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. Author manuscript; available in PMC: 2022 Mar 23.
Published in final edited form as: Dement Geriatr Cogn Disord. 2021 Mar 23;50(1):17–28. doi: 10.1159/000513979

Neurobehavioral Characteristics of FDG-PET Defined Right Dominant Semantic Dementia: a longitudinal study

Alexis X Curet Burleson 1,2, Nha Trang Thu Pham 3, Marina Buciuc 2, Hugo Botha 2, Joseph R Duffy 2, Heather M Clark 2, Rene L Utianski 2, Mary M Machulda 4, Matthew C Baker 5, Rosa Rademakers 5, Val J Lowe 3, Jennifer L Whitwell 3, Keith A Josephs 2
PMCID: PMC8243786  NIHMSID: NIHMS1665783  PMID: 33756466

Abstract

Introduction:

Semantic dementia (SD) is characterized by fluent speech, anomia and loss of word and object knowledge with varying degrees of right and left anterior-medial temporal lobe hypometabolism on [18F] fluorodeoxyglucose (FDG) PET. We assess neurobehavioral features in semantic dementia patients across three FDG-PET defined metabolic patterns, and investigated progression over time.

Methods:

Thirty-four subjects with SD who completed FDG-PET were classified into a left and right dominant group based on the degree of hypometabolism in each temporal lobe. The left dominant group was further sub-divided depending on whether hypometabolism in the right temporal lobe was more or less than 2 standard deviations from controls (left+ group). Neurobehavioral characteristics determined using the Neuropsychiatric Inventory-Questionnaire (NPI-Q) were compared across groups. Progression of NPI-Q scores and FDG-PET hypometabolism was assessed in 14 subjects with longitudinal follow-up.

Results:

The right-dominant group performed worse on the NPI-Q, had a greater frequency of abnormal behaviors and more severe disinhibition compared to the left-dominant group. Performance on the NPI-Q and severity of disinhibition correlated with right medial and lateral, but not left, temporal lobe hypometabolism. Severity of abnormal behaviors worsened over time in most left-dominant and left+ subjects, but appeared to improve in the two right-dominant subjects with longitudinal follow-up. All groups showed progressive worsening of metabolism in both temporal lobes over time, with hypometabolism spreading from anteromedial to posterior temporal regions. However, degree of temporal lobe asymmetry remained relatively constant over time.

Conclusion:

In semantic dementia, neurobehavioral features, especially disinhibition, are associated with right medial and lateral temporal lobe hypometabolism and commonly develop over time even in subjects that present with left-dominant patterns of hypometabolism.

Keywords: semantic dementia, FDG-PET, right temporal variant, right temporal pole, C9ORF72

INTRODUCTION

Semantic dementia (SD), a term first coined by Snowden and colleagues in 1989[1] refers to a neurodegenerative syndrome described by Elizabeth Warrington in 1975[2]. Patients with SD have fluent speech with evidence of loss of word and object knowledge. Neurological examination in patients with SD reveals anomia, surface dyslexia and word and object associative agnosia with preserved episodic memory, while neuroimaging identifies brain atrophy of the left and right anteromedial temporal lobes[2, 1]. Neurobehavioral features, particularly disinhibition, aberrant motor behaviors and changes in appetite, as measured by the Neuropsychiatric Inventory Questionnaire (NPI-Q)[3, 4], have been associated with SD[5], particularly in those with right-dominant patterns of atrophy[6–11]. However, little is known about the relationship of neurobehavioral features in SD and [18F]fluorodeoxyglucose PET (FDG-PET), and it is unclear whether abnormal behaviors are truly associated with right-temporal SD (i.e. only cases where right temporal involvement is greater than left) or rather degree of involvement of the right temporal lobe independent of whether the right or left temporal lobe is more atrophic. Furthermore, little is known about the progression of abnormal behaviors over time in SD. We hypothesized that neurobehavioral features in SD are associated with hypometabolism of the right temporal lobe and not to a distinct right-temporal variant of SD, and that neurobehavioral features will worsen over time with worsening of right temporal hypometabolism.

MATERIALS AND METHODS

Patients

Thirty-four patients who fulfilled diagnostic criteria for SD[12, 13] were enrolled into one of two NIH-funded grants by the Mayo Clinic Neurodegenerative Research Group (NRG), between 10–1–2010 and 9–30–2018. All 34 SD patients underwent detailed speech and language, neurological and neuropsychological evaluations, an [18F]fluorodeoxyglucose (FDG)-PET and a 3T head MRI, as previously described[13]. Thirty-one also underwent Pittsburgh Compound B (PiB)-PET. Neurobehavioral abnormalities were assessed with the NPI-Q[3, 4]. To fulfill criteria for SD[12, 13] all patients must have had evidence of a perceptual disorder/associative agnosia, e.g. prosopagnosia, impaired object/animal recognition, or auditory agnosia. Patients were excluded if they met criteria for Alzheimer’s disease[14] or logopenic/agrammatic primary progressive aphasia[15], if they had concurrent illnesses that could account for the clinical symptoms, or structural brain abnormalities. Patients meeting criteria for behavioral variant frontotemporal dementia (bvFTD)[16] without evidence of a perceptual/associative agnosia were excluded. Fourteen patients underwent longitudinal follow-up, with two-six yearly longitudinal FDG-PET scans performed, spanning up to 6 years of the disease illness (total of 43 FDG-PET scans available for analysis). All patients were screened for mutations in the microtubule associated protein tau (MAPT) and progranulin genes, and for repeat expansions in C9ORF72[17].

Neuroimaging analysis

All FDG-PET scans were acquired using a GE PET/CT scanner. Participants were injected with 18F-FDG of approximately 459 MBq (range 367–576 MBq) and after a 30-minute uptake period an 8-minute scan was performed. FDG-PET images were normalized to the pons. All participants also underwent a 3T MRI protocol including a 3D magnetization-prepared rapid-acquisition gradient-echo (MPRAGE)[18]. Individual-level patterns of hypometabolism were analyzed using 3D stereotactic surface projections[19] using CortexID suite (GE Healthcare https://www.gehealthcare.co.uk/-/media/13c81ada33df479ebb5e45f450f13c1b.pdf) whereby activity at each voxel is normalized to the pons and Z-scored to an age-segmented normative database. Average Z-scores for left and right medial and lateral temporal lobes were outputted from CortexID (negative scores represent hypometabolism). Asymmetry scores (left Z-score minus right Z-score) were calculated for medial and lateral temporal regions. Patients were classified into three groups based on the baseline FDG-PET: 1) Left-dominant = left medial and lateral temporal Z-score worse than right, at least a 0.5 difference in Z-scores between hemispheres, and Z-scores for right temporal regions greater than −2.0 (i.e. relatively preserved). 2) Left+ = same as above, except Z-score for one of the right temporal regions was less than −2.0 (i.e. shows significant hypometabolism). 3) Right-dominant = right medial and lateral temporal Z-scores worse than left, and at least 0.5 difference between hemispheres. All patients could be classified using these rules into left-dominant (n = 20), left+ (n = 7) and right-dominant (n = 7) groups.

Voxel-level comparisons of FDG-PET metabolism and MRI grey matter volume were performed between the three SD groups and 20 age-matched healthy controls using SPM12 in order to visualize global patterns of degeneration in each group, using methods that have been previously described[20, 18]. Healthy controls were included if they did not have any complaints of cognitive, motor or behavioral abnormalities and performed normally on the Mini-Mental State Examination (≥26) (median(range) = 29(26–30)). Voxel-wise t-tests were used to compare SD groups to controls, including age and gender as covariates. Results were assessed after family wise error (FWE) correction at p < 0.05. The FDG-PET analysis was repeated using a two-compartment correction for partial volume correction. PiB-PET positivity was determined using global uptake, as previously described[18].

Statistical analysis

Group comparisons were performed using Chi-squared test/Fisher’s exact tests (categorical variables) or Kruskall-Wallis test (continuous variables). Intergroup post-hoc testing using Mann Whitney U was performed if the Kruskall-Wallis test was significant. For the NPI-Q, severity scores for each abnormal behavior, and the percentage of participants which showed each abnormal behavior (i.e. scored 1 or more) were assessed. Spearman rank correlations were performed to assess associations between FDG-PET Z scores and clinical variables. All statistical analyses were performed using JMP Pro 14.1.0 (SAS Institute Inc.) software, significance p < 0.05. Longitudinal NPI-Q and FDG scores were plotted and annualized rates of change calculated using first and last available visit; no statistical analyses were performed across groups due to small patient numbers.

RESULTS

Of the 34 SD patients in the study, 18 (53%) were female. No demographic features differed across groups (Table 1). One right-dominant patient screened positive for C9ORF72 repeat expansions; no family history was present in this patient.

Table 1:

Demographic, clinical and FDG-PET variables at baseline across SD groups

Characteristic (% or median (Interquartile Range))
Left-dominant (n=20) left+ (n=7) Right-dominant (n=7) p-valuea
DEMOGRAPHICS
Sex, % female 11 (55%) 3 (42.9%) 4 (57.1%) 0.8359
Education, years 15.5 (14,16) 15 (13, 16) 18 (13, 18) 0.3871
Age at Onset, years 64 (56.25, 67) 61 (52, 68) 58.5 (53, 65) 0.6281
Age at Evaluation, years 67.5 (59, 72) 64 (56, 69) 67 (60, 68) 0.6256
Onset to Evaluation, years 3 (2, 4) 3 (2, 6) 4 (1.5, 5) 0.7304
Amyloid-PET, % positive 6/19 (32%) 1/6 (17%) 3/6 (50%) 0.4640
COGNITIVE TESTS
Montreal Cognitive Assessment/30b,c 21 (19.25, 23) 18 (15, 23) 24 (24, 26) 0.0353
Neuropsychiatric inventory/36b,c 4 (2, 5) 4 (3, 10) 9 (8,5, 12) 0.0391
Facial recognition/10c 10 (6.25, 10) 7 (3, 7) 1 (0, 6) 0.0093
Western aphasia battery-Revised AQ/100 90 (80.9, 93.55) 82.3 (70.5, 93.4) 91.2 (86.8, 95) 0.323
SYDBAT naming/30 13.5 (8, 18.3) 4.5 (2.3, 7) 8 (5, 11) 0.1788
SYDBAT semantic association/30c,d 20 (19, 23) 15 (10, 17) 10 (8, 15) 0.0066
Picture Peabody Vocabulary 80 (61, 86) 62 (51.5, 80.5) 71.5 (68.75, 82.25) 0.3518
Pyramids and Palm Trees (word-word)/52 44.5 (40.5, 47) 31 (30, 41) 42 (39, 43) 0.0770
Reading Irregular words/10 9 (7, 10) 4 (3.5, 8) 9 (7.5, 10) 0.2935
Animal Fluency 9.5 (5.8, 14) 8 (3, 9) 9 (7.5, 10) 0.3504
Frontal Assessment Battery/18 15.5 (14.25, 17) 14 (14, 16) 16 (15, 18) 0.3101
Trail Making Test B, secs 80 (65, 148) 110 (98, 125) 134 (96, 153) 0.5087
Trail Making Test B-A, secs 53 (35, 94) 59 (56, 83) 61 (38, 77) 0.6662
FDG-PET MEASURES
Right Lateral Temporal z-scoreb,c,d −0.8 (−1.19, −0.355) −1.89 (−1.92, −1.36) −3.07 (−3.6, −2.3) 0.0001
Left Lateral Temporal z-scoreb,c −2.63 (−3.32, −2.13) −2.82 (−3.08, −2.02) −1.36 (−1.8, −0.94) 0.0074
Right Medial Temporal z-scorec,d −0.76 (−1.49, 0.302) −2.94 (−3.47, −2.16) −3.14 (−5.1, −2.99) 0.0001
Left Medial Temporal z-scoreb,c −3.41 (−4.44, −2.40) −4.11 (−4.65, −3.79) −1.93 (−3.04, −1.39) 0.0143
Asymmetry Score (Lateral) b,c,d −1.93 (−2.22, −1.38) −0.97 (−1.09, −0.19) 1.66 (1.07, 2.17) 0.0001
Asymmetry Score (Medial) b,c,d −2.93 (−3.60, −2.29) −1.09 (−2.14, −0.85) 1.75 (1.16, 1.96) 0.0001
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a=

p-value from Kruskal-Wallis test

b=

significant difference between left+ and right-dominant.

c=

significant difference between right-dominant and left-dominant

d=

significant difference between left+ and left-dominant.

AQ = Aphasia Quotient; SYDBAT = Sydney Language Battery; PET=positron emission tomography

FDG-PET and MRI patterns across groups

The voxel-level maps showed expected patterns of temporal lobe hypometabolism in all three groups (shown in Fig. 1). The left-dominant group only showed hypometabolism of left anteromedial temporal lobe, while the left+ group showed hypometabolism of both left and right anteromedial temporal lobes, most severe on the left. The right-dominant group showed hypometabolism in right anteromedial temporal lobe, with mild involvement of the left. Results were the same after partial volume correction. The left+ group showed the least amount of absolute temporal asymmetry as would be expected (shown in Table 1). Patterns of volume loss were similar to patterns of hypometabolism, although showed milder abnormalities, particularly in lateral temporal regions.

Fig. 1. Voxel-level maps of FDG-PET hypometabolism and MRI grey matter volume loss in left-dominant, left+ and right-dominant SD compared to controls.

Fig. 1.

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Results are shown after family wise error correction at p < 0.05.

Baseline neurobehavioral and clinical differences across groups

The right-dominant group performed better than both the left-dominant and left+ groups on the Montreal Cognitive Assessment Battery, but showed a greater severity of abnormal behaviors than both as measured by the total NPI-Q (shown in Table 1). The right-dominant group also performed worse than the left-dominant group, but not the left+ group, on facial recognition and the Sydney Language Battery semantic association task. When NPI-Q abnormal behaviors were assessed individually (shown in Fig. 2), severity of disinhibition differed across groups (p = 0.03), with the right-dominant group showing more severe disinhibition compared to the left-dominant group (p = 0.001). There was a trend for percentage of participants with disinhibition to differ across groups (p = 0.06), again with a higher frequency in the right-dominant compared to left-dominant group (p = 0.03). The left+ group tended to show greater severity and frequency of disinhibition, anxiety and appetite/eating behaviors compared to left-dominant group, although differences were not significant.

Fig. 2. Relationship of abnormal behaviors to FDG-PET in SD.

Fig. 2.

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Top panel shows box-plots of severity of each of the NPI-Q abnormal behavior, and percentage of patients with each NPI-Q behavior, by group. Bottom panel shows scatter-plots of NPI-Q total score versus right medial and lateral temporal lobe Z scores.

Correlations between FDG-PET and clinical features

Total NPI-Q score correlated with right medial and lateral temporal Z scores (Rs = −0.43/p = 0.01 and Rs = −0.39/p = 0.02, shown in Fig. 2). Right medial and lateral temporal Z scores also correlated with severity of disinhibition (Rs = −0.51/p = 0.002 and Rs = −0.39/p = 0.02) and facial recognition score (Rs = 0.62/p < 0.0001 and Rs = 0.60/p = 0.0002). No correlations were identified with the left temporal lobe.

Longitudinal progression

Demographic features of the subset of patients with longitudinal data are shown in Table 2. Performance on the NPI-Q worsened over time in the majority of the left-dominant and left+ patients, while the two right-dominant patients showed improvement in their NPI-Q scores over time (shown in Fig. 3 and Table 2). Medial and lateral temporal Z scores progressively worsened over time in both hemispheres in the majority of patients (shown in Fig. 4). There was a tendency for rates of decline in metabolism to be greater in right-dominant patients compared to left-dominant and left+ patients (Table 2). Degree of temporal lobe asymmetry did not change much over time (shown in Fig. 4 and Table 2). Hypometabolism in individual patients showed spreading from anteromedial temporal regions to posterior temporal lobe over time, with some spread observed in medial and orbital frontal regions (shown in Fig. 5).

Table 2:

Demographic and longitudinal FDG-PET and NPI-Q change data for the longitudinal sample

Characteristic (% or median (Interquartile Range))
Left-dominant (n=10)a left+ (n=3) Right-dominant (n=3)b
DEMOGRAPHICS
Sex, % female 4 (40%) 1 (33%) 2 (50%)
Education, years 15.5 (14,16) 15 (14, 16) 18 (16.7, 18)
Age at Onset, years 62.5 (58, 67) 53 (53, 57) 60 (57, 63)
Age at Evaluation, years 65.5 (62, 69) 56 (56, 60) 67 (66, 67)
Onset to baseline evaluation, years 2 (2, 4) 3 (2, 4) 4.5 (3.8, 7)
Number of serial clinical evaluations 2.5 (2, 3.3) 2 (2, 2) 2 (2, 2)
Number of serial FDG-PET 3 (2.8, 4.3) 2 (2, 2.5) 2 (2, 3)
Baseline to last NPI-Q, years 3.8 (1.8, 5.2) 2.4 (1.7, 4.4) 1.6 (1.3, 1.9)
Baseline to last FDG-PET, years 4.8 (3, 5.3) 3.6 (2.8, 5.0) 1.9 (1.3, 2.5)
ANNUALIZED RATES OF CHANGE
Neuropsychiatric Inventory 0.61 (−0.61, 1.38) 1.64 (0.82, 1.69) −2.87 (−2.91, −2.83)
Right Lateral Temporal z-score −0.27 (−0.34, −0.11) −0.27 (−0.28, −0.23) −0.54 (−0.63, −0.36)
Left Lateral Temporal z-score −0.25 (−0.37, −0.19) −0.25 (−0.25, −0.24) −0.61 (−0.70, −0.35)
Right Medial Temporal z-score −0.41 (−0.50, −0.37) −0.34 (−0.51, −0.26) −0.83 (−0.93, −0.68)
Left Medial Temporal z-score −0.47 (−0.61, −0.37) −0.38 (−0.41, −0.16) −0.75 (−1.04, −0.72)
Asymmetry Score (Lateral) −0.06 (−0.15, 0.05) 0.02 (−0.01, 0.03) −0.06 (−0.07, 0.01)
Asymmetry Score (Medial) −0.14 (−0.23, 0.10) 0.23 (0.10, 0.24) −0.23 (−0.36, 0.06)
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Annualized rates of change were calculated as (last time-point – first time point)/time interval in years. Positive rates of change for the NPI-Q represent an increase in scores over time. Negative rates of change for FDG-PET z scores represent reduced metabolism over time.

a=

ten left-dominant patients had serial NPI-Q, with eight having serial FDG-PET

b=

three right-dominant patients had serial FDG-PET, with two having serial NPI-Q data

Fig 3.

Fig 3.

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Longitudinal change in NPI-Q total score across patients.

Fig 4.

Fig 4.

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Longitudinal change in FDG-PET temporal lobe Z scores and asymmetry scores across patients.

Fig 5. Longitudinal FDG-PET CortexID Z score maps from a left-dominant, left+ and right-dominant patient.

Fig 5.

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Time from disease onset to scan is shown in the top left of each FDG-PET panel, with lateral and medial Z scores shown on the plots for each patient.

DISCUSSION

This study examined the frequency and severity of abnormal behaviors in SD according to relative hypometabolism of the right and left temporal lobes. We found abnormal behaviors to occur most frequently when hypometabolism of the right temporal lobe was worse than left. However, we also found that in the left-dominant patients, abnormal behavior frequency and severity was greater in those with more right temporal lobe hypometabolism. Furthermore, severity of abnormal behaviors correlated with right temporal metabolism. Over time we found some evidence for behaviors to worsen in those with more left temporal hypometabolism and to improve in those with more right temporal hypometabolism.

Of all the abnormal behaviors, disinhibition was the only one that was significantly different between the left and right-dominant groups. Disinhibition was also more common in the left+ group compared to the left-dominant group; suggesting that dysfunction in the right temporal lobe may contribute to this abnormal behavior. In fact, disinhibition severity correlated with degree of hypometabolism in the right temporal lobe. Disinhibition was not found to differ between left and right variants in other studies of SD but was found to occur in more than 25% of the right-variant[7]. We also observed a similar pattern with performance on our facial recognition test. Indeed, in addition to abnormal behaviors occurring more frequently in the right-temporal variant of SD, more impairment on facial recognition tasks has also been reported in this variant[7, 9] which is not surprising since loss of facial recognition has been linked to the right fusiform gyrus[21, 22].

Longitudinal follow-up was available in 14 patients. Hypometabolism progressed over time in both temporal lobes in the majority of patients regardless of group and the degree of temporal lobe asymmetry remained relatively constant. Previous longitudinal MRI[23–25, 10, 26] and FDG-PET[27, 28] studies in SD have shown progressive degeneration in both temporal lobes of left-dominant patients, with two studies also showing atrophy of both temporal lobes in right-dominant patients [25, 10]. Studies assessing left-dominant patients found faster rates of temporal atrophy in the right hemisphere compared to the left [23, 24], suggesting the right hemisphere may be starting to catch up with the left. In our cohort, we did not find any evidence for faster rates of decline in metabolism in the right hemisphere of the left-dominant patients. Furthermore, we found a tendency for faster rates of decline in right-dominant compared to left-dominant and left+ patients in both temporal lobes. This may suggest a more aggressive disease course in right-dominant SD, although the small number of patients with longitudinal data limited our ability to perform statistical comparisons. Larger studies will be needed to confirm these findings.

The severity of abnormal behaviors measured using the NPI-Q also worsened over time in the majority of the left-dominant and left+ patients, showing that abnormal behaviors can progress in these patients, as others have found[25, 29, 10, 11]. Interestingly, the two right-dominant patients that started with a high NPI-Q score (≥13) showed improvement over time. Improvement was also observed in one left-dominant patient that started with an NPI-Q score of 14. On further review of these three patients, different explanations accounted for the improvement. In one right-dominant patient we noted that the agitation/aggression, depression, anxiety and irritability scores at baseline became less severe over time but striking apathy and indifference developed; moderate disinhibition was consistent over time. In the other two patients, abnormal behaviors present at baseline were rated as less severe at follow-up. It is unclear if the behaviors indeed became less severe or whether the caretakers became more tolerate of the behaviors over time, resulting in a lower rating of severity. It is also possible that treatments may have influenced some reduction in frequency/severity of behaviors, particularly anxiety and depression which are often treated in SD. Other behaviors such as disinhibition can also respond to treatment. Unfortunately, it was not possible to determine the relationship between medication implementation or dose changes and change in behavioral severity in this study. These issues could also explain why a previous study failed to find any correlation between change over time in abnormal behavior and temporal lobe atrophy in SD[25].

Atrophy and hypometabolism has been reported in the frontal lobes in patients with SD in some studies [10, 26, 28], particularly in left-dominant patients [25], although not in others [27, 9, 30]. We did not observe frontal hypometabolism at the group-level at baseline to account for the behaviors and, hence, we hypothesize that the observed behaviors were most likely related to involvement of the right temporal lobe. With-that-said, we did observe mild frontal hypometabolism at the individual-level at baseline and we also did see progressive involvement of the frontal lobe over time in some patients. The frontal lobe has been strongly associated with behavioral changes, with right orbitofrontal cortex associated with disinhibition[31, 32] and medial frontal and prefrontal cortex associated with both disinhibition and apathy[33, 34]. Hence, we cannot exclude the frontal lobe playing a role in behavioral changes in some of our SD patients.

One of our right-dominant patients had a mutation in C9ORF72 demonstrating that this FTD mutation can cause a right-dominant SD. Repeat expansions in C9ORF72 have previously been associated with SD[35, 36], and, in fact, C9ORF72 positive SD cases have been reported with right-dominant temporal atrophy[35] and with concomitant behavioral abnormalities[36], supporting a link between C9ORF72 and right-dominant SD.

An issue worth discussing is the differential diagnosis between right-temporal SD and bvFTD. Both syndromes are characterized by behavioral dyscontrol. However, right-temporal SD requires impairment on tests of nonverbal associative knowledge, while bvFTD does not [12]. Most patients meeting criteria for right temporal SD will also meet current criteria for bvFTD [16] because prosopagnosia, loss of object knowledge, or even alexia, does not exclude a diagnosis of bvFTD. This makes the bvFTD criteria very sensitive[16] but also explains why bvFTD is associated with multiple pathologies[37]. In fact, we have previously demonstrated that right-dominant SD is associated with TDP-43 pathology, while right-temporal variant bvFTD (without loss of non-verbal knowledge) was associated with microtubule-associated protein tau mutations and tau pathology [9]. Furthermore, it has been shown that behaviors in bvFTD are different from behaviors in SD[38] further supporting separating right temporal SD from bvFTD.

The strength of this study includes the relatively large cohort of SD patients with FDG-PET. However, not all patients had undergone longitudinal follow-up. We also cannot rule out potential bias in which patients returned for follow-up.

In summary, abnormal behaviors and impaired facial recognition in SD appear to be related to degree of involvement of the right temporal lobe. The evidence support treating SD as a single entity which is associated with varying degrees of left and right temporal lobe involvement, which in turn dictates degree of behavioral dyscontrol.

ACKNOWLEDGEMENTS

We would like to acknowledge Dr. Clifford Jack and the Alzheimer’s Disease Imaging Research (ADIR) laboratory at Mayo Clinic, Rochester, MN, for providing FDG-PET analysis pipelines.

FUNDING SOURCES

The study was funded by the National Institute of Health grants R01-DC010367, R21-NS94684 and R01-NS103870.

Footnotes

STATEMENT OF ETHICS

The study was approved by the Mayo Clinic Institutional Review Board (IRB # 16-001703 and 09-008772) and all patients gave written informed consent to participate in the study.

CONFLICT OF INTEREST

The authors do not have any conflicts of interest.

REFERENCES

  • 1.Snowden J, PJ G, D N. Semantic dementia: a form of circumscribed cerebral atrophy. Behav Neurol. 1989;2:167–82. [Google Scholar]
  • 2.Warrington EK. The selective impairment of semantic memory. Q J Exp Psychol. 1975. November;27(4):635–57. [DOI] [PubMed] [Google Scholar]
  • 3.Cummings JL, Mega M, Gray K, Rosenberg-Thompson S, Carusi DA, Gornbein J. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology. 1994. December;44(12):2308–14. [DOI] [PubMed] [Google Scholar]
  • 4.Kaufer DI, Cummings JL, Ketchel P, Smith V, MacMillan A, Shelley T, et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. The Journal of neuropsychiatry and clinical neurosciences. 2000. Spring;12(2):233–9. [DOI] [PubMed] [Google Scholar]
  • 5.Singh TD, Duffy JR, Strand EA, Machulda MM, Whitwell JL, Josephs KA. Neuropsychiatric symptoms in primary progressive aphasia and apraxia of speech. Dement Geriatr Cogn Disord. 2015;39(3–4):228–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Snowden JS. Semantic dysfunction in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord. 1999;10 Suppl 1:33–6. [DOI] [PubMed] [Google Scholar]
  • 7.Thompson SA, Patterson K, Hodges JR. Left/right asymmetry of atrophy in semantic dementia: behavioral-cognitive implications. Neurology. 2003. November 11;61(9):1196–203. [DOI] [PubMed] [Google Scholar]
  • 8.Seeley WW, Bauer AM, Miller BL, Gorno-Tempini ML, Kramer JH, Weiner M, et al. The natural history of temporal variant frontotemporal dementia. Neurology. 2005. April 26;64(8):1384–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Josephs KA, Whitwell JL, Knopman DS, Boeve BF, Vemuri P, Senjem ML, et al. Two distinct subtypes of right temporal variant frontotemporal dementia. Neurology. 2009. November 3;73(18):1443–50. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Kumfor F, Landin-Romero R, Devenney E, Hutchings R, Grasso R, Hodges JR, et al. On the right side? A longitudinal study of left- versus right-lateralized semantic dementia. Brain. 2016. March;139(Pt 3):986–98. [DOI] [PubMed] [Google Scholar]
  • 11.Ulugut Erkoyun H, Groot C, Heilbron R, Nelissen A, van Rossum J, Jutten R, et al. A clinical-radiological framework of the right temporal variant of frontotemporal dementia. Brain. 2020. September 1;143(9):2831–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, et al. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology. 1998. December;51(6):1546–54. [DOI] [PubMed] [Google Scholar]
  • 13.Botha H, Duffy JR, Whitwell JL, Strand EA, Machulda MM, Schwarz CG, et al. Classification and clinicoradiologic features of primary progressive aphasia (PPA) and apraxia of speech. Cortex. 2015. August;69:220–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. 2011. May;7(3):263–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Gorno-Tempini ML, Hillis AE, Weintraub S, Kertesz A, Mendez M, Cappa SF, et al. Classification of primary progressive aphasia and its variants. Neurology. 2011. March 15;76(11):1006–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Rascovsky K, Hodges JR, Knopman D, Mendez MF, Kramer JH, Neuhaus J, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011. September;134(Pt 9):2456–77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Flanagan EP, Baker MC, Perkerson RB, Duffy JR, Strand EA, Whitwell JL, et al. Dominant frontotemporal dementia mutations in 140 cases of primary progressive aphasia and speech apraxia. Dement Geriatr Cogn Disord. 2015;39(5–6):281–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Whitwell JL, Martin PR, Duffy JR, Clark HM, Machulda MM, Schwarz CG, et al. The influence of beta-amyloid on [(18)F]AV-1451 in semantic variant of primary progressive aphasia. Neurology. 2019. February 12;92(7):e710–e22. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Minoshima S, Frey KA, Koeppe RA, Foster NL, Kuhl DE. A diagnostic approach in Alzheimer’s disease using three-dimensional stereotactic surface projections of fluorine-18-FDG PET. Journal of Nuclear Medicine. 1995;36(7):1238. [PubMed] [Google Scholar]
  • 20.Schwarz CG, Gunter JL, Ward CP, Vemuri P, Senjem ML, Wiste HJ, et al. The Mayo Clinic Adult Lifespan Template: Better Quantification Across the Lifespan. Alzheimers & Dementia. 2017;13:792. [Google Scholar]
  • 21.Josephs KA, Whitwell JL, Vemuri P, Senjem ML, Boeve BF, Knopman DS, et al. The anatomic correlate of prosopagnosia in semantic dementia. Neurology. 2008. November 11;71(20):1628–33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Omar R, Rohrer JD, Hailstone JC, Warren JD. Structural neuroanatomy of face processing in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. 2011. December;82(12):1341–3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Whitwell JL, Anderson VM, Scahill RI, Rossor MN, Fox NC. Longitudinal patterns of regional change on volumetric MRI in frontotemporal lobar degeneration. Dement Geriatr Cogn Disord. 2004;17(4):307–10. [DOI] [PubMed] [Google Scholar]
  • 24.Rohrer JD, McNaught E, Foster J, Clegg SL, Barnes J, Omar R, et al. Tracking progression in frontotemporal lobar degeneration: serial MRI in semantic dementia. Neurology. 2008. October 28;71(18):1445–51. [DOI] [PubMed] [Google Scholar]
  • 25.Brambati SM, Rankin KP, Narvid J, Seeley WW, Dean D, Rosen HJ, et al. Atrophy progression in semantic dementia with asymmetric temporal involvement: a tensor-based morphometry study. Neurobiol Aging. 2009. January;30(1):103–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Cousins KAQ, Ash S, Olm CA, Grossman M. Longitudinal Changes in Semantic Concreteness in Semantic Variant Primary Progressive Aphasia (svPPA). eNeuro. 2018. November-December;5(6). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Diehl-Schmid J, Grimmer T, Drzezga A, Bornschein S, Perneczky R, Forstl H, et al. Longitudinal changes of cerebral glucose metabolism in semantic dementia. Dement Geriatr Cogn Disord. 2006;22(4):346–51. [DOI] [PubMed] [Google Scholar]
  • 28.Bejanin A, Tammewar G, Marx G, Cobigo Y, Iaccarino L, Kornak J, et al. Longitudinal structural and metabolic changes in frontotemporal dementia. Neurology. 2020. July 14;95(2):e140–e54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Kashibayashi T, Ikeda M, Komori K, Shinagawa S, Shimizu H, Toyota Y, et al. Transition of distinctive symptoms of semantic dementia during longitudinal clinical observation. Dement Geriatr Cogn Disord. 2010;29(3):224–32. [DOI] [PubMed] [Google Scholar]
  • 30.Routier A, Habert MO, Bertrand A, Kas A, Sundqvist M, Mertz J, et al. Structural, Microstructural, and Metabolic Alterations in Primary Progressive Aphasia Variants. Front Neurol. 2018;9:766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Hornberger M, Geng J, Hodges JR. Convergent grey and white matter evidence of orbitofrontal cortex changes related to disinhibition in behavioural variant frontotemporal dementia. Brain. 2011. September;134(Pt 9):2502–12. [DOI] [PubMed] [Google Scholar]
  • 32.Krueger CE, Laluz V, Rosen HJ, Neuhaus JM, Miller BL, Kramer JH. Double dissociation in the anatomy of socioemotional disinhibition and executive functioning in dementia. Neuropsychology. 2011. March;25(2):249–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Franceschi M, Anchisi D, Pelati O, Zuffi M, Matarrese M, Moresco RM, et al. Glucose metabolism and serotonin receptors in the frontotemporal lobe degeneration. Ann Neurol. 2005. February;57(2):216–25. [DOI] [PubMed] [Google Scholar]
  • 34.Rosen HJ, Allison SC, Schauer GF, Gorno-Tempini ML, Weiner MW, Miller BL. Neuroanatomical correlates of behavioural disorders in dementia. Brain. 2005. November;128(Pt 11):2612–25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H, et al. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain. 2012. March;135(Pt 3):723–35. [DOI] [PubMed] [Google Scholar]
  • 36.Snowden JS, Adams J, Harris J, Thompson JC, Rollinson S, Richardson A, et al. Distinct clinical and pathological phenotypes in frontotemporal dementia associated with MAPT, PGRN and C9orf72 mutations. Amyotroph Lateral Scler Frontotemporal Degener. 2015;16(7–8):497–505. [DOI] [PubMed] [Google Scholar]
  • 37.Josephs KA, Hodges JR, Snowden JS, Mackenzie IR, Neumann M, Mann DM, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol. 2011. August;122(2):137–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Snowden JS, Bathgate D, Varma A, Blackshaw A, Gibbons ZC, Neary D. Distinct behavioural profiles in frontotemporal dementia and semantic dementia. J Neurol Neurosurg Psychiatry. 2001. March;70(3):323–32. [DOI] [PMC free article] [PubMed] [Google Scholar]

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