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 Neurology
David J. Irwin, Penn Frontotemporal Degeneration Center, Department of Neurology; Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Corey T. McMillan, Penn Frontotemporal Degeneration Center, Department of Neurology
Sharon Ash, Penn Frontotemporal Degeneration Center, Department of Neurology
Katya Rascovsky, Penn Frontotemporal Degeneration Center, Department of Neurology
David A. Wolk, Alzheimer’s Disease Center, Department of Neurology
Vivianna M. Van Deerlin, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Edward B. Lee, Translational Pathology lab, Perelman School of Medicine, University of Pennsylvania
John Q. Trojanowski, Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine
Murray 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, MD
Frontotemporal Degeneration Center
University of Pennsylvania Perelman School of Medicine
Hospital of the University of Pennsylvania
3600 Spruce Street, Philadelphia, PA 19104
Phone (215)-662-3361
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 andparagrammatisms), memory function (verbal episodic memoryandvisual 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, dysarthricand/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 andparaphasias (phonemic, semantic or NOS) in speech, andagrammatism (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).
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.Difficultyin 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 consideredboth 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 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 withinconsistent 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.
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 clinicalfeatures
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 <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.
e-Methods, Figure 1Availability 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-1Phenotypic change of patients from baseline to follow-up
N / NPDx1 / DY baseline / Baseline phenotype / DY follow-up / Follow-up phenotype / AD criteriona1 / 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- / +
17 / AD / 3 / lvPPA+ / 5 / lvPPA+ / -
18 / AD / 4 / lvPPA+ / 6 / lvPPA+ / +
19 / AD / 1 / lvPPA+ / 3 / lvPPA+ / -
20 / FTLD-Tau / 3 / naPPA / 5 / naPPA / -
21 / FTLD-Tau / 1 / Unclassifiable / 3 / lvPPA+ / -
22 / FTLD-Tau / 1 / naPPA / 3 / naPPA / -
23 / FTLD-Tau / 3 / naPPA / 5 / naPPA / -
24 / FTLD-Tau / 1 / lvPPA+ / 3 / lvPPA+ / -
25 / FTLD-Tau / 4 / naPPA / 6 / naPPA / ?
26 / FTLD-Tau / 6 / naPPA / 8 / naPPA / -
27 / FTLD-TDP / 4 / lvPPA- / 6 / svPPA / -
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.
Table e-2 Supplementary neuropathological information: sampled hemisphere, primary/secondary neuropathology, staging and mutation status
N / Hemisphere / NPDx1 / NPDx1 stage / NPDx2 / NPDx2stage / 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 / Rarecorticala / 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 / Mediumcorticalb / V/VI / C
18 / Right / AD / High ADNC / V/VI / C
19 / Left / AD / High ADNC / V/VI / C
20 / Right / CBD / NA / 0 / 0
21 / Right / CBD / NA / AD / Low ADNC / I/II / A
22 / Left / CBD / NA / ? / 0
23 / Left / CBD / NA / ? / ?
24 / Left / CBD / NA / I/II / A
25 / Unknown / PSP / NA / III/IV / 0
26 / Left / PSP / NA / DLB / Limbic / I/II / 0
27 / Right / TDP / NA / AD / Low ADNC / 0 / B
28* / Unknown / TDP / NA / I/II / 0 / GRN
29 / Unknown / TDP / NA / 0 / 0 / GRN
30 / Left / TDP / NA / AGD / Rarecorticala / I/II / 0 / GRN
31 / Left / TDP / NA / I/II / A
32 / 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 = 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 proteinopathy1 (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.
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) / 0.42
Follow-up / 16/16 (100.0) / 13/13 (100.0) / -
Repetition
Imp word repetition / Baseline / 6/17 (35.3) / 2/13 (15.4) / 0.41
Follow-up / 11/13 (84.6) / 6/11 (54.5) / 0.18
Imp sentence/NOS repetition / Baseline / 13/19 (68.4) / 5/15 (33.3) / 0.08
Follow-up / 16/16 (100.0) / 11/13 (84.6) / 0.19
Imp DF (≤4 digits) / Baseline / 16/18 (88.9) / 5/15 (33.3) / 0.00
Follow-up / 16/16 (100.0) / 6/10 (60.0) / 0.01
Imp DB (≤2 digits) / Baseline / 12/18 (66.7) / 4/14 (28.6) / 0.07
Follow-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) / 0.46
Follow-up / 15/16 (93.8) / 9/12 (75.0) / 0.29
Imp object knowledge / Baseline / 1/14 (7.1) / 5/14 (35.7) / 0.17
Follow-up / 5/8 (62.5) / 5/9 (55.6) / 1.00
Imp sentence/NOS comprehension / Baseline / 16/16 (100.0) / 9/14 (64.3) / 0.01
Follow-up / 16/16 (100.0) / 10/12 (83.3) / 0.18
Imp grammatical comprehension / Baseline / 11/18 (61.1) / 10/14 (71.4) / 0.71
Follow-up / 11/16 (68.8) / 9/13 (69.2) / 1.00
Speech
Imp fluency / Baseline / 10/19 (52.6) / 10/15 (66.7) / 0.50
Follow-up / 9/16 (56.3) / 9/13 (69.2) / 0.70
Effortful speech / Baseline / 4/19 (21.1) / 9/15 (60.0) / 0.03
Follow-up / 6/16 (37.5) / 9/13 (69.2) / 0.14
Empty speech / Baseline / 9/19 (47.4) / 2/15 (13.3) / 0.06
Follow-up / 10/16 (62.5) / 5/13 (38.5) / 0.27
Apraxia of speech / Baseline / 1/19 (5.3) / 1/15 (6.7) / 1.00
Follow-up / 1/16 (6.3) / 2/13 (15.4) / 0.57
Other language features
Agrammatism / Baseline / 9/19 (47.4) / 8/15 (53.3) / 1.00
Follow-up / 10/16 (62.5) / 8/13 (61.5) / 1.00
Phonemic paraphasias/NOS / Baseline / 16/19 (84.2) / 9/15 (60.0) / 0.14
Follow-up / 15/16 (93.8) / 11/13 (84.6) / 0.57
Semantic paraphasias/NOS / Baseline / 14/19 (73.7) / 10/15 (66.7) / 0.72
Follow-up / 14/16 (87.5) / 10/13 (76.9) / 0.63
Neologisms / Baseline / 3/19 (15.8) / 2/15 (13.3) / 1.00
Follow-up / 8/16 (50.0) / 4/13 (30.8) / 0.45
Paragrammatisms / Baseline / 4/19 (21.1) / 3/15 (20.0) / 1.00
Follow-up / 6/16 (37.5) / 3/13 (23.1) / 0.45
Reading and writing
Reading / Baseline / 4/15 (26.7) / 1/13 (7.7) / 0.33
Follow-up / 9/12 (75.0) / 5/12 (41.7) / 0.21
Surface dyslexia / Baseline / 7/19 (36.8) / 3/15 (20.0) / 0.45
Follow-up / 11/16 (68.8) / 5/13 (38.5) / 0.14
Imp written comprehension / Baseline / 3/14 (21.4) / 2/7 (28.6) / 1.00
Follow-up / 12/14 (85.7) / 5/7 (71.4) / 0.57
Imp writing / Baseline / 14/19 (73.7) / 11/15 (73.3) / 1.00
Follow-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.
Table e-4Frequency of non-language features in pathology-defined groups
AD path(n=19) / non-AD path
(n=15) / Sig.
Memory
Imp verbal recognition memory / Baseline / 3/17 (17.6) / 2/13 (15.4) / 1.00
Follow-up / 10/16 (62.5) / 4/7 (57.1) / 1.00
Imp visual recall memory / Baseline / 1/18 (5.6) / 0/12 (0) / 1.00
Follow-up / 5/13 (38.5) / 1/8 (12.5) / 0.34
Parietal lobe function
Imp visuospatial functioning / Baseline / 3/19 (15.8) / 0/15 (13.3) / 0.24
Follow-up / 9/16 (56.3) / 3/13 (23.1) / 0.13
Imp numerical calculation / Baseline / 6/12 (50.0) / 4/11 (36.4) / 0.68
Follow-up / 9/11 (81.8) / 4/7 (57.1) / 0.33
Imp praxis / Baseline / 8/15 (53.3) / 7/13 (53.8) / 1.00
Follow-up / 10/15 (66.7) / 8/11 (72.7) / 1.00
Frontal lobe function
Imp 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) / 1.00
Legend:AD = Alzheimer’s disease;Imp = impaired;n = number of cases;path = pathology; Sig. = statistical significance.
Table e-5Neuropsychological performance by pathology-defined groups
AD path / Non-AD path / Sig.Onset to testing visit / 4.4 ± 2.4
n = 17 / 2.8 ± 1.9
n = 12 / 0.08
MMSE(max=30), meana / 20.1 ± 5.7
n = 17 / 23.3 ± 4.8
n = 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 ± 3.7
n = 12 / 15.9 ± 3.6
n = 11 / 0.88
FAS, meana / 17.4 ± 13.0
n = 13 / 10.2 ± 5.3
n = 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.
Table e-6 Post-mortem pathology and preliminary ante-mortemneuroimaging findings in corresponding cortical brain regions
AD / Non-AD / Sig.Superior mid-temporal gyrus
Neuropath / Composite score / 3.0 (3.0 – 3.0) / 2.0 (1.0 – 3.0) / < .01
Neuronal loss / 3.0 (2.0 – 3.0) / 2.0 (1.0 – 2.0) / 0.05
Gliosis / 3.0 (2.0 – 3.0) / 1.0 (0.0 – 2.0) / 0.02
Median (IQR) / n = 19 / n = 14
MRI / Atrophy (z-score)a / -2.31 ± 0.65 / -1.68 ± 0.58 / 0.04
Mean ± SD / n = 6 / n = 6
Angular gyrus
Neuropath / Composite score / 3.0(3.0 – 3.0) / 2.0 (1.8 – 3.0) / < .01
Neuronal loss / 2.0(1.0 – 3.0) / 1.0 (0.0 – 2.0) / 0.02
Gliosis / 2.0 (1.0 – 3.0) / 0.5 (0.0 – 2.0) / 0.02
Median (IQR) / n = 19 / n = 14
MRI / Atrophy (z-score)a / -2.21 ± 0.68 / -1.40 ± 0.95 / 0.01
Mean ± SD / n = 6 / n = 6
Mid-frontal cortex
Neuropath / Composite score / 3.0 (3.0 – 3.0) / 2.0 (1.0 – 2.0) / < .01
Neuronal loss / 2.0 (1.0 – 3.0) / 2.0 (1.0 – 2.0) / 0.61
Gliosis / 2.0 (1.0 – 3.0) / 1.0 (1.0 – 2.0) / 0.35
Median (IQR) / n = 19 / n = 15
MRI / Atrophy (z-score)a / -1.75 ± 1.20 / -1.35 ± 1.01 / 0.06
Mean ± SD / n = 6 / n = 6
Cingulate cortex
Neuropath / Composite score / 3.0 (3.0 – 3.0) / 3.0 (2.0 – 3.0) / 0.18
Neuronal loss / 2.0 (1.0 – 3.0) / 1.0 (1.0 – 2.0) / 0.07
Gliosis / 1.0 (1.0 – 3.0) / 1.0 (0.0 – 1.0) / 0.03
Median (IQR) / n = 19 / n = 15
MRI / Atrophy (z-score)a / -0.31 ± 1.13 / -0.08 ± 0.65 / 0.52
Mean ± SD / n = 6 / n = 6
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).