Behavioral symptomatology and psychopharmacology of Lewy body dementia

Handbook of Clinical Neurology, Vol. 165 (3rd series) Psychopharmacology of Neurologic Disease V.I. Reus and D. Lindqvist, Editors https://doi.org/10.1016/B978-0-444-64012-3.00005-8 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 5

Behavioral symptomatology and psychopharmacology of Lewy body dementia 1

RAJESH R. TAMPI1,2*, JUAN JOSEPH YOUNG3, AND DEENA TAMPI4 Department of Psychiatry & Behavioral Sciences, Cleveland Clinic Akron General, Akron, OH, United States

2

Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States 3

Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States 4

Diamond Healthcare, Richmond, VA, United States

Abstract Lewy body dementia (LBD) is an umbrella term for major neurocognitive disorders caused by Lewy body pathology. Parkinson’s disease dementia (PDD) and Dementia with Lewy bodies (DLB) are the two main syndromes in LBD. LBDs typically present with cognitive impairment, cholinergic deficiency, neuropsychiatric symptoms such as visual hallucinations and paranoid delusions, as well as parkinsonian symptoms. Due to the urgency in diagnosing LBD early in the disease course to provide the most optimal management of these syndromes, it is important that clinicians elicit the most clinically significant symptoms during patient encounters. The focus of this chapter is to discuss current LBD classification systems and assessments, neuropathology of LBDs, behavioral symptomatology, contemporary management options, and possible future targets of treatment. PubMed was searched to obtain reviews and studies that pertain to classification, behavioral symptomatology, neurobiology, neuroimaging, and treatment of LBDs. Articles were chosen with a predilection to more recent clinical trials and systematic reviews or meta-analyses. Updates to diagnostic criteria have increased clinical diagnostic sensitivity and specificity. Current therapeutic modalities are limited as there is no current disease-modifying drug available. Cholinesterase inhibitors have been reported to be effective in decreasing neuropsychiatric and cognitive symptoms. Neuroleptics should be avoided unless clinically indicated. There is a paucity of studies investigating treatment options for mood symptoms. Current novel targets of treatment focus on decreasing a-synuclein burden. LBDs are a group of dementia syndromes that affect a significant portion of the elderly population. Early diagnosis and treatment is necessary to improve patient quality of life with current treatment options more focused on alleviating severe symptomatology rather than modifying disease pathology.

INTRODUCTION Lewy body dementia (LBD) is an umbrella term for neurocognitive disorders characterized by both cognitive and parkinsonian symptoms associated with Lewy body pathology. These dementias are divided into two clinically similar but separate syndromes: dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD) (Gomperts, 2016). The Lewy bodies that are

the hallmark of these disorders consist of cytoplasmic inclusions that were first described by Friedrich Heinrich Lewy in 1912 while examining the brains of deceased individuals who were previously diagnosed with Parkinson’s disease (PD). Following Lewy’s discovery, Konstantin Nikolaevich Tretiakoff determined that these protein aggregates appeared to more commonly accumulate in the substantia nigra of PD patients suggesting a link between the cerebral localization of

*Correspondence to: Rajesh R. Tampi, M.D., M.S., DFAPA, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, United States. Tel: +1-203-809-5223, Fax: +1-330-344-2943, E-mail: [email protected]

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these inclusions and the subsequent pathologic PD presentations that eventually appear in these individuals. These observations were later confirmed by Rolf Hassler whose research indicated a causal relationship between substantia nigra degeneration and the development of parkinsonian symptoms. Additionally, he described the pathognomonic nerve cell loss centered specifically within the caudal and ventrolateral areas of the substantia nigra (Holdorff, 2002). In the 1960s, researchers discovered reduced dopaminergic activity in the striatum of PD patients, leading to the development of treatments such as levodopa that helped alleviate parkinsonian symptoms (Goedert et al., 2013). However, it was not until the 1990s, when researchers discovered that Lewy bodies were immunoreactive to a-synuclein and associated with a genetic risk in PD patients, that these proteinopathies become a central aspect of PD neurodegenerative pathology (Vekrellis et al., 2011). Since then, there have been significant advances in our understanding of LBD neurobiology, leading to novel targets for pharmacologic management of Lewy body disorders. Therefore, the objective of this chapter is to discuss the contemporary understanding of Lewy body symptomatology, pathology, biologic correlates, current psychopharmacologic treatments of LBDs, and possible future directions of clinically relevant research.

EPIDEMIOLOGY Despite being the second most common cause of dementia, DLB is a relatively underrecognized and underdiagnosed entity, owing to difficulties differentiating DLB from Alzheimer’s disease (AD). As a result, DLB’s true prevalence and incidence rates in the community are difficult to estimate. Previously, measurements of DLB prevalence varied wildly, with estimates ranging from 0% to 30% of dementia populations (Zaccai et al., 2005). A review of population and clinical studies using the 2005 revised diagnostic criteria indicated that DLB accounted for approximately 4.2% of all dementia cases in the community (Vann Jones and O’Brien, 2014). In addition, a more recent systematic review suggested that the incidence of DLB may range from 0.5 to 1.6 per 1000 people, although the authors indicated that methodologic variations and differing diagnostic criteria between studies limited estimation accuracy (Hogan et al., 2016). Similarly, the point prevalence of dementia in PD is estimated to be up to be 30% (Aarsland et al., 2005), although a landmark 20-year multicenter study indicated that dementia prevalence rates may reach as high as 80% at more advanced stages of PD (Reid et al., 2011). Notably, a high percentage of patients with AD may also have Lewy Bodies at autopsy (Zaccai et al., 2005). These mixed cases are sometimes called the LB (Lewy Body) variant of Alzheimer’s disease (LBV-AD) and further confound attempts at accurately estimating prevalence and incidence rates for pure LBDs.

When assessing risk of progression to dementia from PD, it has been estimated that 50% of those with PD will likely develop dementia in 10 years since diagnosis and, eventually, will increase to 80% after 20 years with a relative risk ranging from 1.7 to 5.1 (Cosgrove et al., 2015). The prevalence rates of mild cognitive impairment (MCI) in PD (PD-MCI) is more difficult to ascertain as it is a relatively new diagnosis, with studies reporting varying prevalence rates due to the existence of different definitions for MCI and the study of different subject populations. Consequently, education of primary care clinicians on these syndromes, as well as the development of biomarkers (Lewis et al., 2010; Sinha et al., 2012) will enable more accurate estimates of prevalence and incidence rates in the future.

NEUROPATHOLOGY Lewy bodies are the primary lesions that are found in degenerating neurons of the limbic system, brainstem (e.g., substantia nigra, locus coeruleus), and neocortex in LBD patients. As previously noted, Lewy bodies consist of abnormal eosinophilic intracytoplasmic filamentous aggregates of misfolded a-synuclein protein (Vekrellis et al., 2011). These abnormal neurofilaments have been found to also contain τ and ubiquitin (Hanson and Lippa, 2009). However, LBD patients may also have amyloid deposition due to the high occurrence of mixed AD and PD pathology found postmortem. This is supported by evidence that a-synuclein stimulates the fibrillation of amyloid b and τ proteins (Wong and Krainc, 2017). Elevated AD biomarker profiles in the cerebrospinal fluid of DLB patients were also correlated with increased severity of neuropsychiatric symptoms and were more likely to require nursing home admittance or hospitalization (Lemstra et al., 2017). Consequently, amyloid deposition is often an important component in the disease progression of PDD and DLB patients when present (Cosgrove et al., 2015). In contrast, the pathognomonic protein of LBDs, a-synuclein, is thought to be associated with the disruption of synaptic vesicle release within presynaptic terminals (Bellani et al., 2010). Histopathologic studies have linked a-synuclein oligomerization, fibril formation, and accumulation in the presynaptic terminals with dendritic spine degeneration (a sign of decreased neuroplasticity), causing decreased neurotransmission and eventual synaptic dysfunction. Interestingly, observations of dendritic spine retraction with relatively preserved presynapses despite significant presynaptic a-synuclein accumulation have given way to the hypothesis that a-synuclein pathology does not produce disease burden predominantly through neurodegeneration or neuronal cell loss alone, but does so through direct disruption of neurotransmission as well (Schulz-Schaeffer, 2010). Pathologic accumulation of

BEHAVIORAL SYMPTOMATOLOGY AND PSYCHOPHARMACOLOGY a-synuclein is thought to be caused by specific mutations in genes such as the SNCA gene located on 4q21, which has also been associated with decreased proteasome activity and increased mitochondria-dependent apoptosis due to repeat mitochondrial DNA damage (Bogaerts et al., 2008; Spano et al., 2015). Dopaminergic neurons are particularly sensitive to mitochondrial stress, as dopamine itself may play a role in limiting neuronal mitochondrial redistribution and promoting a-synuclein aggregation (Spano et al., 2015). a-Synuclein has also been associated with neuroinflammation and the activation of microglia leading to dopaminergic neurotoxicity and neuronal cell loss (Surendranathan et al., 2015). Other studies report an early cholinergic deficit with signs of dysfunctional dopaminergic activity, which is consistent with neuroimaging studies that suggest decreased striatal dopamine and cortical acetylcholine transmission in both PDD and DLB subjects (Francis and Perry, 2007; Risacher and Saykin, 2013). Behavioral symptoms such as depression could be connected to the hypothalamic–pituitary–adrenal axis hyperactivity that results from parasympathetic nervous system deterioration present during the prodromal phase of LBDs. More complex neuropsychiatric symptoms, including visual hallucinations (VHs), delusions, and diurnal rhythm disturbances, are also exacerbated by this anticholinergic activity as these disorders worsen (Hori et al., 2016). In fact, cholinergic changes appear to be the most pronounced in the occipital region, which may contribute to the VHs that are commonly described in DLB (O’Brien et al., 2008). Supporting this, one study reported that subjects that convert to DLB from rapid eye movement sleep behavior disorder (RBD) tend to have lower glucose hypometabolism in the parietal and lateral occipital cortex than those that do not convert, despite having had no significant difference in psychologic profiles before the onset of severe cognitive dysfunction (Fujishiro et al., 2013). Although extensive Lewy body formations are found in the brains of patients with both PDD and DLB, cerebral distribution of these proteinopathies may differ between the two syndromes during the early stages of the disease. Representative of this, postmortem studies suggest a rostral progression from the dorsal IX/X motor nucleus in PDD patients (Braak et al., 2003), while individuals with DLB may not particularly follow this same caudorostral disease pattern (Parkkinen et al., 2008). More recent evidence supports the hypothesis that DLB neuropathology originates in the vagus nerve and propagates in a transsynaptic, retrograde pathway through the brainstem, with monoamine nuclei affected early on before eventually spreading to subcortical regions of the brain (Beach et al., 2010). This could account for the contrasting timelines concerning the

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progression of symptoms when comparing DLB and PDD patients. However, the exact mechanisms of propagation are not known, with some postulating a prion-like expansion or a retrograde and linear degenerative process via deposition of a-synuclein through hyperbranching axons (Uchihara, 2017). Identifying these exact mechanisms of neuropathologic progression could be instrumental in producing more novel pharmaceutical targets in the future.

ASSESSMENT AND EVALUATION When diagnosing either DLB or PDD, a thorough neurocognitive and neuropsychological examinations are necessary. The main criterion preceding a major neurocognitive disorder diagnosis is severe cognitive decline sufficient enough to interfere with complex daily activities, leading to a decrease in independent functioning. However, the progression of LBDs differs from AD in that these Lewy body syndromes may not exhibit early memory impairment unless there is concomitant AD pathology. Additionally, it has been suggested that DLB may progress more rapidly than AD during their respective clinical courses (Galasko, 2017). Accordingly, organizations and consortiums have developed revised criteria to more accurately diagnose LBDs. Table 5.1 shows the revised diagnostic criteria for DLB (McKeith et al., 2017) while Tables 5.2 and 5.3 show the diagnostic criteria established by the Movement Disorders Society for PDD and PD-MCI, respectively (Emre et al., 2007; Litvan et al., 2012). These revised criteria have led to an increase in clinical diagnostic sensitivity and specificity by including more objective diagnostic criteria, such as neuroimaging biomarkers, and by aiding physicians in eliciting features that indicate probable dementia (Walker et al., 2015). In fact, one study suggested a high positive predictive value for the revised DLB criteria after diagnosing DLB postmortem (Fujishiro et al., 2008). The 1-year rule was conceived to separate DLB and PDD diagnosis. This rule dictates that PDD, rather than DLB is diagnosed if motor symptomatology presents a year or more before cognitive dysfunction, although clinically, this arbitrary separation is questionable due to the shared neuropathology and similar overall management of LBDs as a whole (Galasko, 2017). The MiniMental State Examination (MMSE) was previously the mainstay screening tool for early cognitive changes, but the more novel Montreal Cognitive Assessment (MoCA) was found to demonstrate superior sensitivity and specificity when screening for mild cognitive impairment in LBDs (Hoops et al., 2009). However, more extensive neurocognitive and neuropsychologic batteries are generally required for in-depth characterization when

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Table 5.1 Revised criteria for the clinical diagnosis of DLB (McKeith et al., 2017) 1. Central feature (essential for a diagnosis of possible or probable DLB) ● Dementia defined as progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. ● Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. ● Deficits on tests of attention, executive function, and visuospatial ability may be especially prominent. 2. Core features (two core features are sufficient for a diagnosis of probable DLB, one for possible DLB) ● Fluctuating cognition with pronounced variations in attention and alertness ● Recurrent VHs that are typically well formed and detailed ● Spontaneous features of parkinsonism 3. Suggestive features (If one or more of these is present in the presence of one or more core features, a diagnosis of probable DLB can be made. In the absence of any core features, one or more suggestive features is sufficient for possible DLB. Probable DLB should not be diagnosed on the basis of suggestive features alone.) ● REM sleep behavior disorder ● Severe neuroleptic sensitivity ● Low dopamine transporter uptake in basal ganglia demonstrated by SPECT or PET imaging 4. Supportive features (commonly present but not proven to have diagnostic specificity) ● Repeated falls and syncope ● Transient, unexplained loss of consciousness ● Severe autonomic dysfunction, e.g., orthostatic hypotension, urinary incontinence ● Hallucinations in other modalities ● Systematized delusions ● Depression ● Relative preservation of medial temporal lobe structures on CT/MRI scan ● Generalized low uptake on SPECT/PET perfusion scan with reduced occipital activity ● Abnormal (low uptake) MIBG myocardial scintigraphy ● Prominent slow wave activity on EEG with temporal lobe transient sharp waves

screening is positive for cognitive changes. Yet overall diagnostic accuracy is still relatively poor, and patients with LBDs are often misdiagnosed as with AD, as it is difficult to determine the pathologic cause of functional decline during the early stages of cognitive impairment. It is for this reason that certain criteria of these syndromes are emphasized in order to improve clinical accuracy allowing for more prompt and appropriate treatment of the syndromes described.

Although PDD is characterized by motor symptoms appearing a year or more before signs of cognitive impairment, which helps differentiate this syndrome from AD, prodromal symptoms for DLB may initially present similar to other dementia cohorts when they are exhibiting MCI symptoms. However, several symptoms may help differentiate this prodromal stage from prodromal AD. These unique symptoms typically include autonomic dysfunction (e.g., constipation, orthostatic hypotension, increased saliva), olfactory dysfunction, RBD, VHs, and early motor symptoms (Chiba et al., 2012; Donaghy et al., 2015). It has been postulated that RBD could represent the prodromal phase of LBDs, with one study reporting a high rate of conversion from RBD to either PD or DLB (Iranzo et al., 2013). Thus, it is important to closely monitor patients diagnosed with RBD and discuss possible long-term outcomes with them, specifically, the likelihood of developing LBD (Chan et al., 2018). VHs due to Lewy body pathology are typically well-formed and yield stronger positive predictive value compared to the other core criteria, including fluctuating cognition/alertness and parkinsonian symptoms. VHs are usually recurring and well-formed complex images that are vivid in the patient’s mind and are often associated with poor prognosis and functional outcome. The vividness of these VHs in patients with DLB and PDD are suspected to be a result of the significant Lewy body pathologic burden within the inferior temporal cortex, parahippocampal cortex, and amygdala (Cagnin et al., 2013). In contrast, neurodegeneration of sympathetic ganglions in DLB are reported to explain autonomic clinical manifestations such as orthostatic falls, atrial fibrillation, syncope, constipation, and even detrusor instability (Andersson et al., 2008). This is important as DLB patients might be on warfarin for concomitant atrial fibrillation. In addition to the increased risk of intracranial bleeding, warfarin has significant anticholinergic properties which often worsen LBD symptoms. These observations underscore the fact that treatment of LBD patients needs to be tailored to the specific patient and situation and would ideally involve a multidisciplinary approach, as lack of proper management of these symptoms could lead to an increase in hospitalizations or morbidity. One frequently used term that is often misunderstood is “waxing and waning” of consciousness, as a true definition of “cognitive fluctuation” has not yet been agreed upon (Lee et al., 2012). This refers both to changes in cognition and to the level of alertness, which might be observed over minutes, hours, or days. Especially in its initial stages, a patient with LBD might have a “good day” and score a 25 on the MMSE, while on another occasion, the score might be an 18, only to return to a 24 later on the same day. This does not occur in AD.

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Table 5.2 Criteria for the clinical diagnosis of Parkinson’s disease dementia (PDD) 1. Core features ● Diagnosis of Parkinson’s disease according to Queen Square Brain Bank criteria ● A dementia syndrome with insidious onset and slow progression, developing within the context of established Parkinson’s disease and diagnosed by history, and clinical and mental examination, defined as:  Impairment in more than one cognitive domain  Representing a decline from premorbid level  Deficits severe enough to impair daily life (social, occupational, or personal care), independent of the impairment ascribable to motor or autonomic symptoms 2. Associated clinical features ● Cognitive features:  Impaired attention, executive functions, visuospatial functioning, memory, and language may be present ● Behavioral features:  Apathy: decreased spontaneity; loss of motivation, interest, and effortful behavior  Changes in personality and mood including depressive features and anxiety  Hallucinations: mostly visual, usually complex, formed visions of people, animals, or objects  Delusions: usually paranoid, such as infidelity or phantom boarder (unwelcome guests living in the home) delusions  Excessive daytime sleepiness 3. Features which do not exclude PDD, but make the diagnosis uncertain ● Coexistence of any other abnormality which may by itself cause cognitive impairment, but judged not to be the cause of dementia, e.g., presence of relevant vascular disease in imaging ● Time interval between the development of motor and cognitive symptoms not known 4. Features suggesting other conditions or diseases as cause of mental impairment, which, when present make it impossible to reliably diagnose PDD ● Cognitive and behavioral symptoms appearing solely in the context of other conditions such as: ● Acute confusion due to  Systemic diseases or abnormalities  Drug intoxication ● Major depression according to DSM V 5. Probable PDD ● Core features: Both must be present ● Associated clinical features:  Typical profile of cognitive deficits including impairment in at least two of the four core cognitive domains (impaired attention which may fluctuate, impaired executive functions, impairment in visuospatial functions, and impaired free recall memory which usually improves with cueing)  The presence of at least one behavioral symptom (apathy, depressed or anxious mood, hallucinations, delusions, excessive daytime sleepiness) supports the diagnosis of probable PDD; lack of behavioral symptoms, however, does not exclude the diagnosis ● None of the group III features present ● None of the group IV features present 6. Features suggesting other conditions or diseases as cause of mental impairment, which, when present make it impossible to reliably diagnose PDD ● Cognitive and behavioral symptoms appearing solely in the context of other conditions such as:  Acute confusion due to 1. Systemic diseases or abnormalities 2. Drug intoxication From Dubois B., Burn D., Goetz C., et al., 2007. Diagnostic procedures for Parkinson’s disease dementia: recommendations from the movement disorder society task force. Mov Disord 22, 2314–2324; Emre M., Aarsland D., Brown R., et al., 2007. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22, 1689–1707; quiz 1837, with permission from John Wiley and Sons.

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Table 5.3 Criteria for the clinical diagnosis of Parkinson’s disease mild cognitive impairment (PD-MCI) 1. Inclusion criteria ● Diagnosis of Parkinson’s disease (PD) ● Progressive decline, in the context of established PD, in cognitive ability reported by either the patient or informant, or observed by the clinician ● Cognitive deficits on either formal neuropsychologic testing or a scale of global cognitive abilities ● Cognitive deficits do not interfere significantly with functional independence 2. Exclusion criteria ● Diagnosis of PD dementia ● Other primary explanations for cognitive impairment (e.g., delirium, stroke, major depression, metabolic abnormalities, adverse effects of medication, or head trauma) ● Other PD-associated comorbid conditions (e.g., motor impairment or severe anxiety, depression, excessive daytime sleepiness, or psychosis) that, in the opinion of the clinician, significantly influence cognitive testing From Emre M., Aarsland D., Brown R., et al., 2007. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22, 1689–1707; quiz 1837; Litvan I., Goldman J.G., Troster A.I., et al., 2012. Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: movement disorder society task force guidelines. Mov Disord 27, 349–356, with permission from John Wiley and Sons.

Consciousness might be decreased to the point where the patient barely responds to mildly painful stimuli, yet retains the ability to open his or her eyes to command. Typically, the neurologic evaluation is normal except for the state of decreased consciousness. Visuospatial abilities and attention are typically lost first. For example, in the very early stages of dementia, a patient might only miss one point on the MMSE due to an inability to draw the intersecting pentagons. Periods of hyperactivity might alternate with periods of hypersomnia. As a result of these complex presentations, LBDs are very debilitating to patients and their caregivers (Lee et al., 2018). In addition to the cognitive deficits, these neuropsychiatric manifestations and mobility impairment severely limit the quality of life of the affected individual. Frequent misdiagnosis compounds the problem. Therefore, delusions (frequently paranoid in nature), VHs, depression, and other distressing symptoms need to be evaluated and addressed in a timely manner. 123I-metaiodobenzylguanidine (MIBG) cardiac scintigraphy is a common tool used to evaluate cardiac sympathetic functioning in Lewy body disorders and has been used to differentiate DLB from AD, as well as predict risk of conversion to probable DLB (Sakamoto et al., 2017). Presynaptic dopaminergic activity imaging using

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I-FP-CIT (DaTSCAN) has been reported to exhibit high diagnostic accuracy in differentiating DLB from AD (Papathanasiou et al., 2012). Other assessments that could be used to assess risk of developing PDD or DLB include genetic markers. Typical genetic markers associated with LBDs include genetic mutations involving the glucocerebrosidase enzyme (GBA1), catechol-O-methyl transferase, MAPT H1/H1gene related to microtubules composed of τ protein, and apolipoprotein E (APOE 4) (Vasconcellos and Pereira, 2015). SNCA and Leucinerich repeat kinase 2 (LRRK2) are the two most common genes associated with Lewy body deposition in both familial and sporadic disease. Relatively rare recessive mutations of genes including Parkin, PINK, and DJ-1 are associated with familial PD forms that often present with early onset of symptoms (Giraldez-Perez et al., 2014; Dzamko et al., 2017). Additionally, there is a strong association of familial Lewy body disease with the chromosome 2q35-q36 region (Castro-Chavira et al., 2015). Studies of genetic markers to assess their ability in determining risk of developing these disorders are ongoing and will likely provide new insights into diagnosis, treatment, and management of LBDs in the coming decades. Although novel biomarkers are currently being investigated for the diagnosis of LBD, the workup for this type of major neurocognitive disorder is virtually identical to that for other types of dementia. This typically includes a medical workup of reversible conditions, including vitamin B12 levels, thyroid studies, syphilis tests, and any other medical tests that may be appropriate for specific situations. Careful assessment to rule out DLB or PDD as early as possible is crucial because inappropriate use of neuroleptics can double or triple the mortality rate in this population (Weisman and McKeith, 2007). Typically, a clinician might encounter a patient that has undergone several evaluations for “syncope” and has had perhaps “a bad reaction to a neuroleptic medication” (Idiaquez and Roman, 2011). The patient may also present with parkinsonian symptoms such as bradykinesia and rigidity, but typically would not exhibit tremors, although in some cases limited tremors are present. In this setting, many geriatric psychiatrists avoid the use of any neuroleptics (i.e., antipsychotics), including quetiapine. Akinetic crisis syndrome, which is similar to neuroleptic malignant syndrome (NMS) in presentation, with the exception that it is not necessary for a patient to be exposed to neuroleptics, is highly suggestive of DLB or PD, but more fatal in DLB patients. It presents as a distinct clinical tetrad of altered mental status change, motor symptomatology (bradykinesia, rigidity), autonomic dysfunction, and hyperthermia similar to NMS, and does not respond to dopaminergic rescue medications (Bonanni et al., 2016).

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NEUROIMAGING

TREATMENT RECOMMENDATIONS

Neuroimaging scans have proven to be invaluable in diagnosing PDD or DLB in later stages of clinical disease as neuroimaging findings could be used to distinguish LBD from AD based on neurologic changes demonstrated on different imaging modalities. For example, magnetic resonance imaging (MRI) typically demonstrates preservation of hippocampal and medial temporal lobe volumes in DLB when compared to AD. (Treglia and Cason, 2012). Additionally, decreased occipital activity on perfusion SPECT is a common and highly sensitive finding in DLB (Minoshima et al., 2001). However, neither MRI nor SPECT are performed unless other indications exist. In contrast, computed tomography is part of a comprehensive dementia workup, but there are no distinctive diagnostic findings for DLB or PDD that are specific enough to suggest a clinical diagnosis without a thorough neuropsychologic assessment. Neuroimaging’s main strength, however, is in its role in clinical and neuropathologic research. Through neuroimaging, it has been shown that neocortical involvement occurs later than in AD, which likely accounts for the difference in clinical presentations and in the rapidity of the progression of cognitive impairment. Consequently, imaging findings that could screen for cognitive impairment attributable to Lewy body pathology rather than AD pathology would be useful as clinical diagnostic tools. One example of this is a study that reported increased regional cerebral blood flow in the hippocampal regions of MCI patients, which indicated increased risk of conversion from MCI to DLB or PDD as well as the more rapid progression of neurodegenerative changes (Meles et al., 2017). An 18F-fluoro-deoxy glucose positron emission tomography (FDG PET) study also reported that preservation of the mid or posterior cingulate gyrus (what is described as the “cingulate island sign”) was highly specific in DLB patients when compared to imaging scans of patients with AD (Lim et al., 2009). Higher levels of amyloid detected in PET imaging has also been correlated with a more rapid progression of dementia (Xia and Dickerson, 2017). More recently, proton magnetic resonance spectroscopy (MRS) has been proposed to be capable of differentiating AD from DLB, as AD patients demonstrated lower N-acetylaspartate/creatinine ratios in the posterior cingulate voxels, in contrast to MRS data obtained from DLB subjects (Zhang et al., 2015). As in the past, ongoing improvements and advances in neuroimaging diagnostics will help in clinically separating Lewy body neurocognitive disorders from clinically similar syndromes. Further research regarding their use in clinical settings will likely aid in augmenting primarily clinical assessments currently being used in existing standards of practice.

The treatment of patients with DLB and PDD requires a thorough evaluation of cognitive, psychiatric, and motor symptoms. Pharmacologic treatment may become difficult in the context of the complex neuropsychiatric features that are often present in LBDs. For example, in treating parkinsonian symptoms with antiparkinsonian medications such as L-dopa, clinicians may exacerbate psychotic elements of a patient’s clinical presentation. Conversely, treatment of neuropsychiatric features could also lead to an increase in parkinsonian symptoms. Therefore, targets for treatment must be identified with a focus on addressing those symptoms that are most distressing to the patient and the family, as high-level evidence concerning pharmacologic management is rare in LBD and no disease-modifying drugs are currently available (Stinton et al., 2015). Pharmacologic treatments include cholinesterase inhibitor (ChEI) therapy for cognitive impairment and neuropsychiatric symptoms. A recent randomized controlled trial (RCT) reported that higher plasma donepezil concentrations correlated with improved MMSE scores while not causing significant adverse events (Mori et al., 2016). Galantamine has also been shown to improve fluctuating cognition, hallucinations, and sleep disturbances (Bhasin et al., 2007). Several RCTs conducted for memantine reported encouraging results, although the strength of these trials are limited due to these studies including both PDD and DLB patients, without attempts to separate them during data analysis, and due to the fact that they have very limited power (Aarsland et al., 2009; Emre et al., 2010). Interestingly, there is some evidence that ChEIs are more effective in DLB than in AD in treating dementia symptoms (Ballard et al., 2011). A meta-analysis (Wang et al., 2015) of studies investigating the efficacy of donepezil, rivastigmine, and memantine in treating PD, PDD, and DLB patients suggested improvement of overall global impression with administration of all three medications, but only the ChEIs produced some modest improvement in cognitive functioning. However, the studies investigated found that patients prescribed donepezil or rivastigmine at therapeutic dosages exhibited a higher likelihood of improvement in behavioral symptoms, cognitive functioning, and activities of daily living compared to those who were only prescribed memantine. The authors also reported that patients prescribed rivastigmine had a higher relative risk of adverse events (mostly cholinergic side effects including nausea, vomiting, diaphoresis, low appetite), although the severity of these adverse events ranged from mild to moderate symptoms only. None of the studies investigated demonstrated any improvement in parkinsonian symptoms when utilizing

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these medications. Despite these findings, the authors reported a significant heterogeneity between studies that may impact the overall validity of the study’s conclusions. Another meta-analysis (Stinton et al., 2015), investigating a broader set of pharmacologic treatment options for LBD, also found improvement in cognitive and neuropsychiatric symptoms (i.e., hallucinations and delusions) when patients were prescribed donepezil or rivastigmine. Similarly, a more recent meta-analysis of 17 RCTs (Matsunaga et al., 2015) evaluating the safety and tolerability of ChEIs reported overall improvement of cognition, behavioral disturbances, activities of daily living, and global function in LBD patients treated with ChEIs while not worsening motor functions. The authors found donepezil to have the greatest effect size (0.51) followed by rivastigmine (0.29), although they didn’t find a significant difference between galantamine and placebo. As with Wang and colleagues, the authors also found increased side effects, such as nausea and tremors, in groups that were treated with ChEIs, especially when they were prescribed rivastigmine, which was found to increase the risk of adverse events such as dizziness and vomiting. Again, heterogeneity of studies and their respective subject populations prevented overall generalizability of data analyzed in this meta-analysis. Hallucinations and agitation are particularly troublesome from a clinical perspective, as antipsychotics are typically avoided in elderly patients due to the increased risk of mortality and the antidopaminergic effect that could worsen Parkinsonian symptoms (Swann and O’Brien, 2018). Additionally, there is limited high-quality data concerning the effectiveness, safety, and efficacy of antipsychotics for use in LBDs (Stinton et al., 2015). Clozapine is currently the atypical antipsychotic of choice for psychosis in PD, due to its greater serotonergic affinity and selective binding of D1 mesolimbic receptors while sparing striatal dopamine D2 receptors implicated in the deterioration of motor symptoms (Goldman and Holden, 2014). It is also the only atypical antipsychotic with multiple studies demonstrating consistent improvement in psychotic symptoms in PD (Factor et al., 2001; Klein et al., 2003; Merims et al., 2006). However, the side effect profile of sedation and orthostatic hypotension and the small but significant risk of agranulocytosis may cause some reluctance in providers prescribing this medication (Goldman and Holden, 2014). There are no current RCTs of clozapine efficacy in DLB or PDD patients, but there is one systematic chart review (Lee et al., 2007) investigating the efficacy of clozapine use in improving agitation in PDD patients. The authors found overall improvement in treatment-resistant agitation symptoms with clozapine administration, although the power of the study was low (they reviewed 16 dementia patients). A recent

systematic review (Desmarais et al., 2016) of five double-blind RCTs and two open-label RCTs investigating the efficacy of quetiapine (another atypical antipsychotic that demonstrates more serotonergic receptor affinity than dopaminergic receptor affinity) in patients with PD and LBDs found that only one of the open-label trials reviewed showed any significant reduction in psychotic symptoms at tolerable doses. Notably, all seven trials reported that quetiapine was well tolerated at dosages around 100 mg daily, without worsening of motor symptoms, although these dosages were not found to be effective in improving psychotic symptoms. Only one RCT (Cummings et al., 2002) investigated the efficacy of olanzapine administration in LBD patients, finding that individuals treated with 5 mg daily dosages of olanzapine demonstrated improvements in hallucinations and delusions compared to the placebo group. Interestingly, higher doses did not appear to indicate higher efficacy, but were actually found be no more effective than placebo. Nevertheless, caution should be exercised when prescribing neuroleptics, due to their potential to cause rigidity, NMS, and death, especially as DLB and PDD patients exhibit neuroleptic sensitivity from the underlying disruption of dopaminergic neurotransmission (McKeith et al., 1992). Many clinicians avoid neuroleptics altogether and opt for the judicious use of a benzodiazepine such as clonazepam, which has the added benefit of treating the REM sleep behavior disorder that is very common in LBD (Gold, 2009). Pimavanserin, a 5HT2A receptor inverse agonist, has demonstrated efficacy in improving psychosis symptoms in PD (Kianirad and Simuni, 2017), but no trials or studies have been conducted in LBD populations. Anticholinergic medications should also be avoided in LBD patients due to the central cholinergic deficiency in LBD pathology (Iranzo et al., 2009). Restless leg syndrome (RLS) is common in LBDs and is typically treated with dopamine agonists (e.g., pramipexole, ropinirole) and gabapentin (Ooms and Ju, 2016). It is important to note that iron supplementation may also improve RLS symptoms, due to iron’s role as an important cofactor in dopamine production and reports of iron insufficiency in patients diagnosed with RLS (Patrick, 2007). Parkinsonian symptoms can be treated with levodopa and carbidopa, although their effectiveness is reduced in LBDs when compared to PD (Drach, 2011). Clinicians must take note that antiparkinsonian medications can worsen hallucinations and orthostatic hypotension, so caution should be exercised in prescribing these medications. There is a paucity of studies investigating antidepressant efficacy for depressive symptoms in LBDs, although Stinton and colleagues reported a small trial investigating

BEHAVIORAL SYMPTOMATOLOGY AND PSYCHOPHARMACOLOGY antidepressant therapy in PDD patients that reported improvements in mood symptoms within the escitalopram and trazodone treatment groups (Stinton et al., 2015). Nonpharmacologic treatments that are helpful include correcting sensory impairments with glasses and hearing aids, providing education to the patients and their families, providing a structured environment, and evaluating for assistive devices such as walkers. A recent systematic review of psychotherapy efficacy in all types of dementia indicated the strongest evidence for short-term group therapy after diagnosis, and multifaceted interventions for nursing home patients, although the authors report that further research is still necessary (Cheston and Ivanecka, 2017). Currently, more novel targets of treatment include inhibiting aggregation of a-synuclein to decrease the pathologic disease burden. Proposed therapeutic targets focus on reducing the synthesis or increasing clearance of a-synuclein, either through silencing SNCA or promoting proteasomal activity and enhancing autophagy to decrease a-synuclein burden (Dehay et al., 2015). More recently, one study reported the viability of multifunctional dopamine agonists in preventing a-synuclein aggregation (Yedlapudi et al., 2016). Further research is still pending concerning the efficacy of these proposed treatment modalities.

CONCLUSIONS PDD and DLB are the two main clinical syndromes in LBDs, and they typically present with cognitive impairment, cholinergic deficiency, neuropsychiatric symptoms, and parkinsonian symptoms. It is imperative that LBDs be diagnosed early in the disease course in order to implement early treatment of the most severe and distressing symptoms that are detrimental to a patient’s quality of life. Recent revisions and updates to diagnostic criteria have improved diagnostic sensitivity and specificity, although overall diagnostic accuracy is still relatively poor. However, patients may exhibit unique clinical presentations that are suggestive of LBDs. VHs are highly predictive of LBD diagnosis. Likewise, RBD has been postulated to be a prodromal phase of LBDs. Autonomic dysfunction due to cholinergic deficiency is a common and problematic part of LBD clinical presentations. These symptoms should be managed in a multidisciplinary manner due to the complex medical decision-making LBD treatment often requires. Genetic markers are likely to have increasing utility in assessing risk of developing LBDs in the future as more clinical research is conducted. Neuroimaging modalities are useful tools in increasing accuracy of LBD diagnosis and augmenting clinical assessments, although they are typically performed only when there is a clinical indication.

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Therapeutic modalities are limited as there is no diseasemodifying drug currently available. As a result, pharmacologic management focuses mainly on alleviating the most distressing of symptoms. Cholinesterase inhibitors have been reported to be effective in improving neuropsychiatric and cognitive symptoms, although certain medications like rivastigmine may cause adverse events. Neuroleptics, including quetiapine, should be avoided unless clinically indicated due to increased risk of morbidity in dementia patients and their propensity to exacerbate parkinsonian symptoms. There is a paucity of studies investigating treatment options for mood symptoms. Current novel targets of treatment focus on decreasing a-synuclein burden, although most studies are still at the preclinical stage. Nevertheless, clinicians should be aware of how to diagnose and treat LBDs due to the growing geriatric population and the increasingly common presentation of dementia in the community.

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