Two Rare Variants in PLAU and BACE1 Genes—Do They Contribute to Semantic Dementia Clinical Phenotype?

We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in β-site APP-cleaving enzyme 1 (BACE1)—along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced PLAU and elevated BACE1 mRNA and protein levels compared to control fibroblasts. Successful rescue of PLAU mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the PLAU variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the PLAU and BACE1 genes should be considered in future studies on early-onset dementias.

Characteristics of behavioral symptoms in right-sided predominant semantic dementia and their impact on caregiver burden: a cross-sectional study

Background This study aimed to clarify the neuropsychiatric symptoms of right-sided predominant semantic dementia (SD-R) by comparing them with those of behavioral variant frontotemporal dementia (bvFTD), left-sided predominant SD (SD-L), and Alzheimer’s disease (AD). This study also aimed to identify clinical factors related to caregiver burden for bvFTD, SD-R, and SD-L. Methods The neuropsychiatric symptoms of 28 patients with bvFTD, 14 patients with SD-R, 24 patients with SD-L, and 43 patients with AD were evaluated using the Neuropsychiatric Inventory (NPI) and the Stereotypy Rating Inventory (SRI). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Dementia severity was assessed using the Clinical Dementia Rating. Activities of daily living were assessed using the Lawton Instrument Activities of Daily Living (IADL) scale and the Physical Self-Maintenance Scale. We compared the NPI and SRI scores among the four groups using the Kruskal-Wallis test. In addition, clinical factors related to caregiver burden, represented by the Japanese version of the Zarit Burden Interview (J-ZBI), were analyzed using multiple regression analysis in the bvFTD, SD-R, and SD-L groups. Results The NPI total score and the NPI subscale scores of apathy and disinhibition were significantly higher in the bvFTD group than in the SD-L and AD groups. The SD-R group scores were closer to those of the bvFTD group than the SD-L group. The SRI total score and SRI subscale scores for eating and cooking and speaking were significantly higher in the bvFTD, SD-R, and SD-L groups than in the AD group. The NPI total score was significantly associated with the J-ZBI score in the bvFTD group. The NPI total score and Lawton IADL scale score were independently associated with the J-ZBI score in the SD-R group. Furthermore, the NPI total score and MMSE score were independently associated with the J-ZBI score in the SD-L group. Conclusions SD-R seemed to be a similar condition to bvFTD rather than SD-L regarding behavioral symptoms. Our results suggest that each frontotemporal dementia subgroup requires different approaches to reduce the caregiver burden.

Considering Hemispheric Specialization in Emotional Face Processing: An Eye Tracking Study in Left- and Right-Lateralised Semantic Dementia

Face processing relies on a network of occipito-temporal and frontal brain regions. Temporal regions are heavily involved in looking at and processing emotional faces; however, the contribution of each hemisphere to this process remains under debate. Semantic dementia (SD) is a rare neurodegenerative brain condition characterized by anterior temporal lobe atrophy, which is either predominantly left- (left-SD) or right-lateralised (right-SD). This syndrome therefore provides a unique lesion model to understand the role of laterality in emotional face processing. Here, we investigated facial scanning patterns in 10 left-SD and 6 right-SD patients, compared to 22 healthy controls. Eye tracking was recorded via a remote EyeLink 1000 system, while participants passively viewed fearful, happy, and neutral faces over 72 trials. Analyses revealed that right-SD patients had more fixations to the eyes than controls in the Fear (p = 0.04) condition only. Right-SD patients also showed more fixations to the eyes than left-SD patients in all conditions: Fear (p = 0.01), Happy (p = 0.008), and Neutral (p = 0.04). In contrast, no differences between controls and left-SD patients were observed for any emotion. No group differences were observed for fixations to the mouth, or the whole face. This study is the first to examine patterns of facial scanning in left- versus right- SD, demonstrating more of a focus on the eyes in right-SD. Neuroimaging analyses showed that degradation of the right superior temporal sulcus was associated with increased fixations to the eyes. Together these results suggest that right lateralised brain regions of the face processing network are involved in the ability to efficiently utilise changeable cues from the face.

On-Reading (Chinese-Style Pronunciation) Predominance Over Kun-Reading (Native Japanese Pronunciation) in Japanese Semantic Dementia

Japanese kanji (morphograms) have two ways of reading: on-reading (Chinese-style pronunciation) and kun-reading (native Japanese pronunciation). It is known that some Japanese patients with semantic dementia read kanji with on-reading but not with kun-reading. To characterize further reading impairments of patients with semantic dementia, we analyzed data from a total of 9 patients who underwent reading and writing tests of kanji and kana (Japanese phonetic writing) and on-kun reading tests containing two-character kanji words with on-on reading, kun-kun reading, and specific (so-called Jukujikun or irregular kun) reading. The results showed that on-reading preceding (pronouncing first with on-reading) and kun-reading deletion (inability to recall kun-reading) were observed in nearly all patients. In the on-kun reading test, on-reading (57.6% correct), kun-reading (46.6% correct), and specific-reading (30.0% correct) were more preserved in this decreasing order (phonology-to-semantics gradient), although on-reading and kun-reading did not significantly differ in performance, according to a more rigorous analysis after adjusting for word frequency (and familiarity). Furthermore, on-substitution (changing to on-reading) errors in kun-reading words (27.0%) were more frequent than kun-substitution (changing to kun-reading) errors in on-reading words (4.0%). These results suggest that kun-reading is more predominantly disturbed than on-reading, probably because kun-reading and specific-reading are closely associated with the meaning of words.

Anhedonia in Semantic Dementia—Exploring Right Hemispheric Contributions to the Loss of Pleasure

Semantic dementia (SD) is a younger-onset neurodegenerative disease characterised by progressive deterioration of the semantic knowledge base in the context of predominantly left-lateralised anterior temporal lobe (ATL) atrophy. Mounting evidence indicates the emergence of florid socioemotional changes in SD as atrophy encroaches into right temporal regions. How lateralisation of temporal lobe pathology impacts the hedonic experience in SD remains largely unknown yet has important implications for understanding socioemotional and functional impairments in this syndrome. Here, we explored how lateralisation of temporal lobe atrophy impacts anhedonia severity on the Snaith–Hamilton Pleasure Scale in 28 SD patients presenting with variable right- (SD-R) and left-predominant (SD-L) profiles of temporal lobe atrophy compared to that of 30 participants with Alzheimer’s disease and 30 healthy older Control participants. Relative to Controls, SD-R but not SD-L or Alzheimer’s patients showed clinically significant anhedonia, representing a clear departure from premorbid levels. Overall, anhedonia was more strongly associated with functional impairment on the Frontotemporal Dementia Functional Rating Scale and motivational changes on the Cambridge Behavioural Inventory in SD than in Alzheimer’s disease patients. Voxel-based morphometry analyses revealed that anhedonia severity correlated with reduced grey matter intensity in a restricted set of regions centred on right orbitofrontal and temporopolar cortices, bilateral posterior temporal cortices, as well as the anterior cingulate gyrus and parahippocampal gyrus, bilaterally. Finally, regression and mediation analysis indicated a unique role for right temporal lobe structures in modulating anhedonia in SD. Our findings suggest that degeneration of predominantly right-hemisphere structures deleteriously impacts the capacity to experience pleasure in SD. These findings offer important insights into hemispheric lateralisation of motivational disturbances in dementia and suggest that anhedonia may emerge at different timescales in the SD disease trajectory depending on the integrity of the right hemisphere.

No negative impact of word retraining on vocabulary use or clarity of communication in Semantic Dementia

Word retraining techniques can improve picture naming of treated items in people with semantic dementia (SD). The utility of this, however, has been questioned given the propensity for under- and overgeneralisation errors in naming in SD. Few studies have investigated the occurrence of such errors. This study examined whether, following tailored word retraining: 1) misuse of words increases, 2) the type of naming errors changes, and/or 3) clarity of communication is reduced. Performance on trained and untrained word naming from nine participants with SD who completed a word retraining program were analysed. Responses from baseline and post-intervention assessments were coded for misuse (i.e., trained word produced for another target item), error type, and communication clarity. All participants showed significant improvement for trained vocabulary. There was no significant increase in misuse of words, with such errors occurring rarely. At a group level, there was an increased tendency toward omission errors for untrained items, and a reduction in semantically related responses. However, this did not impact on clarity scores with no consistent change across participants. In sum, we found no negative impacts following tailored word retraining, providing further evidence of the benefit of these programs for individuals with SD.

Emotional Comparison Between Semantic Dementia and Alzheimer's Disease

Background: Previous studies have suggested that Alzheimer's disease (AD) and semantic dementia (SD) are both associated with emotional processing impairment. However, the degree and type of emotional symptoms between the two types of dementia have not been previously compared.Method: We used the Apathy Evaluation Scale (AES), the Toronto Empathy Questionnaire (TEQ), the Geriatric Depression Scale (GDS) and the Self-rating Anxiety Scale (SAS) to examine apathy, empathy, depression and anxiety, respectively.Results: Between mild AD and mild SD, moderate-to-severe AD and moderate-to-severe SD, the total scores of TEQ are significantly different, but the total scores of GDS, SAS and AES have no significant differences. In addition, normal individuals, AD and SD patients got the similar scores in SAS and GDS.Conclusions: Empathy emotion in SD patients is more severe than that in AD patients. However, apathy, depression and anxiety emotion is similar between the two groups.