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Giannini e-1

Online Supplement for:

Clinical marker for Alzheimer’s disease pathology in logopenic primary progressive aphasia

Lucia A.A. Giannini, BSc; David J. Irwin, MD; Corey T. McMillan, PhD; Sharon Ash, PhD; Katya Rascovsky, PhD; David A. Wolk, MD; Vivianna M. Van Deerlin, MD, PhD; Edward B. Lee, MD, PhD; John Q. Trojanowski, MD, PhD; Murray Grossman, MD

Lucia A.A. Giannini, Department of Neurology, University Medical Center Groningen, University of Groningen; Penn Frontotemporal Degeneration Center, Department of NeurologyDavid J. Irwin, Penn Frontotemporal Degeneration Center, Department of Neurology; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineCorey T. McMillan, Penn Frontotemporal Degeneration Center, Department of NeurologySharon Ash, Penn Frontotemporal Degeneration Center, Department of NeurologyKatya Rascovsky, Penn Frontotemporal Degeneration Center, Department of NeurologyDavid A. Wolk, Alzheimer’s Disease Center, Department of NeurologyVivianna M. Van Deerlin, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineEdward B. Lee, Translational Pathology lab, Perelman School of Medicine, University of PennsylvaniaJohn Q. Trojanowski, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory MedicineMurray Grossman, Penn Frontotemporal Degeneration Center, Department of Neurology

Supplemental Data:

e-Methods (e-Methods, Table 1; e-Methods, Table 2; e-Methods, Figure 1)

Table e-1, Table e-2, Table e-3, Table e-4, Table e-5, Table e-6, Table e-7

Figure e-1, Figure e-2

Corresponding author: Murray Grossman, MDFrontotemporal Degeneration CenterUniversity of Pennsylvania Perelman School of MedicineHospital of the University of Pennsylvania3600 Spruce Street, Philadelphia, PA 19104Phone (215)[email protected]

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e-Methods

All included patients had >1 clinical visits (e-Methods, Figure 1) with an average mean time from

onset to first visit of 3.5 years (range 0.8-10.5 years) and mean time from last visit to death of 2.3

years (range 0.0-7.6 years). We had follow-up clinical data (i.e. > 2 years after diagnosis) for 30/34

(88%) patients of the total cohort. Follow-up data were not available for three patients with AD

pathology and one patient with FTLD-TDP neuropathology. Another patient with FTLD-TDP

neuropathology was severely impaired (mute, with no comprehension) at follow-up and was

therefore only assessed for non-language-mediated functions (praxis, visuospatial functioning,

motor and behavioral symptoms).

Chart Extraction: Specific elements of the cognitive exam were extracted using the following

parameters.

Clinical features were extracted from the medical charts using criteria specified below. We

recorded clinical assessments of language functions (repetition, single-word retrieval,

comprehension, speech quality, reading and writing), additional language features (paraphasias,

agrammatism, neologisms and paragrammatisms), memory function (verbal episodic memory and

visual memory), parietal lobe function (visuospatial functioning, numerical calculation, praxis) and

frontal lobe function (executive functioning). We recorded behavioral features when reported by

the clinician or by the patient and/or caregiver in the clinical history.

Repetition

Repetition was assessed qualitatively in the medical charts and we differentiated whether the

impairment was at sentence level, word level, or both. When an impairment was present but the

level of impairment was not specified, we recorded it as impaired repetition not otherwise specified

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(NOS). We recorded digit span scores from clinical evaluations and we defined a score of ≤ 4 on

forward digit span and a score of ≤ 2 on backward digit span as the cut-off values for impairment.

Single-word retrieval

The assessment of single-word retrieval included word-finding difficulties and confrontation

naming. The presence of word-finding difficulties was based on qualitative evaluations given by

the clinician (report of word-finding difficulties, word-finding pauses and/or circumlocutions).

Assessment of confrontation naming was mostly qualitative. When the score of a naming test (BNT

or shorter versions) was reported, impairment was defined as ≤80% of total possible score.

Comprehension

Comprehension was evaluated qualitatively by the clinician. We distinguished sentence

comprehension (ability to comprehend commands and propositions) and single-word

comprehension (ability to comprehend semantic material at the single-word level). When the level

of impairment was not specified, we recorded it as impairment of comprehension not otherwise

specified (NOS). We recorded qualitative assessment of object knowledge (impaired or preserved)

when such information was available.

Speech quality

Assessment of speech was qualitative, including parameters of fluency and motor speech. Fluency

was defined as the rate of speech output reflecting the process of word retrieval. We reported an

impairment of fluency when speech was described as hesitant, sparse, stuttering, slow and/or

halting. An impairment of motor speech (i.e. effortful speech characteristic of

nonfluent/agrammatic PPA) was recorded when speech was characterized as effortful, dysarthric

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and/or disarticulated speech. Content of speech was marked as impaired when speech was

described as empty or jargon aphasic.

Reading and writing

Assessment of reading and writing was qualitative. We distinguished the function of reading

(patient able/unable to read) from that of written comprehension (patient able/unable to read for

comprehension). We recorded the presence of surface dyslexia. Writing was recorded as impaired

or preserved based on qualitative evaluations, and it was further characterized as an impairment of

spelling, grammar and/or word content, or NOS.

Additional language features

Together with quality of speech assessment, we recorded the occurrence of additional language

features, namely apraxia of speech and paraphasias (phonemic, semantic or NOS) in speech, and

agrammatism (agrammatic errors and omissions), paragrammatism (such as incorrect inflection of a

verb or noun) and neologisms in speech and/or writing.

Memory

Assessments of verbal and visual episodic memory were obtained from the medical charts.

Assessment of verbal episodic memory was based on the recognition of a word list of variable

length (range 3-16). It was marked as impaired when qualified as random/unreliable (or synonyms)

by the clinician, or quantitatively in a few instances using a cut-off score of <50%. Visual memory

assessment was based on a qualitative statement of the clinician testing recall of a visual geometric

design. Impairment in visual recall was reported when the patient was able to reproduce none or

only few details of the geometric figure (i.e. recall was substantially compromised).

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Parietal lobe function

Within this field, we looked at visuospatial functioning, ability to calculate and praxis. For

visuospatial functioning, we considered the qualitative evaluations of the physician based on tests

of drawing a visual geometric design and of judgement of line orientation (JOLO), when available.

An impairment in visuospatial functioning was recorded when there was substantial difficulty in

performing these tasks. Difficulty in drawing the visual design because of poor organization (or

synonyms) was marked as an impairment of executive functioning rather than visuospatial (unless

further evidence was present for a visuospatial impairment, e.g. JOLO). When calculation ability

was assessed, we considered the qualitative evaluation of the physician based on the patient’s

performance of simple calculations. From the assessment of praxis, we considered both the

presence of oral and limb apraxia.

Frontal lobe function

Executive functioning was defined as impaired or preserved based on qualitative evaluations of the

physician. We considered both verbal assessments (category naming fluency and oral trails) and

non-verbal assessments (non-verbal alternating patterns). Behavioral symptoms were extracted

from the clinical history at each visit, and complemented with the evaluations of the physician

during clinical examination. We recorded behavioral symptoms suggestive of bvFTD (apathy,

social disinhibition/poor judgement, ritualistic behavior, loss of empathy, apathy and lack of

initiative, hypersexual and hyperoral behavior). Impairment was defined as the presence of three or

more behavioral symptoms.

Chart Extraction: Standardized criteria to define clinical features upon chart extraction

We used the qualitative evaluations reported by the clinician to record the presence of language and

non-language features. For the purpose of the analyses, we used a binary outcome for clinical

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features (i.e. impaired/non-impaired, or present/absent). In most cases, impairment of clinical

features was reported consistently and was therefore recorded accordingly. In some cases, features

were reported in an inconsistent manner (i.e. with fluctuation of symptomatology). These

borderline cases with inconsistent reporting were counted as impaired when the fluctuating

symptoms were present in the majority of visits.

Neuropsychological data

Digit span was reported as the highest number of digits that the patient could reproduce, either in

the forward or backward format. The MMSE was measured out of 30. Boston Naming Test was

measured out of 15 items in the majority of patients (n=24) and out of 30 in a subset (n=5). The

scores of this 30-item BNT were divided by two. FAS fluency test was reported as the total number

of words (beginning with letters F, A and S) produced during three 1-minute trials. Word list recall

was expressed as the number of items recalled after a 1-minute delay (max. score 10) following

three learning trials. Word list recognition was counted as the sum of true positives (items from the

word list correctly recognized) and true negatives (distractor items correctly not recognized). In

most cases, the target list was 10 words in length, resulting in a maximum score of 20.

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e-Methods, Table 1 Criteria for patient exclusion

Reason for exclusion Criterion Excluded (n)

Not sufficient clinical information

Less than two visits providing a complete assessment of language function (i.e. including evaluations of word retrieval, comprehension, repetition and speech)

10

Suspected non-degenerative cause

Presence of other nondegenerative nervous system or medical disorders which may explain the cognitive deficit(s)

1

Suspected psychiatric diagnosis

Presence of other psychiatric symptoms/diagnosis which may explain the cognitive disturbance

0

Prominent initial episodic memory, visual memory, and visuospatial impairments

No evidence of preserved memory function (based on assessments of episodic verbal recognition and visual recall) AND visuospatial difficulties during the initial phase of diseasea

2

Prominent initial behavioral disturbance

Presence of substantial behavioral impairment (three or more behavioral signs/symptoms, main cause of complaint) during the initial phase of diseasea

0

Legend: n = number of cases.

aThe initial phase of disease was assessed based on the clinical visits falling within the first two

years of disease, when available, and on the clinical history as well as the performance at first visit

for those who presented at a later stage (>2 years after disease onset).

e-Methods, Table 2 Scale to assess the prominence of clinical features

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Reporting of clinical feature Definition Binary (Fisher Exact)Preserved orRelatively preserveda Preserved / Absent Preserved / Absent

Impairment with fluctuationsb Borderline impaired / Mild feature Impaired / Present

Impaired consistentlyc Impaired / Prominent featureaImpairment inconsistent in time; impaired in <1/2 evaluations following first report of impairment

with preserved function at the latest evaluation in time.

bImpairment inconsistent in time; impaired in ≥1/2 evaluations following first report of impairment.

cImpairment consistent in time; impaired in all evaluations following first report of impairment.

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e-Methods, Figure 1 Availability of clinical records for each patient per year of disease

Legend: The number in each cell indicates the number of clinical records available for that year.

AD = Alzheimer’s disease pathology; DLB = Lewy body disease; FTLD = frontotemporal lobar

degeneration; N = patient number; n = number of cases; NPD = neuropathological diagnosis.

Table e-1 Phenotypic change of patients from baseline to follow-up

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N NPDx1 DY baseline

Baseline phenotype

DY follow-up

Follow-up phenotype

AD criteriona

1 AD 1 Unclassifiable 3 lvPPA -2 AD 10 Unclassifiable / ? -3 AD 3 lvPPA+ / ? ?4 AD 4 lvPPA 6 lvPPA+ -5 AD 3 lvPPA- 5 lvPPA -6 AD 3 lvPPA+ 5 lvPPA+ -7 AD 2 lvPPA+ 4 lvPPA+ +8 AD 4 lvPPA 7 lvPPA+ -9 AD 4 lvPPA 6 lvPPA+ -10 AD 6 lvPPA / ? -

11 AD 4 lvPPA- 7 lvPPA -

12 AD 3 lvPPA 5 lvPPA -

13 AD 2 lvPPA+ 4 lvPPA+ -

14 AD 3 naPPA 5 naPPA -

15 AD 5 lvPPA+ 7 lvPPA+ +

16 AD 3 lvPPA- 5 lvPPA- +


18 AD 4 lvPPA+ 6 lvPPA+ +


20 FTLD-Tau 3 naPPA 5 naPPA -

21 FTLD-Tau 1 Unclassifiable 3 lvPPA+ -



24 FTLD-Tau 1 lvPPA+ 3 lvPPA+ -

25 FTLD-Tau 4 naPPA 6 naPPA ?


27 FTLD-TDP 4 lvPPA- 6 svPPA -

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28 FTLD-TDP 1 Unclassifiable 4 ? -

29 FTLD-TDP 1 lvPPA / ? -

30 FTLD-TDP 0 lvPPA+ 2 lvPPA+ -

31 FTLD-TDP 2 svPPA 4 svPPA -

32 FTLD-TDP 4 svPPA 6 svPPA -

33 DLB 2 lvPPA- 4 lvPPA -

34 DLB 2 lvPPA- 4 lvPPA- -

Legend: + = patient meets AD criterion on follow-up; - = patient does not meet AD criterion on

follow-up; ? = none or insufficient clinical information; / = no follow-up (i.e. no clinical

information >2 years after first visit); AD = Alzheimer’s disease; CBD = corticobasal degeneration;

DLB = Lewy body disease; DY = disease year; FTLD-TDP= frontotemporal lobar degeneration

with TDP inclusions; lvPPA = logopenic variant of primary progressive aphasia; N = patient

number; naPPA = nonfluent/agrammatic variant of primary progressive aphasia; NPDx1 = primary

neuropathological diagnosis; PSP = progressive supranuclear palsy; svPPA = semantic variant of

primary progressive aphasia.

aImpaired episodic memory (no evidence of preserved memory function, based on assessments of

verbal recognition and visual recall when available) accompanied by visuospatial dysfunction,

suggesting Alzheimer’s disease phenotype.

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Table e-2 Supplementary neuropathological information: sampled hemisphere, primary/secondary neuropathology, staging and mutation status

N Hemisphere NPDx1 NPDx1 stage NPDx2 NPDx2

stage Braak CERAD Gene Mut

1 Left AD High ADNC DLB Limbic V/VI C2 Right AD High ADNC V/VI C3 Left AD High ADNC V/VI C

4 Left AD High ADNC CLL, dural NA V/VI C

5 Left AD High ADNC CAA NA V/VI C6 Left AD High ADNC V/VI C7 Right AD High ADNC V/VI C8 Left AD High ADNC V/VI C9 Left AD High ADNC DLB Limbic V/VI C10 Left AD High ADNC V/VI C11 Left AD High ADNC MSA Rare corticala V/VI C12 Unknown AD High ADNC V/VI C13 Left AD High ADNC V/VI C14 Left AD High ADNC V/VI C15 Right AD High ADNC CAA NA V/VI C16 Left AD High ADNC V/VI C

17 Left AD High ADNC FTLD-TDP

Medium corticalb V/VI C

18 Right AD High ADNC V/VI C19 Left AD High ADNC V/VI C20 Right CBD NA 0 021 Right CBD NA AD Low ADNC I/II A22 Left CBD NA ? 023 Left CBD NA ? ?24 Left CBD NA I/II A25 Unknown PSP NA III/IV 026 Left PSP NA DLB Limbic I/II 027 Right TDP NA AD Low ADNC 0 B28* Unknown TDP NA I/II 0 GRN29 Unknown TDP NA 0 0 GRN30 Left TDP NA AGD Rare corticala I/II 0 GRN31 Left TDP NA I/II A32 Right TDP NA I/II 0

33 Left DLB Neocortical AD Intermed ADNC III/IV B

34 Unknown DLB Neocortical AD Intermed ADNC III/IV B

Legend: ? = unknown; AD = Alzheimer’s disease; ADNC = Alzheimer’s disease neuropathologic

change; AGD = argyrophilic grain disease; CAA = cerebral amyloid angiopathy; CBD =

corticobasal degeneration; CLL = chronic lymphocytic leukemia; DLB = Lewy body disease; GRN

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= progranulin gene; MSA = multiple system atrophy; Mut = mutation; N = patient number; NA =

not applicable; NPDx1 = primary neuropathology; NPDx2 = secondary neuropathology; PSP =

progressive supranuclear palsy; TDP = frontotemporal lobar degeneration with TDP inclusions.

aOrdinal scores of proteinopathy < 1 (rare) in all cortical regions (mid-frontal, anterior cingulate,

superior mid-temporal, angular).

bOrdinal scores of proteinopathy ≤ 2 (intermediate) in all cortical regions (mid-frontal, anterior

cingulate, superior mid-temporal, angular).

* Brain tissue of this patient for superior mid-temporal cortex (STC) was sampled from a more

posterior portion (Wernicke’s area) compared to the samples of the other patients.

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Table e-3 Frequency of language features in pathology-defined groups

AD path(n=19)

non-AD path(n=15) Sig.

Word retrieval

Imp single-word retrieval Baseline 19/19 (100.0) 15/15 (100.0) -Follow-up 16/16 (100.0) 13/13 (100.0) -

Imp confrontation naming Baseline 19/19 (100.0) 13/14 (92.9) 0.42Follow-up 16/16 (100.0) 13/13 (100.0) -

Repetition

Imp word repetition Baseline 6/17 (35.3) 2/13 (15.4) 0.41Follow-up 11/13 (84.6) 6/11 (54.5) 0.18

Imp sentence/NOS repetition Baseline 13/19 (68.4) 5/15 (33.3) 0.08Follow-up 16/16 (100.0) 11/13 (84.6) 0.19

Imp DF (≤4 digits) Baseline 16/18 (88.9) 5/15 (33.3) 0.00Follow-up 16/16 (100.0) 6/10 (60.0) 0.01

Imp DB (≤2 digits) Baseline 12/18 (66.7) 4/14 (28.6) 0.07Follow-up 14/15 (93.3) 5/9 (55.6) 0.05

Comprehension

Imp single-word comprehension Baseline 8/15 (53.3) 5/14 (35.7) 0.46Follow-up 15/16 (93.8) 9/12 (75.0) 0.29

Imp object knowledge Baseline 1/14 (7.1) 5/14 (35.7) 0.17Follow-up 5/8 (62.5) 5/9 (55.6) 1.00

Imp sentence/NOS comprehension Baseline 16/16 (100.0) 9/14 (64.3) 0.01Follow-up 16/16 (100.0) 10/12 (83.3) 0.18

Imp grammatical comprehension Baseline 11/18 (61.1) 10/14 (71.4) 0.71Follow-up 11/16 (68.8) 9/13 (69.2) 1.00

Speech

Imp fluency Baseline 10/19 (52.6) 10/15 (66.7) 0.50Follow-up 9/16 (56.3) 9/13 (69.2) 0.70

Effortful speech Baseline 4/19 (21.1) 9/15 (60.0) 0.03Follow-up 6/16 (37.5) 9/13 (69.2) 0.14

Empty speech Baseline 9/19 (47.4) 2/15 (13.3) 0.06Follow-up 10/16 (62.5) 5/13 (38.5) 0.27

Apraxia of speech Baseline 1/19 (5.3) 1/15 (6.7) 1.00Follow-up 1/16 (6.3) 2/13 (15.4) 0.57

Other language features

Agrammatism Baseline 9/19 (47.4) 8/15 (53.3) 1.00Follow-up 10/16 (62.5) 8/13 (61.5) 1.00

Phonemic paraphasias/NOS Baseline 16/19 (84.2) 9/15 (60.0) 0.14Follow-up 15/16 (93.8) 11/13 (84.6) 0.57

Semantic paraphasias/NOS Baseline 14/19 (73.7) 10/15 (66.7) 0.72Follow-up 14/16 (87.5) 10/13 (76.9) 0.63

Neologisms Baseline 3/19 (15.8) 2/15 (13.3) 1.00Follow-up 8/16 (50.0) 4/13 (30.8) 0.45

Paragrammatisms Baseline 4/19 (21.1) 3/15 (20.0) 1.00Follow-up 6/16 (37.5) 3/13 (23.1) 0.45

Reading and writing

Reading Baseline 4/15 (26.7) 1/13 (7.7) 0.33Follow-up 9/12 (75.0) 5/12 (41.7) 0.21

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Surface dyslexia Baseline 7/19 (36.8) 3/15 (20.0) 0.45Follow-up 11/16 (68.8) 5/13 (38.5) 0.14

Imp written comprehension Baseline 3/14 (21.4) 2/7 (28.6) 1.00Follow-up 12/14 (85.7) 5/7 (71.4) 0.57

Imp writing Baseline 14/19 (73.7) 11/15 (73.3) 1.00Follow-up 16/16 (100.0) 12/13 (92.3) 0.45

Legend: AD = Alzheimer’s disease; DB = backward digit span; DF = forward digit span; Imp =

impaired; NOS = not otherwise specified; path = pathology; Sig. = statistical significance.

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Table e-4 Frequency of non-language features in pathology-defined groups

AD path (n=19)

non-AD path(n=15)

Sig.

MemoryImp verbal recognition memory Baseline 3/17 (17.6) 2/13 (15.4) 1.00

Follow-up 10/16 (62.5) 4/7 (57.1) 1.00Imp visual recall memory Baseline 1/18 (5.6) 0/12 (0) 1.00

Follow-up 5/13 (38.5) 1/8 (12.5) 0.34Parietal lobe functionImp visuospatial functioning Baseline 3/19 (15.8) 0/15 (13.3) 0.24

Follow-up 9/16 (56.3) 3/13 (23.1) 0.13Imp numerical calculation Baseline 6/12 (50.0) 4/11 (36.4) 0.68

Follow-up 9/11 (81.8) 4/7 (57.1) 0.33Imp praxis Baseline 8/15 (53.3) 7/13 (53.8) 1.00

Follow-up 10/15 (66.7) 8/11 (72.7) 1.00Frontal lobe functionImp executive functioning Baseline 18/19 (94.7) 14/14 (100.0) 1.00

Follow-up 16/16 (100.0) 13/13 (100.0) -Imp behavior (≥3 symptoms) Baseline 1/19 (5.3) 1/15 (6.7) 1.00

Follow-up 2/16 (12.5) 2/14 (14.3) 1.00Legend: AD = Alzheimer’s disease; Imp = impaired; n = number of cases; path = pathology; Sig. =

statistical significance.

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Table e-5 Neuropsychological performance by pathology-defined groups

AD path Non-AD path Sig.

Onset to testing visit 4.4 ± 2.4n = 17

2.8 ± 1.9n = 12 0.08

MMSE (max=30), meana 20.1 ± 5.7n = 17

23.3 ± 4.8n = 12 0.12

DF, median (IQR)b 4.0 (3.0 – 4.0)n = 16

5.0 (4.0 – 7.0)n = 12 0.01

DB, median (IQR)b 2.0 (2.0 – 3.0)n = 16

3.0 (3.0 – 6.5)n = 12 0.02

BNT (max=15), median (IQR)b

11.0 (8.0 – 12.8)n = 17

13.0 (9.0 – 14.8)n = 12 0.10

Word list recall (max=10), median (IQR)b

1.0 (0.0 – 3.5)n = 13

2.0 (0.0 – 5.0)n = 11 0.49

Word list recognition (max=20), meana

15.7 ± 3.7n = 12

15.9 ± 3.6n = 11 0.88

FAS, meana 17.4 ± 13.0n = 13

10.2 ± 5.3n = 9 0.13

Legend: AD = Alzheimer’s disease; BNT = Boston naming test; DB = backward digit span; DF =

forward digit span; IQR = interquartile range; MMSE = Mini-mental state examination; path =

pathology; Sig. = statistical significance.

aData described in the table with mean and standard deviation have been tested with the

independent sample Student t-test.

bData described in the table with median and interquartile range (IQR) have been tested with the

Mann-Whitney U test.

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Table e-6 Post-mortem pathology and preliminary ante-mortem neuroimaging findings in corresponding cortical brain regions

AD Non-AD Sig.Superior mid-temporal gyrus

Neu

ropa

th

Composite score 3.0 (3.0 – 3.0) 2.0 (1.0 – 3.0) < .01Neuronal loss 3.0 (2.0 – 3.0) 2.0 (1.0 – 2.0) 0.05Gliosis 3.0 (2.0 – 3.0) 1.0 (0.0 – 2.0) 0.02Median (IQR) n = 19 n = 14

MR

I Atrophy (z-score)a -2.31 ± 0.65 -1.68 ± 0.58 0.04Mean ± SD n = 6 n = 6

Angular gyrus

Neu

ropa

th


MR


Mid-frontal cortex

Neu

ropa

th


MR


Cingulate cortex

Neu

ropa

th

Composite score 3.0 (3.0 – 3.0) 3.0 (2.0 – 3.0) 0.18Neuronal loss 2.0 (1.0 – 3.0) 1.0 (1.0 – 2.0) 0.07Gliosis 1.0 (1.0 – 3.0) 1.0 (0.0 – 1.0) 0.03Median (IQR) n = 19 n = 15

MR


Comparative analysis of ante-mortem MRI grey matter loss and post-mortem pathology was

performed (Table e-6). In the subset with ante-mortem neuroimaging (n=12), the AD group (n=6)

had more MRI atrophy in STC and ANG compared with non-AD (n=6, p<0.05) (Figure e-2). Of

these patients, 6/6 (100%) AD cases had impaired baseline DF, compared to 2/6 (33%) non-AD

(p=0.06). A supplementary analysis showed significantly lower GMD in AD for left-hemisphere

ANG, but no such effect in the right hemisphere (Table e-7).

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Legend: AD = Alzheimer’s disease; IQR = interquartile range; MRI = magnetic resonance imaging;

n = number of cases; Neuropath = neuropathology; SD = standard deviation.

aWe report average grey matter density (GMD) scores from left and right hemispheres because of

random sampling of left and right hemispheres in our autopsy series.

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Table e-7 Exploratory neuroimaging analysis: hemispheric grey matter density scores and lateralization

Total (n=12) AD (n=6) non-AD (n=6) Sig.Superior mid-temporal gyrusRight, mean ± SD -2.11 ± 0.80 -1.32 ± 0.83 0.03Left, mean ± SD -2.51 ± 0.66 -2.04 ± 0.60 0.19Average, mean ± SD -2.31 ± 0.65 -1.68 ± 0.58 0.04Left > Right, n (%)a 5/6 (83.3) 5/6 (83.3) 1.00Tot. Left > Right, n (%)b 10/12 (83.3) 0.04Angular gyrusRight, mean ± SD -2.06 ± 0.65 -1.16 ± 0.89 0.01Left, mean ± SD -2.37 ± 0.93 -1.65 ± 1.02 0.04Average, mean ± SD -2.21 ± 0.68 -1.40 ± 0.95 0.01Left > Right, n (%)a 4/6 (66.7) 6/6 (100.0) 0.46Tot. Left > Right, n (%)b 10/12 (83.3) 0.04Mid-frontal cortexRight, mean ± SD -1.79 ± 1.28 -1.24 ± 1.06 0.05Left, mean ± SD -1.72 ± 1.16 -1.46 ± 1.00 0.11Average, mean ± SD -1.75 ± 1.20 -1.35 ± 1.01 0.06Left > Right, n (%)a 2/6 (33.3) 4/6 (66.7) 0.57Tot. Left > Right, n (%)b 6/12 (50.0) 1.00Cingulate cortexRight, mean ± SD -0.36 ± 1.23 -0.14 ± 0.87 0.42Left, mean ± SD -0.26 ± 1.11 -0.02 ± 0.60 0.71Average, mean ± SD -0.31 ± 1.13 -0.08 ± 0.65 0.52Left > Right, n (%)a 3/6 (50.0) 3/6 (50.0) 1.00Tot. Left > Right, n (%)b 6/12 (50.0) 1.00Legend: AD = Alzheimer’s disease; Left > Right = atrophy lateralized to the left; n = number of

cases; Path = pathology; SD = standard deviation; Sig. = statistical significance.

aLateralization of atrophy tested across neuropathology groups (AD/non-AD) using the Fisher

Exact test.

bLateralization of atrophy tested in the total group of patients with available MRI data using the

Binomial test.

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Figure e-1 Clinical spectrum of Alzheimer’s disease pathology in primary progressive aphasia

Legend: The number in each cell indicates the frequency of listed clinical features (%) in the group

of AD patients by year of disease. Compr = comprehension; diff = difficulties; DB = backward

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digit span; DF = forward digit span; Imp = impaired; n = number of cases; PP = paraphasias;

recogn = recognition; Sent/NOS = at the sentence level or not otherwise specified.

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Figure e-2 Ante-mortem MRI grey matter density loss in pathology-defined groups

Legend: AD = Alzheimer’s disease; GMD = grey matter density; L = left; MRI = magnetic

resonance imaging; R = right.

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