High Frequency of Crossed Aphasia in Dextral in an Italian Cohort of Patients with Logopenic Primary Progressive Aphasia

Abstract

Background:

Primary progressive aphasia (PPA) has been described as a neurodegenerative language disorder mainly affecting the left hemisphere. Few cases of right hemisphere damage in right-handed PPA subjects have been reported. This condition, named crossed aphasia in dextral (CAD), is relatively rare and probably related to an alteration during neurodevelopment of language networks.

Objective:

To explore the prevalence of CAD in an Italian cohort of 68 PPA patients, in order to evaluate whether right hemisphere language lateralization could be a risk factor for PPA.

Methods:

Clinical-demographic and cerebral [¹⁸F]-fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) scan were analyzed, resulting in 23 logopenic variant (lvPPA) patients, 26 non-fluent variant (nfvPPA) patients, and 19 semantic variant (svPPA) patients. SPM single subject routine was performed for diagnostic purposes in order to identify the hypometabolic pattern of each patient. Based on brain metabolic profile, PPA patients were divided in right and left lvPPA, nfvPPA, and svPPA. [¹⁸F]FDG-PET group analyses were performed with SPM two-sample t-test routine.

Results:

26% of lvPPA cases were identified as CAD based on right hypometabolic pattern. CAD patients did not differ from left lvPPA regarding demographic features and general cognitive performance; however, they performed better in specific working memory tasks and showed brain hypometabolism limited to the superior, middle, and supramarginal temporal gyri.

Conclusion:

Atypical lateralization of language function could determine a vulnerability of the phonological language loop and in that way could be a risk factor for lvPPA.

Keywords

Crossed-aphasia in dextral dementia language lateralization logopenic variant primary progressive aphasia risk factor

INTRODUCTION

Primary progressive aphasia (PPA) is a neurodegenerative disorder in which language impairment is the predominant symptom in the initial phase of the disease. Several neuroimaging and histopathological studies have demonstrated that PPA is related to the neurodegeneration of specific language networks [1, 2]. PPA has been recently classified into three main variants [1]: nonfluent variant (nfvPPA), semantic variant (svPPA), and logopenic variant (lvPPA).

In right-handed subjects and most of the left-handed subjects, language functions are lateralized to the left hemisphere [3, 4]. In fact, PPA has been described as a syndrome of the left hemisphere, in particular involving the left posterior fronto-insular region in nfvPPA, the left anterior temporal lobe in svPPA, and the left posterior perisylvian-parietal region in lvPPA [2, 5]. There is a rare condition named crossed-aphasia in dextral (CAD) that represents a condition in which right-handed subjects develop aphasia after a right-side brain insult [6]. The etiology of CAD is still unknown, but several hypotheses have been suggested including an arrested developmental stage in the lateralization of language function [7 –9]. The frequency of CAD is still unknown, but in the literature, it has been estimated to be 1 to 3% of cases, mainly based on single case reports due to vascular damages [6, 10]. Since this anomalous lateralization has been pointed out to determine a weak point of the language network [7 , 12], it would be interesting to explore its frequency in PPA pathologies. In the literature, only 10 cases of CAD in PPA patients have been reported so far, of whom 6 cases were nfvPPA [13 –17] and 5 cases were lvPPA [18 –22].

The aim of the present paper is to systematically explore the prevalence of CAD in an Italian cohort of PPA patients [23], in order to describe the clinical and neuropsychological peculiarities, and to evaluate whether there is an association between anomalous language lateralization in dextral and the risk of PPA.

MATERIALS AND METHODS

Subjects

PPA subjects were retrospectively selected among patients referred to the Neurology Unit of the Careggi Hospital, Florence, Italy in the period between January 2011 to December 2017. The study has been previously described [23]. Briefly, a total of 68 patients were collected, and were classified according to the Gorno-Tempini clinical and neuroimaging criteria [1], resulting in 23 lvPPA, 26 nfvPPA, and 19 svPPA.

Diagnostic assessment

Clinical information included age, sex, age at symptom onset, family history for dementia, level of education, handedness, personal medical history, and treatments. All the patients underwent a neurological examination and a comprehensive neuropsychological [24 –34] and language assessment [35, 36].

All patients underwent brain magnetic resonance imaging (MRI) or brain computed tomography (CT), and cerebral [¹⁸F] fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) at baseline, as part of their diagnostic routine.

Brain MRI scans were acquired by means of T1-weighted MPRAGE 3D Slab Selective, scanner 1.5T (Siemens Magnetom Symphony), using the following parameters: repetition time (RT) = 2100 ms, echo time (ET) = 5 ms, invertion time (IT) = 1100 ms, flip angle (FA) = 15°. MRI data were reconstructed using a 256×256 matrix in 124 contiguous slices of 1 mm thickness.

[¹⁸F]FDG-PET were acquired following the EANM (European Association of Nuclear Medicine) procedure guidelines [37], using advanced hybrid PET-CT scanner in 3D list mode. PET data were reconstructed using 3D iterative algorithm, corrected for attenuation, randoms, and scatter using the manufacturer’s software. Patients showing predominant right hypometabolism at [¹⁸F]FDG-PET (CADlvPPA) were re-evaluated. They underwent the Edinburg Handedness Questionnaire [38, 39] to confirm the handedness predominance and information about handedness in family members was also collected.

Amyloid biomarkers were available for a subsample of the entire cohort: 16 cerebrospinal fluid Aβ_1–42 [40] and 11 amyloid-PET imaging with fluorbetapir tracer [41]. Genetic screening was performed on 40 out of the 68 patients and included Apolipoprotein E (APOE) genotype and causative mutations for Alzheimer’s disease (PSEN1, PSEN2, APP) and Frontotemporal dementia (MAPT, GRN, C9orf72) [42].

The study was approved by the local Ethics Committee.

Statistical analysis

The comparison of clinical-demographic profiles of the three clinical variants was performed by χ² test for categorical variable, and Student’s t-test or analysis of variance for continuous data. The frequency of CAD was calculated in each clinical subgroup.

Due to the high frequency of CAD in the logopenic cohort, we performed a within-group comparison to explore whether lvPPA and CADlvPPA cases showed differences in demographic or neuropsychological profiles. Nonparametric analysis was used to compare the lvPPA and CADlvPPA subgroups: the Fisher’s exact test and the Mann-Whitney test were used as appropriate.

Statistical analyses were performed using IBM SPSS Statistics 20.0 (IBM Corp., New York, NY).

SPM analysis

In order to assess the metabolic pattern characteristic for each variant, [¹⁸F]FDG-PET images were normalized to the MNI space using a validated procedure [43]. Images were smoothed with an isotropic 3D Gaussian kernel with a FWHM of 8 mm in each direction, and then were used for a single subject SPM-based routine [44] for diagnostic purposes. Age was included in the two-sample t-test analysis as a covariate. The healthy controls (HC) were selected among subjects included in the [¹⁸F]FDG-PET HC database of the Italian Association of Nuclear Medicine. HC were included in SPM analysis only if data on age, sex, education, cognitive status, and follow-up assessment of at least one year were available (n = 77; age 62.32±13.89; MMSE 29.23±0.94; education 11.16±4.29).

The SPM t-map of hypometabolism resulting from statistical comparison with the normal FDG-PET image database (i.e., one patient versus 77 HC) allowed the definition of disease-specific metabolic patterns. The threshold was set at p = 0.05, FWE-corrected for multiple comparisons at the voxel level. Only clusters containing more than 100 voxels were considered significant.

In the logopenic cohort, a whole-brain SPM two-sample t-test analysis was computed in order to identify brain metabolic pattern of the lvPPA group and CADlvPPA group as compared to HC. The threshold was set at p = 0.05, FWE-corrected for multiple comparisons at the voxel level. Only clusters containing more than 100 voxels were considered significant.

RESULTS

In this Italian cohort of 68 right-handed PPA subjects, 7 PPA patients with CAD (10.3%) were identified: 6 of the 23 lvPPA subjects (26%) and 1 among the nfvPPA cases (3.8%) (Fig. 1). In the svPPA group, there were no CAD cases, but 4 patients showed bilateral temporo-polar hypometabolism on FDG-PET. The study population was described in a previous paper [23], and there were no statistical differences among the three clinical variants. The clinicodemographic characteristics of the 7 CAD patients are shown in Table 1. Each subject reveals a strong right-handedness on the Edinburgh Questionnaire and met all the other criteria for CAD [6] (lesions restricted to right hemisphere; absence of familial left handedness; and no history of early brain damage or seizures).

Fig.1

Comparison between the number of CAD cases detected in the three PPA cohorts (cohort) and the expected number of CAD (estimation) based on an estimated 3% rate of the general population.

Table 1

Clinical-demographic characteristics of the 7 CAD-PPA patients

Patient	Age at onset	Sex	Diagnosis	Schooling	MMSE baseline	Family history for dementia	APOE status	Handedness	Edinburgh scale	Amyloid biomarkers
Case 1	68	M	lvPPA	8 y	22	Maternal	ɛ3ɛ3	right	12/12	NA
Case 2	69	M	lvPPA	8 y	28	None	ɛ3ɛ3	right	12/12	Amy-PET+
Case 3	73	M	lvPPA	13 y	18	None	ɛ3ɛ3	right	12/12	CSF + (492 pg/mL)
Case 4	68	F	lvPPA	18 y	20	None	ɛ3ɛ3	right	12/12	Amy-PET+
Case 5	80	F	lvPPA	13 y	26	Maternal	ɛ3ɛ3	right	12/12	NA
Case 6	64	M	lvPPA	12 y	23	None	ɛ4ɛ4	right	12/12	CSF + (320 pg/mL)
Case 7	78	F	nfvPPA	5 y	18	Paternal	ɛ3ɛ3	right	12/12	Amy PET-

CSF+, in case of Aβ_1–42 < 625 pg/mL [40]; Amy-PET+, scans are visually inspected and classified as positive or negative, according to manufacturer’s recommendations (two or more cortical areas with reduction or loss of the normally distinct gray-white contrast) [41].

The mean age at the first evaluation was 74.1 years (range 69 to 80): 4 males and 3 females, mean years of schooling was 11 (range 5 to 18 years). Mean MMSE at baseline was 21.7 (range 18 to 28). Family history for dementia was positive in 3 cases: 2 lvPPA patients and in the nfvPPA subject. Mutations for Alzheimer’s disease and Frontotemporal dementia were negative in all subjects. The APOE status was ɛ3/ɛ3 in all but one case (ɛ4/ɛ4, see Table 1). Amyloid biomarkers were available for 5 of the 7 cases and resulted positive in the lvPPA cases and negative in the nfvPPA patient. Language assessment showed in all the lvPPA cases the prototypical deficits in sentence repetition and phonological errors (phoneme substitutions and transposition) in the connected speech and in word and non-word repetition test. The nfvPPA subject showed agrammatism and phonetic-motor errors in the connected speech [1].

Logopenic cohort

The six CADlvPPA patients showed demographic features comparable to the 17 left lateralized lvPPA patients. There were no differences in functional and behavioral aspects as well as in the global cognitive performance (Table 2). The analysis of single cognitive domains revealed differences in the working memory tests, both verbal and visual, in a way that lvPPA patients performed worse than the CAD subjects (Table 2). There were no significant differences in the linguistic profile between CADlvPPA and lvPPA, except for the “Writing sentences task”, in which CADlvPPA showed significant better performance (Table 3).

Table 2

Clinical-demographic and neuropsychological data of the logopenic patients (n = 23) by the lateralization of brain hypometabolism

	lvPPA (n = 17)	CADlvPPA (n = 6)	p
Sex M (%)	9 (52.9)	4 (66.6)	0.66
Age at onset (SD)	68 (8.4)	71.8 (5.7)	0.29
Positive family history for dementia (%)	11 (64.7)	2 (33.3)	0.15
Education (SD)	8.56 (4.5)	11.8 (3.7)	0.20
MMSE baseline (SD) [24]	20.9 (4.5)	22.6 (4.8)	0.35
RAVL (SD) [25]
Immediate	17.6 (7.9)	20.35 (7.9)	0.5
Recall	1.8 (2.5)	3 (2.1)	0.33
Short Story (SD) [26]
Immediate	4 (3.4)	3 (2.5)	0.46
Recall	5.9 (5.5)	5.4 (3.9)	0.5
Digit span (SD) [27]
Forwards	3.9 (0.5)	4.3 (0.8)	0.3
Backwards	2.8 (0.57)	3.5 (0.51)	0.02^*
Visual span (SD) [27]
Forwards	3.8 (1)	3.6 (0.44)	0.9
Backwards	2.6 (0.7)	3.7 (0.66)	0.01^*
ROCF (SD) [28]
Copy	19.6 (11.8)	13.3 (13.9)	0.35
ROCF delay	5.9 (4.5)	3.8 (5.6)	0.30
TMT-A (SD) [26]	64 (32)	4.4 (60)	0.36
TMT-B (SD) [26]	N.A. (2 patients)	N.A. (1 patient)
FAB (SD) [29]	10.7 (2.4)	10 (4.2)	0.44
Ideomotor apraxia (SD) [30]	61.7 (6)	62 (9.8)	0.7
Oral apraxia (SD) [31]	18.8 (0.9)	18.4 (0.9)	0.5
ADL baseline (SD) [32]	6	6	1
IADL baseline (SD) [33]	5.9 (0.5)	7.6 (0.4)	0.08
NPI (SD) [34]	5.3 (3.4)	5.6 (3.8)	0.7

RAVL, Rey Auditory Verbal Learning test; ROCF, Rey-Osterrich copy figure; TMT-A/TMT-B, Trail Making Test A and B; FAB, Frontal Assessment Battery; NPI, Neuropsychiatric Inventory Scale. ^*p < 0.05; N.A., not applicable due to small sample size.

Table 3

Language assessment within logopenic group (ENPA [35])

	lvPPA	CADlvPPA	p
Repetition-words (SD)	8.50 (3.1)	9.60 (0.5)	0.75
Repetition-non words	3.20 (1.6)	3.74 (1.3)	0.54
Repetition of sentences	1.8 (1)	2 (0.7)	0.75
Reading-words	7.24 (2.1)	7.48	0.69
Reading-non words	3.67 (1.4)	3.2 (1.9)	0.63
Reading-sentences	1.42 (0.5)	1.52 (0.5)	0.63
Writing-words	6.13 (2.6)	7.37 (1.2)	0.35
Writing-non words	2.10 (1.4)	3.10 (0.9)	0.31
Writing-sentences	0.13 (0.3)	1.2 (0.7)	0.006
Naming-oral nouns	8.22 (2.2)	9.25 (1.5)	0.23
Naming-oral verbs	6.16 (1.8)	6.67 (1.1)	0.73
Naming-writing nouns	2.30 (1.8)	3.9 (1.5)	0.26
Naming-writing verbs	2.04 (1.9)	3.82 (1.2)	0.12
Naming-oral color	5	5	1
Phonological fluency-F	6.2 (4.3)	7.1 (4.3)	0.57
Phonological fluency-A	4.45 (4.2)	5.08 (2.7)	0.45
Phonological fluency-S	5.33 (4.47)	6.41 (3.8)	0.66
Semantic fluency-animals	7.7 (3.8)	6.72 (4.2)	0.51
Semantic fluency-objects	3.36 (5)	7.4 (6)
Auditory words comprehension	18.82 (1)	19.10 (0.8)	0.63
Visual words comprehension	18.43 (1.2)	18.85 (0.41)	0.8
Auditory sentences comprehension	13.00 (1)	10.68 (3)	0.14
Visual sentences comprehension	11.87 (2.2)	12.03 (1.2)	0.64

SPM results

lvPPA patients as compared to HC showed a broad pattern of significant hypometabolism ranging from the left middle temporal gyrus (Brodmann Area (BA) 39 and 21), the inferior temporal gyrus (BA 20 and 37), to superior temporal gyrus (BA 22), inferior parietal lobule (BA 40), and precuneus (BA 19). CADlvPPA showed a more limited pattern of significant hypometabolism involving the right middle temporal gyrus (BA 19, 20, 21, 37, 39), the superior temporal gyrus (BA 38), and the supramarginal gyrus (BA 40) (Fig. 2).

Fig.2

The SPM t-maps of significant hypometabolism as compared to HC in the CADlvPPA patients (a, b) and in the lvPPA patients with left language lateralization (c, d).

DISCUSSION

We explored the frequency of CAD in the three main PPA variants in an Italian cohort of 68 patients, describing a case series of 7 PPA CAD patients, and we showed that the dextral language lateralization was common (26%) in the logopenic variant, while in the other variants, the frequency was comparable to the general population. In our cohort, CADlvPPA cases presented positive amyloid biomarkers or positive family history for dementia, suggesting Alzheimer’s disease as the underlying pathology. The analysis within the logopenic cohort demonstrated that CADlvPPA patients had a more focal brain hypometabolism and performed better in specific working memory tasks in comparison to the lvPPA subjects with left language lateralization. The etiology and significance of CAD are unknown; however, there is a consensus on the advantage of the left lateralization for language functions, that is prevalent in the whole population, including the left-handedness subjects [3, 4]. The high frequency of CAD detected among the lvPPA cohort could suggest that right lateralization determines a weak point in the phonological language network in a way that makes it more susceptible to the neurodegenerative process. The idea that abnormal formation of language network could determine vulnerability for PPA has been already suggested [45 –47], and in that way learning disability has been explored as possible risk factor for PPA. The studies that have explored the frequency of learning disability in the three main PPA subtypes [46, 47], found an association only with the logopenic variant. The authors suggested that learning disability could be a risk factor for lvPPA by determining a neurodevelopmental vulnerability of the phonological loop. They supported their hypothesis by demonstrating a more focal brain atrophy in lvPPA patients with learning disability compared with lvPPA patients without learning disability [47]. Consistent with this hypothesis, in our cohort we found that CADlvPPA patients showed a pattern of brain hypometabolism restricted to the right middle, superior, and supramarginal temporal gyri, as compared to the more extended left temporo-parietal hypometabolic pattern of lvPPA subjects. On the other hand, CADlvPPA patients were similar to the lvPPA subgroup, in terms of age at disease onset, high educational level, slight prevalence of male gender, and global cognitive performance. Most of the literature on CAD has been focused on the study of the other cognitive functions lateralized to the right hemisphere as the visuo-spatial skills. In lesioned CAD cases, left visuo-spatial neglect and visuo-constructional apraxia were often reported [9, 48]. In PPA patients, this association was also pointed out; however, some exceptions were reported [14 , 19]. In the present cohort, visuo-spatial skills and visuo-constructional praxia were not influenced by the language lateralization, that suggests that in case of CAD, the lateralization occurs by chance for all the cognitive functions [19]. However, compared to CADlvPPA, lvPPA patients performed worse in the visual and verbal backwards span tests. There is no consensus on which brain areas are involved in these types of tasks, but likely working memory requires the involvement of more complex networks [49]. A recent study on patients with strategic stroke demonstrated that different tasks exploring working memory involved different neuronal networks lateralized on the left hemisphere, as the inferior frontal gyrus for a rehearsal and cue-dependent test and the superior and middle temporal gyri in an updating/auditory recognition task [50]. Moreover, it has been reported that the left inferior parietal cortex is involved both in the auditory/verbal storage and in the spatial span [50 –52]. Consistent with these data, in our logopenic cohort, the lvPPA patients showed brain hypometabolism in the left inferior parietal lobule and a wider involvement of the left temporal cortex. That could explain the worst result in the backwards cognitive performance in comparison with CADlvPPA patients. Similarly, in the language assessment, CADlvPPA differ from lvPPA subjects in the dictation of sentences, in which working memory is involved. From a neuropathological point of view, logopenic aphasia has been associated in the majority of cases with Alzheimer’s disease pathology [53, 54]. In the case of CADlvPPA, three of the five previous described patients were tested for amyloid biomarkers: two resulted positive [18, 19] and one negative [22]. In our CAD cohort, the four tested subjects presented positive amyloid biomarkers. Based on these initial reports [18 , 22], the variability of Alzheimer’s disease biomarkers in CADlvPPA seems similar to that reported in the lvPPA with left language lateralization [55].

Although these results need caution due to the small sample size, to our knowledge this is the first study that systematically explored the frequency of CAD in a cohort of PPA subjects, finding a high frequency in the logopenic variant. Altogether the data support the hypothesis that atypical lateralization of language function determines a vulnerability of the phonological language loop, and in that way it represents a risk factor for lvPPA. Anyhow, to confirm this intriguing hypothesis replicative larger studies are required.

Footnotes

ACKNOWLEDGMENTS

We thank the Italian Association of Nuclear Medicine (AIMN), the following Institutions and researchers for sharing their FDG-PET scans as well as demographic and clinical information of subjects of the database of healthy subjects utilized in the present research: Flavio Nobili and Silvia Morbelli, University of Genoa and IRCCS Ospedale Policlinico San Martino, Genoa; Stelvio Sestini, Nuclear Medicine Unit, Santo Stefano Prato Hospital, Prato; Angelina Cistaro, PET centre AFFIDEA IRMET, Turin; Sabina Pappatà, Institute of Biostructure and Bioimaging of the CNR, Naples; Duccio Volterrani, Regional Center of Nuclear Medicine, Hospital University of Pisa, Pisa; Valentina Berti and Alberto Pupi, Nuclear Medicine Unit, University of Florence; Maria Lucia Calcagni, Nuclear Medicine Unit, Università Cattolica del Sacro Cuore, Rome.

Authors’ disclosures available online ().

References

Gorno-Tempini

, Hillis

, Weintraub

, Kertesz

, Mendez

, Cappa

, Ogar

, Rohrer

, Black

, Boeve

, Manes

, Dronkers

, Vandenberghe

, Rascovsky

, Patterson

, Miller

, Knopman

, Hodges

, Mesulam

, Grossman

(2011) Classification of primary progressive aphasia and its variants. Neurology 76, 1006–1014.

Mesulam

, Rogalski

, Wieneke

, Hurley

, Geula

, Bigio

, Thompson

, Weintraub

(2014) Primary progressive aphasia and the evolving neurology of the language network. Nat Rev Neurol 10, 554–569.

Geschwind

, Miller

, DeCarli

, Carmelli

(2002) Heritability of lobar brain volumes in twins supports genetic models of cerebral laterality and handedness. Acad Sci U S A 99, 3176–3181.

Szaflarski

, Binder

, Possing

, McKiernan

, Ward

, Hammeke

(2002) Language lateralization in left-handed and ambidextrous people. Neurology 59, 238–244.

Gil-Navarro

, Llado

, Rami

, Castellví

, Bosch

, Bargalló

, Lomeña

, Reñé

, Montagut

, Antonell

, Molinuevo

, Sánchez-Valle

(2013) Neuroimaging and biochemical markers in the three variants of primary progressive aphasia. Dement Geriatr Cogn Disord 35, 106–117.

Mariën

, Paghera

, De Deyn

, Vignolo

(2004) Adult crossed aphasia in dextrals revisited. Cortex 40, 41–74.

Kim

, Yang

, Paik

(2013) Neural substrate responsible for crossed aphasia. Korean Med Sci 28, 1529–1531.

Bramwell

(1899) On “crossed” aphasia and the factors which go to determine whether the “leading” or “driving” speech-centers shall be located in the left or in the right hemisphere of the brain: With notes of a case of “crossed” ahasia (aphasia with right-sided hemiplegia) in a left-handed man. Lancet 1, 1473–1479.

, Pyun

, Hwang

, Sim

(2012) Lateralization of cognitive functions in aphasia after right brain damage. Yonsei Med J 53, 486–494.

10.

Mariën

, Engelborghs

, Vignolo

, De Deyn

(2001) The many faces of crossed aphasia in dextrals: Report of nine cases and review of literature. Eur J Neurol 8, 643–658.

11.

Alexander

, Annett

(1996) Crossed aphasia and related anomalies of cerebral organization: Case reports and a genetic hypothesis. Brain Lang 55, 213–239.

12.

Vanderauwera

, Altarelli

, Vandermosten

, De Vos

, Wouters

, Ghesquière

(2018) Atypical structural asymmetry of the planum temporale is related to family history of dyslexia. Cereb Cortex 28, 63–72.

13.

Repetto

, Manenti

, Cotelli

, Calabria

, Zanetti

, Borroni

, Padovani

, Miniussi

(2007) Right hemisphere involvement in non-fluent primary progressive aphasia. Behav Neurol 18, 239–243.

14.

Jeong

, Lee

, Kwon

, Kim

, Na

, Lee

(2014) Agrammatic primary progressive aphasia in two dextral patients with right hemispheric involvement. Neurocase 1, 46–52.

15.

Spinelli

, Caso

, Agosta

, Gambina

, Magnani

(2015) A multimodal neuroimaging study of a case of crossed nonfluent/agrammatic primary progressive aphasia. J Neurol 262, 2336–2345.

16.

San Pedro

, Deutsch

, Liu

, Mountz

(2000) Frontotemporal decreases in rCBF correlate with degree of dysnomia in primary progressive aphasia. J Nucl Med 41, 228–233.

17.

Bessi

, Piaceri

, Padiglioni

, Bagnoli

, Berti

, Sorbi

, Nacmias

(2018) Crossed aphasia in nonfluent variant of primary progressive aphasia carrying a GRN mutation. J Neurol Sci 392, 34–37.

18.

Demirtas-Tatlidede

, Gurvit

, Oktem-Tanor

, Emre

(2012) Crossed aphasia in a dextral patient with logopenic/phonological variant of primary progressive aphasia. Alzheimer Dis Assoc Disord 26, 282–284.

19.

Parente

, Giovagnoli

(2015) Crossed aphasia and preserved visuospatial functions in logopenic variant primary progressive aphasia. J Neurol 262, 216–218.

20.

Cabrera-Martín

, Matías-Guiu

, Yus-Fuertes

, Valles-Salgado

, Moreno-Ramos

, Matías-Guiu

, Carreras Delgado

(2016) 18F-FDG PET/CT and functional MRI in a case of crossed logopenic primary progressive aphasia. Rev Esp Med Nucl Imagen Mol 35, 394–397.

21.

Jang

, Park

, Kim

, Cho

, Lyoo

, Seo

, Na

(2016) A dextral primary progressive aphasia patient with right dominant hypometabolism and tau accumulation and left dominant amyloid accumulation. Case Rep Neurol 8, 78–86.

22.

Nishida

, Hayashi

, Ban

, Kudo

, Harada

, Sakurai

(2019) A case of crossed logopenic primary progressive aphasia in a dextral patient with underlying frontotemporal dementia. Intern Med, doi: 10.2169/internalmedicine.2301-18

23.

Ferrari

, Polito

, Vannucchi

, Piaceri

, Bagnoli

, Lombardi

, Lucidi

, Berti

, Nacmias

, Sorbi

(2019) Primary progressive aphasia: Natural history in an Italian cohort. Alzheimer Dis Assoc Disord 33, 42–46.

24.

Folstein

, Folstein

, McHugh

(1975) “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. . J Psychiatr Res 12, 189–198.

25.

Carlesimo

, Caltagirone

, Gainotti

(1996) The Mental Deterioration Battery: Normative data, diagnostic reliability and qualitative analyses of cognitive impairment. The Group for the Standardization of the Mental Deterioration Battery. Eur Neurol 36, 378–384.

26.

Mondini

, Mappelli

, Vestri

, Arcara

, Bisiacchi

(2001) Esame Neuropsicologico Breve 2. Raffaele Cortina Editore.

27.

Monaco

, Costa

, Caltagirone

, Carlesimo

(2013) Forward and back ward span for verbal and visuo-spatial data: Standardization and normative data from an Italian adult population. Neurol Sci 34, 749–754.

28.

Caffarra

, Vezzadini

, Dieci

, Zonato

, Venneri

(2002) Rey-Osterrieth complex figure: Normative values in an Italian population sample. Neurol Sci 22, 443–447.

29.

Apollonio

, Leone

, Isella

, Piamarta

, Consoli

, Villa

, Forapani

, Russo

, Nichelli

(2005) The Frontal Assessment Battery (FAB): Normative values in an Italian sample. Neurol Sci 26, 108–116.

30.

De Renzi , Faglioni

, Scarpa

, Crisi

(1986) Limb apraxia in patients with damage confined to the left basal ganglia and thalamus. J Neurol Neurosurg Psychiatry 49, 1030–1038.

31.

Spinnler

, Tognoni

(1987) Standardizzazione e taratura italiana di test neuropsicologici (Italian standardization of neuropsychological tests). Ital J Neurol Sci S8, 1–120.

32.

Katz

, Ford

, Moskowitz

, Jackson

, Jaffe

(1963) Studies of illness in the aged. The Index of ADL: A standardized measure of biological and psychosocial function. JAMA 185, 914–919.

33.

Lawton

(1969) Instrumental Activities of Daily Living. Gerontologist 19, 179–186.

34.

Cummings

(1997) The Neuropsychiatric Inventory: Assessing psychopathology in dementia patients. Neurology 48, S10–S16.

35.

Capasso

, Miceli

(2001) Esame Neuropsicologico per l’afasia (E.N.P.A.). Metologie Riabilitative in Logopedia, Vol 4. Springer-Verlag.

36.

Novelli

, Papagno

, Capitani

, Laiacona

, Vallar

, Cappa

(1986) Tre test clinici di ricercar e produzine lessicale:taratura su soggetti normali. Neuropsicol Psichiatr 47, 477–506.

37.

Varrone

, Asenbaum

, Vander Borght

, Booij

, Nobili

, Någren

, Darcourt

, Kapucu

, Tatsch

, Bartenstein

, Van Laere

; European Association of Nuclear Medicine Neuroimaging Committee (2009) EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2. Eur J Nucl Med Mol Imaging 36, 2103–2110.

38.

Oldfield

(1971) The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9, 97–113.

39.

Viggiano

, Borelli

, Vannucci

, Rocchetti

(2001) Hand preference in Italian students. Laterality 6, 283–286.

40.

Molinuevoa

, Gispertc

, Dubois

, Heneka

, Lleo

, Engelborghs

, Pujol

, de Souza

, Alcolea

, Jessen

, Sarazin

, Lamari

, Balasa

, Antonell

, Rami

(2013) The AD-CSF-Index discriminates Alzheimer’s disease patients from healthy controls: A validation study. J Alzheimers Dis 36, 67–77.

41.

Clark

, Schneider

, Bedell

, Beach

, Bilker

, Mintun

, Pontecorvo

, Hefti

, Carpenter

, Flitter

, Krautkramer

, Kung

, Coleman

, Doraiswamy

, Fleisher

, Sabbagh

, Sadowsky

, Reiman

, Zehntner

, Skovronsky

; AV45-A07 Study Group (2011) Use of florbetapir-PET for imaging beta-amyloid pathology. JAMA 305, 275–283.

42.

Nacmias

, Piaceri

, Bagnoli

, Tedde

, Piacentini

, Sorbi

(2014) Genetics of Alzheimer’s disease and frontotemporal dementia. Curr Mol Med 14, 993–1000.

43.

Minoshima

, Drzezga

, Barthel

, Bohnen

, Djekidel

, Lewis

, Mathis

, McConathy

, Nordberg

, Sabri

, Seibyl

, Stokes

, Van Laere

(2016) SNMMI procedure standard/EANM practice guideline for amyloid PET imaging of the brain. J Nucl Med 57, 1316–1322.

44.

Perani

, Della Rosa

, Cerami

, Gallivanone

, Fallanca

, Vanoli

, Panzacchi

, Nobili

, Pappatà

, Marcone

, Garibotto

, Castiglioni

, Magnani

, Cappa

, Gianolli

; EADC-PET Consortium (2014) Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting. Neuroimage Clin 6, 445–454.

45.

Rogalski

, Johnson

, Weintraub

, Mesulam

(2008) Increased frequency of learning disability in patients with primary progressive aphasia and their first-degree relatives. Arch Neurol 65, 244–248.

46.

Rogalski

, Rademaker

, Wieneke

, Bigio

, Weintraub

, Mesulam

(2014) Association between the prevalence of learning disabilities and primary progressive aphasia. JAMA Neurol 71, 1576–1577.

47.

Miller

, Mandelli

, Rankin

, Henry

, Babiak

, Frazier

, Lobach

, Bettcher

, Wu

, Rabinovici

, Graff-Radford

, Miller

, Gorno-Tempini

(2013) Handedness and language learning disability differentially distribute in progressive aphasia variants. Brain 136 (Pt 11), 3461–3473.

48.

Castro-Caldas

, Confraria

, Poppe

(1987) Non-verbal disturbances in crossed aphasia. Aphasiology 1, 403–413.

49.

Baddeley

(2003) Working memory: Looking back and looking forward. Nat Rev Neurosci 4, 829–839.

50.

Ivanova

, Dragoy

, Kuptsova

, Akinina

, Petrushevskii

, Fedina

, Turken

, Shklovsky

, Dronkers

(2018) Neural mechanisms of two different verbal working memory tasks: A VLSM study. Neuropsychologia 115, 25–41.

51.

Baldo

, Dronkers

(2006) The role of inferior parietal and inferior frontal cortex inworking memory. Neuropsychology 20, 529–538.

52.

Chein

, Moore

, Conway

ARA

(2011) Domain-general mechanisms of complex working memory span. Neuroimage 54, 550–559.

53.

Rabinovici

, Jagust

, Furst

, Ogar

, Racine

, Mormino

, O’Neil

, Lal

, Dronkers

, Miller

, Gorno-Tempini

(2008) Abeta amyloid and glucose metabolism in three variants of primary progressive aphasia. Ann Neurol 64, 388–401.

54.

Mesulam

, Wicklund

, Johnson

, Rogalski

, Lèger

, Rademaker

, Weintraub

, Bigio

(2008) Alzheimer and frontotemporal pathology in subsets of primary progressive aphasia. Ann Neurol 63, 709–719.

55.

Santos-Santos

, Rabinovici

, Iaccarino

, Ayakta

, Tammewar

, Lobach

, Henry

, Hubbard

, Mandelli

, Spinelli

, Miller

, Pressman

, O’Neil

, Ghosh

, Lazaris

, Meyer

, Watson

, Yoon

, Rosen

, Grinberg

, Seeley

, Miller

, Jagust

, Gorno-Tempini

(2018) Rates of amyloid imaging positivity in patients with primary progressive aphasia. JAMA Neurol 75, 342–352.