Abstract
Background:
Posterior Cortical Atrophy (PCA) and Logopenic Progressive Aphasia (LPA) are two common atypical Alzheimer’s Disease (AD) variants. Little is known about behavioral and neuropsychiatric symptoms or activities of daily living (ADLs) in PCA and LPA, and whether they differ across syndromes.
Objective:
To characterize the behavioral and neuropsychiatric profiles and ADLs of PCA and LPA and compare presence/absence and severity of symptoms between syndromes.
Methods:
Seventy-eight atypical AD patients, 46 with PCA and 32 with LPA, completed the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Cambridge Behavioral Inventory-Revised (CBI-R) at baseline and longitudinally over-time. Mann-Whitney U and Fisher’s Exact Tests assessed for differences in symptoms between the two syndromes with significance set at p ≤ 0.01. To eliminate demographic differences as confounders the groups were matched, and differences reanalyzed.
Results:
PCA were younger at onset (p=0.006), at time of baseline assessment (p=0.02) and had longer disease duration (p=0.01). Neuropsychiatric symptoms were common in PCA and LPA, although more common and severe in PCA. At baseline, PCA had a higher NPI-Q total score (p=0.01) and depression subscore (p=0.01) than LPA. Baseline total CBI-R scores were also higher in PCA than LPA (p=0.001) with PCA having worse scores in all 10 CBI-R categories. Longitudinally, there was no difference between groups on the NPI-Q. However, on the CBI-R, PCA had faster rates of worsening on self-grooming (p=0.01) and self-dressing (p=0.01) compared to LPA.
Conclusions:
Behavioral and neuropsychiatric symptoms are common in PCA and LPA although these symptoms are more common and severe in PCA.
Keywords: Logopenic Progressive Aphasia, Posterior Cortical Atrophy, Neuropsychiatric, Behavioral, Alzheimer’s disease, atypical Alzheimer’s disease
INTRODUCTION
Many patients with amnestic Alzheimer’s disease (AD) experience behavioral and neuropsychiatric symptoms during their disease. These symptoms may include depression, anxiety, apathy, disinhibition, euphoria, irritability, agitation, appetite/eating disorders, delusions, hallucinations, and nighttime behaviors [1]. However, 25–50% [2] of individuals with AD do not present with an amnestic syndrome but have an impaired visuospatial/perceptual presentation known as Posterior Cortical Atrophy (PCA) or an aphasic presentation known as Logopenic Progressive Aphasia (LPA) [3] [4] [2] [5]. Neuropathological series demonstrate that AD is the primary cause of PCA in anywhere from 62 to 100% of individuals while in LPA, AD represents 55 to 100% of individuals [6] [7] [8] [9, 10] [11]. Because most patients with PCA and LPA have AD pathology at autopsy, these syndromes are considered atypical variants of AD. [12] [13] [14].
PCA is characterized by a progressive decline in visuospatial and visuoperceptual abilities with a relative sparing of memory and language functions. Individuals with PCA have difficulties with driving, navigating their environment, reading, and identifying objects [8] [15]. These deficits are frequently accompanied by features of Balint’s and/or Gerstman’s syndromes. Accordingly, later in the disease, individuals with PCA perceive and interact with their environments in a similar manner to blind individuals, regardless of their lack of ophthalmologic impairment. The clinical presentation of LPA differs from PCA as it is primarily characterized by a progressive worsening of language abilities, including hesitant speech, anomia, as well as impairments in word finding, and difficulties with sentence repetition, as a result of verbal working memory deficits [4] [3]. Individuals with LPA are often unable to find the right words, which is emulated in prolonged pauses when speaking, and frequently have difficulty understanding complex sentences and retaining verbal information [16].
Many investigations have focused on characterizing the cognitive and languages profiles of PCA and LPA patients [17] [18] However, very little is known about their behavioral and neuropsychiatric profiles and it is not known how these profiles differ between the two syndromes. Studies have shown that behavioral and neuropsychiatric symptoms can be associated with the severity of cognitive decline in a variety of other neurodegenerative conditions [17] [19]. Furthermore, knowledge of the various psychiatric and behavioral symptoms associated with PCA and LPA enables the potential for targeted pharmacological intervention, which may positively affect function in daily life. Recognition of the prevalence and course of behavioral and neuropsychiatric symptoms is imperative for patient planning purposes, providing families with accurate information regarding prognosis, and managing treatment [1]. A better understanding of behavioral and neuropsychiatric symptoms in individuals with PCA and LPA is critical as such symptoms can have a direct influence on patient quality of life, caregiver distress, and hospitalization [18].
To address this knowledge gap, the current study aimed to characterize the neuropsychiatric, behavioral and activities of daily living (ADLs) profiles of PCA and LPA and to determine if there are differences in behavioral, and neuropsychiatric symptoms and ADLs between LPA and PCA participants. Based on the existing literature that shows lower neuropsychiatric scores in LPA [14] compared to PCA [18], and that depression and anxiety are two of the three most commonly reported neuropsychiatric symptoms in PCA [17], we hypothesized that PCA participants would have more severe depression and anxiety than LPA. We also hypothesized that ADLs would be more affected in participants with PCA than LPA given that the Clinical Dementia Rating Scale[20], a measure of functional performance in day-to-day life, scores on average are higher (more affected) in PCA than LPA, when matched for global cognitive impairment[21].
MATERIALS AND METHODS
Participants
This study included participants with atypical Alzheimer’s disease recruited and prospectively followed by the Neurodegenerative Research Group (NRG), at Mayo Clinic, Rochester MN, between June 8th, 2016, and February 2nd, 2023, and enlisted in an NIH-funded study. All participants met clinical criteria for LPA or PCA [3] [22] [15] and all completed detailed neuropsychological (MMM) and neurological evaluations (KAJ or JGR). Of the total 78 participants, 32 (41%) were classified as LPA and 46 (59%) as PCA. All participants also underwent Pittsburgh Compound-B (PiB) PET to assess beta-amyloid (Aβ) deposition, flortaucipir (FTP) PET to assess tau deposition, and gave blood samples to allow for apolipoprotein-E (APOE) genotyping. All LPA and PCA participants were determined to be Aβ and tau-positive using a previously published global PiB Standardized Uptake Value Ratio (SUVr) and temporal lobe tau meta-region of interest. The cutoff for Aβ positivity was ≥1.48 and the cutoff for tau positivity was ≥1.29 as described by previous investigations [23] [24] [25]. Participants were excluded from the study if they had not completed both the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Cambridge Behavioral Inventory-Revised (CBI-R), if they were negative for tau or Aβ, or if they met criteria for another neurodegenerative disease. Twenty-six (81.3%) LPA and 33 (71.7%) PCA participants completed longitudinal yearly follow-up visits, with identical clinical assessments at each visit.
Utilizing Mayo Clinic’s electronic health records system, Epic, we searched participant medical records for data regarding anti-depressant, anti-anxiety, anti-psychotic, sleep aid and anticholinesterase inhibitor usage started after a participant’s baseline assessment.
Clinical evaluations
All patients underwent detailed neurological examination by an experienced behavioral and movement disorder specialist (KAJ or JGR), as well as neuropsychological testing overseen by a board-certified neuropsychologist (MMM). All patients completed the Clinical Dementia Rating Scale (CDR) to measure the severity of functional impairment [26] the Montreal Cognitive Assessment (MoCA) to assess for general cognitive functioning [27], the 15-item Boston Naming Test (BNT) as a measure of confrontation naming [28] the Boston Diagnostic Aphasia Examination (BDAE) to measure aphasia severity and global language ability [29] and the auditory verbal learning test (AVLT) to measure verbal episodic memory [30]. The Letter Fluency test evaluated aspects of executive function, the Western Aphasia Battery animal subtest (WAB-animal) assessed semantic fluency [31], and the Visual Object and Space Perception Battery (VOSP) letters and cubes measured visuoperceptual and visuospatial function [32].
Neuropsychiatric Assessment
Neuropsychiatric symptoms were evaluated with the short version of the neuropsychiatric inventory (NPI-Q) [33]. The NPI-Q measured 12 neuropsychiatric domains, including delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, apathy/indifference, disinhibition, irritability/lability, abnormal motor behavior, sleep and nighttime behaviors, and appetite and eating behaviors, based on the presence/absence and severity of symptoms and the distress experienced by the caregiver as a result of those symptoms over the last 30 days [33] [34]. We did not focus on the distress index in this investigation. The severity of symptoms was graded as 0–3, by the caregivers, with 0 indicating absence of symptom, 1 indicating mild (noticeable but not significant change), 2 indicating moderate (significant but not dramatic change), and 3 indicating severe (prominent and dramatic change). Summing the total scores of the 12 neuropsychiatric domains produced the total NPI score.
Cognitive, Behavioral, and Assessment of Activities of daily living (ADLs)
Behavioral and ADL assessment was completed with the Cognitive Behavioral Inventory-revised version (CBI-R) [35] by the caregivers. The CBI-R evaluates 45 behaviors and ADLs and rates the frequency or occurrence of a specific outcome/behavior, in the last 30 days, on a scale of 0–4. A score of 0 denotes no occurrence, 1 denotes occurrence a few times per month, 2 occurrence a few times per week, 3 a daily occurrence, and 4 a constant occurrence. Scores of 3 and 4 indicate severe behavioral impairment. The CBI-R evaluates domains such as (1) memory and orientation, (2) everyday skills (e.g. managing money/bills), self-care (e.g. including ability to self-dress), (3) abnormal behavior (e.g. socially embarrassing behavior), (4) mood (e.g. sadness/depression), (5) beliefs (e.g. visual hallucinations), (6) eating habits (e.g. table manners), (7) sleep, (8) stereotypic and motor behaviors, and (9) motivation (e.g. enthusiasm for usual interests). The rating of each question is summed to give a total CBI-R score.
Statistical analyses
All statistical analyses were performed using R studio (version 4.2.3). Non-parametric tests including Mann-Whitney U tests were used to compare continuous variables, while Fisher’s Exact tests were used to compare categorical variables. Spearman rank correlations were used to assess for correlations between cognitive scores, and neuropsychiatric and behavioral scores, to assess whether domain specific cognitive differences may have played a role in any of our findings. In all analyses, we set significance at p≤0.01 to reduce the chances of false positive results. For the CBI-R, given the number of different item level variables, we only assessed for significance at the item level if there was evidence for a difference at the higher (compositive) level (p<0.10). For all longitudinal data, worsening over time was calculated using the average rate of change (points change on each scale per year) from a participant’s initial research visit and their last research visit divided by the years between visits. To adjust for significant differences observed between groups in age of onset we performed secondary analyses with matched cohorts. Specifically, we removed the LPA participants with the oldest age of onset (n=6) and the PCA participants with the lowest age of onset (n=6) and performed all analyses with cohorts (26 LPA vs 40 PCA) matched for age of onset (p=0.31). One PCA participant did not have data available for age at onset; thus, there were 39 PCA participants in this analysis. For age at baseline test, we similarly removed the 6 LPA participants with the oldest age at baseline test and performed all analyses with cohorts (26 LPA vs 46 PCA) matched for age at baseline test (p=0.20). To adjust for the significant difference in disease duration between groups, we removed the 10 participants from the PCA group with the longest disease duration and performed all analyses with cohorts (32 LPA vs 36 PCA) matched for disease duration (p=0.50).
Ethics Approval
This study was approved by the Mayo Clinic Institutional Review Board and all patients, or their proxies signed a written informed consent form before taking part in any research activities in accordance with the Declaration of Helsinki.
RESULTS
Demographic and clinical results
Demographic and clinical data are summarized in Table 1. All participants were White and non-Hispanic except for one PCA participant who was Asian. There were no significant differences in demographic features or APOE genotype between groups, aside from PCA participants having a younger age of onset, younger age at baseline test, and longer disease duration compared to LPA participants. On clinical evaluations, the PCA group demonstrated worse performance on the CDR sum of boxes (p=.004), Letter fluency test (p=.003), and VOSP letters (p=<.0001) compared to the LPA group, while the LPA group performed worse on the BNT (p=.004) and BDAE repetition (p=0.004) compared to the PCA group. Importantly, these differences remained significant when we matched the groups for age at onset, age at baseline test, and disease duration.
Table 1:
Demographic, genetic, and clinical features
| Variable of interest | LPA (N=32) | PCA (N=46) | P-value |
|---|---|---|---|
| Men % | 31.3% (N=10) | 29.8% (N=14) | 1.00 |
| Education (yrs.) | 15.7 (11.0, 20.0) | 15.8 (12.0, 20.0) | 0.74 |
| Age at onset (yrs.) | 63.7 (43.7, 77.0) | 59.1 (48.5, 76.8) | 0.006 |
| Age at baseline test (yrs.) | 67.0 (53.4, 80.0) | 63.0 (53.0, 77.0) | 0.02 |
| Time from onset to baseline (yrs.) | 3.2 (0.4, 9.7) | 4.1 (0.2, 12.9) | 0.06 |
| Time between baseline and last visit (yrs.) | 1.0 (1, 2) | 1.3 (1, 3) | 0.01 |
| Number with longitudinal visits % | 26 (81.3%) | 33 (71.7%) | |
| PiB status % (pos = >1.48) | 100% | 100% | |
| Tau status % (pos = >1.25) | 100% | 100% | |
| Positive APOE ε4 (%) | 12 (38.7%) (/31) | 23 (51.1%) (/44) | 0.24 |
| Clinical Dementia Rating Scale score/18 | 2.6 (0, 11.0) | 4.4 (0.5, 18.0) | 0.004 |
| Montreal Cognitive Assessment test/30 | 17.0 (6.0, 26.0) | 16.5 (1.0, 29.0) | 0.72 |
| AVLT delayed recall MOANS | 5.8 (2.0, 11.0) | 6.1 (2.0, 17.0) | 0.62 |
| Boston Naming Test/15 | 9.1 (0, 15.0) | 11.7 (6.0, 15.0) | 0.004 |
| Letter fluency (A, S, F) | 22.9 (4.0, 49.0) | 34.2 (3.0, 63.0) | 0.0003 |
| BDAE repetition/10 | 6.3 (3.0, 10.0) | 7.8 (2.0, 10.0) | 0.004 |
| Western Aphasia Battery - animal | 10.6 (2.0, 22.0) | 12.2 (2.0, 22.0) | 0.13 |
| Visual Object and Space Perception Letters/20 | 18.2 (11.0, 20.0) | 9.8 (0, 20.0) | <0.0001 |
Data shown as mean (minimum, maximum). Key: Boston Diagnostic Aphasia Examination repetition (BDAE).
AVLT = Auditory Verbal Learning Test; MOANS = Mayo Older American Normative scores
Significance adjusted to p≤0.01
Baseline neuropsychiatric symptoms analyses
The frequency of neuropsychiatric features on the NPI-Q is shown in Figure 1. Although not statistically significant, the frequency of delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, motor behavior, nighttime behaviors, and appetite/eating behaviors were greater in PCA than LPA. In particular, depression/dysphoria was observed in over 50% of the PCA cohort. When comparing both groups based on the NPI-Q severity of symptoms (Table 2), we observed that the PCA group had a higher severity on the NPI-Q total score (p=0.01) and had a higher severity on the NPI-Q depression subscore (p=0.01) than the LPA group. There were no differences for the other neuropsychiatric symptoms between the two groups.
Figure 1. Percentage of symptoms on the NPI-Q at baseline.
Horizontal bar graph displaying the percentage of symptoms experienced by participants on the NPI-Q at baseline. Key: *** denotes significant variables. Posterior Cortical Atrophy (PCA), Loeoperic Progressive Aphasia (LPA).
Table 2.
NPI-Q severity scores at baseline
| NPI-Q symptom of interest | LPA (N=32) | PCA (N=46) | P-value |
|---|---|---|---|
| Total score/36 | 2.1 (0, 11) | 4.5 (0, 14) | 0.01 |
| Delusions/3 | 0.03 (0, 1) | 0.2 (0, 3) | 0.30 |
| Hallucinations/3 | 0.06 (0, 1) | 0.2 (0, 2) | 0.41 |
| Agitation/3 | 0.2 (0, 2) | 0.5 (0, 2) | 0.07 |
| Depression/3 | 0.3 (0, 2) | 0.8 (0, 3) | 0.01 |
| Anxiety/3 | 0.4 (0, 2) | 0.7 (0, 3) | 0.22 |
| Euphoria/3 | 0 (0, 0) | 0.07 (0, 1) | 0.30 |
| Apathy/3 | 0.30 (0, 3) | 0.5 (0, 3) | 0.21 |
| Disinhibition/3 | 0 (0, 0) | 0.2 (0, 3) | 0.14 |
| Irritability/3 | 0.3 (0, 1) | 0.5 (0, 3) | 0.30 |
| Motor behavior/3 | 0.1 (0, 2) | 0.1 (0, 2) | 0.99 |
| Nighttime behavior/3 | 0.2 (0, 2) | 0.4 (0, 2) | 0.21 |
| Appetite/3 | 0.2 (0, 2) | 0.4 (0, 2) | 0.14 |
Data shown as mean (minimum, maximum).
Higher scores denote worse performance.
A comparison of the percentage of participants having each symptom on the CBI-R for PCA vs LPA is shown in Figure 2. The biggest differences were observed in the categories of Everyday Skills, Mood, and Motivation. A comparison of severity scores for each symptom on the CBI-R between PCA and LPA participants is shown in Table 3. PCA participants had an overall higher severity of symptoms based on the CBI-R total score (p=0.0001). PCA participants also had higher severity scores for symptoms related to memory and orientation, everyday skills, self-care, grooming self, and dressing self, compared to LPA. Abnormal behaviors, including temper outbursts (p=0.01) and being uncooperative (p=0.004), were also more severe in the PCA group. Regarding mood, motor behavior, and motivation, compared to the LPA participants, PCA participants reported higher severity of symptoms. The PCA group also demonstrated less enthusiasm for usual interests, had less interest in doing new things, more often failed to keep in contact with friends/family, were more indifferent to worries/concerns of family, and had more reduced affection. The LPA participants reported higher severity of forgetting the names of objects/things (p=0.001), compared to the PCA participants.
Figure 2. Percentage of symptoms on the CBI-r at baseline.
Vertical bar graph displaying the percentage of symptoms experienced by participants on the CBI-R at baseline. Key: *** denotes significant variables. Posterior Cortical Atrophy (PCA), Logopenic Progressive Aphasia (LPA).
Table 3.
Severity of symptoms on the CBI-R at baseline
| Symptom of interest | LPA (N=32) | PCA (N=46) | P-value |
|---|---|---|---|
| CBI-R total | 22.6 (5, 62) | 45 (8, 110) | 0.0001 |
| CBI memory & orientation (p=0.065) | |||
| Poor day to day memory | 1.4 (0, 4) | 1.8 (0, 4) | 0.20 |
| Asks same questions | 0.1 (0, 3) | 1.6 (0, 4) | 0.03 |
| Loses/misplaces things | 1.8 (0, 4) | 2.6 (0, 4) | 0.004 |
| Forgets names of people | 1.5 (0, 4) | 1.3 (0, 4 | 0.60 |
| Forgets names of objects/things | 2.6 (0, 4) | 1.7 (0, 4) | 0.001 |
| Poor concentration | 0.8 (0, 4) | 1.4 (0, 3) | 0.03 |
| Forgets what day it is | 1.2 (0, 4) | 1.8 (0, 4) | 0.05 |
| Becomes confused in unusual surroundings | 1.2 (0, 4) | 2.1 (0, 4) | 0.001 |
| Everyday skills (p < 0.001) | |||
| Difficulty using electrical appliances | 0.4 (0, 2) | 1.9 (0, 4) | <0.0001 |
| Difficulty writing | 1.8 (0, 4) | 2.8 (0, 4) | 0.002 |
| Difficulty using phone | 0.7 (0, 4) | 1.8 (0, 4) | 0.0005 |
| Difficulties making hot drink | 0.09 (0, 2) | 1.0 (0, 4) | 0.0002 |
| Problems with money/bills | 0.6 (0, 4) | 2.2 (0, 4) | <0.0001 |
| Self-care (p < 0.001) | |||
| Difficulty grooming self | 0.09 (0, 2) | 0.9 (0, 4) | 0.0004 |
| Difficulty dressing self | 0.1 (0, 2) | 1.3 (0, 4) | <0.0001 |
| Difficulty feeding self w/out help | 0.09 (0, 2) | 0.39 (0, 3) | 0.08 |
| Difficulty bathing | 0.06 (0, 1) | 0.3 (0, 4) | 0.33 |
| Abnormal behavior (p=0.015) | |||
| Misplaced humor | 0.2 (0, 2) | 0.4 (0, 4) | 0.44 |
| Temper outburst | 0.2 (0, 2) | 0.7 (0, 4) | 0.01 |
| Uncooperative | 0.2 (0, 3) | 0.6 (0, 3) | 0.004 |
| Socially embarrassing behavior | 0.2 (0, 4) | 0.3 (0, 3) | 0.42 |
| Tactless/suggestive remarks | 0.2 (0, 3) | 0.2 (0, 3) | 0.92 |
| Acts impulsively | 0.2 (0, 3) | 0.4 (0, 4) | 0.20 |
| Mood (p< 0.001) | |||
| Cries | 0.5 (0, 3) | 0.8 (0, 3) | 0.05 |
| Sad/depressed | 0.8 (0, 3) | 1.2 (0, 3) | 0.03 |
| Restless/agitated | 0.3 (0, 2) | 0.9 (0, 3) | 0.002 |
| Irritable | 0.2 (0, 2) | 0.8 (0, 4) | 0.01 |
| Beliefs (p=0.009) | |||
| Visual hallucinations | 0.09 (0, 1) | 0.5 (0, 4) | 0.05 |
| Auditory hallucinations | 0 (0, 0) | 0.1 (0, 2) | 0.14 |
| Odd/bizarre ideas | 0.06 (0, 2) | 0.3 (0, 3) | 0.06 |
| Eating habits (p=0.017) | |||
| Prefers sweets | 0.2 (0, 2) | 0.6 (0, 4) | 0.06 |
| Wants to eat same food repeatedly | 0.2 (0, 2) | 0.6 (0, 4) | 0.05 |
| Larger appetite | 0.06 (0, 1) | 0.3 (0, 3) | 0.10 |
| Decline in table manners | 0.06 (0, 2) | 0.5 (0, 4) | 0.02 |
| Sleep (p=0.204) | |||
| Sleep disturbances | 0.8 (0, 4) | 1.0 (0, 4) | NP |
| Sleeping more during the day | 0.7 (0, 3) | 1.2 (0, 4) | NP |
| Stereotypic & motor behaviors (p=0.060) | |||
| Rigid/fixed in ideas/opinions | 0.4 (0, 2) | 0.9 (0, 4) | 0.04 |
| Develops routines | 0.06 (0, 1) | 0.6 (0, 3) | 0.003 |
| Pre-occupied with time | 0.03 (0, 1) | 0.2 (0, 3) | 0.20 |
| Repeats same phrases/expressions | 0.6 (0, 4) | 0.3 (0, 4) | 0.42 |
| Motivation (p<0.001) | |||
| Less enthusiasm for usual interests | 0.3 (0, 2) | 1.3 (0, 4) | 0.0001 |
| Little interest in doing new things | 0.4 (0, 3) | 1.4 (0, 4) | 0.0004 |
| Fails to keep in contact with friends/family | 0.3 (0, 2) | 1.0 (0, 4) | 0.0005 |
| Indifferent to worries/concerns of family | 0 (0, 0) | 0.4 (0, 3) | 0.004 |
| Reduced affection | 0.09 (0, 2) | 0.7 (0, 4) | 0.0007 |
Data shown as mean (minimum, maximum). NP = Not performed
Higher scores denote worse performance.
All NPI-Q and CBI-R significant differences between PCA and LPA remained in our subsamples that were matched by age and disease duration. The only exception to this was NPI-Q depression p=0.03; restless/agitation p=0.03; and indifferent to friends/family p=0.02, where the p values were above 0.01 in the matched samples.
Longitudinal neuropsychiatric symptoms analyses
The groups showed no significant differences on any symptom on the NPI-Q longitudinally (Table 4). PCA participants had an average rate of worsening of neuropsychiatric symptoms of 1.2 and LPA participants of 1.3. On the longitudinal CBI-R analyses (Table 5), there were few significant differences observed between groups. On self-care subscores, the PCA group demonstrated faster rates of worsening over time on difficulty with grooming self (p=0.01) and with dressing self (p=0.01) in comparison to the LPA group.
Table 4.
Rate of change of symptom severity on the NPI-Q over time
| Symptoms | LPA (N=26) | PCA (N=33) | p-value |
|---|---|---|---|
| Total score/36 | 1.3 (−3, 7) | 1.2 (−5, 8) | 0.99 |
| Delusions/3 | −0.04 (−1, 0) | 0.2 (0, 2) | 0.03 |
| Hallucinations/3 | 0 (0, 0) | −0.03 (−1, 1) | 0.72 |
| Agitation/3 | 0.02 (−2, 1) | 0.06 (−2, 2) | 0.99 |
| Depression/3 | 0.3 (−1, 2) | 0.2 (−1, 2) | 0.81 |
| Anxiety/3 | 0.3 (−.5, 2) | 0.1 (−2, 2) | 0.60 |
| Euphoria/3 | 0.04 (0, 1) | 0.03 (−1, 1) | 0.99 |
| Apathy/3 | 0.08 (−2, 1) | 0.1 (−2, 2) | 0.90 |
| Disinhibition/3 | 0.2 (0, 1) | 0.1 (−2, 2) | 0.99 |
| Irritability/3 | 0.1 (−1, 2) | 0.04 (−2, 1) | 0.71 |
| Motor behavior/3 | 0.08 (0, 1) | 0.2 (0, 1) | 0.44 |
| Nighttime behavior/3 | 0.2 (−1, 1) | 0.3 (−1, 3) | 0.80 |
| Appetite/3 | 0.2 (0, 2) | 0.3 (−.5, 2) | 0.30 |
Data shown as mean (minimum, maximum).
Higher scores denote worse performance.
Table 5.
Rate of change of severity symptoms on the CBI-R over time
| Symptom | LPA (N=26) | PCA (N=33) | P-value |
|---|---|---|---|
| CBI total | 11.5 (−18, 46) | 10.5 (−13, 34) | 0.86 |
| CBI memory & orientation (p=0.748) | |||
| Poor day to day memory | 0.7 (−1, 4) | 0.4 (−1, 2) | NP |
| Asks same questions | 0.6 (−1, 3) | 0.5 (−2, 2) | NP |
| Loses/misplaces things | 0.3 (−2, 4) | 0.04 (−1, 1) | NP |
| Forgets names of people | 0.3 (−2, 2) | 0.2 (−1, 2) | NP |
| Forgets names of objects/things | 0.2 (−2, 2) | 0.3 (−2, 2) | NP |
| Poor concentration | 0.5 (−1, 2) | 0.2 (−3, 3) | NP |
| Forgets what day it is | 0.4 (−1, 3) | 0.6 (−1, 3) | NP |
| Becomes confused in unusual surroundings | 0.4 (−4, 3) | 0.3 (−1, 3) | NP |
| Everyday skills (p=0.304) | |||
| Difficulty using electrical appliances | 0.7 (−1, 3) | 0.7 (−2, 3) | NP |
| Difficulty writing | 0.8 (−1, 3) | 0.4 (−4, 4) | NP |
| Difficulty using phone | 0.9 (−2, 3) | 0.3 (−3, 3) | NP |
| Difficulties making hot drink | 0.3 (−1, 3) | 0.6 (−2, 4) | NP |
| Problems with money/bills | 1.1 (0, 4) | 0.6 (−3, 4) | NP |
| Self-care (p<0.001) | |||
| Difficulty grooming self | 0.06 (0, 1) | 0.5 (−2, 4) | 0.01 |
| Difficulty dressing self | 0.02 (−1, 1) | 0.4 (−3, 2) | 0.01 |
| Difficulty feeding self w/out help | −0.08 (−1, 0) | 0.2 (−1, 2) | 0.04 |
| Difficulty bathing | −0.04 (−1, 0) | 0.2 (0, 2) | 0.03 |
| Abnormal behavior (p=0.660) | |||
| Misplaced humor | 0.2 (−1, 3) | 0.1 (−3, 2) | NP |
| Temper outburst | 0.4 (−2, 3) | 0 (−3, 2) | NP |
| Uncooperative | 0.3 (−1, 3) | −0.06 (−1, 1) | NP |
| Socially embarrassing behavior | 0.2 (−2, 2) | 0.2 (−2, 3) | NP |
| Tactless/suggestive remarks | 0 (−1, 2) | 0.09 (−2, 2) | NP |
| Acts impulsively | 0.2 (−1, 2) | −0.03 (−2, 2) | NP |
| Mood (p=0.576) | |||
| Cries | 0.2 (−1, 1) | 0.05 (−1, 1) | NP |
| Sad/depressed | 0.3 (−1, 3) | −0.04 (−1, 2) | NP |
| Restless/agitated | 0.2 (−2, 2) | 0.4 (−2, 2) | NP |
| Irritable | 0.3 (−1, 2) | 0.09 (−2, 2) | NP |
| Beliefs (p=0.801) | |||
| Visual hallucinations | −0.04 (−1, 0) | −0.06 (−2, 3) | NP |
| Auditory hallucinations | 0 (0, 0) | −0.08 (−2, .33) | NP |
| Odd/bizarre ideas | 0.04 (0, 1) | 0.03 (−1, 1) | NP |
| Eating habits (p=0.184) | |||
| Prefers sweets | 0.2 (−1, 2) | 0.5 (−2, 3) | NP |
| Wants to eat same food repeatedly | 0.6 (−1, 3) | 0.5 (−2, 2) | NP |
| Larger appetite | −0.08 (−1, 1) | 0.2 (−3, 3) | NP |
| Decline in table manners | 0.1 (0, 2) | 0.2 (−1, 3) | NP |
| Sleep (0.177) | |||
| Sleep disturbances | 0 (−3, 2) | 0.07 (−2, 3) | NP |
| Sleeping more during the day | −0.1 (−2, 2) | 0.2 (−1, 4) | NP |
| Stereotypic & motor behaviors (0.745) | |||
| Rigid/fixed in ideas/opinions | 0.06 (−2, 2) | 0.03 (−4, 2) | NP |
| Develops routines | 0.2 (−1, 2) | 0.02 (−3, 3) | NP |
| Pre-occupied with time | 0.2 (0, 3) | 0.4 (0, 3) | NP |
| Repeats same phrases/expressions | −0.08 (−3, 2) | 0.3 (−2, 4) | NP |
| Motivation (0.171) | |||
| Less enthusiasm for usual interests | 0.4 (−1, 3) | 0.03 (−2, 2) | NP |
| Little interest in doing new things | 0.3 (−1, 3) | −0.02 (−2, 2) | NP |
| Fails to keep in contact with friends/family | 0.4 (−1, 2) | 0.3 (−1, 2) | NP |
| Indifferent to worries/concerns of family | 0.3 (0, 3) | 0.2 (−2, 2) | NP |
| Reduced affection | 0.2 (−2, 3) | 0.06 (−1, 3) | NP |
Data shown as mean (minimum, maximum).
Higher scores denote worse performance.
NP = Not performed
Correlations between cognitive tests and NPI-Q and CBI-R
There were no correlations between performance on cognitive test scores (AVLT, BNT, Letter fluency test or VOSP Letters) and performance on the NPI-Q total and CBI-R total with one exception (Table 6). We did see a negative correlation between performance on the VOSP fragmented letter test and the NPI-Q and CBI-R total scores across the entire cohort, and between the VOSP and the CBI-R total in the PCA only cohort.
Table 6:
Correlations between cognitive tests and performance on the NPI-Q and CBI-R
| Test | LPA + PCA | LPA only | PCA only | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| NPI-Q | CBI-R | NPI-Q | CBI-R | NPI-Q | CBI-R | |||||||
| Rho | p-value | Rho | p-value | Rho | p-value | Rho | p-value | Rho | p-Value | Rho | p-value | |
| AVLT | −2.62 | 0.023 | −0.276 | 0.017 | −0.318 | 0.081 | −0.253 | 0.169 | −0.244 | 0.111 | −0.283 | 0.066 |
| BNT | −0.003 | 0.977 | −0.031 | 0.801 | −0.180 | 0.333 | −0.133 | 0.477 | −0.094 | 0.558 | −0.252 | 0.177 |
| Letter Fluency | −0.003 | 0.980 | −0.031 | 0.794 | 0.010 | 0.957 | −0.103 | 0.575 | −0.210 | 0.171 | −0.327 | 0.032 |
| VOSP Letters | −0.357 | 0.002 | −0.553 | <0.001 | −0.149 | 0.415 | −0.284 | 0.116 | −0.234 | 0.131 | −0.472 | 0.002 |
AVLT = Auditory Verbal Learning Test, BNT = Boston, Naming Test, VOSP = Visual Object and Space Perception Battery
LPA = Logopenic Progressive Aphasia, PCA = Posterior Cortical Atrophy
CBI -R = Cambridge Behavioral Inventory-Revised, NPI-Q = Neuropsychiatric Inventory Questionnaire
Participant medication data
There were no significant differences in the proportion of patients taking, antidepressants, anti-anxiety medications, antipsychotics, sleep aids or cholinesterase inhibitors between groups (Table 7). After their baseline assessment, 45.7% of PCA participants were on antidepressants, 28.3% were on anti-anxiety medications, 21.7% were on anti-psychotic medications, and 39.1% were on anti-cholinesterase inhibitors. In the LPA group, 43.8% of participants were taking antidepressants post-baseline, 46.9% were taking anti-anxiety medications, 18.8% were taking antipsychotic medications, 3.1% were using a sleep aid, and 68.8% were taking anti-cholinesterase inhibitors. Four LPA participants and seven PCA participants showed improvement in the severity of symptoms over time (Table 7). We did not see fluctuations of scores as only one of the 11 participants had been evaluated more than twice. We did not observe any patterns of symptom improvement in either the PCA or the LPA cohort and with any specific medication class. Hence, there was no obvious relationship between which symptom/s improved and the class of medication the participant took after the baseline evaluation.
Table 7:
Percentage of participants on different categories of medications while in the study
| Medication | LPA (N=32) | PCA (N=46) | |||
|---|---|---|---|---|---|
| Anti-depressants (Sertraline, Escitalopram, Citalopram, Venlafaxine, Paroxetine, Duloxetine, Bupropion, Trazodone, Vortioxetine, Mirtazapine) | 46.9% (N=15) | 47.8% (N=22) | |||
| Anti-anxiety medications (Lorazepam, Alprazolam, Clonazepam) | 46.9% (N=15) | 34.8% (N=16) | |||
| Anti-psychotic medications (Cariprazine, Risperidone, Haloperidol, Quetiapine, Olanzapine) | 18.8% (N=6) | 21.7% (N=10) | |||
| Sleep aid (Zopiclone) | 3.1% (N=1) | 0% (N=0) | |||
| Cholinesterase inhibitors (Donepezil, Memantine, and Rivastigmine) | 68.8% (N=22) | 39.1% (N=18) | |||
| Participants whose neuropsychiatric symptoms improved after starting medication. | |||||
| Change in total NPI-Q score between years | Anti-depressant | Anti-anxiety | Anti-psychotic | Sleep aid | Cholinesterase inhibitors |
| LPA-1 (4 -> 3) | N/A | Lorazepam (0.5mg) | N/A | Zopiclone (3mg) | N/A |
| LPA-2 (2 -> 1) | Citalopram (20mg) | N/A | Quetiapine (25mg) | N/A | Donepezil |
| LPA-3 (3 -> 0) | Citalopram (20mg) | Lorazepam (0.5mg) | N/A | N/A | Donepezil |
| LPA-4 (4 -> 2) | Escitalopram (10mg) | N/A | Quetiapine (50mg) | N/A | Donepezil |
| PCA-1 (6 ->1) | Mirtazapine | N/A | Quetiapine | N/A | N/A |
| PCA-2 (13 -> 9) | Bupropion (150mg), Citalopram (40mg), Trazodone (50mg) | Lorazepam (2mg) | Haloperidol (2mg), Quetiapine (100mg) | N/A | Donepezil |
| PCA-3 (2 -> 1 -> 0) | N/A | Lorazepam (0.5mg) | N/A | N/A | N/A |
| PCA-4 (14 -> 12) | Sertraline (100mg) | Lorazepam (0.5 mg) | Risperidone (0.5mg) | N/A | N/A |
| PCA-5 (4 -> 3) | Trazodone (100mg) | N/A | Risperidone (3mg) | N/A | N/A |
| PCA-6 (8 -> 7) | Escitalopram (20mg), Bupropion (150mg) | N/A | N/A | N/A | N/A |
| PCA-7 (5 -> 4) | Duloxetine (60mg) | Lorazepam (0.5mg) | N/A | N/A | Memantine |
New drug was administered after baseline testing in all 11 patients.
DISCUSSION
The present study describes the behavioral, neuropsychiatric, and ADL profiles of PCA and LPA. By comparing the presence/absence and severity of caregiver-reported symptoms at baseline and longitudinally using the NPI-Q and CBI-R, we show that neuropsychiatric symptoms are more common and severe in PCA compared to LPA.
Baseline analyses of the presence of neuropsychiatric symptoms on the NPI-Q and CBI-R demonstrate that neuropsychiatric symptoms are extremely common in PCA and LPA. At baseline, most caregivers in both groups reported at least one neuropsychiatric symptom. On the NPI-Q at baseline, the most common neuropsychiatric symptoms in the PCA group were depression/dysphoria, anxiety, and agitation/aggression. The PCA group also endorsed the highest severity of depression/dysphoria, anxiety, apathy/indifference, irritability/lability, and agitation/aggression at baseline. It is difficult to compare these findings with previous literature on neuropsychiatric symptoms in PCA because published data differs with respect to the criteria and methods used for capturing and measuring symptoms. A previous study conducted by Isella et al [18] compared NPI scores of 20 PCA with 20 typical AD participants and found that behavioral and psychological symptoms were present in 95 percent of PCA participants with the most prevalent and severe being apathy, anxiety, depression, and irritability. Moreover, a separate study [17] compared the neuropsychiatric profiles of 28 PCA and 34 typical AD participants by examining the presence of neuropsychiatric symptoms on the NPI and showed that the four most common neuropsychiatric symptoms in PCA were depression, irritability, apathy, and anxiety. These investigations utilized different methods for capturing and scoring symptoms and had smaller sample sizes which likely accounts for the slight variability in results. However, despite differences in methods, we found a similar neuropsychiatric profile in our PCA group. This study builds on prior studies by assessing behavioral, neuropsychiatric symptoms and ADLs in PCA using the CBI-R. Our results suggest that the most prominent (experienced by over 75 percent of participants) and severe (average score of 1.8 or above) behavioral symptoms or ADL changes experienced by individuals with PCA pertain to losing and misplacing things, difficulty writing, becoming confused in unusual surroundings, poor day to day memory, difficulty using electrical appliances, problems with money/bills, difficulty using the phone, and forgetting what day it is. It would be expected that these behavioral symptoms would be frequently affected in PCA participants given that PCA patients have impaired calculation [8, 13, 36] which would cause problems with money/paying bills, and poor visual memory, visuospatial, and visuoperceptual function [5, 8, 36] which could lead to confusion in unusual surroundings, and difficulty using appliances and the phone. Patients with PCA, like with any other dementia syndrome, tend to lose track of what day it is, most commonly from a combination of not caring about the day and not being engaged in an occupation requiring knowledge about what day it is.
On the NPI-Q at baseline, the most common neuropsychiatric symptoms in the LPA group were anxiety, depression/dysphoria, and irritability/lability. With respect to NPI-Q severity of symptoms at baseline, the LPA participants endorsed the highest severity of anxiety, depression/dysphoria, apathy/indifference, and irritability/lability. To our knowledge, only one previous investigation has evaluated neuropsychiatric symptoms in LPA. Employing the NPI-Q, Singh et al [14]compared neuropsychiatric symptoms among three subtypes of primary progressive aphasia (PPA). In 37 LPA participants, the most common and severe neuropsychiatric symptoms were irritability in 48.6 percent of participants, depression in 46 percent, anxiety in 38 percent, and apathy in 32.4 percent. Remarkably, in our LPA group, we show almost the exact same neuropsychiatric profile. No prior studies have evaluated behavioral and neuropsychiatric symptoms in LPA using the CBI-R. Nonetheless, the most prominent (experienced by over 75 percent of participants) and severe (average score of 1.8 or above) behavioral symptoms experienced by individuals with LPA related to forgetting the names of objects/things, losing and misplacing things, and difficulty writing. These findings are conformant with the clinical profile of LPA. It would be expected that these behavioral symptoms would be frequently affected in the LPA participants given that LPA patients have impaired language function affecting naming, spelling, grammar, and comprehension, in spoken and written language. LPA patients also have mild-moderate executive dysfunction [37, 38] which is likely to lead to impaired organization which in turn could lead to them losing and misplacing things.
The main differences between participants with PCA and LPA at baseline were that PCA participants demonstrated a worse NPI-Q total score and had a higher occurrence and severity of depression. Given that it has been shown that depressed individuals perform worse on memory and motor tasks [39], depression could help to explain the higher occurrence and severity of memory difficulties and difficulty with motor tasks in the PCA group. Additionally, depression has been associated with motivational deficits [39], which could also explain the higher occurrence and severity of problems with motivation in the PCA group. Another consideration is that disease pathology is playing a role in this difference. Poor performance on motor task could be related to underlying co-existing Lewy body disease pathology, as Lewy body disease have been reported to co-occur in PCA and to a lesser extent in LPA [40, 41], as well as regional burden of the primary Alzheimer’s disease pathology which may be greater in PCA than in LPA.
Further, at baseline, a larger proportion of PCA compared to LPA participants caregivers endorsed memory and orientation deficits such as becoming confused in unusual surroundings, difficulties with everyday skills and self-care, abnormal behaviors such as temper outbursts and being uncooperative, mood changes including crying, sadness/depression, and restlessness/agitation, stereotypic behaviors such as developing routines, and problems with motivation. Similarly, PCA participants had a worse CBI-R total score than LPA and higher severities of losing and misplacing things, forgetting the names of objects/things, becoming confused in unusual surroundings, difficulties with everyday skills and self-care including grooming and dressing, abnormal behaviors such as temper outbursts and being uncooperative, mood changes including restlessness/agitation and irritability, stereotypic behaviors like developing routines, and problems with motivation. Results pertaining to memory tasks, motor tasks, and motivation again could be explained by the higher occurrence and severity of depression in PCA participants. Additional findings could be driven by the profound visual impairments, including visuospatial and visuoperceptual deficits, that individuals with PCA experience. Problems with abnormal behaviors and mood may occur as a result of the frustration and apprehension caused by functional deficits. Importantly, after matching groups according to age at onset, age at baseline test, and disease duration all significant results, except for three variables that were at or below p<0.05, were maintained. Thus, exemplifying that differences between groups are related to the syndromes rather than differences in disease phase. The longitudinal results demonstrated that the PCA group had faster rates of worsening over time on difficulty with grooming self and with dressing self, compared to the LPA group, which again is likely related to worsening visual impairments in PCA participants.
We did not find evidence for performance on the NPI-Q and CBI-R to be related to the severity of cognitive impairment in executive function, language, or episodic memory. There was a significant correlation between performance on the VOSP fragment letter test, a test of visuoperceptual function, and the NPI-Q and CBI-R total scores. While it is possible that there is a direct relationship between impaired visuoperceptual function and more neuropsychiatric and behavioral change, we suspect that disease severity is confounding the relationship.
A high proportion of the PCA and LPA patients in this cohort were taking medications at the time of the baseline evaluation and when they returned for follow-up. In this study, we observed improvement on the NPI-Q total score in eleven participants with improvement occurring in the context of having started taking new medications. With-that-said, of the participants who improved, six had an NPI-Q total score that decreased by only 1-point and two had a score that decreased by 2-points. Hence, in eight of the 11 with a lower score at the second time point, the change may be unrelated to any medication use and was simply due to variability in how the caregiver decided to rate the severity of the symptom on that particular day. Of the remaining three patients whose score changed by more than 2-points, it was difficult to determine whether the change was related to any one medication use, although we suspect medication use may be one of the reasons for improvement in the score. Future studies are needed to address this important issue.
The findings from this study have clinical implications for the assessment and treatment of patients with PCA and LPA. We have provided evidence of neuropsychiatric and behavioral impairment, beyond the core features that define these two atypical AD variants. Clinicians need to be cognizant of neuropsychiatric and behavioral deficits and changes in ADLs when evaluating PCA and LPA patients, and monitor change over time whether intervention has been initiated or not. It is important to address neuropsychiatric and behavioral symptoms in all PCA and LPA patients, regardless of whether the patient or caregiver reports symptoms. Treatment with medication use and/or behavioral therapy may offer benefit to these patients. We did find that patients with PCA have more severe and frequent neuropsychiatric and behavioral change, and more difficulty with ADLs suggesting that these problems may be more of an issue with PCA than LPA. We strongly, however, advocate for a similar approach when addressing these issues in both variants.
Strengths and limitations
The strengths of our study included a relatively large sample size and the availability of two behavioral and neuropsychiatric questionnaires. Because the NPI-Q is a measure of neuropsychiatric symptoms, utilizing the CBI-R as a more extensive assessment of the patient as a whole allowed us to comprehensively evaluate additional behavioral symptoms and performance on ADLs in our cohort. We also considered both symptom presence/absence and symptom severity in our analyses and had available longitudinal data for the large majority of our participants. Further, we matched participants according to age at onset, age at baseline, and disease duration. Limitations of our study include a predominantly female and highly educated cohort, and a lack of racial and ethnic diversity which limits generalizability of the findings to a more racial and ethnically diverse population. We also acknowledge that although we decreased our significance threshold to P<0.01, with the assumption that the NPI-Q, CBI-I, and longitudinal assessments should each be considered independent, there is still a small risk of reporting a few type-I errors.
Conclusions
To summarize, to our knowledge, this is the first study to compare behavioral, neuropsychiatric, and ADL profiles of PCA and LPA, and it is among the limited number of studies that have described the behavioral and neuropsychiatric profiles of PCA and LPA. We demonstrated that neuropsychiatric symptoms are quite common in PCA and LPA, although they are more common and severe in PCA. These findings are clinically relevant given that both PCA and LPA participants experienced neuropsychiatric symptoms which could be improved with pharmacological interventions as well as additional modes of therapy. In fact, in our cohort, we found that four LPA and seven PCA participants had improvements in neuropsychiatric symptoms after starting medications post-baseline. Further, our results also may be meaningful with respect to patient care and prognosis given that PCA patients had higher frequencies and severity of depression at baseline and had faster rates of worsening over time on tasks pertaining to self-care which will lead to different care challenges.
Acknowledgments
The authors would like to acknowledge their gratuity to the patients and families who participated in this longitudinal investigation. We are also grateful for the clinical and administartive support staff at the Mayo Clinic in Rochester, MN.
Funding
This project is funded by NIH grant R01-AG50603.
Footnotes
Conflicts of Interest
Dr. Whitwell is an Associate Editor of this journal but was not involved in the peer-review process nor had any information regarding its peer-review. All other authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
Data Availability
Anonymized data are available from the corresponding author upon request from any qualified investigator for purposes of replicating procedures and results.
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Associated Data
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Data Availability Statement
Anonymized data are available from the corresponding author upon request from any qualified investigator for purposes of replicating procedures and results.