Giannini e-1

Online Supplement for:

Clinical marker for Alzheimers 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, Alzheimers 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)-662-3361mgrossma@mail.med.upenn.edu

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 (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 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 2 years after disease onset).

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

Reporting of clinical feature

Definition

Binary (Fisher Exact)

Preserved or

Relatively preserveda

Preserved / Absent

Preserved / Absent

Impairment with fluctuationsb

Borderline impaired / Mild feature

Impaired / Present

Impaired consistentlyc

Impaired / Prominent feature

aImpairment inconsistent in time; impaired in 2 years after first visit); AD = Alzheimers 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 Alzheimers disease phenotype.

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

C

2

Right

AD

High ADNC

V/VI

C

3

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

C

6

Left

AD

High ADNC

V/VI

C

7

Right

AD

High ADNC

V/VI

C

8

Left

AD

High ADNC

V/VI

C

9

Left

AD

High ADNC

DLB

Limbic

V/VI

C

10

Left

AD

High ADNC

V/VI

C

11

Left

AD

High ADNC

MSA

Rare corticala

V/VI

C

12

Unknown

AD

High ADNC

V/VI

C

13

Left

AD

High ADNC

V/VI

C

14

Left

AD

High ADNC

V/VI

C

15

Right

AD

High ADNC

CAA

NA

V/VI

C

16

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

C

19

Left