Behavioral and Neurophysiological Characteristics of Lewy Body Dementia— Implications for Intervention

US Neurology, 2007;4(1):
Citation US Neurology, 2007;4(1):

With the aging of the population, promotion of cognitive health has emerged as a priority in public health. Most notably, Alzheimer’s disease (AD) alone remained one of the top 10 causes of mortality throughout the 20th century.1 The public health implications of cognitive status increase dramatically when it is recognized that AD is but one form of cognitive impairment, which, in addition to including several forms of dementia, also encompasses mild cognitive impairment,2 which is often, arguably, a predictor of the emergence of a dementing illness.

Another common form of dementia is Lewy body dementia (LBD). As its name suggests, LBD is characterized by the presence of Lewy bodies— eosinophilic inclusion bodies—in the brainstem and cerebral cortex and has been roughly estimated to comprise about 25% of all dementia cases.3 In this article we examine the behavioral and diagnostic characteristics and neuropathology of LBD, and summarize the latest findings concerning the treatment of this disease.

Studies selected for this review were identified by a search of PubMed for literature referenced to the keywords ‘Lewy body dementia’ or ‘dementia of the Lewy bodies’ and ‘epidemiology.’ In order to ensure the timeliness and clinical relevance of the investigations included, studies selected were limited to those published in the last 10 years featuring human subjects, which were written in English and appeared in core clinical journals (n=39). Furthermore, studies were generally limited to those that largely focused on LBD and provided definitional or diagnostic criteria and a specified interval of observation (n=24), with additional studies being added by expert input.

Results—Behavioral and Diagnostic Characteristics

Although AD is the most common form of dementia in older adults,4 investigators claim that LBD accounts for between 15 and 20% of lateonset cases of dementia.5,6 Part of the prevalence variance may stem from the use of different criteria for the diagnosis of LBD. Diagnostic criteria for LBD have evolved over the years. As summarized by Graham, Ballard, and Saad,7 the Nottingham Criteria for Dementia with Lewy Bodies included dementia having a gradual onset, pronounced deficits in attention or episodes of acute confusion, and parkinsonism (nervous disorders similar to those seen in Parkinson’s disease [PD]), slow or restricted body movements, postural problems, resting tremor, or rigidity.

Contemporary diagnostic criteria delineated in the third report of the Dementia with Lewy Bodies (DLB) consortium include progressive cognitive decline, prominent or persistent memory impairment (typically evident with disease progression), and prominent deficits in tests of attention, visuospatial ability, and executive function as central features essential for the diagnosis of possible or probable DLB. Cognitive fluctuation with marked variations in alertness and attention, recurrent visual hallucinations, and features of parkinsonism are considered core features of DLB, two of which must be present for a diagnosis of probable DLB. Suggestive features of DLB include, among others, rapid eye movement (REM) sleep behavior disorder (RBD) and severe neuroleptic sensitivity. Repeated falls and syncope, severe autonomic dysfunction, and transient, unexplained loss of consciousness are among an array of criteria comprising supportive features of DLB.8

Lewy Body Dementia Can Be Distinguished from

Alzheimer’s Disease

Perhaps most commonly viewed as similar in its course to AD, distinguishing LBD from AD is crucial to the appropriate treatment of persons suffering from either of these forms of dementia. Bolla et al.9 proposed a set of characteristics distinguishing AD from LBD. Specifically, in comparison with persons with AD, those suffering from LBD more frequently show signs of frontal lobe dysfunction, more prominent visual and auditory hallucinations, fluctuating cognitive performance, and greater sensitivity to neuroleptics. Notably, the visual hallucinations experienced by persons with LBD, among other disorders, are strikingly complex and often evoke stereotypical imagery that involves human and animal figures in dramatic settings featuring bright colors.10

The course of LBD and AD also differs, with persons with LBD presenting extrapyramidal syndrome and cognitive slowing, and more markedly impaired attention and line drawing earlier in the course of the disease than those with AD. While both dementias are characterized by deficits in verbal fluency, persons with AD retain good phonemic but poor categorical fluency, and LBD is typified by poor verbal fluency in both semantic and categorical domains. However, the neurofibrillary tangles and plaques characteristic of AD are observed to be less prevalent in LBD.11

Capgras’ Syndrome and Personality Traits

Notably, both forms of dementia may feature Capgras’ syndrome,9 which is a form of delusion in which the afflicted individual believes people in the
environment are not themselves, but doubles. In a longitudinal study of 290 adults (34 non-demented controls, 128 with LBD, and 128 with AD) averaging across 77.8 years, across a mean of 4.8 visits, personality traits were identified that distinguished persons with LBD from their peers with AD. Specifically, factor analysis revealed a cluster of passive personality traits (diminished emotional responsivity, relinquishing hobbies, increasing apathy, and purposeless hyperactivity) that were significantly more common among those with LBD than persons with AD.12

Neurophysiological Characteristics

As might be expected given that Lewy bodies are also common among persons with PD, many people with LBD also manifest signs of parkinsonism,13 such as difficulties in initiating movements, slowness of gait, muscular rigidity, and resting tremor. Given the confluence of Lewy bodies in both LBD and PD, the distinctiveness of these two disorders has been questioned. In an autopsyconfirmed examination of the brains of 57 prospectively assessed individuals (29 with LBD and 28 with PD dementia [PDD]), Ballard et al.14 found that there was a pronounced relationship between the duration of PD prior to dementia onset and important neuropathologies characterizing cognitive impairment. However, these investigators observed a gradation of these pathologies across both the LBD and PDD groups, and concluded that these findings did not support an arbitrary distinction between these two disorders.

Although sometimes co-occurring, the underlying neuropathology of LBD appears distinct from that of either AD or configurations evoking AD-like symptoms. Examining the neuropathological substrates of psychiatric symptoms in a group of 112 autopsy-confirmed cases of LBD, Ballard et al.15 noted that the main neuroanatomical marker of persistent visual hallucinations was the absence of severe neurofibrillary tangle pathology. These investigators note that this finding represents a marked departure from the previously identified mechanism for psychotic symptoms among persons with AD.15 This finding is consistent with the results of other investigators who found that a low Braak stage—a measure of the extensiveness of neurofibrillary tangles—was more strongly related to LBD than to Lewy body distribution.16

Clinically, the results suggest that identification of LBD is inversely related to the extensiveness of AD pathology. Alternatively stated, a lower Braak stage is associated with a more definite diagnosis of LBD.15

Family History

Family history of dementia may also be useful in identifying persons with LBD.17 While genetics have long been associated with AD and PD, the role of genetic factors in LBD appears to have been investigated only recently.4 In a study of consecutive cases of AD and LBD obtained from the State of Florida AD Initiative Brain Bank, Woodruff et al.4 mailed questionnaires to family members of patients with pathologically confirmed AD (n=70) and LBD (n=18) to gather information regarding behavior of the decedent during the course of the disease, as well as family history. Family history data were also obtained from relatives of a living control group (n=60). As had been previously observed, males accounted for the majority of the LBD. Notably, 67% of LBD cases had a positive family history of dementia, relative to 49 and 13% of AD and control cases, respectively. These results corroborate familial clustering of LBD in an isolated Dutch population,18 suggesting that a family history of dementia appears to be a risk factor for LBD, as well as for AD.4

The Protein Tau

One factor distinguishing AD from LBD appears to be the abundance of the protein tau in the cerebrospinal fluid (CSF) and, presumably, brains of persons living with AD, but not as strikingly in those with LBD. Tau, a protein constituent of neurotubules necessary for normal neuron development and function, is believed to be a component of the neuropathophysiology of AD. Specifically, in the brains of persons with advanced AD, tau protein structure is altered (through hyper-phosphorylation it grows twisted, resulting in the hallmark neurofibrillary tangles of this disease). Evaluation of tau levels in the CSF of persons with AD, LBD, and other neurological or psychiatric disorders demonstrated significant elevation of tau proteins in the CSF of persons with AD, compared with lower levels reported in vascular dementia, LBD, subjects with other neurological or psychiatric disorders, and healthy controls.19,20 These results may not seem surprising in light of previous research that reported that the presence of neurofibrillary tangles was much more strongly associated with AD than with LBD,15,16 but may, conceivably, afford an opportunity for examination of the distinction between the two disorders prior to post mortem brain autopsy.

Sleep Disturbance

As disruptive as LBD can be to the health and functioning of persons with this disease, it is perhaps not surprising that sleep disturbance has also been implicated as a potential marker of this disease. Specifically, an association between LBD and RBD has been posited.21 RBD is a parasomnia characterized by the absence of muscle atonia normally present during REM sleep (the phase of sleep when dreaming occurs). Consequently, persons with RBD may assault their bed partners or engage in other bizarre motoric behaviors during REM sleep.22 Notably, an autopsy of the brain of an individual with LBD who also manifested RBD revealed the presence of Lewy bodies and pronounced neuronal loss in the locus coeruleus and substantia nigra, which inhibit cholinergic neurons in the specific region of the brain mediating REM sleep atonia.21

Interventions

Not surprisingly, interventions proposed in the management of LBD are generally in keeping with the neuropathology determined to characterize this disorder. A case study featuring one new intervention—immunization with a compound consisting largely of beta-amyloid—was associated with a subsequently stable Mini Mental State Examination in the three years prior to the subject’s death. While initially diagnosed with ‘clinical’ features of AD, the subject subsequently developed clinical features of LBD. A post mortem examination of the patient’s brain revealed significant clearance of amyloid deposits, although tau accumulation remained. While no inflammation was reported, it must be remembered that this was a case study,23 and these results await replication with a larger number of representative subjects.

Cholinesterase Inhibitors

Cholinesterase inhibitors have long been used in the management of mild to moderate AD. These drugs have resulted in slight cognitive improvement and retardation of the trajectory of cognitive decline in AD, as well as improvements in mood and behavior. Patients with LBD have also been posited to improve with administration of cholinesterase inhibitors.24 However, recent clinical reports have suggested that these agents be administered cautiously to patients with LBD as they can result in severe worsening of the parkinsonism characteristic of this form of dementia. Fortunately, parkinsonism was reported to reverse itself once the cholinesterase inhibitor was discontinued, which was inadvertently administered in dosages exceeding its recommended usage.25 One patient was hospitalized for a 30-day course of observation and treatment,26 suggesting that cholinesterase inhibitors be titrated slowly and that all caregivers of persons with LBD be carefully familiarized with the correct dosage of these agents.

The results of a randomized controlled trial suggest that cholinesterase inhibitors administered at the correct dosages appear to benefit persons with LBD. McKeith et al.27 conducted a multicenter (UK, Spain, and Italy) double-blind, placebo-controlled trial featuring 120 patients with LBD given the active drug or placebo for 20 weeks followed by a rest period of three weeks. Neuropsychiatric testing was conducted at baseline as well as at weeks 12, 20, and 23, and patients received medical and laboratory monitoring to note any adverse effects and to ensure their safety.

Relative to controls, patients on the cholinesterase inhibitor had significantly fewer hallucinations and delusions, as well as being less apathetic and anxious. Nearly twice the number of patients on rivastigmine (63%) than placebo (30%) demonstrated at least a 30% improvement on baseline, with particular gains evidenced on tasks measuring speed of completion as well as attention. Nausea, vomiting, and anorexia were reported significantly more frequently among patients receiving the cholinesterase inhibitor relative to placebo controls. However, the safety and tolerability of this agent in a patient population who mostly had multiple medical comorbidities were judged to be acceptable.27

Among the hallmark signs of dementia are hallucinations, which have been reported to be particularly vivid and distressing among persons with LBD and are often particularly colorful and complex.9,10 Treatment of the often distressing hallucinations experienced by persons with LBD must be undertaken with great caution as these persons are exceedingly sensitive to extrapyramidal effects of conventional antipsychotics,3 thus rendering their condition worse than when such treatment was initiated.Second-generation (atypical) antipsychotics appear to be better tolerated by persons with LBD if pharmacotherapy is warranted.3 The behavioral management of the hallucinations of LBD patients must be extremely judicious, given their apparent sensitivity to adverse drug effects.

Conclusions

Named for the proliferation of Lewy bodies throughout the brainstem and cerebral cortex, LBD may be difficult to distinguish from AD, especially during its early stages. While both forms of dementia are progressive in course, there is characteristically more short-term fluctuation in symptoms with LBD. However, extrapyramidal symptoms and parkinsonism characteristically emerge in LBD, which pose important implications for its treatment. Neuropathologically, the two dementias differ in the greater proliferation of neurofibrillary tangles in AD, which appear attributable to the presence of abnormal forms of tau.

While the dementias may more accurately represent a continuum of neuropathology rather than discretely demarcated categories, special caution must be exercised in the care of persons with LBD. Traditional antipsychotics appear contraindicated in the treatment of the distressing hallucinations often experienced by persons with LBD as they often yield extensive extrapyramidal side effects. However, second-generation (atypical) antipsychotics appear to be better tolerated by persons with LBD and may provide a safer route of symptom management. Similarly, modest cognitive and behavioral improvements have been reported among persons with LBD receiving cholinesterase inhibitors, although these agents must be administered judiciously and potential adverse effects closely monitored

The opinions expressed by the authors do not necessarily reflect the opinions of the US Department of Health and Human Services, the Public Health Service, the Centers for Disease Control and Prevention, or the authors’ affiliated institutions. Use of trade names is for identification only and does not imply endorsement by any of the groups named above.

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