper we will review the epidemiology, course, clinical and biomarker profiles, and treatment of cognitive impairment in PD and DLB.

Section snippets

Epidemiology

Several recent studies have reported on the frequency of mild cognitive impairment in PD. At the time of PD diagnosis, 15–20% of patients have already been classified as MCI using different definitions. In 2014, the MDS criteria for MCI were published, which require impairment of one or more cognitive domains. PD-MCI can be diagnosed at a basic Level 1 and a more sophisticated Level 2 [2].

The cognitive profile in PD-MCI is heterogeneous, but differs from that of MCI due to AD by relatively more

Pathology

The underlying mechanisms of cognitive decline in PD and DLB are heterogeneous. The many different potential mechanisms vary between PD and DLB syndromes as well as inter-individually within the syndromes. Neurotransmitter changes such as cholinergic, dopaminergic and glutamatergic changes contribute, and provide an opportunity for transmitter-based pharmacological treatment (see below). Most studies suggest that limbic and cortical Lewy body pathology is the main driver of cognitive decline in

Genetics

The last decade has seen an impressive increase in the knowledge of the genetics of PD and AD, but less is known regarding the genetics of PDD and DLB (Table 1). Given the clinical and pathological overlap, genes known to be associated to AD and PD may be related to DLB. Association studies have shown that APOE genotype and GBA mutations [9] are associated with DLB. Full genome-wide or exon-wide association studies of DLB have not yet been performed. However, using the NeuroX array, designed

Diagnostic procedures

It is crucial for clinicians to focus on cognition in PD patients, and to systematically search for the core features of DLB in patients with dementia. There is evidence that cognitive impairment is not always detected in PD patients, and that DLB is frequently underdiagnosed. In patients with MCI and mild dementia, neuropsychological assessment is recommended in order to more accurately characterize the impairment of the key cognitive domains, and thereby identify the cognitive profile. Global

Dopamine transporter imaging

A number of biomarkers have been explored for DLB and cognitive decline PD (Table 2). Dopamine transporter imaging with SPECT, or PET, has a high sensitivity and specificity for the differentiation between probable DLB and AD [13], can predict conversion from possible DLB to probable DLB, and is included in the clinical criteria for DLB [5]. Abnormal uptake also occurs in PD, and thus DAT imaging cannot distinguish between DLB and PDD, or between PD and PDD. However, reduced caudate uptake has

Clinical symptoms and course

In PD, the typical initial cognitive decline is dominated by executive, attentional, and visuospatial problems. However, memory is often impaired, both due to retrieval difficulties secondary to the executive impairment, but a storage deficits related to medial temporal changes are also common. With progressing cognitive decline, a combination of cortical and subcortical cognitive symptoms are common, and behavioral symptoms such as apathy, hallucinations and agitation become more prevalent.

Management

Management of cognitive impairment in PD and DLB includes informing patients and caregivers, identification and removal of secondary contributory causes such as physical or psychiatric diseases or adverse effects of drugs, refining the anti-parkinson treatment, supportive measures, and considering symptomatic treatment.

Conflict of interest

Dr Aarsland has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals and GE Health.

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Citation Excerpt :
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^☆: Milan congress proceedings: Plenary session 4.1 cognitive impairment in PD PDD and DLB 12/9/2015 10:15:00 AM–11:45:00 AM.

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Cognitive impairment in Parkinson's disease and dementia with Lewy bodies☆

Abstract

Introduction

Section snippets

Epidemiology

Pathology

Genetics

Diagnostic procedures

Dopamine transporter imaging

Clinical symptoms and course

Management

Conflict of interest

Lancet Neurol.

Neurobiol. Aging

Park. Relat. Disord.

Lancet Neurol.

DLB and PDD boundary issues: diagnosis, treatment, molecular pathology, and biomarkers

Neurology

Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society Task Force guidelines

Mov. Disord.

Evolution of cognitive dysfunction in an incident Parkinson's disease cohort

Brain

Clinical diagnostic criteria for dementia associated with Parkinson's disease

Mov. Disord.

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium

Neurology

15-year population-based cohort study of the incidence of Parkinson's disease and dementia with Lewy bodies in an elderly French cohort

J. Neurol. Neurosurg. Psychiatry

Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?

Brain

Parkinson's disease dementia: convergence of alpha-synuclein, tau and amyloid-beta pathologies

Nat. Rev. Neurosci.

GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology

Neurology

Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies

Hum. Mol. Genet.

Genetic impact on cognition and brain function in newly diagnosed Parkinson's disease: ICICLE-PD study

Brain