MCI of Lewy body disease

Cognitive changes of insufficient severity to diagnose clinical dementia would logically precede the onset of dementia in a gradually progressive disease process. Just as the early predementia or prodromal clinical state of AD, characterized by amnestic difficulties, is embodied by the diagnostic criteria of mild cognitive impairment (MCI), so might we expect measurable cognitive changes prior to the onset of DLB or PDD. Cognitive impairment in the Lewy body diseases is progressive and advances with age [65, 66].

In a retrospective analysis of patients followed longitudinally prior to death, and ultimately with neuropathological diagnosis of DLB, those demonstrating mild cognitive impairments had a profile that differed from MCI seen in AD cases [67]. The MCI-DLB cases were more likely to express features of parkinsonism (cases of PD were excluded), hallucinations or delirium provoked by medication or medical illness, and fluctuations in cognitive performance. It should be noted that these challenging symptoms, when presenting without an underlying cause, may bias diagnosis toward a dementia rather than MCI. Letter (phonemic) fluency performance was significantly lower in the MCI-DLB group, and performance of Wechsler Logical Memory-I, a test of immediate recall, was significantly better in MCI-DLB compared to MCI-AD cases. In another analysis of patients diagnosed with MCI, in those ultimately diagnosed pathologically with DLB, the cognitive domains most frequently affected were attention, executive functioning, and visuospatial functioning [68]. Interestingly, in this study all cases with REM sleep behavior disorder plus mild cognitive impairment eventually were shown to have autopsy-proven LRP.

Although one might expect a cognitive profile similar to that seen in more advanced DLB and PDD, it is not necessarily assumed that the cognitive profiles of MCI prior to DLB and PDD diagnosis will necessarily match the profile seen once dementia is evident. As yet, no clearly defined criteria exist to reliably establish a prodromal diagnosis of MCI-DLB; however, to aid in standardizing the assessment of MCI in PD, diagnostic criteria have been proposed (Table 18.2) [69]. Mild cognitive impairment has been found to be surprisingly common in newly diagnosed PD patients. Prevalence of MCI was 19% (two-thirds had a non-amnestic subtype of MCI and one-third had amnestic MCI) in one study of incident PD [70], and as high as 57% in prevalent PD [71]. Consistent with MCI-PD as a prodrome to dementia, one study found 62% of the patients with MCI-PD developed dementia during the 4-year follow-up period, while only 20% of the cognitively intact patients with PD progressed to dementia during that same timeframe [72].

Frontal executive dysfunction seems to be the most prominent cognitive domain affected in PD prior to the development of dementia [73], although the nature of cognitive deficits in MCI-PD is global, affecting multiple cognitive domains in the vast majority of patients. One explanation for this may be involvement of frontal and subcortical circuitry, important for attentional allocation, executive, and multimodal processing, inherent in the neuropsychometric assessment of cognitive domains [74]. Also worth mentioning is the co-occurrence of AD pathology and LRB in about a third of patients, which may modify the clinical phenotype [21], and implies the need to investigate therapies targeting Aβ for improving cognitive performance in PD and LBD.

Clinical features of the DLB and PDD spectrum

Ancillary studies

As in the approach to all dementias, careful consideration should be given to a differential diagnosis with focus on potentially treatable or reversible conditions. Laboratory studies typically include screening for thyroid deficiencies, vitamin B12 deficiency, syphilis serology as well as screening for metabolic organ dysfunction in general with a comprehensive metabolic panel that includes screens for liver and kidney dysfunction and a complete blood count.

CSF analysis may be used to aid in the diagnosis of AD, although no specific CSF screen for PDD or DLB has been developed. Abnormalities in the CSF core biomarkers for AD (amyloid beta 1–42 [Aβ₄₂], total tau, and phosphorylated tau) are not specific to AD: they cannot be relied upon alone to differentiate between causes of dementia, such as AD vs. DLB [118]; however, they may assist in estimating the certainty of a diagnosis in certain clinical situations. Reduced CSF Aβ₄₂ is associated with cognitive decline in PD [119], possibly reflecting overlapping pathologies as the cognitive disease advances [49]. However, some CSF biomarkers or combinations of biomarkers do show some promise in differentiating disease pathologies in vivo. Both DJ-1 and SNCA, two proteins potentially involved in PD/DLB pathogenesis, have been tested as disease biomarkers; although early studies were unrevealing, improved techniques have demonstrated sensitivity and specificity for cases with PD versus controls to be 90 and 70% for DJ-1, and 92 and 58% for SNCA [120]. A combination of the two markers did not enhance the test performance, and there was no association between DJ-1 or SNCA and the severity of Parkinson’s disease. In another study, CSF SNCA has was found to be significantly lower in DLB and PD patients than in patients with AD and aged controls [121]. Combinations of DJ-1 and SNCA with other biomarkers have shown promise in differentiation of PD patients not only from normal controls but also from patients with Alzheimer disease and multiple system atrophy [122], although DLB patients were not included in the study.

Lower levels of the metabolite 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in CSF has been shown to improve differentiation of AD and DLB cases [123]. Slightly, but significantly, lower levels of Aβ₄₂, total tau, phosphorylated tau₁₈₁, SNCA, and total-tau/Aβ₄₂ were seen in subjects with PD compared with healthy controls, although with a marked overlap between groups [124]. CSF studies alone are insufficient for providing a diagnosis, but may be useful in combination with other clinical information to increase diagnostic accuracy during early phases of the disease, and to assist in the clinical process of differentiating between neurodegenerative disorders [125].

Imaging with CT and MRI is not helpful in establishing a diagnosis of DLB, PD or PDD; however, imaging studies can show relative preservation of medial temporal lobe volume in DLB compared to AD [126].

PET and SPECT studies show consistent evidence of occipital hypometabolism (reduced O₂ uptake and reduced glucose utilization) in DLB and PD/PDD [127–131]. Unfortunately, it is unclear how often this characteristic imaging finding is negative in patients with DLB or PD/PDD. Such studies alone are not sufficient to establish a diagnosis; however, when occipital hypometabolism is present it can be combined with other diagnostic criteria, such as RBD, to increase diagnostic accuracy [132].

A more recent SPECT study of PD and PDD patients failed to show longitudinal progression of occipital hypoperfusion, although increasing perfusion was seen in striatal areas [133]. One speculative reason for not finding occipital hypoperfusion in this study was that treatment with acetyl-cholinesterase inhibitors (ACEIs) in the impaired subjects could have reduced the occipital abnormality.

FP-CIT SPECT or other dopamine transporter imaging of the presynaptic dopamine uptake site shows similar degeneration of the nigrostriatal dopaminergic projection to the basal ganglia in DLB and PD, and the consensus criteria for DLB consider such an abnormality on DAT scans to be a supportive feature for a diagnosis of DLB (Table 18.1) [19]. Similar to FTG-PET, there is a need for better data on how often these transporter scans are negative (“false negative”) in DLB. In PD the false negative rate appears to be low [134].

I-123 MIBG scan can identify postganglionic autonomic dysfunction, and this finding may support a diagnosis of DLB and PD/PDD; however, cautious interpretation is needed as reduced uptake may also be seen with other autonomic insufficiency in other diseases like diabetes, or with severe congestive heart failure [135, 136].

As discussed above, sleep polysomnography, a non-invasive and safe investigation, may also assist with diagnosis. The observation of loss of usual muscle atonia during REM sleep can identify REM sleep behavior disturbance, a feature suggestive of synucleinopathy, and a potentially treatable source of discomfort and sleep disruption, particularly for bed partners.

Cognitive impairment

A focus of treatment of dementia in AD has been the reversal of the well-characterized loss of cholinergic activity in the brain [137]. ACEIs increase availability of central nervous system acetylcholine by blocking its enzymatic breakdown via the cholinesterases. Current ACEIs approved for use in the USA include donepezil, rivastigmine, and galantamine. All have been consistently shown, in double-blind placebo-controlled studies, to have modest, but statistically significant positive cognitive and behavioral effects in AD. Examination of the cholinergic system in DLB has also demonstrated a significant reduction in cholinergic activity that appears to be more severe than that observed in AD [138]. Several open-label trials have suggested that patients with DLB can tolerate ACEIs, with few reports of worsened parkinsonism, and can have a positive clinical response. Small double-blind/placebo controlled trials of rivastigmine and donepezil in DLB patients have demonstrated improvements in both cognition and neuropsychiatric symptoms [139, 140–142]. A similar cholinergic deficit is seen in PD/PDD patients, and suggests that this group of patients may also respond well to cholinesterase inhibitors [143]. A large placebo-controlled trial confirmed a benefit of rivastigmine for cognitive and behavioral symptoms in PD [144], while a similar-sized study using donepezil had more limited positive results [145]. The 2006 AAN published guideline “Practice parameter: Evaluation and treatment of depression, psychosis, and dementia in Parkinson disease” supports use of donepezil or rivastigmine in the treatment of dementia symptoms in PDD and rivastigmine in DLB [146].

Memantine, approved by the FDA for the symptomatic treatment of mild to moderate dementia, has been studied in DLB and PDD, but the results have been mixed [147, 148]. In one study, memantine improved neuropsychiatric symptoms for DLB patients when compared to placebo, but there was no significant effect in PDD patients.

Psychiatric features

As already mentioned psychotic symptoms present a common clinical problem in the treatment of DLB and PD/PDD. As with other behavioral disturbances, psychotic symptoms such as paranoia are associated with significant morbidity and early nursing home placement [149]. As noted in the previous section, cholinesterase inhibitors have shown some benefit in neuropsychiatric symptoms in DLB and PDD [144].

The use of antipsychotic medications in DLB and PD/PDD is challenging, because of the known sensitivity of these patients to dopaminergic blockade, resulting in worsening of motor symptoms. Although typical antipsychotics should be avoided in such patients, several of the newer atypical antipsychotic medications may be better tolerated and safer. Even in these newer agents higher doses may still produce worsening of motor symptoms and there may be individual variability in the sensitivity to these agents. In one study olanzepine was shown to reduce psychotic symptoms in DLB, without worsening of motor symptoms [150]. In another study of PD patients, olanzepine worsened motor symptoms, but clozapine was better tolerated [151]. In a study of clozapine and quetiapine in PD patients, improvements were seen in psychotic symptoms for both drugs, but unlike with clozapine in this study, quetiapine had no measurable worsening of motor symptoms [152]. Retrospective analysis does support the efficacy and safety of treating psychosis with quetiapine in PD [153, 154] and DLB [155]. The 2006 AAN published guideline, mentioned above, also suggests that clozapine or quetiapine may be considered for treatment of psychosis symptoms in PD. That being said, the potential for serious adverse effects with clozapine, particularly blood dyscrasias, and the need for close laboratory monitoring for such adverse events, makes this drug more challenging to use in routine clinical practice, and quetiapine is likely to be preferred by most clinicians [156].

The FDA has raised concerns regarding the increased mortality associated with use of antipsychotic medications; however, this must be considered on an individual basis, along with the risk of morbidity and mortality due to the psychotic symptoms to the patient and sometimes the caregiver. As a final caveat, in some patients, psychotic symptoms do not appear to be a significant stressor to the patient or caregivers. In this latter circumstance, it is generally wise to avoid medications that specifically target psychotic symptoms.

Pimavanserin, a selective serotonin 5-HT2A receptor inverse agonist, has recently been shown in a placebo-controlled trial to improve psychotic symptoms in PD without worsening motor function [157]. This medication may benefit patients with PD/PDD and possibly benefits patients with DLB-associated psychosis.

Mood

Depression and anxiety are common in PD and DLB. Clinicians need to proactively screen these patients for the presence of depression and anxiety symptoms, as studies have shown these problems, though frequent, often go unrecognized and untreated [158]. No specific therapy for treating such symptoms in PD or DLB has yet been defined, and antidepressant trials in DLB and PDD specifically are needed [159]. Selective serotonin reuptake inhibitors (SSRIs), serotonergic and noradrenergic reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs) may benefit depression symptoms in non-demented PD, and one study showing efficacy for depression in PD of an SSRI and SNRI did not differ from those with better versus worse (MMSE score < 27) cognitive performance [160]. Although antidepressants have not been shown to be beneficial for depressive symptoms in dementia (mostly AD) patients as a whole [161], clinicians may consider lower doses of SSRIs, e.g., sertraline (25–50 mg/day) and citalopram (10–20 mg/day) in individual patients, where there may be some benefit for other neuropsychiatric symptoms in dementia, such as agitation [162]. Trazodone, a 5-HT2 antagonist, at 50 mg at bedtime, has been useful for dementia patients with insomnia or a nocturnal agitated state. Anxiolytics and benzodiazepines are generally avoided or used with great caution due to their sedative and adverse cognitive effects [156]. Depression in PD has been reported to respond to amitriptyline, although in those with significant cognitive impairment, this drug and others likely to have significant anticholinergic effects are probably best avoided.

Motor symptoms

Motor symptoms in DLB patients are somewhat unique, in that there tends to be less resting tremor than observed in PD, while there are similar levels of rigidity, bradykinesia, and postural instability. In addition, the clinical response of motor symptoms to levodopa is modest in DLB, in comparison with the almost universal response in PD. In one study of levodopa treatment of motor symptoms in DLB, 19 patients were treated for 6 months (mean daily dose 323 mg). Two subjects withdrew prematurely with gastrointestinal symptoms and two with worsening confusion. The overall impression was that a modest dose of L-dopa was generally well tolerated in DLB, but produced a significant motor response in only about one-third of patients. This was not deemed to be particularly efficacious, although younger DLB cases were more likely to respond to dopaminergic treatment [163]. Consideration of treatment with levodopa should be individualized. Dopaminergic agonists tend to have greater cognitive and behavioral side effects compared to levodopa, and should be avoided if possible in DLB. As well, in PDD the clinician may want to taper dopamine agonists and increase levodopa as necessary for motor symptoms.

Sleep and other non-motor or cognitive symptoms

As previously described, RBD is a common symptom in DLB, PD/PDD and other synucleinopathies. Although benzodiazepines are typically to be avoided in dementia patients, a low dose of clonazepam can be very effective and well tolerated for treatment of this symptom. There is also some evidence to support the effective and safe use of melatonin. Typically used doses are in the range of 3 mg to 9 mg (median dose of 6 mg), to treat this symptom [164]. In PD, periodic limb movements are frequent, and may respond to dopaminergic therapy [114], although, as noted above, levodopa is probably preferable to dopaminergic agonists in patients experiencing more significant cognitive impairment or behavioral disturbances. A wide range of other sleep disturbances, while less specific to the synucleinopathies, are common and warrant appropriate evaluation and management.

Dysautonomia, particularly postural hypotension, may be treated initially with compression stockings, preferably up to thigh height, or with addition of abdominal binders. The clinician may also need to modify antihypertensive medications. Sympathomimetic agents such as midodrine can be tried, and mineralocorticoids such as fludrocortisone 0.1 mg may also be helpful.

Incontinence may be managed non-pharmacologically with adult pads. Scheduled bathroom breaks can also be useful. Pharmacological management with bladder antispasmodic agents should aim to avoid use of more centrally acting drugs, such as oxybutynin, in favor of those with less central activity such as darifenacin, tolterodone solifenacin, trospium [165, 166] or mirabegron, a beta-3 agonist that may be a useful alternative for patients intolerant of anticholinergic medicines [167]. Clinical review for the effectiveness of the drug should ensue, as if it is not effective it should be discontinued or changed.

It is not surprising that with early involvement of the myenteric plexus, as discussed earlier, constipation is common in the diseases with LRP. High fiber diet and bulking agents are first-line therapy, and GI stimulants such as senna should be used with restraint due to potential for habituation.

Pathological

Pathological characterization of DLB using new histological techniques has been a major focus of recent clinical–pathological studies. The clinical and pathophysiologic significance of the high frequency of SNCA lesions in the amygdala of AD patients [19], or the prominence of SNCA pathology in autosomal dominant AD [51], are important observations that may lead to increased understanding of this pathology with further research.

Neurochemistry

Neurobiological investigations have focused on understanding the pathophysiological basis of the unique clinical symptomatology of DLB. As already mentioned, it has been established that DLB patients have substantial loss of cholinergic function [168]. Specific alterations in cholinergic receptors also occur in DLB and alterations in this system are associated with delusions and hallucinations [169]. The well-established cholinergic disturbance in DLB and the beneficial response to cholinesterase inhibitors are important findings and clues to future directions of DLB research.

As would be expected, alterations in the substantia nigra-based dopaminergic system have been demonstrated in DLB, with reduction in dopamine transporter sites and dopamine levels in the striatum. There is some evidence that dopaminergic system degenerative changes in DLB differ from those observed in PD [170] and may account for the differential clinical response of DLB patients to dopaminergic agents. Of course, alterations in the dopamine system have been implicated in psychotic disorders, and disruption of this system in DLB may also be important in the development of hallucinations and delusions.

In addition to the abnormalities of the dopaminergic and cholinergic systems in DLB, the locus ceruleus and its neurotransmitter norepinephrine are also affected. Neuronal counts of the locus ceruleus in PD show a substantial loss of neurons [171]. Norepinephrine levels are also significantly reduced in the striatum of DLB, and receptors for norepinephrine are abnormally increased in locus ceruleus projection sites [59].

Neurotransmitter system alterations in dementia, and particularly in DLB, are complex, dopaminergic, cholinergic, serotonergic, and adrenergic systems [172]. More detailed understanding of the alterations of these systems and the impact on cognitive and behavioral symptoms will be important in the development of effective treatments for clinical symptoms.

Genetics

A number of genes have now been implicated in PD, PDD, and DLB [173, 174], and although familial grouping of these diseases is uncommon, familial cases of PD and DLB have been reported. Mutation of the SNCA gene has been reported in familial PD [33, 175], as has a mutation of SNCA in familial DLB [176], and mutations of synuclein genes including alpha, beta, and gamma variants have been associated with clinically diagnosed DLB [177, 178]. Triplication of the SNCA gene has been suggested to more likely result in dementia than duplication of the same gene, which tends to be more strongly associated with motor parkinsonism [31].

Other genes may play a role in SNCA pathology: for example, the mutations in the Parkin gene have typically been associated with non-LRP parkinsonism; however, heterozygous mutations have been reported in several familial presentations where LRP was identified [179–182]. LRRK2 mutations, reported to be the most common mutation in sporadic PD, and present in as many as 5% of PD cases with a family history of PD, typically show pathology with LB and LN [183], though it has also been suggested that the most common mutation of this gene presents with a less severe clinical expression of the disease, and has less cognitive impairment compared to sporadic PD [184].

The frequent presence of AD and LB pathology together in familial AD would also suggest a possible pathophysiologic connection between AD and DLB [51]. In contrast to PD and AD, only a few families with familial DLB have been described [185–191]. Identification of additional cases of familial DLB and of mutations could be critical to our understanding of the etiologic processes that lead to the development of this disease. As noted earlier, the APOE ε4 allele, well known to be strongly associated with an increased risk for AD, is also found with elevated frequency in autopsy confirmed cases of DLB and PDD in which the overall brain neuritic plaque burden (a marker of AD pathology) was low, suggesting APOE ε4 involvement in synucleinopathy may be unrelated to AD-specific mechanisms [50].

An advancement in the understanding of the genetics of synucleinopathies came from the observation that in patients with Gaucher’s disease, caused by a mutation in the glucocerebrosidase (GBA) gene, those carrying a GBA mutation had an increased risk for developing PD [192]. GBA mutations are strongly associated with LRP and are associated with both PD and DLB [193–195]. Heterozygous GBA mutation status not only increases the risk of PD and DLB, but appears to be an independent risk factor for the development of cognitive impairment [196–198]. While several mechanisms have been proposed, including gain or loss of enzymatic function hypotheses, the precise role of this mutation has yet to be elucidated [199].