Dementia in parkinsonism.

Movement disorders originate from malfunctioning of the basal ganglia, whereas dementia is the result of cortical aberrations. Therefore, conceptually, these two disorders are due to involvement of different anatomical areas of brain. But with the passage of time, newer concepts have come up, which eventually explain the co-occurrence of these two seemingly divergent clinical problems. On one hand, with the demonstration of basal ganglia circuit it is now evident that this area has got rich connections with cerebral cortex, particularly prefrontal cortex, through thalamus. On the other hand, newly discovered circuits for cognition have stressed on the role of basal ganglia, particularly the caudate nucleus and thalamus, in different aspects of cognition. The central point in the understanding of dementia in movement disorders is the prefrontal network for attention and the prefrontal cortex, caudate nucleus, and dorsomedial thalamus that form the different components of this network. This network subserves behavioral aspects that require an integration of thought with emotion and motivation, personality, and attention. In terms of the concept of network theory dysfunctions restricted to subcortical components can present with frontal lobe-like features even when the frontal lobe has not been pathologically involved. Apart from this anatomical explanation, there are other possible explanations of dementia in movement disorders. Moreover, biochemically it has been seen that not only are these related to dopaminergic system, but other neurotransmitters, such as acetylcholine and serotonin are also at fault, which explain the cognitive and psychiatric disturbances in movement disorders.

The different parkinsonian syndromes where dementia is a prominent feature include the following:

Parkinson's Disease

When James Parkinson first described the “shaking palsy” in 1817, it was considered as a purely motor system disease. In recent times Parkinson's disease with dementia (PDD) along with dementia with Lewy body (DLB), collectively called Cortical Lewy Body Disease comprises 10%–15% of all degenerative dementia and is only second to Alzheimer's disease (AD) in terms of prevalence.

Lewy body, an intracytoplasmic inclusion containing α-synuclein, is the pathological hallmark of PD and is found in nigral cells. However, it is found in neocortical and paralymbic regions in PDD and DLB as well. In contrast to their brainstem counterpart, the neocortical Lewy bodies are smaller, lack halo, and are difficult to see under routine staining conditions. Moreover, brains of PDD and DLB patients have pathological findings of AD, which is more common than in healthy controls. Biochemically, dopamine deficiency due to nigral degeneration has been implicated for the pathogenesis of dementia. However, loss of noradrenergic input from locus ceruleus and cholinergic input from nucleus of basalis of Meynert are also important for the development of dementia. It is interesting to note that there is more cholinergic deficiency in PDD than AD.

Frequency of dementia in PD varies from 0% to 81% in different studies depending on the associated comorbidity, methodology used, and the criteria used to define dementia. Brown and Marsden in a seminal paper in Lancet estimated that it is in the order of 15%–20%, the inordinately high values being attributed to serious methodological flaws.[1-3] The cognitive disturbances range from specific deficits, demonstrated by formal neuropsychological tests, to overt dementia and there is a continuous spectrum between these two extremes.[4] There is some evidence of a preclinical phase of dementia, and tests of verbal fluency may be a good predictor of later development of dementia.[5] The risk factors for the development of dementia in PD are advanced age, treatment-induced visual hallucination, more severe motor symptoms (Unified Parkinson's Disease Rating Scale > 25), development of mania, agitation, disorientation, or psychosis when treated with levodopa, exposure to psychological stress, low socioeconomic status, low education level, and clinical presentation as postural instability gait difficulty variety. Facial masking at presentation has also been observed as a risk factor by some workers.[6] It has been found that the relative risk of developing dementia with PD is 1.7 as compared with patients without PD. Severity of dementia has been related to bradykinesia, postural and gait disturbances, atypical neurological features of PD, such as early autonomic failure, symmetrical onset, and poor response to levodopa. Some investigators have been able to correlate the severity of disability and the extent of the disease on one hand and the degree of intellectual impairment on the other.[7-9] Duration of illness has often been implicated in the development of dementia,[10] although others believe that this is an inconsistent association.[11] Lieberman et al[7] showed that those who were demented, were at least 5 years older than the nondemented ones, developed the disease later in life and the illness was of brief duration. Importantly, they were poorly responsive to levodopa as well. What emerged from this study was that possibly there are two subsets of patients, where one group suffers predominantly from motor disabilities and are young in age where the progression of the disease is rather slow and the therapeutic response to levodopa is good; the other subset is often termed the motor–cognitive group whose predominant feature is cognitive impairment. Errea et al showed that cognitive decline correlated well with low educational level.[12]

The clinical profile of PDD is one of frontostriatal in nature.[1314] Dysphasia, dysphoria, apraxia, and agnosia, which characterize AD, are classically lacking in PDD, while executive dysfunction, visuospatial deficit, large fluctuation in attention, and frequent visual hallucination are the significant features. Executive dysfunction is characterized by mental inflexibility and impaired set sifting, whereas visuospatial deficits are in the domain of block designing, picture arrangement, and line orientation.[15] Visuoperceptual matching, a feature disturbed in PDD, is retained in AD and selective impairment in the dating of historical photographs is impaired in PD in contradistinction to the inability even to recognize the scenes as well, a feature found in AD.[1617] Memory sphere is less involved as compared with AD and when involved it is more of a retrieval deficit in declarative memory and procedural memory. Patients perform better in recognition tasks. Mild language dysfunction may be there and it is characterized by “tip of the tongue” phenomenon, decreased naming and fluency, impaired comprehension of syntactically difficult questions and decreased melody of speech.

Dementia with Lewy Body

Cortical Lewy bodies are found in different types of degenerative dementia, which are collectively called as LBD. Clinicopathologically, it encompasses PDD, DLB, and Lewy body variant of Alzheimer's disease (LBV). The last of the three is characterized by cortical Lewy bodies and Alzheimer's type neuropathological changes in the brain and constitutes about 70% of LBD. In different literatures the terms LBD and DLB have been used interchangeably and the term diffuse LBD has been used to denote classical DLB. Because 25%–30% of PD patients develop dementia (PDD) and most DLB patients have parkinsonism, it has been hypothesized that PD, PDD, and DLB are not distinct entities, but may exist along the spectrum of LBD. A DLB/PDD Working Group recently proposed the use of LBD as an umbrella for studying the biology of these disorders, although they also suggested that the three individual terms should be maintained for clinical needs. Consensus criteria artificially divide patients with PDD and DLB by the “one year rule” where dementia appears within 1 year of appearance of parkinsonian features in the latter condition.

DLB is the second most common cause of degenerative dementia in the elderly with prevalence up to 30.5% among dementia patients. Pathologically three types of DLB are recognized—brain stem predominant, limbic (transitional), and neocortical.[18] The areas that are particularly vulnerable to cortical Lewy bodies are hypothalamus, basal forebrain, amygdala, and temporal neocortex. Additionally, Aβ42 amyloid plaques are abundant with paucity of tau-positive neuritis as opposed to what is found in AD. Both dopamine and acetylcholine deficiency are implicated in the genesis of dementia in this condition.

DLB consensus criteria has been put forward by McKeith et al.[19] see Table 1.

Table 1

Revised criteria for the clinical diagnosis of dementia with Lewy bodies (DLB)

Impaired visual construction and attention with preserved memory and naming skills distinguish DLB from AD.[20] Few features are helpful in the diagnosis of probable DLB. Visual hallucination is most specific (90%) for DLB, but its sensitivity is low (22%). Intersecting pentagon test is helpful in mild to moderate dementia (MMSE > 13) to differentiate DLB from AD. Intrusions are more common in DLB.

MRI voxel-based morphometry reveals that DLB has little cortical involvement but does show a discrete cluster of gray matter loss in basal forebrain and dorsal midbrain. Occipital hypoperfusion in SPECT study is found in both PDD and DLB.

Progressive Supranuclear Palsy

It is grouped under the rubric of parkinsonism plus syndrome. The cardinal manifestations are symmetric bradykinesia and rigidity (axial > appendicular) without tremor with predominant vertical supranuclear gaze palsy. Cognitive decline, although less stressed upon, is present in 22% cases at presentation and around 80% in life time. It is predominantly of the frontal subcortical in variety with involvement of executive function and attention.[21] Executive dysfunction is characterized by impaired set sifting, motor inhibition, verbal fluency, and abstract thinking. Atypical cases are not uncommon who present predominantly with cognitive decline simulating progressive aphasia or frontotemporal degeneration (FTD). Pathologically it is characterized by neurofibrillary tangles, which are composed of aggregates of tau-protein.

Management of Dementia in Parkinsonism

The management of dementia and related problems in Parkinsonism is difficult. One of the chief reasons is that any attempt to ensure mobility with levodopa and related drugs is fraught with the danger of exacerbating mental and behavioral problems and the physician is almost always caught in the cleft stick in order to determine which classes of drugs need to be augmented and which should be restricted so that the subject can lead an optimally healthy life. However, conventional antipsychotics do not work well for the management of the behavioral problems in Parkinsonism and they significantly worsen the motor problems as well.[22] Of all the atypical antipsychotics clozapine has been shown to superior to others in various placebo-controlled studies. It reduces the positive symptoms of psychosis and there is no worsening of the motor symptoms or global cognition and a recent structured review and meta-analysis concluded that only clozapine can be recommended for the management of drug-induced psychosis in Parkinsonism.[23-25] Olanzepine, on the other hand, led to significant worsening of the motor symptoms.[2627] Trials on quetiapine have not shown any worsening of the symptoms, although some works have doubted the efficacy of this compound for the management of psychosis in Parkinsonism.[2829] Aripiprazole, an atypical antipsychotic with partial agonism at D2 receptors, showed promise as an antipsychotic in Parkinsonism when it was first introduced, but two small open-label studies at varying dosages reported worsening of symptoms or lack of improvement in psychosis.[3031] Another recently introduced compound, ziprasidone showed significant overall improvement in total Neuropsychiatric Inventory score and no change in the Unified Parkinson's Disease Rating Scale motor score.[32]

There is some evidence that cholinesterase inhibitors may have antipsychotic properties for the management of behavioral symptoms in Parkinsonism. A number of open-label studies have documented the beneficial effects of donepezil and rivastigmine in the management of dementia in Parkinsonism. A large placebo-controlled study of rivastigmine found that the rivastigmine group had significant improvement of the neuropsychiatric symptoms than the control group and were less likely to develop hallucinations.[33] Furthermore, patients who suffered from visual hallucination at the time of initiation of treatment benefited the most.[34]

The management of psychosis in DLB is equally frustrating and only a prospective randomized study in this regard has been reported to date.[35] Rivastigmine led to significant improvement in delusions, hallucinations, depression, and apathy; and therefore, cholinesterase inhibitors are now recommended as the first line of management for this condition. Mementine has also been found useful in one small retrospective study.[36] However, cholinesterase inhibitors can increase tremor in Parkinsonism by their procholinergic actions.[35]

One of the major problems of management of psychosis and related problems in Parkinsonism is that stopping drugs often lead to worsening of symptoms.[37] However, some trials show that patients can be switched from clozapine to quetiapine after stability has been earned, provided they responded earlier to the latter agent.[38]