Comparing Individuals With PPA to Individuals With AD: Cognitive and Linguistic Profiles

Introduction

Aphasia is an impairment of language which affects the production and/or comprehension of speech, as well as the ability to read or write. Aphasia can result from a variety of causes including stroke, brain tumor, head injury and dementia. Dementia is an umbrella term used to describe syndromes which affect cognitive, social, and functional abilities (World Health Organization, 2012). Alzheimer's disease (AD) is the most common form of dementia. Another less common form of dementia is Primary Progressive Aphasia (PPA), a degenerative condition characterized by progressive loss of language function. In PPA, aphasia is the most prominent deficit at onset (Mesulam, 2001), but there may be subtle evidence of deficits in other domains, reflecting a spread of the disease to areas adjacent in the language network. Nevertheless, these types of non-language deficits do not restrict daily living activities to a significant degree.

PPA is classified into three variants, the logopenic variant of PPA (lvPPA), the nonfluent agrammatic variant of PPA (nfvPPA), and the semantic variant of PPA (svPPA). Each PPA variant has a distinct clinical, neuropathological and neuroimaging profile (Gorno-Tempini et al., 2011). The characteristic clinical profiles of PPA variants include linguistic, as well as non-linguistic features, namely apraxia in nfvPPA, behavioral changes in svPPA and working memory deficits in lvPPA (Harris et al., 2019). The profiles evolve with disease progression and other domains are increasingly affected, most notably behavior and executive functions.

Executive functions comprise a set of cognitive processes that enable us to adjust our behavior to environmental demands. According to a widely accepted framework, three core executive functions, i.e. inhibition, working memory and cognitive flexibility, set the basis for other higher-order executive functions such as problem solving, reasoning and planning (Diamond, 2013). Impairment of executive function has been shown to play an important role in aphasia recovery and rehabilitation in stroke aphasia (El Hachioui et al., 2014; Geranmayeh et al., 2017; Simic et al., 2020), as well as management of language disorders in persons with PPA (Beeson et al., 2011; Henry et al., 2019).

Initial reports of symptoms in PPA have typically focused on analyzing language function. However, neuropsychological testing has revealed additional executive impairment in PPA variants (Kamath et al., 2019, 2020). Individuals with nfvPPA have shown executive deficits on verbal tasks of working memory, verbal fluency, as well as on non-verbal tasks of mental flexibility and abstract reasoning (Macoir et al., 2017). There are nonetheless reports of unimpaired non-verbal executive functioning (e.g., Butts et al., 2015), even though executive functions seem to decline over the course of the disease (Libon et al., 2009). In svPPA, a person may have difficulty comprehending instructions and/or stimuli due to the underlying semantic impairment. This difficulty affects performance on neuropsychological tests. Mixed results have been reported about the presence of executive deficits in the early stages of this variant and the progression of the decline (Macoir et al., 2017). In lvPPA, executive deficits have been found on the Trail-Making Test (TMT) (Butts et al., 2015) and time to complete part B of the TMT is significantly slower than in svPPA. Moreover, working memory in lvPPA seems to be more affected than in nfvPPA and svPPA (Eikelboom et al., 2018). More research, however, is needed to better describe executive decline in lvPPA (Macoir et al., 2017).

Memory deficits, on the other hand, are the hallmark of AD, even though other cognitive domains such as orientation, visuospatial abilities, executive function, and language may also be affected. A recent systematic review of executive functions in AD (Guarino et al., 2019) has highlighted the importance of incorporating executive tasks in a neuropsychological evaluation, as executive functions can be impaired from the mildest stages. Working memory, inhibitory and attentional abilities are compromised to a greater extent (Amieva et al., 2004; Collette et al., 2009; Tse et al., 2010) and have been linked to degeneration of the prefrontal cortex (Salat et al., 2001; Stuss, 2011). Language problems in AD have been associated with semantic and pragmatic processing deficits. People with AD may have word-finding difficulties or make semantic paraphasias. They may also have trouble participating in conversations and may repeat themselves. Lexical retrieval deficits have been reported both in formal testing and connected speech production (Kavé and Goral, 2018). The phonological and syntactic level of language processing seems to be more resilient (Ferris and Farlow, 2013). However, reduced syntactic complexity, morphosyntactic impairment, as well as phonetic and phonological manifestations have been documented in AD (Ahmed et al., 2012; Cera et al., 2018; Fyndanis et al., 2018). Linguistic deficits in AD have been commonly linked to working memory impairment and decreased processing speed (Jokel et al., 2019; Boxtel and Lawyer, 2021).

Individuals with a neurodegenerative disease may present with impaired performance on executive measures as a consequence of an underlying executive deficit or even due to the linguistically demanding nature of the task used to evaluate executive function. In fact, it is difficult to devise “pure” tasks able to evaluate a specific process in isolation from other cognitive processes. Even though the complex relationship between language and executive function has yet to be unraveled, evidence suggests that executive deficits associated with language may be domain-general rather than domain-specific (e.g., Kuzmina and Weekes, 2017; Murray, 2017). In healthy individuals, greater recruitment of executive function seems to be related with more demanding language activities, whereas, in individuals with brain lesions, with more severe pathology as a means of compensating for linguistic deficits (Gonçalves et al., 2018).

Differentiating between PPA and AD is clinically valuable for disease management. The two conditions resemble each other more in the later stages as the diseases evolve. Information about typical performance on specific neuropsychological and linguistic tasks is invaluable in documenting deficits in PPA and AD, differentiating between the two conditions and monitoring changes over time.

Diagnosing PPA is often challenging and there is no agreement on how language assessment should be performed. Different research groups employ different methodologies and several instruments have been used for the overall description of speech and language abilities in PPA and the evaluation of individual cognitive domains. A published review of the neuropsychological tests that have been developed for the assessment of speech and language disorders in PPA (Battista et al., 2017) has provided information about the available neuropsychological tools in English. More recently, tests have been developed for the evaluation of PPA in other languages, French, for example (Epelbaum et al., 2021). The situation is more complicated in languages like Greek where available tools for the assessment of speech and language in PPA are extremely limited (Peristeri et al., 2021). More research has been conducted regarding cognitive functioning. Current research has yet to explore which instruments or battery of tests can be used to evaluate language and cognitive performance in Greek-speaking individuals with PPA.

Thus, the main aim of this study was to establish differences between Greek-speaking individuals with AD and PPA on a comprehensive battery of tests to inform clinical practice. A secondary aim was to examine the executive deficit involvement in these two degenerative conditions, as executive function and linguistic ability are closely related.

Summarizing the evidence, we would expect to find more severe linguistic deficits in individuals with PPA. We would also expect individuals with AD to be more affected in cognitive measures tapping into memory in comparison to individuals with PPA. Finally, some degree of executive deficit would be expected in both conditions.

Materials and Methods

Participants

A total of 34 individuals (12 male and 22 female) participated in this study. The control group consisted of 15 neurotypical adults with a mean age of 67.93 (SD = 6.17) years and a mean of 13.13 (SD = 3.482) years of education. The AD group consisted of 9 participants (mean age 76.22, SD = 6.833 and mean years of education 12.67, SD = 4.153). Ten individuals participated in the PPA group (mean age 66.80, SD = 7.525 with mean years of education 13.60, SD = 4.088). Three of the participants with PPA met the criteria for svPPA, six for lvPPA and one had a mixed PPA phenotype.

General cognitive status, as indicated by scores on the Mini-Mental State Examination (MMSE) (Folstein et al., 1975; Fountoulakis et al., 2000; Solias et al., 2014), was similar for participants with AD and PPA (see Table 1). There was a statistically significant difference in age between the groups [H(2) = 7.943, p = 0.019] with a median of 69 years for neurotypical controls, 69.5 for the PPA group and 75 for the AD group. Post-hoc analysis revealed that the AD group was significantly older than the control group (U = 10.867, z = 2.595, p = 0.028), but not significantly older than the PPA group (U = 10.900, z = 2.389, p = 0.051). The three groups did not differ significantly in education and gender composition. Information about years post-onset, communication abilities, general cognitive functioning, neuropsychiatric, and functional status of the three groups can be found in Table 1.

TABLE 1

Table 1. Years post onset, communicative, general cognitive, neuropsychiatric, and functional status of the participants.

All participants were right-handed, apart from one neurotypical male who was ambidextrous. All individuals were native Greek speakers. They all reported to have normal or corrected-to-normal vision and hearing.

Procedure

Participants with PPA were recruited through the memory clinic of the Dementia Day Care Center (DDCC) of the Athens Alzheimer's Association and referral from other memory clinics and specialists (neurologists and psychiatrists) working in the private sector. As a result, referral data were not uniform. Enrollment was consecutive.

All participants with AD were diagnosed at the DDCC using a neuropsychological battery which included the MMSE, the Addenbrooke's Cognitive Examination (ACE) (Mioshi et al., 2006; Konstantinopoulou et al., 2011), the Greek Verbal Learning Test (GVLT) (Vlahou et al., 2013), the Georgia Complex Figure Test (Loring and Meador, 2003), the Frontal Assessment Battery (FAB) (Dubois et al., 2000), the short form of the Geriatric Depression Scale (GDS) (Sheikh and Yesavage, 1986; Fountoulakis et al., 1999) or the Beck Depression Inventory (BDI) (Beck et al., 1996; Giannakou et al., 2013) for participants younger than 65 years.

The diagnosis of PPA and AD was based on neurological examination, standard neuropsychological testing and brain imaging according to currently acceptable research criteria (Gorno-Tempini et al., 2011; McKhann et al., 2011; Albert et al., 2013; Chare et al., 2014). The presence of other major systemic, psychiatric, or neurological diseases, uncorrected visual and hearing impairment and difficulty completing the assessment procedure constituted reasons for exclusion from participating in the study. Participants had to be in the mild or moderate stage of the disease, as specified by severity ratings (Clinical Dementia Rating – CDR score < 3 and Boston Diagnostic Aphasia Examination – BDAE severity scale >3). Moreover, they should have at least 6 years of formal education and be native Greek speakers.

Assessment was completed over 3 or 4 hourly sessions depending on disease severity and practical issues, such as fatigue and time constraints. Assessment of the neurotypical individuals was completed in two 90-minutes-sessions.

The study was approved by the ethics committee of the Athens Alzheimer's Association and research was conducted in accordance with the principles of the Declaration of Helsinki and the European General Data Protection Regulation (GDPR). All participants provided written informed consent.

Assessment Battery

Participants were evaluated using a comprehensive battery of neuropsychological tests. The assessment battery included neuropsychological tools for the evaluation of speech, language, and other cognitive functions. Linguistic assessment targeted auditory comprehension, naming, repetition, reading, writing, and narrative production. In addition, information about the level of functioning and the presence of neuropsychiatric symptoms was collected by each participant's primary caregiver.

Cognitive Assessment

The MMSE was administered to all participants as a measure of general cognitive functioning. Attention and executive functioning was assessed by the Trail Making Test (TMT) (Corrigan and Hinkeldey, 1987; Zalonis et al., 2008). The TMT-A evaluates scanning and visuomotor tracking. It was employed to measure information processing speed. The TMT-B was used to assess divided attention and cognitive flexibility. For data analysis, the scores were reversed. Actual completion time was deducted from the maximum allowed time for completion, that is, 180s for TMA-A and 300 for TMA-B. In this way, higher scores reflect better performance. The Verbal Fluency Test (Kosmidis et al., 2004) was included as a measure of executive function. Phonemic (letter) and semantic (category) fluency was assessed using 3 letters and 3 categories, respectively. A total score was calculated based on the number of responses for each verbal fluency category. The Clock Drawing Test (CDT) (Bozikas et al., 2008) which measures both executive and visuospatial abilities was also administered adopting the scoring scheme of the original validation study. The Forward and Backward Digit Span (DGS) tasks from the WAIS-IV were used as measures of short-term auditory memory and verbal working memory, respectively. The delayed conditions of 5-Words Test (Dubois et al., 2002; Economou et al., 2016), the 5-Objects Test (Papageorgiou et al., 2014) and the Benson Figure Test (Possin et al., 2011) were administered in order to assess auditory and visuospatial memory, whereas the copy condition of Benson Figure Test to assess visuospatial processing. The 5-Words Test uses written words which are encoded using explicit semantic information. The 5-Objects Test has been developed as a measure of non-verbal episodic memory and is based on recalling the position of 5 objects. Finally, the picture version of the Pyramids and Palm Trees Test (PPTT) (Howard and Patterson, 1992) was included as a measure of semantic abilities. In this test a person needs to identify two semantically related pictures in the presence of a third distractor. A short form of the PPTT (Breining et al., 2015) was previously administered to a small number of Greek-speaking individuals with svPPA and found to be culturally appropriate. The complete version was administered to all participants, but scores were calculated for both versions.

Linguistic Assessment

Linguistic assessment included six subsets of the Greek version of the BDAE-short form (Goodglass and Kaplan, 1983) to assess naming (the short form of Boston Naming Test), Narrative writing, auditory processing (Commands and Complex Ideational Material) and reading comprehension (Word and picture matching and Sentence comprehension). The subset Embedded Sentences from the BDAE-3 includes 10 reversible sentences (subject object relative clauses) and was selected as a measure of syntactic comprehension. The 45-item version of the Boston Naming Test (BNT) validated in Greek by Simos et al. (Simos et al., 2011) was used to assess confrontation naming. This version includes 12 out of the 15 items that make up the BNT short form. The additional stimuli were added in the assessment battery to enable comparison of the two versions. The Sentence Repetition Test by Bayles et al. (Bayles et al., 1996) was adapted to Greek and was used to examine the effect of sentence frequency and length, as well as semantic content on repetition. It consists of 25 sentences organized in 5 sets: short meaningful, short non-meaningful, long meaningful, long non-meaningful and long frequent sentences. The short form of the Peabody Picture Vocabulary Test (PPVT) (Simos et al., 2014), a spoken word-picture matching test consisting of 32 items, was used for assessing single word comprehension. Reading fluency (Simos et al., 2013) for words and non-words was assessed in two tasks, in which the participant has to read as quickly as possible a list of words and non-words. Performance is evaluated by counting the number of items that have been read correctly in 45 seconds. Twenty words (10 high frequency and 10 low frequency words) and 14 matched non-words were selected for assessing spelling (Sideridis et al., 2008; Simos et al., 2013). Narrative writing was evaluated using the “Cookie Theft” picture and scoring instructions from the BDAE. Finally, a Grammaticality Judgment test (unpublished) was used to assess receptive ability and knowledge of tense and agreement. The test consists of 80 sentences: 40 sentences are included in the agreement condition (20 sentences for person; 20 sentences for number agreement) and 40 in the tense condition (20 sentences for past; 20 sentences for future tense). Half of the sentences were well-formed and half ill-formed. In this task, participants must decide on the grammatical status of each sentence.

Concerning connected speech analysis, the Quantitative Production Analysis (QPA) (Saffran et al., 1989; Gordon, 2006; Varkanitsa, 2012) was selected for the quantification of fluency, discourse, lexical and grammatical production. The procedure was employed for the analysis of two narrative productions from a picture description task (“Cookie Theft” from the BDAE) and a story retell task (from the Multilingual Assessment Instrument for Narratives - MAIN) (Gagarina et al., 2019). Detailed information about the QPA and the connected speech analysis procedure employed in this study can be found in Karpathiou et al. (2018).

Motor Speech Assessment

Motor speech evaluation included oral motor assessment, maximum phonation time, diadochokinetic (DDK) rates, repetition of utterances of increasing articulatory complexity (two-syllable words, polysyllabic words, sentences) and passage reading (Wertz et al., 1984). The test was informally adapted to Greek. Acoustic analysis was performed using the Praat software (Boersma, 2001) in order to calculate temporal measures for diadochokinetic rates, passage reading and sentence repetition. The Western Aphasia Battery (WAB) apraxia subtest (Kertesz, 1982) was also used to assess face and limb ideomotor apraxia.

Neuropsychiatric Evaluation

Mood was evaluated through the use of a 15-item questionnaire, the short form of the Geriatric Depression Scale (GDS) or the Beck Depression Inventory (BDI) for younger individuals (<65years). For data analysis, scores on the BDI were rescaled to match the GDS scoring system. Scores were reversed so that higher scores indicate fewer reported depressive symptoms. The new combined variable was labeled Mood Scale.

The Neuropsychiatric Inventory (NPI) (Cummings et al., 1994) has been widely used to measure the frequency and severity of neuropsychiatric symptoms in PPA. The NPI assesses 12 domains: delusions, hallucinations, agitation-aggression, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behavior, sleep, and appetite. Each domain is scored for its frequency, its severity, and the distress that the symptom causes to the caregiver. Higher scores indicate more severe deficits and distress. The Greek version of NPI (Politis et al., 2004) was used in this study.

Functional Assessment

The Frontotemporal Dementia Rating Scale (FRS) (Mioshi et al., 2010; Maiovis et al., 2016) was used as a measure of severity and functional ability. Scoring is based on the reported frequency of behaviors and daily activities explored by a 30-item caregiver questionnaire.

Statistical Analysis

As the number of participants in each group was small, the most appropriate statistical test was the non-parametric Kruskal-Wallis H test. In cases where the test was significant, a series of 3 Mann-Whitney U post-hoc tests were conducted to compare pairs of groups. The corrected α value (α = 0.016) was used to interpret the results. In order to determine whether the distributions in each group had the same variability, the corresponding histograms were visually inspected. Median and mean ranks are reported accordingly.

Z-scores were computed for each variable and averaged to yield a composite score for executive, memory, visuospatial, semantic, and linguistic measures. Mean z-scores were compared across groups using Welch's ANOVA due to unequal variances and sample size. The Games-Howell correction was used for post-hoc pairwise comparisons between groups. Correlations between cognitive and linguistic measures were performed using the Pearson correlation coefficients with Bonferroni corrections for multiple comparisons.

Results

Several differences were found among the groups that participated in the study. Group results are presented in Table 2 for cognitive measures and Table 3 for speech and language measures. Statistically significant differences for narrative analysis measures are provided in Table 4.

TABLE 2

Table 2. Group results for the cognitive-linguistic battery.

TABLE 3

Table 3. Group results for the speech and language assessment battery.

TABLE 4

Table 4. Statistically significant results for narrative measures.

Comparing Individuals With PPA to Neurotypical Adults

Concerning executive function, participants with PPA needed more time to complete the TMT, recalled shorter digit sequences and produced fewer words in both conditions of the Verbal Fluency Test. They were as a group less reliable in identifying semantic relations in the PPTT. Regarding memory, they performed worse than neurotypical controls on the figure delayed recall. Even though their performance was affected on the total score of the 5-Words Test, their performance was within normal limits for the delayed recall of words and objects' positioning.

As far as linguistic abilities are concerned, participants with PPA were found to be impaired on all sentence repetition tests, and the BNT. Spoken language comprehension was found to be impaired at the word level, as suggested by scores on the PPVT (U = 13.55, z = 3.35, p = 0.02) with a median of 24 correct compared to 30 for the neurotypical group. At the phrase level, the PPA group showed greater difficulty in following commands, processing complex ideational material and syntactically difficult sentences. Participants with PPA were impaired in understanding written sentences, detecting grammatical violations, reading and spelling real words, and narrative writing. Their articulation rate for passage reading was slower (mean rank = 9.44) compared to the neurotypical group (mean rank = 21.57), (U = 11.92, z = 4.06, p = 0.01). Speech rate may be affected by long pauses. Articulation rate on the other hand is computed by excluding silent pausing time. This measure better reflects speech motor execution, as speech rate involves motor, linguistic aspects of speech production (e.g., word-finding pauses) or non-linguistic processes (e.g., inattention).

Differences for fluency and narrative measures between the PPA and the control group that were found to be statistically significant are depicted in Figures 1, 2.

FIGURE 1

Figure 1. Differences between individuals with PPA and neurotypical adults for fluency measures.

FIGURE 2

Figure 2. Differences between individuals with PPA and neurotypical adults for narrative measures.

Comparing Individuals With AD to Neurotypical Adults

Participants with AD performed worse than controls on all episodic memory measures and most executive measures with the exception of Digit Span tasks and the letter condition of the Verbal Fluency Test. They were impaired on the BNT, the long non-meaningful sentences of the SRT, the Reading Fluency Test both for words and non-words, the Grammaticality Judgment task, and the Narrative writing. Differences were also detected for articulation and speech rate, total dysfluencies, and percentage of narrative to total words in story retell, as well as total time, mean pause duration and pauses per total words, semantic errors and frequency of the words used in picture description. There was finally a statistically significant difference in the temporal measures for the production of two sentences from the motor speech evaluation.

Comparing Individuals With PPA to Individuals With AD

Even though differences did not reach statistical significance, participants with PPA, performed better than participants with AD on almost all the measures of the cognitive-linguistic battery that do not heavily rely on linguistic and semantic processing. They scored lower than participants with AD just on the forward condition of the DGS, both conditions of the VFT and the PPPT. The opposite pattern was observed on the linguistic battery. Participants with AD scored better on linguistic tests, with the exception of the Reading Fluency for words and non-words, and two motor speech measures (diadochokinetic rates and sentence duration per syllable). Finally, participants with AD scored better on almost all narrative measures.

Several measures have differentiated participants with PPA from participants with AD. Participants with PPA performed significantly worse than participants with AD on the long frequent sentences of the Sentence Repetition Test. They produced fewer narrative and unique words (type) in describing the “Cookie Theft” picture from the BDAE. In comparison to participants with AD, they produced shorter and less elaborated sentences, as measured by mean sentence length and sentence elaboration index in the story retell task. Finally, they made more phonological errors in both narrative tasks.

Group Comparisons Using Mean z-Scores

Composite scores for executive, memory, visuospatial, semantic, and linguistic measures were compared across groups. Welch's Anova results and post-hoc group comparisons using the Games-Howell test are presented in Table 5. The only statistically significant difference that was detected between the AD and the PPA group was for the language composite measure.

TABLE 5

Table 5. Group comparisons with mean z-scores.

Correlations Between Linguistic and Cognitive Composite Scores

A statistically significant correlation between the executive and the language composite measures was found for participants with PPA (r = 0.86, p = 0.001). For participants with AD, the correlation between the executive and the language z scores was not significant (r = 0.47, p = 0.202). No other significant correlations were detected between cognitive and linguistic measures.

Discussion

The present study examined the cognitive and linguistic abilities of Greek-speaking individuals with AD and PPA. A group of neurotypical adults served as a control group. The first aim of the study was to compare their performance on a comprehensive battery of tests to inform clinicians about test selection. A secondary aim was to evaluate the executive impairment component to shed light on its involvement in linguistic deficits.

The two groups differed significantly on linguistic measures. Participants with PPA did not differ significantly from participants with AD on executive, memory, visuospatial functioning, and object semantics, as shown by comparing their composite mean z scores. Both groups differed from the control group on executive function, language, and memory. Participants with PPA were also impaired in semantics. Concerning linguistic assessment, production of phonological errors, difficulty in repeating long frequent sentences, and production of simple and short sentences has differentiated the participants with PPA not only from the neurotypical group but from participants with AD as well.

Even though both groups were impaired on measures of executive function to a similar extent, the pattern of deficits was different in each group. Participants with PPA scored better than participants with AD in the TMT and the CDT, which are non-verbal, but worse on the DGS and the VF tests. Moreover, the results of this study indicate that there is a relation between executive function and linguistic ability in individuals with PPA. No relation was found concerning individuals with AD. This suggests that linguistic and executive tasks measure, at least to some degree, different constructs. At first glance, the association between language and executive skills in this study seems to indicate an interrelation between language ability and domain-general cognitive processing. Individuals with PPA may exhibit executive deficits early in the course of the disease (Harciarek and Cosentino, 2013; Macoir et al., 2017) and while executive deficits have been linked to language impairments, evidence suggests that nonverbal executive tasks are also affected (Macoir et al., 2017). However, the executive tasks that were included in the assessment battery are not “pure”. For example, the TMT relies on fine-motor skills and visual scanning, and the VF test on phonological and semantic processing. Verbal executive tasks may be useful for evaluating verbal abilities but are less useful for drawing conclusions about the association between language performance and cognitive functioning. Nevertheless, the fact that the executive and linguistic composite measures were correlated in the PPA and not the AD group may reflect the linguistic load of the tests used and the recruitment of executive processes to compensate for the difficulties faced by the participants with PPA. This compensatory mechanism has been put forward to account for over-reliance on executive processing under demanding conditions (Gonçalves et al., 2018). Selecting simple, nonverbal executive function tasks seems preferable for documenting executive deficits, examining their contributions to language performance, and planning intervention in individuals with degenerative diseases.

The AD group was the only group that differed from controls on measures of episodic memory. Even though the PPA group scored lower than controls on the 5-Words Test (total score), the group's performance on the delayed conditions was similar to controls. The total score of the 5-Words Test combines scores from encoding, consolidation, and retrieval conditions. An impaired total score, in the presence of intact delayed recall ability, may be attributed to reduced short-term memory capacity as suggested by the group's low forward-DGS score and difficulties in almost all repetition tasks. These results are heavily influenced by the composition of the PPA group and more specifically by the larger proportion of individuals with the logopenic variant. Impaired short-term memory is considered to underly difficulties in lvPPA which is characterized by impaired sentence repetition and word retrieval deficits. Individuals with the semantic variant did not have repetition nor short-term memory deficits. This is consistent with previous studies which underly the differential nature of short-term memory deficits in PPA variants (Foxe et al., 2021).

The opposite pattern can be noted for the semantic tasks. Difficulties with non-verbal semantic associations and single-word comprehension can be attributed to the inclusion of individuals with the semantic variant of PPA. To be classified as svPPA, a person must be impaired in single-word comprehension and confrontation naming. Additional features of this variant include impaired object knowledge, surface dyslexia or dysgraphia, spared repetition, grammaticality, and motor speech abilities.

The PPA group did not include participants with the third PPA variant, the nfvPPA. The diagnosis of nfvPPA is based on either agrammatism in language production or apraxia of speech and impaired comprehension of syntactically complex structures.

Results concerning praxis and visuospatial functioning are consistent with previous research. On the WAB Apraxia subtest both the AD and PPA groups performed significantly lower compared to the control group. Limb apraxia has been documented in AD and lvPPA (Ahmed et al., 2016). Johnen et al. (2018) using a tool that assesses limb apraxia and buccofacial apraxia concluded that AD, nfvPPA and svPPA have different praxis profiles which contribute to differential diagnosis. Participants with PPA did not differ from neurotypical adults on visuospatial construction measures, i.e., figure copy and CDT). Nevertheless, they were impaired on the delayed recall condition of the Benson Figure Test, albeit to a lesser extent than participants with AD. Research has shown that visual memory may be impaired in both lvPPA and svPPA (Watson et al., 2018) and that participants with lvPPA and AD can be equally impaired (Foxe et al., 2013).

Several measures of language comprehension have been found to differ between the PPA and the neurotypical group. Performance of the PPA group on following commands, understanding complex auditory material, embedded sentences, and processing written sentences is not necessarily related to agrammatism. Concerning receptive language, sentence comprehension deficits in the logopenic variant are frequently reported and have been associated with short-term memory demands for sentence processing (Wilson et al., 2012). As Ash et al. (2019) point out, impaired grammaticality with disease progression in lvPPA contributes to difficulty in distinguishing lvPPA from nfvPPA. As there were no participants with the nonfluent/agrammatic variant in our sample, other underlying deficits, such as single word comprehension deficits relevant to participants with svPPA or short-term and working memory difficulties pertinent to participants with lvPPA provide a more likely explanation for the observed difficulties. In the same way, difficulties in detecting grammatical violations are most probably associated with reduced working memory capacity. Indeed, concerning the PPA group, performance on the grammaticality judgement task was significantly correlated with the backward condition of the DGS and the B form of TMT.

The timed and temporal measures used in the battery suggest slower motor ability for the participants with AD. This is more clearly reflected in slower articulation rate which does not include pauses and hesitations. The AD group was older than the control group and speech rate and articulatory movement have been found to decline as a function of age (Bilodeau-Mercure et al., 2015). Slower articulation rate was found for narrative production and may have contributed to lower scores on the two reading fluency tasks. However, DDK rates and speech rate for passage reading was within normal limits. This suggests an additional processing difficulty factor imposed by the nature of the reading fluency task, where participants are asked to read as fast as possible a list of words and non-words, and discourse demands. Passafiume et al. (2000) have also reported longer reading latency in participants with AD than in normal subjects for words and non-words.

Participants with AD did not encounter any difficulty with spelling words and non-words. Previous studies have revealed variable spelling abilities in AD. Hughes et al. (1997), for example, found no spelling impairment in mild AD. Other studies (e.g., González-Nosti et al., 2020) have documented difficulties with spelling in the earliest stages of AD. Differences between studies may be explained by task selection and cross-linguistic factors, such as the degree of orthographic transparency of each language.

Reading and spelling performance of the PPA group was mildly impaired for real words. Reading fluency and spelling for non-words were within normal limits. Intact spelling performance with non-words, reflects spare phonology to orthography conversion, and reliance on sub-lexical mechanisms to spell. This explanation also accommodates impaired performance with real words. The words that have been selected for spelling assessment were highly dependent on the ability to access stored orthographic representations (e.g., “$\alpha \lambda \lambda \iota \acute{\omega }\tau \iota \kappa o\varsigma$” —different, “$\delta \iota \epsilon \upsilon \theta \upsilon \nu \tau \acute{\eta }\varsigma$” —director). Surface dysgraphia, i.e., difficulty with exceptional, low-frequency words and regularization errors, is one of the hallmarks of svPPA. Nevertheless, it is the second most common pattern of spelling impairment in the logopenic variant of PPA (Graham, 2014).

The inclusion of connected speech measures has proven valuable. Concerning narrative production, the PPA group was impaired in discourse and sentence productivity measures but did not differ from the neurotypical control group in measures of grammatical accuracy. The increased proportion of dysfluencies and more specifically of pauses, prolongations, and fillers together with the lower number and proportion of unique words can be attributed to lexical difficulties. For the AD group, increased duration of pauses, proportion of pauses, semantic errors, use of higher frequency words and incomplete sentences in the picture description task are indicative of word-finding difficulties. This is also supported by lower scores on the naming test. These results are in line with the findings of a recent meta-analysis concerning connected speech in AD (Kavé and Goral, 2018). Taken together, results of the AD group support the presence of memory, executive and lexical retrieval deficits.

Some of the findings of this study have practical implications for clinicians working with individuals with degenerative diseases. First, both the long and short forms of the BNT and the PPTT that have been used in the assessment battery have led to similar results. This suggest that the short forms of these tests can be used in busy settings. Second, the long frequent sentences subset of the SRT has differentiated participants with PPA from participants with AD. Increased processing difficulty with the long non-meaningful sentences subset resulted in impaired performance compared to controls. Given the fact that the entire test is quite long and, in our experience, demanding for individuals with more pronounced deficits, the use of the long frequent sentences' subtest may be preferable in the clinical setting. Third, the assessment battery revealed difficulty with sentences with increased articulatory complexity, as shown by the temporal measures of sentence production during the motor speech assessment. It must be noted that this is a common finding in participants with severe co-existing repetition deficits and has been previously reported (Duffy et al., 2017). Thus, repetition of single multisyllabic words seems to be more reliable for evaluating motor speech function. Finally, the study provides a reference group for potential useful comparisons. A clinician may compare an individual with PPA or AD with this reference group and establish a z-score profile and an indication of the severity of a cognitive-linguistic disorder.

The main limitation of the study is the small sample size. This is particularly relevant to the extensive assessment battery. Another limitation was the fact that the non-fluent variant of PPA was not represented in the PPA group. Fluency and grammatical measures may have been more impaired with the inclusion of individuals with nfvPPA. Difficulty recruiting individuals with this variant has been reported before (Epelbaum et al., 2021). Furthermore, the composition of the PPA group was unbalanced in respect to the number of participants with the logopenic and the semantic variant. However, the same may also be true for the AD group. The group is not homogeneous and different single or multiple deficits were documented for participants with AD. For example, one participant with a prominent memory deficit was also impaired in language measures at a similar degree to some of the participants with PPA. These limitations arise from the difficulty to include individuals with PPA in clinical research and the consecutive recruitment method that was employed. PPA is a rare disorder with a prevalence that is estimated in the range of 1.1–6 per 100.000 (Grossman, 2014). In addition to that, many individuals with PPA receive a diagnosis when they are no longer in the early stages of the disease and cannot thus participate in diagnostic studies. This may be related to the delay in seeking medical attention, or even to limitations of the health system (Bertsias et al., 2020).

Finally, it must be noted that the AD group was older than the control group. Participants with PPA were also younger than the participants with AD, but the age difference did not reach statistical significance. This is because the control group was matched demographically to the PPA group and age of onset of PPA is typically younger than AD.

Conclusion

Neuropsychological testing combined with narrative analysis has documented language and other cognitive deficits in participants with lvPPA, svPPA and AD. Participants with AD were impaired in memory, and executive function. Moreover, they exhibited lexical retrieval difficulties, as well as difficulties in linguistic tasks with an increased processing load such as repetition of long non-meaningful sentences and fast reading of words and non-words. Participants with PPA were also affected on verbal executive function measures, reflecting the linguistic load of the tests used and the recruitment of executive processes to compensate for their difficulties. Naming, single word comprehension, auditory comprehension of complex material, repetition, reading, and writing were all affected.

The most informative measures in differentiating participants with lvPPA and svPPA from participants with AD, were sentence repetition, phonological errors, mean sentence length and sentence elaboration index in a connected speech sample. These findings should be interpreted with caution given the small sample size.

Speech and language deficits may be the core features of Primary Progressive Aphasia (PPA), but other cognitive domains are also affected, especially with disease progression. In order to develop an accurate profile of deficit patterns in PPA variants, linguistic and additional neuropsychological testing should uncover manifestation of all symptoms.

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The studies involving human participants were reviewed and approved by Ethics Committee of Athens Alzheimer Association. The patients/participants provided their written informed consent to participate in this study.

Author Contributions

NK and MK designed the study. NK was responsible for data collection, data analysis, and drafting the manuscript. MK critically revised the work. Both gave their final approval of the version to be published.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's Note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Acknowledgments

We would like to thank all the individuals who participated in the study. We would also like to thank Valantis Fyndanis for kindly allowing us to use the grammaticality judgment test.

References

Ahmed, S., Baker, I., Thompson, S., Husain, M., and Butler, C. R. (2016). Utility of testing for apraxia and associated features in dementia. J. Neurol. Neurosurg. Psychiatry. 87, 1158–1162. doi: 10.1136/jnnp-2015-312945

PubMed Abstract | CrossRef Full Text | Google Scholar

Ahmed, S., de Jager, C. A., Haigh, A.-M. F., and Garrard, P. (2012). Logopenic aphasia in Alzheimer's disease: clinical variant or clinical feature? J. Neurol. Neurosurg. Psychiatry. 83, 1056–1062. doi: 10.1136/jnnp-2012-302798

PubMed Abstract | CrossRef Full Text | Google Scholar

Albert, M. S., DeKosky, S. T., Dickson, D., Dubois, B., Feldman, H. H., Fox, N. C., et al. (2013). The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's association workgroups on diagnostic guidelines for Alzheimer's Disease. Focus. 11, 96–106. doi: 10.1176/appi.focus.11.1.96

PubMed Abstract | CrossRef Full Text | Google Scholar

Amieva, H., Phillips, L. H., Della Sala, S., and Henry, J. D. (2004). Inhibitory functioning in Alzheimer's disease. Brain. 127, 949–964. doi: 10.1093/brain/awh045

PubMed Abstract | CrossRef Full Text | Google Scholar

Ash, S., Nevler, N., Phillips, J., Irwin, D. J., McMillan, C. T., Rascovsky, K., et al. (2019). A longitudinal study of speech production in primary progressive aphasia and behavioral variant frontotemporal dementia. Brain Lang. 194, 46–57. doi: 10.1016/j.bandl.2019.04.006

PubMed Abstract | CrossRef Full Text | Google Scholar

Battista, P., Miozzo, A., Piccininni, M., Catricalà, E., Capozzo, R., Tortelli, R., et al. (2017). Primary progressive aphasia: A review of neuropsychological tests for the assessment of speech and language disorders. Aphasiology. 31, 1359–1378. doi: 10.1080/02687038.2017.1378799

CrossRef Full Text | Google Scholar

Bayles, K. A., Tomoeda, C. K., and Rein, J. A. (1996). Phrase repetition in Alzheimer's disease: effect of meaning and length. Brain Lang. 54, 246–261. doi: 10.1006/brln.1996.0074

PubMed Abstract | CrossRef Full Text | Google Scholar

Beck, A. T., Steer, R. A., and Brown, G. K. (1996). Manual for the Beck Depression Inventory (San Antonio, TX: The Psychological Corporation).

Google Scholar

Beeson, P. M., King, R. M., Bonakdarpour, B., Henry, M. L., Cho, H., and Rapcsak, S. Z. (2011). Positive effects of language treatment for the logopenic variant of primary progressive aphasia. J. Mol. Neurosci. 45, 724–736. doi: 10.1007/s12031-011-9579-2

PubMed Abstract | CrossRef Full Text | Google Scholar

Bertsias, A., Symvoulakis, E., Tziraki, C., Panagiotakis, S., Mathioudakis, L., Zaganas, I., et al. (2020). Cognitive impairment and dementia in primary care: current knowledge and future directions based on findings from a large cross-sectional study in Crete, Greece. Front. Med. 7, 592924. doi: 10.3389/fmed.2020.592924

PubMed Abstract | CrossRef Full Text | Google Scholar

Bilodeau-Mercure, M., Kirouac, V., Langlois, N., Ouellet, C., Gasse, I., and Tremblay, P. (2015). Movement sequencing in normal aging: speech, oro-facial, and finger movements. AGE. 37, 78. doi: 10.1007/s11357-015-9813-x

PubMed Abstract | CrossRef Full Text | Google Scholar

Boersma, P. (2001). Praat, a system for doing phonetics by computer. Glot Int. 5, 341–345. Retrieved from http://www.praat.org

PubMed Abstract | Google Scholar

Boxtel, W., and Lawyer, L. (2021). Sentence comprehension in ageing and Alzheimer's disease. Lang. Linguis. Compass 15, e12430. doi: 10.1111/lnc3.12430

CrossRef Full Text | Google Scholar

Bozikas, V. P., Giazkoulidou, A., Hatzigeorgiadou, M., Karavatos, A., and Kosmidis, M. H. (2008). Do age and education contribute to performance on the clock drawing test? Normative data for the Greek population. J. Clin. Exp. Neuropsychol. 30, 199–203. doi: 10.1080/13803390701346113

PubMed Abstract | CrossRef Full Text | Google Scholar

Breining, B. L., Lala, T., Martínez, M., and Manes, F. (2015). A brief assessment of object semantics in primary progressive aphasia. Aphasiology. 37–41. doi: 10.1080/02687038.2014.973360

CrossRef Full Text | Google Scholar

Butts, A. M., Machulda, M. M., Duffy, J. R., Strand, E. A., Whitwell, J. L., and Josephs, K. A. (2015). Neuropsychological Profiles Differ among the Three Variants of Primary Progressive Aphasia. J. Int. Neuropsychol. Soc. 21, 429–435. doi: 10.1017/S1355617715000399

PubMed Abstract | CrossRef Full Text | Google Scholar

Cera, M. L., Ortiz, K. Z., Bertolucci, P. H. F., and Minett, T. (2018). Phonetic and phonological aspects of speech in Alzheimer's disease. Aphasiology. 32, 88–102. doi: 10.1080/02687038.2017.1362687

PubMed Abstract | CrossRef Full Text | Google Scholar

Chare, L., Hodges, J. R., Leyton, C. E., McGinley, C., Tan, R. H., Kril, J. J., et al. (2014). New criteria for frontotemporal dementia syndromes: clinical and pathological diagnostic implications. J. Neurol. Neurosurg. Psychiatry. 85, 866–871. doi: 10.1136/jnnp-2013-306948

PubMed Abstract | CrossRef Full Text | Google Scholar

Collette, F., Schmidt, C., Scherrer, C., Adam, S., and Salmon, E. (2009). Specificity of inhibitory deficits in normal aging and Alzheimer's disease. Neurobiol. Aging. 30, 875–889. doi: 10.1016/j.neurobiolaging.2007.09.007

PubMed Abstract | CrossRef Full Text | Google Scholar

Corrigan, J. D., and Hinkeldey, N. S. (1987). Relationships between Parts A and B of the trail making test. J. Clin. Psychol. 43, 402–409. doi: 10.1002/1097-4679(198707)43:4<402::aid-jclp2270430411>3.0.co;2-e

PubMed Abstract | CrossRef Full Text | Google Scholar

Cummings, J. L., Mega, M., Gray, K., Rosenberg-Thompson, S., Carusi, D. A., and Gornbein, J. (1994). The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology. 44:2308–14 doi: 10.1212/WNL.44.12.2308

PubMed Abstract | CrossRef Full Text | Google Scholar

Diamond, A. (2013). Executive functions. Ann. Rev. Psychol. 64, 135–168. doi: 10.1146/annurev-psych-113011-143750

PubMed Abstract | CrossRef Full Text | Google Scholar

Dubois, B., Slachevsky, A., Litvan, I., and Pillon, B. (2000). The FAB: A frontal assessment battery at bedside. Neurology 55, 1621–1626. doi: 10.1212/WNL.55.11.1621

PubMed Abstract | CrossRef Full Text | Google Scholar

Dubois, B., Touchon, J., Portet, F., Ousset, P-. J., Vellas, B., and Michel, B. (2002). “Les 5 mots”, épreuve simple et sensible pour le diagnostic de la maladie d'Alzheimer. Presse Medicale. 31, 1696–9.

Google Scholar

Duffy, J. R., Hanley, H., Utianski, R., Clark, H., Strand, E., Josephs, K. A., et al. (2017). Temporal acoustic measures distinguish primary progressive apraxia of speech from primary progressive aphasia. Brain Lang. 168, 84–94. doi: 10.1016/j.bandl.2017.01.012

PubMed Abstract | CrossRef Full Text | Google Scholar

Economou, A., Routsis, C., and Papageorgiou, S. G. (2016). Episodic Memory in Alzheimer Disease, frontotemporal dementia, and dementia with lewy bodies/parkinson disease dementia. Alzheimer Dis. Assoc. Disord. 30, 47–52. doi: 10.1097/WAD.0000000000000089

PubMed Abstract | CrossRef Full Text | Google Scholar

Eikelboom, W. S., Janssen, N., Jiskoot, L. C., van den Berg, E., Roelofs, A., and Kessels, R. P. C. (2018). Episodic and working memory function in Primary Progressive Aphasia: A meta-analysis. Neurosci. Biobehav. Rev. 92, 243–254. Elsevier. doi: 10.1016/j.neubiorev.2018.06.015

PubMed Abstract | CrossRef Full Text | Google Scholar

El Hachioui, H., Visch-Brink, E. G., Lingsma, H. F., van de Sandt-Koenderman, M. W. M. E., Dippel, D. W. J., Koudstaal, P. J., et al. (2014). Nonlinguistic cognitive impairment in poststroke aphasia. Neurorehabil. Neural Repair. 28, 273–281. doi: 10.1177/1545968313508467

PubMed Abstract | CrossRef Full Text | Google Scholar

Epelbaum, S., Saade, Y. M., Flamand Roze, C., Roze, E., Ferrieux, S., Arbizu, C., et al. (2021). A reliable and rapid language tool for the diagnosis, classification, and follow-up of primary progressive aphasia variants. Front. Neurol. 11, 1–10. doi: 10.3389/fneur.2020.571657

PubMed Abstract | CrossRef Full Text | Google Scholar

Ferris, S. H., and Farlow, M. (2013). Language impairment in Alzheimer's disease and benefits of acetylcholinesterase inhibitors. Clin. Interven. Aging. 8, 1007–1014. doi: 10.2147/CIA.S39959

PubMed Abstract | CrossRef Full Text | Google Scholar

Folstein, M. F., Folstein, S. E., and McHugh, P. R. (1975). “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J. Psychiatric Res. 12:189–98 doi: 10.1016/0022-3956(75)90026-6

PubMed Abstract | CrossRef Full Text | Google Scholar

Fountoulakis, K. N., Tsolaki, M., Chantzi, H., and Kazis, a. (2000). Mini Mental State Examination (MMSE): a validation study in Greece. Am. J. Alzheimer's Dis. Other Demen. 15:342–5 doi: 10.1177/153331750001500604

CrossRef Full Text | Google Scholar

Fountoulakis, K. N., Tsolaki, M., Iacovides, A., Yesavage, J., O'Hara, R., Kazis, A., et al. (1999). The validation of the short form of the Geriatric Depression Scale (GDS) in Greece. Aging (Milano.). 11:367–72 doi: 10.1007/BF03339814

PubMed Abstract | CrossRef Full Text | Google Scholar

Foxe, D., Cheung, S. C., Cordato, N. J., Burrell, J. R., Ahmed, R. M., Taylor-Rubin, C., et al. (2021). Verbal short-term memory disturbance in the primary progressive aphasias: challenges and distinctions in a clinical setting. Brain Sci. 11:1060. doi: 10.3390/brainsci11081060

PubMed Abstract | CrossRef Full Text | Google Scholar

Foxe, D. G., Irish, M., Hodges, J. R., and Piguet, O. (2013). Verbal and visuospatial span in logopenic progressive aphasia and Alzheimer's disease. J. Int. Neuropsychol. Soc. 19, 247–253. doi: 10.1017/S1355617712001269

PubMed Abstract | CrossRef Full Text | Google Scholar

Fyndanis, V., Arfani, D., Varlokosta, S., Burgio, F., Maculan, A., Miceli, G., et al. (2018). Morphosyntactic production in Greek- and Italian-speaking individuals with probable Alzheimer's disease: evidence from subject–verb agreement, tense/time reference, and mood. Aphasiology. 32, 61–87. Routledge. doi: 10.1080/02687038.2017.1358352

CrossRef Full Text | Google Scholar

Gagarina, N. V., Klop, D., Kunnari, S., Tantele, K., Välimaa, T., Balčiuniene, I., et al. (2019). MAIN: multilingual assessment instrument for narratives. ZAS Papers Linguistics 56, 155. doi: 10.21248/zaspil.56.2019.414

PubMed Abstract | CrossRef Full Text | Google Scholar

Geranmayeh, F., Chau, T. W., Wise, R. J. S., Leech, R., and Hampshire, A. (2017). Domain-general subregions of the medial prefrontal cortex contribute to recovery of language after stroke. Brain. 140, 1947–1958. doi: 10.1093/brain/awx134

PubMed Abstract | CrossRef Full Text | Google Scholar

Giannakou, M., Roussi, P., Kosmides, M. E., Kiosseoglou, G., Adamopoulou, A., and Garyfallos, G. (2013). Adaptation of the beck depression inventory-II to greek population. Hellenic J. Psychol. 10, 120–146.

Google Scholar

Gonçalves, A. P. B., Mello, C., Pereira, A. H., Ferré, P., Fonseca, R. P., and Joanette, Y. (2018). Executive functions assessment in patients with language impairment A systematic review. Dementia Neuropsychologia. 12, 272–283. doi: 10.1590/1980-57642018dn12-030008

PubMed Abstract | CrossRef Full Text | Google Scholar

González-Nosti, M., Cuetos, F., and Martínez, C. (2020). Evolution of writing impairment in Spanish patients with Alzheimer's disease. Curr. Alzheimer Res. 17, 845–857. doi: 10.2174/1567205017666201204162837

PubMed Abstract | CrossRef Full Text | Google Scholar

Goodglass, H., and Kaplan, E. (1983). The Assessment of Aphasia and Related Disorders (2nd edition). Philadelphia, Pennsylvania: Lea and Febiger.

Gordon, J. K. (2006). A quantitative production analysis of picture description. Aphasiology. 20, 188–204. doi: 10.1080/02687030500472777

CrossRef Full Text | Google Scholar

Gorno-Tempini, M. L., Hillis, A. E., Weintraub, S., Kertesz, A., Mendez, M., Cappa, S. F., et al. (2011). Classification of primary progressive aphasia and its variants. Neurology. 76, 1006–1014. doi: 10.1212/WNL.0b013e31821103e6

PubMed Abstract | CrossRef Full Text | Google Scholar

Graham, N. L. (2014). Dysgraphia in primary progressive aphasia: characterisation of impairments and therapy options. Aphasiology. 28, 1092–1111. doi: 10.1080/02687038.2013.869308

CrossRef Full Text | Google Scholar

Grossman, M. (2014). Biomarkers in the primary progressive aphasias. Aphasiology. 28:922–940 doi: 10.1080/02687038.2014.929631

PubMed Abstract | CrossRef Full Text | Google Scholar

Guarino, A., Favieri, F., Boncompagni, I., Agostini, F., Cantone, M., and Casagrande, M. (2019). Executive functions in Alzheimer Disease: a systematic review. Front. Aging Neurosci. 10, 437. doi: 10.3389/fnagi.2018.00437

PubMed Abstract | CrossRef Full Text | Google Scholar

Harciarek, M., and Cosentino, S. (2013). Language, executive function and social cognition in the diagnosis of frontotemporal dementia syndromes. Int. Rev. Psychiatry (Abingdon, England). 25, 178–96. doi: 10.3109/09540261.2013.763340

PubMed Abstract | CrossRef Full Text | Google Scholar

Harris, J. M., Saxon, J. A., Jones, M., Snowden, J. S., and Thompson, J. C. (2019). Neuropsychological differentiation of progressive aphasic disorders. J. Neuropsychol. 13, 214–239. doi: 10.1111/jnp.12149

PubMed Abstract | CrossRef Full Text | Google Scholar

Henry, M. L., Hubbard, H. I., Grasso, S. M., Dial, H. R., Beeson, P. M., Miller, B. L., et al. (2019). Treatment for word retrieval in semantic and logopenic variants of primary progressive aphasia: Immediate and long-term outcomes. J. Speech Lang. Hear. Res. 62, 2723–2749. doi: 10.1044/2018_JSLHR-L-18-0144

PubMed Abstract | CrossRef Full Text | Google Scholar

Howard, D., and Patterson, K. E. (1992). The Pyramids and Palm Trees Test: A Test for Semantic Access from Words and Pictures. Bury St Edmunds, UK: Thames Valley Test Company Ltd.

PubMed Abstract | Google Scholar

Hughes, J. C., Graham, N., Patterson, K., and Hodges, J. R. (1997). Dysgraphia in mild dementia of Alzheimer's type. Neuropsychologia. 35, 533–545. doi: 10.1016/S0028-3932(96)00102-9

PubMed Abstract | CrossRef Full Text | Google Scholar

Johnen, A., Reul, S., Wiendl, H., Meuth, S. G., and Duning, T. (2018). Apraxia profiles—A single cognitive marker to discriminate all variants of frontotemporal lobar degeneration and Alzheimer's disease. Alzheimer's Dementia Diagn. Assess. Dis. Monit. 10, 363–371. doi: 10.1016/j.dadm.2018.04.002

PubMed Abstract | CrossRef Full Text | Google Scholar

Jokel, R., Seixas Lima, B., Fernandez, A., and Murphy, K. J. (2019). Language in amnestic mild cognitive impairment and dementia of Alzheimer's type: quantitatively or qualitatively different? Dementia Geriatric Cogn. Disord. Extra. 9, 136–151. doi: 10.1159/000496824

CrossRef Full Text | Google Scholar

Kamath, V., Chaney, G-. A. S., DeRight, J., and Onyike, C. U. (2019). A meta-analysis of neuropsychological, social cognitive, and olfactory functioning in the behavioral and language variants of frontotemporal dementia. Psychol. Med. 49, 2669–2680. doi: 10.1017/S0033291718003604

PubMed Abstract | CrossRef Full Text | Google Scholar

Kamath, V., Sutherland, E. R., and Chaney, G-. A. (2020). A meta-analysis of neuropsychological functioning in the logopenic variant of primary progressive aphasia: comparison with the semantic and non-fluent variants. J. Int. Neuropsychol. Soc. 26, 322–330. doi: 10.1017/S1355617719001115

PubMed Abstract | CrossRef Full Text | Google Scholar

Karpathiou, N., Papatriantafyllou, J., and Kambanaros, M. (2018). Bilingualism in a Case of the non-fluent/agrammatic variant of primary progressive aphasia. Front. Commun. 3, 52. doi: 10.3389/fcomm.2018.00052

CrossRef Full Text | Google Scholar

Kavé, G., and Goral, M. (2018). Word retrieval in connected speech in Alzheimer's disease: a review with meta-analyses. Aphasiology 32, 4–26. Routledge. doi: 10.1080/02687038.2017.1338663

CrossRef Full Text | Google Scholar

Kertesz, A. (1982). The Western Aphasia Battery New York, NY: Grune & Stratton.

Google Scholar

Konstantinopoulou, E., Kosmidis, M. H., Ioannidis, P., Kiosseoglou, G., Karacostas, D., and Taskos, N. (2011). Adaptation of addenbrooke's cognitive examination-revised for the Greek population. Eur. J. Neurol. 18, 442–447. doi: 10.1111/j.1468-1331.2010.03173.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Kosmidis, M. H., Vlahou, C. H., Panagiotaki, P., and Kiosseoglou, G. (2004). The verbal fluency task in the Greek population: Normative data, and clustering and switching strategies. J. Int. Neuropsychol. Soc. 10, 164–172. doi: 10.1017/S1355617704102014

PubMed Abstract | CrossRef Full Text | Google Scholar

Kuzmina, E., and Weekes, B. S. (2017). Role of cognitive control in language deficits in different types of aphasia. Aphasiology. 31, 765–792. doi: 10.1080/02687038.2016.1263383

PubMed Abstract | CrossRef Full Text | Google Scholar

Libon, D. J., Xie, S. X., Wang, X., Massimo, L., Moore, P., Vesely, L., et al. (2009). Neuropsychological decline in frontotemporal lobar degeneration: a longitudinal analysis. Neuropsychology. 23, 337–346. doi: 10.1037/a0014995

PubMed Abstract | CrossRef Full Text | Google Scholar

Loring, D., and Meador, K. (2003). “The Medical College of Georgia (MCG) complex figures: four forms for follow-up,” in eds. Knight, J, and, Kaplan E. Rey-Osterrieth Handbook. Odessa, Ukraine: Psychological Assessment Resources.

Google Scholar

Macoir, J., Lavoie, M., Laforce, R., Brambati, S. M., and Wilson, M. A. (2017). Dysexecutive symptoms in primary progressive aphasia: beyond diagnostic criteria. J. Geriatric Psychiatry Neurol. 30, 151–161. doi: 10.1177/0891988717700507

PubMed Abstract | CrossRef Full Text | Google Scholar

Maiovis, P., Ioannidis, P., Nucci, M., Gotzamani-Psarrakou, A., and Karacostas, D. (2016). Adaptation of the Cognitive Reserve Index Questionnaire (CRIq) for the Greek population. Neurol. Sci. 37, 633–636. doi: 10.1007/s10072-015-2457-x

PubMed Abstract | CrossRef Full Text | Google Scholar

McKhann, G. M., Knopman, D. S., Chertkow, H., Hyman, B. T., Jack, C. R., Kawas, C. H., et al. (2011). 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. 7, 263–269. doi: 10.1016/j.jalz.2011.03.005

PubMed Abstract | CrossRef Full Text | Google Scholar

Mesulam, M. M. (2001). Primary progressive aphasia. Ann. Neurol. 49, 425–32. doi: 10.1002/ana.91

CrossRef Full Text | Google Scholar

Mioshi, E., Dawson, K., Mitchell, J., Arnold, R., and Hodges, J. R. (2006). The Addenbrooke's Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int. J. Geriatric Psychiatry. 21, 1078–1085. doi: 10.1002/gps.1610

PubMed Abstract | CrossRef Full Text | Google Scholar

Mioshi, E., Hsieh, S., Savage, S., Hornberger, M., and Hodges, J. R. (2010). Clinical staging and disease progression in frontotemporal dementia. Neurology. 74, 1591–1597. doi: 10.1212/WNL.0b013e3181e04070

PubMed Abstract | CrossRef Full Text | Google Scholar

Murray, L. (2017). Focusing attention on executive functioning in Aphasia. Aphasiology. 31, 721–724. doi: 10.1080/02687038.2017.1299854

CrossRef Full Text | Google Scholar

Papageorgiou, S. G., Economou, A., and Routsis, C. (2014). The 5 Objects Test: A novel, minimal-language, memory screening test. J. Neurol. 261:422–31. doi: 10.1007/s00415-013-7219-1

PubMed Abstract | CrossRef Full Text | Google Scholar

Passafiume, D., Di Giacomo, D., and Giubilei, F. (2000). Reading Latency of Words and Nonwords in Alzheimer's Patients. Cortex. 36, 293–298. doi: 10.1016/S0010-9452(08)70531-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Peristeri, E., Messinis, L., Kosmidis, M. H., Nasios, G., Mentis, A. F. A., Siokas, V., et al. (2021). The impact of primary progressive aphasia on picture naming and general language ability. Cogn. Behav. Neurol. 34, 188–199. doi: 10.1097/WNN.0000000000000275

PubMed Abstract | CrossRef Full Text | Google Scholar

Politis, A. M., Mayer, L. S., Passa, M., Maillis, A., and Lyketsos, C. G. (2004). Validity and reliablity of the newly translated Hellenic Neuropsychiatric Inventory (H-NPI) applied to Greek outpatients with Alzheimer's disease: a study of disturbing behaviors among referrals to a memory clinic. Int. J. Geriatric Psychiatry. 19, 203–208. doi: 10.1002/gps.1045

PubMed Abstract | CrossRef Full Text | Google Scholar

Possin, K. L., Laluz, V. R., Alcantar, O. Z., Miller, B. L., and Kramer, J. H. (2011). Distinct neuroanatomical substrates and cognitive mechanisms of figure copy performance in Alzheimer's disease and behavioral variant frontotemporal dementia. Neuropsychologia. 49, 43–48. doi: 10.1016/j.neuropsychologia.2010.10.026

PubMed Abstract | CrossRef Full Text | Google Scholar

Saffran, E. M., Berndt, R. S., and Schwartz, M. F. (1989). The quantitative analysis of agrammatic production: Procedure and data. Brain Lang. 37, 440–479. doi: 10.1016/0093-934X(89)90030-8

PubMed Abstract | CrossRef Full Text | Google Scholar

Salat, D. H., Kaye, J. A., and Janowsky, J. S. (2001). Selective preservation and degeneration within the prefrontal cortex in aging and Alzheimer Disease. Arch. Neurol. 58, 1403–1408. doi: 10.1001/archneur.58.9.1403

PubMed Abstract | CrossRef Full Text | Google Scholar

Sheikh, J. I., and Yesavage, J. A. (1986). Geriatric Depression Scale (GDS) recent evidence and development of a shorter version. Clin. Gerontol. 5, 165–173. doi: 10.1300/J018v05n01_09

PubMed Abstract | CrossRef Full Text | Google Scholar

Sideridis, G. D., Mouzaki, A., Protopapas, A., and Simos, P. (2008). Psychometric evaluation of a spelling test for elementary school students. Psychology. 15, 290–315.doi: 10.12681/psy_hps.23841

CrossRef Full Text

Simic, T., Bitan, T., Turner, G., Chambers, C., Goldberg, D., Leonard, C., et al. (2020). The role of executive control in post-stroke aphasia treatment. Neuropsychol. Rehabil. 30, 1853–1892. doi: 10.1080/09602011.2019.1611607

PubMed Abstract | CrossRef Full Text | Google Scholar

Simos, P. G., Kasselimis, D., and Mouzaki, A. (2011). Age, gender, and education effects on vocabulary measures in Greek. Aphasiology. 25, 475–491. doi: 10.1080/02687038.2010.512118

PubMed Abstract | CrossRef Full Text | Google Scholar

Simos, P. G., Kasselimis, D., Potagas, C., and Evdokimidis, I. (2014). Verbal comprehension ability in aphasia: demographic and lexical knowledge effects. Behav. Neurol. 2014, 258303. doi: 10.1155/2014/258303

PubMed Abstract | CrossRef Full Text | Google Scholar

Simos, P. G., Sideridis, G. D., Kasselimis, D., and Mouzaki, A. (2013). Reading Fluency Estimates of Current Intellectual Function: Demographic Factors and Effects of Type of Stimuli. J. Int. Neuropsychol. Soc. 19, 355–361. doi: 10.1017/S1355617712001518

PubMed Abstract | CrossRef Full Text | Google Scholar

Solias, A., Skapinakis, P., Degleris, N., Pantoleon, M., Katirtzoglou, E., and Politis, A. (2014). [Mini Mental State Examination (MMSE): determination of cutoff scores according to age and educational level]. Psychiatrike = Psychiatriki. 25, 245–256

PubMed Abstract | Google Scholar

Stuss, D. T. (2011). Functions of the Frontal Lobes: Relation to Executive Functions. J. Int. Neuropsychol. Soc. 17, 759–765. doi: 10.1017/S1355617711000695

PubMed Abstract | CrossRef Full Text | Google Scholar

Tse, C-. S., Balota, D. A., Yap, M. J., Duchek, J. M., and McCabe, D. P. (2010). Effects of healthy aging and early stage dementia of the Alzheimer's type on components of response time distributions in three attention tasks. Neuropsychology. 24, 300–315. doi: 10.1037/a0018274

PubMed Abstract | CrossRef Full Text | Google Scholar

Varkanitsa, M. (2012). “Quantitative and error analysis of connected speech: evidence from Greek-speaking patients with aphasia and normal speakers,” in Current Trends in Greek Linguistics, eds. G. Fragaki, T. Georgakopoulos, and C. Themistocleous (Newcastle, UK: Cambridge Scholars Publishing), 313–338.

Vlahou, C. H., Kosmidis, M. H., Dardagani, A., Tsotsi, S., Giannakou, M., Giazkoulidou, A., et al. (2013). Development of the greek verbal learning test: reliability, construct validity, and normative standards. Arch. Clin. Neuropsychol. 28, 52–64. doi: 10.1093/arclin/acs099

PubMed Abstract | CrossRef Full Text | Google Scholar

Watson, C. L., Possin, K., Allen, I. E., Hubbard, H. I., Meyer, M., Welch, A. E., et al. (2018). Visuospatial Functioning in the Primary Progressive Aphasias. J. Int. Neuropsychol. Soc. 25:245–56 doi: 10.1017/S1355617717000984

PubMed Abstract | CrossRef Full Text | Google Scholar

Wertz, R. T., LaPointe, L. L., and Rosenbek, J. C. (1984). Apraxia of Speech in Adults: The Disorder and its Management. Orlando: Grune and Stratton.

Wilson, S. M., Galantucci, S., Tartaglia, M. C., and Gorno-Tempini, M. L. (2012). The neural basis of syntactic deficits in primary progressive aphasia. Brain Lang. 122:190–8. doi: 10.1016/j.bandl.2012.04.005

PubMed Abstract | CrossRef Full Text | Google Scholar

World Health Organization. (2012). Dementia: A Public Health Priority. Retrieved from https://apps.who.int/iris/handle/10665/75263 (accessed May 19, 2020).

Zalonis, I., Kararizou, E., Triantafyllou, N. I., Kapaki, E., Papageorgiou, S., Sgouropoulos, P., et al. (2008). A normative study of the Trail Making Test A and B in Greek adults. Clin. Neuropsychol. 22, 842–850. doi: 10.1080/13854040701629301

PubMed Abstract | CrossRef Full Text | Google Scholar