Psychotic Features Among Patients in the Prodromal Stage of Dementia with Lewy Bodies During Longitudinal Observation

Abstract

Background:

Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described.

Objective:

To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment.

Methods:

The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through indicative and supportive biomarkers of scintigraphy.

Results:

The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1±4.6 (mean±SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean±SD) years.

Conclusion:

Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis.

Keywords

Catatonia delirium delusional-hallucinatory feature dementia with Lewy bodies manic and/or depressive feature prodromal

INTRODUCTION

Considerable information regarding the clinical symptoms and diagnostic biomarkers for dementia with Lewy bodies (DLB) has accumulated in recent years, and the DLB diagnostic guidelines were revised accordingly in 2017 [1]. Thus, research investigating DLB has shifted to the examination of the prodromal state, and early diagnosis during the prodromal stage has become an extremely important area of investigation [2].

It has been established that a wide range of neuropsychiatric symptoms occur during the prodromal stage of DLB before the onset of dementia [3]. The diagnosis cannot be made before the onset of dementia, and the symptoms are considered prodromal symptoms.

McKeith et al. proposed the following three typical forms of prodromal DLB: mild cognitive impairment (MCI)-onset DLB, delirium-onset DLB, and psychiatric-onset DLB [4]. McKeith et al. also attempted to establish diagnostic criteria for prodromal DLB [2]; however, apart from MCI-onset DLB, sufficient data to propose diagnostic criteria for delirium-onset DLB and psychiatric-onset DLB have not yet been collected. As such, it has become the highest-priority area for future research in the field. With regard to prodromal DLB, the prodromal stage has been defined as the period beginning with the onset of DLB-related symptoms and ending with the onset of dementia and diagnostic establishment of DLB. Therefore, the most rational and appropriate approach at present remains a retrospective analysis of prodromal-stage psychotic features after a definitive diagnosis of DLB has been made.

In the present study, the characteristics of psychotic features during the DLB prodromal stage were assessed in 21 patients who exhibited severe psychotic symptoms between the onset of DLB-related psychotic symptoms and transition to definitive DLB. Consequent to this study’s examination, we report considerably interesting result of psychotic features in prodromal DLB.

METHODS

Subjects

Twenty-one subjects initially developed psychotic symptoms between 2005 and 2017, underwent their initial examination at the Department of Psychiatry, Sunagawa City Medical Center (Sunagawa, Japan), and were confirmed to have progressed to DLB during the long-term monitoring. All subjects satisfied the inclusion and exclusion criteria for probable DLB according to the revised diagnostic guidelines published in 2017 [1]. In addition, all subjects fulfilled the following criteria: psychotic and neurological symptoms were assessed by a team of psychiatrists and neurologists who were dementia specialists and advisors at the Dementia Medical Center.

Since there were severe psychotic symptoms (e.g., marked visual hallucinations, auditory hallucinations, delusions, depressive symptoms, and/or manic symptoms) during the entire course of the disease from the initial psychotic symptoms to DLB onset, at least one hospitalization became necessary.

For at least 2 years following the first psychotic episode, overt impairment of activities of daily living, functional impairment, or subjective or objective cognitive impairment was not found during the remission phase, which showed no psychotic symptoms.

Before overt cognitive impairment or at diagnosis of DLB, they also had at least one positive radiological finding of dopamine transporter imaging (DAT) with 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (¹²³I-FP-CIT) single photon emission computed tomography (SPECT), iodine-123 metaiodobenzylguanidine myocardial scintigraphy (MIBG) as indicative biomarkers, and brain perfusion SPECT (perfusion SPECT) as a supportive biomarker (see sections below for details).

In the computed tomography or magnetic resonance imaging conducted in all cases during the prodromal stage, the cases with brain atrophy and infarctions, bleeding, etc., which might affect psychotic symptoms, were excluded.

The psychotic state could not be explained by physical etiology, such as drug and/or alcohol use, and/or abnormal biochemical findings other than Lewy body disease (LBD).

Biomarker evaluation

DAT imaging

The nuclear isotope ¹²³I-IFP was used for DAT imaging. The analysis was conducted using DAT View (Nihon Medi-Physics Co., Ltd., Tokyo, Japan). A cut-off value for the specific binding ratio was adopted from Matsuda et al. [5], who generated a database of normal values according to age and sex based on the results of a collaborative multicenter study.

MIBG imaging

The nuclear isotope ¹²³I-MIBG was used for the MIBG imaging. Early and late images were analyzed using the software smartMIBG v3.1 (FUJIFILM RI Pharma Co., Ltd., Tokyo, Japan) to assess the normal heart/mediastinum ratio (H/M ratio). Late H/M ratios < 2.2 indicated a positive finding of DLB, as proposed by Komatsu et al. [6].

Brain perfusion SPECT imaging

^99mTc-ECD was used for the SPECT imaging. Brain vascularity was assessed using the Patlak plot method of quantitative analysis applied to the three-dimensional stereotaxic region of interest template (3DSRT) and fine stereotaxic region of interest template (fSRT), using stereotaxic region of interest template analysis software.

From a database housing information on healthy individuals at Sunagawa Medical Center, it was determined that DLB was indicated by the following blood flow data: occipital lobe < 41.0 mL/100 g/min on the right and < 42.1 mL/100 g/min on the left according to 3DSRT; and primary visual cortex < 39.4 mL/100 g/min on the right and < 40.8 mL/100 g/min on the left according to fSRT.

Z-scores were calculated using easy Z-score imaging system (eZIS) analysis software developed by Matsuda et al. [7]. A Z-score < –1.7 indicated a positive finding (i.e., hypovascularity of the occipital lobe). At least one positive finding of hypovascularity indicated a diagnosis of DLB.

Psychotic symptoms

The presence or absence of psychotic symptoms, such as visual hallucinations, auditory hallucinations, delusions, depressive and/or manic symptoms, and delirium, were investigated.

Core symptoms of DLB

In addition to visual hallucinations, the core symptoms of DLB, such as fluctuation, parkinsonism, and rapid eye movement sleep behavior disorder, were also examined for their manifestation in the prodromal stage and at all courses.

Symptomatic classification of psychotic features

Psychotic features were classified in accordance with section 06 mental, behavioral, or neurodevelopmental disorders of the International Classification of Diseases, 11th Revision titled “Secondary mental or behavioral syndromes associated with disorders or diseases classified elsewhere.” When≥2 psychotic phases occurred during clinical progression, the most severe and/or most frequently repeated symptoms were considered the principal features used for classification.

Repeatability of the psychotic episode or phase

Remission was defined as breaking away from a psychotic phase, in which mood disorders and psychotic symptoms, such as a catatonic state and delusions-hallucinations, significantly hindered daily and social life; moreover, this is also defined as a return to a premorbid level of life. Recurrence was defined as a clear clinical feature after remission. Based on these definitions, the number of psychotic phases was determined.

Rates of positive radioisotope scanning (RI) findings

The positive rate of each RI finding (DAT, MIBG, and perfusion SPECT) was examined at the prodromal stage and after the onset of DLB.

Ethics

The study protocol was approved by the Regional Ethics Committee of Sunagawa City Medical Center. Patients provided written consent to participate in the study after the study protocols were explained in detail to them and their families (usually the spouse or offspring).

RESULTS

Subject characteristics

The subjects included 21 patients (7 male, 14 female) (Table 1), with a mean age at onset of psychiatric symptoms of 62.2±6.3 (mean±SD) years. The mean age at DLB onset was 71.3±6.1 (mean±SD) years, and they were diagnosed as DLB, on average, 9.1±4.6 (mean±SD) years (range, 2–19 years) after psychotic symptoms were initially noted. The mean score of the Mini-Mental State Examination (MMSE) performed on 19 subjects at DLB diagnosis was 20.6±3.6 (mean±SD). In addition, performing cognitive examinations on patients with severe psychosis is difficult, and an MMSE can be performed in only 12 patients in the remission phase during an intermittent stage of disease, with a mean score of 27.3±1.4 (mean±SD).

Table 1

Psychotic features of all cases

Sex	Age of onset of psychosis	Age at DLB diagnosis	MMSE before DLB diagnosis	MMSE at DLB diagnosis	Initial symptom	Principal psychotic features	Number of psychotic states					mECT	V-Hall	A-Hall	Del	Dep	Man	Fluc	Par	RBD	DAT posi	MIBG posi	SPECT posi
							Cata	Dell-	Man/	Delirium	Total
Hall	Dep
F	54	66	25	14	A-Hall	Cata S + E	7	1	0/1	1	10	+	+	+	+	+	–	(+)	+	–	+	–	+
F	60	63	–	21	Dep	Cata S + E	2	0	0/1	0	3	+	–	+	+	+	–	(+)	(+)	–	N.A.	(–)	(+)
F	62	72	29	27	Dep	Cata S + E	8	0	0/1	1	10	+	+	+	+	+	–	(+)	+	–	+	+	+
M	55	65	26	24	Dep	Cata.S	2	1	2/3	0	8		–	–	+	+	+	–	+	–	+	–	–
F	58	77	25	15	Dep	Cata S	2	3	2/2	1	10		+	+	+	+	+	(+)	–	–	–	–	+
F	63	76	27	–	Dep	Cata S	3	1	0/2	0	6	+	–	+	+	+	–	(+)	–	–	+	+	N.A.
F	64	75	29	–	Dep	Cata S	6	1	0/1	0	8	+	–	+	+	+	–	(+)	+	–	N.A.	–	+
F	66	72	27	22	Dep	Cata S	3	0	0/1	0	4	+	–	+	–	+	–	(+)	–	–	+	N.A.	+
F	73	79	28	24	Dep	Cata S	2	1	0/2	1	6		+	+	+	+	–	(+)	(+)	–	+	N.A.	+
F	52	60	–	16	Dep	Del-Hall	0	2	0/1	0	3	+	+	+	+	+	–	(+)	–	–	+	+	+
F	55	62	27	23	Dep	Del-Hall	0	2	0/1	0	3		+	+	+	+	–	–	+	+	(+)	(–)	(+)
M	63	65	27	24	Dep	Del-Hall	0	1	0/1	0	2		+	–	–	+	–	(+)	–	+	(+)	(+)	(–)
F	64	72	–	19	A-Hall	Del-Hall	0	1	0/1	1	3		+	+	–	+	–	(+)	–	–	+	N.A.	+
F	68	70	–	23	Dep	Del-Hall	0	1	0/1	1	3	+	+	+	+	+	–	–	+	–	+	N.A.	–
F	54	71	28	20	Dep	Man-Dep	0	0	1/3	0	4	+	–	–	–	+	+	(+)	–	–	(+)	N.A.	(–)
M	62	78	–	18	Man	Man-Dep	0	0	3/3	1	7		(+)	–	(+)	+	+	(+)	(+)	–	(+)	(+)	(+)
M	69	77	–	16	Dep	Man-Dep	0	0	4/2	0	6	+	–	–	–	+	+	–	(+)	+	(+)	N.A.	N.A.
M	60	68	–	18	Dep	Dep	0	0	0/2	0	2		(+)	–	–	+	–	–	(+)	–	N.A.	(+)	(+)
M	62	74	–	22	Dep	Dep	0	0	0/3	0	3		–	–	–	+	–	–	(+)	–	+	N.A.	+
M	66	74	28	22	Dep	Dep	0	0	0/1	0	1		–	–	–	+	–	–	(+)	+	+	N.A.	+
F	76	82	–	24	Dep	Dep	0	0	0/2	0	2		(+)	–	–	+	–	–	(+)	+	+	N.A.	+
M/F	Mean±SD	Mean±SD	Mean±SD	Mean±SD			Total	Total	Total	Total	Total	Total	Total	Total	Total	Total	Total	Total	Total	Total	n/Total	n/Total	n/Total
7/14	62.2±6.3	71.3±6.1	27.3±1.4	20.6±3.6			35	15	12/35	7	104	10	9^*1	12^*1	11^*1	21^*1	5^*1	0^*1	6^*1	5^*1	12/13^*1	3/7^*1	11/13^*1
													(42.9%)	(57.1%)	(52.4%)	(100%)	(23.8%)	(0%)	(28.6%)	(23.8%)	(92.3%)	(42.9%)	(84.6%)
													12^*2	12^*2	12^*2	21^*2	5^*2	13^*2	14^*2	5^*2	17/18^*2	6/12^*2	15/19^*2
													(57.1%)	(57.1%)	(57.1%)	(100%)	(23.8%)	(61.9%)	(66.7%)	(23.8%)	(94.4%)	(50.0%)	(78.9%)

(), at or after diagnosis of DLB; ^*1before diagnosis of DLB; ^*2before and at diagnosis of DLB. A-Hall, auditory hallucination; Cata, catatonia; Cata S. catatonic stupor; Cata S + E, catatonic stupor and excitement; DAT posi, positive findings of DLB by ¹²³I-FP-CIT SPECT; Del, delusion; Del-Hall, delusional-hallucinatory state; Dep, depression; F, Female; Fluc, Fluctuation; M, Male; Man, mania; MMSE, Mini-Mental State Examination; mECT, modified electric convulsion therapy; MIBG posi, positive findings of DLB by MIBG; N.A., no assessment; Par, Parkinsonism; RBD, rapid eye movement sleep behavior disorder; SPECT posi, positive findings of DLB by cerebral brain-perfusion SPECT; V-Hall, visual hallucination.

In addition, three patients had a family history of psychiatric disorders. There was one case of depression in the mother, one case of depression in a sibling, and one case of schizophrenia.

Three principal psychotic features

Psychotic symptoms and features of each subject are summarized in Table 1. The principal psychotic features of prodromal DLB were classified into three categories, defined in the International Classification of Diseases, 11th Revision, as follows: 6E69 secondary catatonia syndrome (catatonic features); 6E61 secondary psychotic syndrome (delusional-hallucinatory features), and 6E62 secondary mood syndrome (manic and/or depressive features). In addition, features fulfilling the criteria for delirium (6D70.0) due to disease classified elsewhere were found in seven subjects. However, their delirium states were judged not to be principal features because they were neither the most severe nor the most frequent in monitoring clinical progression.

Repetition of the psychotic phase

Multiple psychotic phases were observed in 20 of the 21 subjects (Table 1), with two–10 phases occurring in different subjects. There were 104 psychotic phases among the 21 subjects consisting of the following features: catatonia (n = 35 [phases]), delusional-hallucinatory (n = 15 phases), manic (n =12), depressive (n = 35), and delirium (n = 7).

Of the three subjects who exhibited catatonic features≥6 times, the duration of each phase varied, even within the same patient. The phase period was as short as one month, while the longest was 5 years, with the most common lasting 2–3 months.

Of the 21 subjects, 17 exhibited severe clinical features requiring hospitalization for all phases. However, within the 7 cases in the Man/Dep group, 3 out of 4 cases that developed only depression required hospitalization across all phases. Although the remaining case and 3 cases with both Man/Dep phases required at least one hospitalization, we identified 8 phases of depression that did not require hospitalization.

Incidence of psychotic symptoms in prodromal DLB and at/after diagnosis of DLB

The rates of occurrence of various psychotic symptoms among the 21 subjects with prodromal DLB were as follows: visual hallucinations (n = 9 [42.9%]), auditory hallucinations (n = 12 [57.1%]), delusion(s) (n = 11 [52.4%]), depressive symptoms (n = 21 [100%]), and manic symptoms (n = 5 [23.8%]) (Table 1). These symptoms are described in detail in the next section.

The rates of occurrence of various psychotic symptoms among the 21 subjects before and at the time of DLB diagnosis were as follows: visual hallucinations (n = 12 [57.1%]), auditory hallucinations (n = 12 [57.1%]), delusions (n = 12 [57.1%]), depressive symptoms (n = 21 [100%]), and manic symptoms (n = 5 [23.8%]) (Table 1).

Catatonic features

Nine subjects exhibited catatonic features, including three cases with both catatonic stupor and catatonic psychomotor excitement and six cases with catatonic stupor only. Delirium was observed in four subjects.

In three subjects with both catatonic stupor and catatonic psychomotor excitement, there was one or two instances that both catatonic stupor and psychomotor excitement were represented in one psychotic phase, and there were catatonic stupor states without psychomotor excitement in later psychotic phases.

Based on these data, even if some subjects repeatedly exhibit catatonic features, they also experience non-catatonic phases involving hallucinatory-delusional and manic and/or depressive states. None of the subjects experienced specific precipitating factors, and repetition of various types of psychotic phases was a common characteristic.

Four subjects experienced visual hallucinations, including adult (n = 2), children (n = 1), colored light (n = 1). The frequency of auditory hallucinations was extremely high (eight of nine subjects). These consisted of verbal hallucinations involving detailed criticism(s) or condemnation of the subject’s behavior (n = 6), calling of the subject’s name (n = 2), sounds of vehicles, telephone ringing and/or other machines (n = 4), and musical hallucinations (n = 2).

Eight subjects experienced various delusions, as follows: poverty (n = 4), persecution (n = 4), perpetration (n = 2), Capgras delusion, believing that one’s family members, physicians, etc., are imposters (n = 3); observation by spy cameras, etc. (n = 3).

All subjects experienced depressive phases, which involved depressed mood, psychomotor retardation, anxiety, and agitation. Five subjects experienced suicidal ideation and four experienced suicidal attempts.

Delusional-hallucinatory features

Five subjects exhibited a hallucinatory-delusional state. Two of the five subjects exhibited delirium. Two subjects repeatedly exhibited two delusional-hallucinatory features. All participants also experienced depressive states.

All subjects experienced visual hallucinations, three subjects experiencing visual hallucinations of children, and one subject having visual hallucinations of adults and another subject seeing bright light. Auditory hallucinations were also relatively frequent and experienced by four subjects, all of whom described verbal hallucinations consisting of harmful content and included criticism or interpretation of the subject’s behavior. Two subjects experienced mechanical auditory hallucinations, including telephones and chimes.

Three subjects experienced delusions as follows: having money or stolen possessions (n = 1), persecution (n = 2), and Capgras delusion, a belief that the physician was an imposter (n = 1).

All subjects experienced depressive phases involving psychomotor retardation, as follows: depressed mood (n = 4), anxiety and agitation (n = 1), and suicidal ideation and attempt (n = 1).

Manic and/or depressive features

During the prodromal stage before the onset of DLB, seven subjects experienced psychotic phases involving affective disorders only, without hallucinations or delusions. Three subjects were bipolar, exhibiting manic and depressive phases, and four exhibited depressive phases only. In one subject, the psychotic phase consisted of a state of delirium. In these seven cases, the manic phases were eight, and the depressive phases were 16.

All subjects experienced psychomotor retardation and depressive mood, but only a small number experienced other conditions, with one subject experiencing anxiety and agitation, three with suicidal ideation, and one with suicidal attempts.

In subjects exhibiting depressive phases only, these were maintained for an extended period, and even if recovery did occur, it tended to be delayed, with a mild depressive phase lasting several years.

In three bipolar subjects, both the manic and depressive phases lasted for several months, with intermittent complete remission. Among the three bipolar subjects, the manic phase involved talkativeness, hyperkinesia, and reduced sleep duration, while irritability, elevated mood, grandiosity, and financial extravagance were observed in two subjects.

Core symptoms of DLB except the visual hallucination

Fluctuation was not observed in any case in the prodromal stage, but was observed in 61.9%of cases after the onset of DLB. In terms of Parkinsonism, minimal muscular rigidity, tremor, and hypokinesia before the onset of DLB were found in six cases (28.6%) and 14 cases (66.7%) in the total process from prodromal to onset of DLB. All rapid eye movement sleep behavior disorders were found in five cases (23.8%) before the onset of DLB.

Rates of positive RI findings

RI was performed before DLB onset in 14 subjects, all of whom were positive for DLB. The rates of positive findings according to the different RI modalities were as follows: DAT, 12 of 13 (92.3%); MIBG, 3 of 7 (42.9%); and perfusion SPECT, 11 of 13 (84.6%). Thus, the rates of positive findings were higher with DAT and perfusion SPECT. In addition, when all subjects were accounted, including the seven in whom RI was performed after DLB onset, the rates of positive results were as follows: DAT, 17 of 18 (94.4%); MIBG, 6 of 12 (50%); and perfusion SPECT, 15 of 19 (78.9%).

Although three cases had only positive DLB findings on perfusion SPECT, which is a supportive biomarker, they subsequently developed DLB. For this reason, psychotic symptoms before DLB onset are considered prodromal symptoms of DLB.

Therapeutic interventions

The effects of pharmacotherapy were limited. Although major tranquilizers were administered to 11 of the 16 patients who experienced hallucinations, only three (27.3%) responded to medication. Side effects were observed in 4 (36.4%). Of these, there were three cases of extrapyramidal symptoms (EPS) and one case of fatigue and sleepiness. To treat depression, antidepressants were administered to 20 subjects, but were effective in only 7 (35%). Side effects were observed in five (25.0%) cases. Of these, there were four cases of EPS and one case of fatigue and sleepiness. Conversely, mECT was performed on 10 subjects and showed efficacy in all subjects. Of the nine subjects who exhibited catatonic features, mECT was performed to treat the stupor state in six, which, in each case, resulted in improvement. Two or more mECT cycles were performed in five subjects, and≥4 cycles were performed in two subjects. In two subjects exhibiting delusional-hallucinatory features, mECT was performed to treat the severely confused state resulting from the hallucinatory-delusional state, and recovery from this state was achieved in both. mECT was performed on two bipolar subjects with manic and/or depressive features. Alleviation of the conditions was achieved in all cases.

DISCUSSION

Psychotic symptoms in prodromal DLB; significance of this study

Several attempts to establish the diagnostic criteria for prodromal DLB have been established [2, 4]; however, these efforts have not been successful thus far. Therefore, the most reliable method for detecting psychotic symptoms of prodromal DLB is longitudinal observation of those presenting with DLB-related symptoms before the onset of DLB. According to a study investigating initial symptoms in 239 patients with DLB who underwent autopsy, hallucinations occurred in 13%and depression in 5%[8]. In addition, Molano et al. [9] reported that six (75%) of the eight cases of DLB autopsy had visual hallucinations prior to the onset of cognitive impairment or at the MCI stage, showing that visual hallucinations were frequently observed as prodromal symptoms. Similarly, Jicha et al. [10] pointed out that four (44.4%) of the nine cases of DLB autopsy in the cohort study had hallucinations or delirium as an initial symptom at the MCI stage, showing that psychotic symptoms were observed in approximately half of the cases. Therefore, the occurrence of psychotic symptoms during prodromal stage is not uncommon.

In a clinical study investigating prodromal DLB, according to reports of initial symptoms at DLB onset [3], the frequency of onset of psychotic symptoms was high (41.9%). In addition, according to reports of DLB onset after follow-up of the MCI stage [11, 12], 9.5%to 36%of subjects experienced visual hallucinations at the MCI stage. There have been several recent clinical studies in which subjects in whom DAT imaging revealed reduced uptake, despite being at the MCI stage, were considered to be at the prodromal stage, and numerous psychotic symptoms have been reported to occur during all prodromal stages [13, 14]. On this basis, although there have been numerous studies in which DLB involved psychotic symptoms before the onset of dementia, the research methods and the selection of patients may be limitations of these studies. The present study was a retrospective analysis of psychotic symptoms that occurred during the confirmed DLB prodromal stage among 21 subjects who developed psychotic symptoms without overt cognitive impairment and later developed DLB during a long monitoring period, with a mean duration of 9.1±4.6 (mean±SD) years. Of the subjects in the present study, the frequencies of visual hallucinations, auditory hallucinations, delusions, and depressive symptoms before DLB onset were 42.9%, 57.1%, 52.4%, and 100%, respectively, which were very high compared to those described in previous reports. However, we could not rule out the possibility that the high frequency of psychotic symptoms may be related to the selection bias since the cases examined in the present study had developed psychotic symptoms.

McKeith et al. recommended that, to determine the psychiatric-onset DLB, patients should exhibit psychotic symptoms that correspond to late-onset major depression or late-onset psychosis that are sufficiently severe to necessitate hospitalized treatment, and biomarkers should be investigated [2].

All subjects in the present study exhibited severe psychotic symptoms and necessitated hospitalization, and all subjects experienced very late-onset catatonia and delusional-hallucinatory states, or mood disorder, in which DAT and MIBG biomarkers yielded positive results for DLB. To our knowledge, this is the first study to describe patients who fulfilled these conditions.

Features of prodromal psychotic DLB:

The features of the psychotic profiles observed in the prodromal stage of the 21 cases in this study are summarized as follows:

Many cases developed features of depression, and hospitalization treatment was required because of the repeated features of various mental disorders.

It is likely that prodromal DLB clinically presents heterogeneous and diverse psychotic features of the disease in geriatric psychiatry. However, longitudinal observation of the features mainly has convergence to three features, namely catatonia and delusional-hallucinatory and depressive and/or manic features.

Although the number of delirium cases was not small, they were rarely prolonged and transient to one of the three features of the disease mentioned above.

Each feature of the disease changed each other and repeatedly transitioned, eventually leading to the onset of DLB.

In the psychiatric clinic, there are some patients who present with serious psychotic symptoms for the first time in middle and old age, and in such cases, the possibilities of the preceding or prodromal condition of DLB must be excluded.

Catatonic features

Catatonia was first described by Karl Ludwig Kahlbaum, who regarded it as a type of schizophrenia—a psychiatric disorder of endogenous origin. However, in recent years, catatonia has been characterized as a non-specific psychotic state that occurs in diverse disorders [15]. It is commonly acknowledged that catatonia develops from physical impairments or neurological diseases [16] at a higher frequency than from endogenous psychosis [17]. This also applies to DLB.

All subjects who exhibited a catatonic state in the present study experienced repeated episodes of catatonia, whose phase cognitive evaluation could be difficult; however, they recovered to premorbid levels during clinical remission where few cognitive impairments and interpretation of performance were observed.

Since the subjects in this study were evaluated through both the core symptoms and indicative biomarkers, which satisfy the DLB diagnosis criteria, it is highly likely that the psychotic symptoms observed in this study might be caused by underlying DLB pathology.

Delusional-hallucinatory features

Five cases presented delusional-hallucinatory features as principal psychotic features, and a total of 15 delusional-hallucinatory states were observed in 11 of 21 cases. Visual hallucinations were observed in nine subjects in the prodromal stage, auditory hallucinations in 12, and delusions in 11. In addition, although depression occurred as the initial symptom in four of five cases with delusional-hallucinatory features as principal psychotic features, hallucinations and delusions were subsequently noted. Thus, it is possible that numerous patients who experience these symptoms are clinically diagnosed with very late-onset schizophrenia [18]. Due to the lack of evidence from magnetic resonance imaging or computed tomography, the presence of coarse organic lesions will be overlooked, thereby leading to a diagnosis of endogenous psychosis.

The International Late Onset Schizophrenia Group issued a consensus [19] stating that schizophrenia occurring at or after 40 years of age is termed “late-onset schizophrenia” (LOS), and that schizophrenia occurring at or after 60 years of age is termed “very-late-onset schizophrenia-like psychosis” (VLOSLP). These two classifications were distinguished from the primary type of schizophrenia. Based on its etiology, VLOSLP can probably be regarded as a unique group of diseases arising from various underlying pathologies. LOS is known to be more common in women [20, 21]. Unlike juvenile-onset schizophrenia, LOS is usually characterized by hallucination-delusion or delusion [22]. These clinical features are very similar to those of the delusional-hallucinatory cases in the present study. Therefore, it can be speculated that a subset of patients diagnosed with VLOSLP may, in fact, have prodromal DLB.

In a neuropathology study, Nagao et al. [23] reported that in patients with VLOSLP and delusional disorders, whose onset occurred at≥65 years of age, the frequency of LBD was 26%. It is important not to overlook the possibility of pathological changes related to DLB occurring in the background. It is important to differentiate between LOS/VLOSLP and DLB when making a diagnosis in elderly patients with psychotic symptoms. Assche et al. [24] used DAT imaging as an indicative biomarker of DLB to distinguish DLB from VLOSLP. DAT showed a decrease in uptake not only in the LBD but also in the PSP and CBD. However, because of long-term observation of clinical symptoms, the subjects in this study developed DLB, and the hallucination-delusional state observed in the prodromal stage was considered as psychotic symptoms based on DLB.

Advances in clinical imaging enable the detection of DLB-induced organic lesions using RI imaging. To exclude the possibility of prodromal DLB, we therefore need to use RI imaging methods on presenile or senile patients who experience delusional-hallucinatory symptoms or depressive symptoms with hallucinations and/or delusions.

Manic and/or depressive features

Among the 21 subjects in the present study, the most frequent initial symptom was depressive episodes (18 subjects). However, subsequent progression involved eight subjects developing a catatonic feature, and four subjects developing a hallucinatory-delusional feature, with most of the latter experiencing hallucinations and delusions. However, hallucinations and delusions did not occur before the onset of DLB in any subject, and manic and/or depressive features occurred as psychotic features that can be considered prodromal DLB in seven subjects, three of whom were bipolar, and the other four experienced depressive phases. Since DLB onset, three subjects experienced visual hallucinations, and one experienced delusions. Seven subjects with affective disorder developed DLB during long-term progression over a period of 6 to 17 years.

When a depressive state occurs as a DLB prodromal symptom, diagnoses of depression are often made in a clinical context [25]. According to Takahashi et al. [26], in 55%of cases, the initial diagnosis of DLB was major depression, and bipolar affective disorder was diagnosed in five (9%) patients. There have been few reports of bipolar affective disorder before DLB onset; however, in the present study, three subjects were diagnosed with bipolar affective disorder and, while being treated, progressed to DLB over a long period of 8 to 17 years.

Autopsy reports have also suggested a link between DLB and depression. In a study involving 239 patients in whom autopsies were performed, Poewe et al. reported that the initial diagnosis was depression in 21 [8]. In addition, with regard to reports addressing the neuropathology of depression with onset at≥65 years of age, Lewy body pathology was found in 5 of 10 patients (50%) by Sweet et al. [27], and in three of five (60%) by Nagao et al. [23]. In autopsies of 153 patients who did not exhibit dementia while alive, Tsopelas et al. reported that depression in the elderly has a significant relationship with subcortical Lewy body pathology in the substantia nigra and the nucleus of the locus coeruleus [28]. Thus, it is suggested that the Lewy body may be involved in geriatric depression.

Delirium features

Delirium occurred in 7 of the 21 subjects in the present study. According to the principal features exhibited by the subjects, delirium occurred in four of nine with catatonic features, two of five with delusional-hallucinatory features, and in one in seven with manic and/or depressive features. The core symptoms of DLB include fluctuating attention and cognitive function. It is extremely difficult to distinguish DLB from delirium when these fluctuations are noted in patients with DLB presenting with psychotic symptoms. Gore et al. [29] reported that because there is a considerable overlap in fluctuations and psychotic symptoms observed in delirium and those observed in DLB, delirium and DLB may be linked, and delirium may indicate a prodromal or early stage of DLB. In addition, McKeith et al. [4] classified prodromal DLB into three subtypes based on the higher central nervous system, with delirium-onset DLB representing one of them. Therefore, the transient and episodic features of prodromal DLB are suggested to reflect the features of delirium.

Based on the above findings, the relation of the four psychotic features in prodromal psychotic DLB are illustrated schematically in Fig. 1.

Fig. 1

The summary of clinical course in prodromal DLB state.

Limitations

In the prodromal stage, impairments in activities of daily life or social life were not found, and overt gross cognitive decline occurred. Detailed cognitive examinations, however, were not performed, and the possibility of an MCI level could not be excluded completely.

This study included only patients hospitalized for psychotic symptoms. Therefore, patients with mild symptoms who did not require hospitalization were excluded from the study.

The diagnosis relied solely on a clinical basis without histopathologic confirmation.

In this study, the rates of positive RI findings at the prodromal stage were slightly higher than those reported previously. Therefore, the possibility of selection bias could not be ruled out in this study because the cases examined were positive for RI findings.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/21-0416r3).

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