Concordance of Clinical Alzheimer Diagnosis and Neuropathological Features at Autopsy

Classified as probably not a substantial claim. May combine two claims.

Shim et al found that AD-Mimics had more impairment on the UPDRS and exhibited more parkinsonian signs than Confirmed-AD participants, concluding that the presence of these signs should warn clinicians of the possibility of an alternate diagnosis.

“Shim et al (1) found that AD-Mimics had more impairment on the Unified Parkinson's Disease Rating Scale (UPDRS) and exhibited more parkinsonian signs than Confirmed-AD participants, concluding that the presence of these signs should warn clinicians of the possibility of an alternate diagnosis.”

• cites [1] Shim, 2013, Clinicopathologic study of Alzheimer’s disease: Alzheimer mimics, JAD sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Visual hallucinations and REM sleep behavior disorder are core clinical features used while diagnosing dementia with Lewy bodies.

“which are core clinical features used while diagnosing dementia with Lewy bodies (16).”

• cites [16] McKeith, 2017, Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB consortium, Neurology sourceSupported

May combine two claims.

Beach et al found that sensitivity of clinical AD diagnosis ranged from 70.9% to 87.3% and specificity from 44.3% to 70.8%.

“Beach et al (6) found that sensitivity ranged from 70.9% to 87.3% and specificity from 44.3% to 70.8%.”

• cites [6] Beach, 2012, Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010, J Neuropathol Exp Neurol sourceSupported

May combine two claims.

Compared with AD-Mimics, participants with autopsy-confirmed AD had a higher prevalence of delusions, agitation or aggression, depression or dysphoria, and motor disturbances.

“Compared with AD-Mimics, participants with autopsy-confirmed AD had a higher prevalence of delusions, agitation or aggression, depression or dysphoria, and motor disturbances.”

• cites [1] Shim, 2013, Clinicopathologic study of Alzheimer’s disease: Alzheimer mimics, JAD sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Misdiagnosed participants were less likely to be depressed.

“The authors found that misdiagnosed participants were less likely to be depressed.”

• cites [8] Gaugler, 2013, Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use: An analysis of the NACC-UDS database, BMC Geriatr sourceSupported

Classified as probably not a substantial claim.

Shim et al compared 533 patients who were diagnosed with AD, referring to the 119 patients who did not meet neuropathological criteria for AD as AD-Mimics.

“Using data from the National Alzheimer's Coordinating Center (NACC), Shim et al (1) compared 533 patients who were diagnosed with AD, referring to the 119 patients who did not meet neuropathological criteria for AD as AD-Mimics.”

• cites [1] Shim, 2013, Clinicopathologic study of Alzheimer’s disease: Alzheimer mimics, JAD sourceSupported

May combine two claims.

AD-Mimics were more likely to have a history of pacemaker insertion, congestive heart failure, hypertension, and resting tremor than participants who had autopsy-confirmed AD.

“AD-Mimics were more likely to have a history of pacemaker insertion, congestive heart failure, hypertension, and resting tremor than participants who had autopsy-confirmed AD.”

• cites [1] Shim, 2013, Clinicopathologic study of Alzheimer’s disease: Alzheimer mimics, JAD sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Previous studies have shown that LBD and cerebrovascular injury are the most common AD-dementia mimics.

“Previous studies (1,15) have shown that LBD and cerebrovascular injury are the most common AD-dementia mimics.”

• cites [1] Shim, 2013, Clinicopathologic study of Alzheimer’s disease: Alzheimer mimics, JAD sourcePartly supported

  The Results (‘Neuropathological diagnoses’) identify dementia with Lewy bodies as the most common Alzheimer mimic (35 cases, 29%). Vascular disease was also a mimic (15 cases, 13%), but ranked third, behind insufficient AD (22 cases, 18%); the source therefore does not support calling both the most common mimics. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [15] Klatka, 1996, Incorrect diagnosis of Alzheimer’s disease. A clinicopathologic study, Arch Neurol sourceNot checked — no full text of the source

May combine two claims.

The study had the strengths of using data on a large group of individuals from multiple institutions across the United States, all of which use standardized techniques and reporting methods for both clinical and autopsy data.

“Despite these limitations, the study had the strengths of using data on a large group of individuals from multiple institutions across the United States, all of which use standardized techniques and reporting methods for both clinical and autopsy data (26).”

• cites [26] Montine, 2016, Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer’s disease, Alzheimers Dement sourcePartly supported

  The Methods describe a collaboration among ten AD Centers, and the Discussion reports high agreement in neuropathologic data across centers. But this paper examined fourteen cases, not a large group of individuals. Its Introduction says there was no consensus on staining methods, and it does not establish standardized clinical-data techniques or reporting across the institutions. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

May combine two claims.

Mixed pathologies were common in both populations, and once age distribution was accounted for, distribution of mixed pathologies among NACC and ACT participants was similar, with AD+LBD and AD+Vascular Brain Injury being the most common mixed pathologies.

“Mixed pathologies were common in both populations, and once the age distribution was accounted for the distribution of mixed pathologies among NACC participants and ACT participants was similar, with ADþ LBD and ADþVascular Brain Injury being the most common mixed pathologies in those populations (18).”

• cites [18] Brenowitz, 2017, Alzheimer’s disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples, Neurobiol Aging sourceSupported

May combine two claims.

Over 80% of participants with pure HS pathology were diagnosed with possible or probable AD prior to death, indicating that HS pathology strongly mimics AD pathology clinically.

“Despite this, over 80% of participants with”

• cites [9] Brenowitz, 2014, Hippocampal sclerosis of aging is a key Alzheimer’s disease mimic: Clinical-pathologic correlations and comparisons with both Alzheimer’s disease and non-tauopathic frontotemporal lobar degeneration, JAD sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Participants with PART and ADNC both have neuropathological tau deposits, but amyloid deposits are absent in definite PART.

“While participants with PART and ADNC both have neuropathological tau deposits, amyloid deposits are absent in definite PART.”

• cites [21] Teylan, 2019, Clinical diagnoses among individuals with primary age-related tauopathy versus Alzheimer’s neuropathology, Lab Invest sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

18.8% of misdiagnosed participants were treated with potentially inappropriate medications.

“In addition, they found that 18.8% of misdiagnosed participants were treated with potentially inappropriate medications”

• cites [8] Gaugler, 2013, Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use: An analysis of the NACC-UDS database, BMC Geriatr sourcePartly supported

  The Results (Medication use in the misdiagnosed group) report 18.18% (16 of 88), not 18.8%, on a potentially inappropriate medication regimen. The Methods also define that regimen to include some participants who were not given indicated medication, so not all 16 were treated with an inappropriate drug. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Over 50% of participants with ADNC had cooccurring LBD pathology or vascular brain injury.

“Another study found that over 50% of participants with ADNC had cooccurring LBD pathology or vascular brain injury (18).”

• cites [18] Brenowitz, 2017, Alzheimer’s disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples, Neurobiol Aging sourceSupported

May combine two claims.

The predominant neuropathological change in LATE is TDP-43 proteinopathy, which is associated with amnestic dementia that can mimic Alzheimer's dementia.

“The predominant neuropathological change in LATE is TDP-43 proteinopathy, which is associated with a clinical presentation of amnestic dementia that can mimic Alzheimer's dementia.”

• cites [20] Nelson, 2019, Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report, Brain sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

A study comparing neuropathological features at autopsy by year of death in NACC showed that presence of microinfarcts has been consistent over time, with 18% from 2002-2011, 19.2% from 2012-2013, and 23.9% from 2014-2018.

“A study comparing neuropathological features at autopsy by year of death in the NACC database showed that the presence of microinfarcts has been consistent over time, with 18% of participants having microinfarcts from 2002 to 2011, 19.2% from 2012 to 2013 and 23.9% from 2014 to 2018 (24).”

• cites [24] Besser, 2018, The revised National Alzheimer’s Coordinating Center’s neuropathology form—Available data and new analyses, J Neuropathol Exp Neurol sourcePartly supported

  Table 3 (reproduced in the Discussion) reports the cited microinfarct percentages: 18.0%, 19.2%, and 23.9%. But the paper describes microinfarcts as becoming more commonly diagnosed, not remaining consistent over time. Its final study period ends in 2017, not 2018. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AD-Mimics and definite PART are both defined as having no neuritic plaques, and PART participants are generally older and experience less severe cognitive dysfunction.

“AD-Mimics and definite PART are both defined as having no neuritic plaques, and like the AD-Mimics in this study, PART participants are generally older and experience less severe cognitive dysfunction (22,23).”

• cites [22] Crary, 2014, Primary age-related tauopathy (PART): A common pathology associated with human aging, Acta Neuropathol sourceSupported
• cites [23] Besser, 2019, Differences in cognitive impairment in primary age-related tauopathy versus Alzheimer disease, J Neuropathol Exp Neurol sourcePartly supported

  The Participants section defines definite PART as having no neuritic plaques, and the Results and Discussion report less severe cognitive impairment in PART than in AD. The Discussion describes PART as typically affecting older people, but says the age distribution was similar for definite PART and AD. This paper does not address the definition of AD-Mimics, so it does not support that part of the jointly cited sentence. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

LATE and PART are common neuropathologies.

“LATE and PART are common neuropathologies, indicating the importance of addressing potential relationships between AD-Mimics, and LATE and PART pathology in future research (20,22).”

• cites [20] Nelson, 2019, Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report, Brain sourceSupported
• cites [22] Crary, 2014, Primary age-related tauopathy (PART): A common pathology associated with human aging, Acta Neuropathol sourceSupported

May combine two claims.

A study examined difference between NACC and ACT and found that, while there was more vascular pathology in ACT participants, they were also older.

“A study examined the difference between NACC and ACT and found that, while there was more vascular pathology in ACT participants, they were also older.”

• cites [18] Brenowitz, 2017, Alzheimer’s disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples, Neurobiol Aging sourcePartly supported

  The Results (§3.1; page not available in our copy) report that autopsied ACT participants with dementia were older at death and had more vascular brain injury than their NACC counterparts. The claim omits that this finding concerns participants with dementia; the paper says participants without dementia were relatively similar in demographic and pathologic characteristics. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim. May combine two claims.

Cognitive trajectories were similar between participants with mixed pathologies and participants who only had ADNC; impact of co-occurring pathologies may have been due to severity of AD more than mixed pathologies.

“Other studies found that cognitive trajectories were similar between participants with mixed pathologies and participants who only had ADNC; though, the impact of co-occurring pathologies may have been due to the severity of AD more than the mixed pathologies (18,19).”

• cites [18] Brenowitz, 2017, Alzheimer’s disease neuropathologic change, Lewy body disease, and vascular brain injury in clinic- and community-based samples, Neurobiol Aging sourceCould not verify

  The Results (§3.3; page unavailable) compare clinical characteristics of participants with ADNC only and mixed ADNC, but do not report cognitive trajectories. The Discussion (§4; page unavailable) addresses co-occurring pathologies and ADNC levels, not whether AD severity explains their cognitive impact. Searches for cognitive trajectories and AD severity found no passage establishing either part of the claim. (LLM, conf=0.74)

  Experimental — accuracy not yet measured
• cites [19] Brenowitz, 2017, Mixed neuropathologies and estimated rates of clinical progression in a large autopsy sample, Alzheimers Dement sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Another study using NACC data compared hippocampal sclerosis (HS) pathology with AD pathology, finding less cognitive impairment in persons with HS versus AD pathology.

“Another study data aimed to address this, using NACC data to compare hippocampal sclerosis (HS) pathology with AD pathology, finding less cognitive impairment in persons with HS versus AD pathology.”

• cites [9] Brenowitz, 2014, Hippocampal sclerosis of aging is a key Alzheimer’s disease mimic: Clinical-pathologic correlations and comparisons with both Alzheimer’s disease and non-tauopathic frontotemporal lobar degeneration, JAD sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

LATE is differentiated from FTLD-TDP-43 pathology by distribution of TDP-43 in the brain and by LATE generally affecting older populations.

“LATE is differentiated from FTLD-TDP-43 pathology by distribution of TDP-43 in the brain and by LATE generally affecting older populations (20).”

• cites [20] Nelson, 2019, Limbic-predominant age-related TDP-43 encephalopathy (LATE): Consensus working group report, Brain sourceSupported

May combine two claims.

Among Unidentified-AD participants, the most common primary diagnoses were FTLD (41.1%), LBD (43.9%), and vascular dementia or stroke (6.7%).

“Among participants in the Unidentified-AD group, the most common primary diagnoses were frontotemporal lobar degeneration (41.1%),LBD (43.9%), and vascular dementia or stroke (6.7%).”

May combine two claims.

Unidentified-AD were less likely to possess the APOEe4 allele than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“Only the comparison for APOEe4 allele became insignificant after Bonferroni correction.”

May combine two claims.

Unidentified-AD were less likely to have Braak stages V and VI than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“After Bonferroni correction, the comparisons between groups for Braak stages V through VI, other or unspecified Lewy bodies, FTLD-TDP-43 pathology, gross infarcts, microinfarcts, and HS became insignificant.”

May combine two claims.

A sensitivity analysis restricted to participants with a primary diagnosis of AD in the AD-Mimics group showed no difference in any association or frequency compared to the main analysis, aside from HS in Supplementary Table S7 (Model 7), which became significant (OR: 2.04, 95% CI: 1.09-3.81; p value: 0.026).

“The results of this sensitivity analy- sis showed no difference in any association or frequency compared to the main analysis, aside from that of HS in Sup- plementary Data Table S7 (Model 7), which became significant (OR: 2.04, 95% CI: 1.09-3.81;p value: 0.026).”

May combine two claims.

Unidentified-AD were less likely to exhibit microinfarcts than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“After Bonferroni correction, the comparisons between groups for Braak stages V through VI, other or unspecified Lewy bodies, FTLD-TDP-43 pathology, gross infarcts, microinfarcts, and HS became insignificant.”

May combine two claims. The quote only partly states this claim.

A larger proportion of Unidentified-AD had FTLD-TDP-43 pathology than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“After Bonferroni correction, the comparisons between groups for Braak stages V through VI, other or unspecified Lewy bodies, FTLD-TDP-43 pathology, gross infarcts, microinfarcts, and HS became insignificant.”

May combine two claims. The quote only partly states this claim.

Unidentified-AD were less likely to exhibit HS than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“After Bonferroni correction, the comparisons between groups for Braak stages V through VI, other or unspecified Lewy bodies, FTLD-TDP-43 pathology, gross infarcts, microinfarcts, and HS became insignificant.”

Borderline on S1 (asserted), S3 (load-bearing), S4 (based): unclear from the text. May combine two claims. The quote only partly states this claim.

AD-Mimics were more likely to have brainstem-predominant Lewy bodies than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“Participants in the AD-Mimics group were more likely to have brainstem-predominant Lewy bodies.”

May combine two claims.

Unidentified-AD were less likely to exhibit gross infarcts than Confirmed-AD, but this comparison became insignificant after Bonferroni correction.

“After Bonferroni correction, the comparisons between groups for Braak stages V through VI, other or unspecified Lewy bodies, FTLD-TDP-43 pathology, gross infarcts, microinfarcts, and HS became insignificant.”

The quote only partly states this claim.

A higher proportion of Unidentified-AD participants had less severe AD (Braak stages III and IV) than Confirmed-AD.

“a higher proportion of participants in the Unidentified-AD group had less severe AD (Braak stages III and IV).”

May combine two claims.

Despite selection toward nonvascular dementia at enrollment, there remains substantial vascular disease pathology at autopsy in NACC with up to 70% of participants displaying arteriolosclerosis and 20% displaying microinfarcts at autopsy as of the September 2019 data freeze.

“However, despite the selection toward nonvascular dementia at enrollment, there remains substantial vascular disease pathology at autopsy in NACC with up to 70% of participants displaying arteriolosclerosis and 20% displaying microinfarcts at autopsy as of the September 2019 data freeze.”

The quote only partly states this claim.

AD-Mimics displayed less language decline than Confirmed-AD participants.

“Participants in the AD-Mimics group did display less language decline”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

It is possible that this result differs from previous studies because we included participants with either a primary or contributing clinical diagnosis of AD, while previous studies likely focused on primary clinical diagnoses.

“It is possible that this result differs from previous studies because we included participants with either a primary or contributing clinical diagnosis of AD, while previous studies likely focused on primary clinical diagnoses.”

May combine two claims.

In our study, parkinsonian signs were associated with increased odds of being included in the Unidentified-AD group, indicating that it is difficult to recognize AD in the face of LBD symptoms.

“However, in our study we found that these signs were associated with increased odds of being included in the Unidentified-AD group, indicating that it is difficult to recognize AD in the face of LBD symptoms.”

May combine two claims.

A greater degree of cognitive impairment was associated with decreased odds of inclusion in both the AD-Mimics and Unidentified-AD groups, indicating that more significant cognitive impairment increases the likelihood that an AD diagnosis is correct.

“A greater degree of cognitive impairment was associated with decreased odds of inclusion in both the AD-Mimics group and the Unidentified-AD group, indicating that more significant cognitive impairment increases the likelihood that an AD diagnosis is correct.”

May combine two claims.

The supplemental analysis supports the notion that the Unidentified-AD group has higher frequencies of underlying mixed pathology, which may explain their undiagnosed AD and the symptoms they displayed at the last visit before death.

“This supplemental analysis supports the notion that the Unidentified-AD group has higher frequencies of underlying mixed pathology, which may explain their undiagnosed AD and the symptoms they displayed at the last visit before death.”

Classified as probably not a substantial claim.

These findings may explain why this study found that a higher proportion of Unidentified-AD had less severe AD (Braak stages III and IV).

“These findings may explain why this study found that a higher proportion of participants in the Unidentified-AD group had less severe AD (Braak stages III and IV).”

May combine two claims.

The prevalence of mixed pathologies may be different between this clinical case series and a community-based cohort, which may limit the generalizability of our results regarding the effect of mixed pathology on an inaccurate diagnosis.

“The prevalence of mixed pathologies may also be different between this clinical case series and a community-based cohort, which may limit the generalizability of our results in regards to the effect of mixed pathology on an inaccurate diagnosis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

A final limitation is that we did not explore differences in diagnostic accuracy by whether Centers use biomarkers to help make their diagnosis as this data is very limited.

“A final limitation of this study is that we did not explore any differences in diagnostic accuracy by whether Centers use biomarkers to help make their diagnosis as this data is very limited.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The ADCs that contribute data to NACC see an increased proportion of rare neurodegenerative phenotypes such as FTLD, which further limits its generalizability to other populations.

“Third, the ADCs that contribute data to NACC see an increased proportion of rare neurodegenerative phenotypes such as FTLD, which further limits its generalizability to other populations.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Participants who consented to autopsy may differ in characteristics from the overall NACC cohort.

“Second, we selected participants who consented to autopsy and these participants may differ in characteristics from the overall NACC cohort.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The NACC database is a case series (or convenience sample) and participants have higher education and are more likely to be white than the general population.

“First, the NACC database is a case series (or convenience sample) and participants have higher education and are more likely to be white than the general population.”

Probably not a substantial claim: may not pass S2 (checkable).

This allows us to draw reasonable conclusions regarding the differences in clinical and neuropathological characteristics among 3 distinct groups.

“This allows us to draw reasonable conclusions regarding the differences in clinical and neuropathological characteristics among 3 distinct groups-Confirmed-AD, AD-Mimics, and Unidentified-AD.”

Classified as probably not a substantial claim.

Because all three groups were defined by Braak stage and frequency of neuritic plaques, these variables were not included in the model comparing neuropathological characteristics between Confirmed-AD and AD-Mimics.

“Since all 3 groups in the study were defined by their Braak stage and frequency of neuritic plaques, we did not include these in the model comparing the neuropathological characteristics between the Confirmed-AD group and AD-Mimics.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

This is especially the case for participants who agree to autopsy.

“This is especially the case for participants who agree to autopsy.”

May combine two claims.

Unidentified-AD participants may have more mixed pathology but the effect on cognition may have been partially offset by the less severe ADNC.

“Unidentified-AD participants may have more mixed pathology but the effect on cognition may have been partially offset by the less severe ADNC.”

Probably not a substantial claim: may not pass S3 (load-bearing).

To correct for multiple comparisons, the authors additionally adjusted p values using the Bonferroni method.

“To correct for multiple comparisons, we additionally adjusted p values using the Bonferroni method.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

The prevalence of rare neurodegenerative diseases such as FTLD in this highly selected sample may not reflect the frequencies seen in community-based cohorts.

“However, the prevalence of rare neurodegenerative diseases such as FTLD in this highly selected sample may not reflect the frequencies seen in community-based cohorts and future studies should explore these neuropathological features in other cohorts.”