4311 11th Avenue NE #300 Seattle, WA 98105 phone: (206) 543-8637; fax: (206) 616-5927 e-mail: [email protected] Department of Epidemiology, School of Public Health and Community Medicine, University of Washington website: https://www.alz.washington.edu NACC Neuropathology (NP) Diagnosis Coding Guidebook Detailed, annotated explanations of the form on an item-level basis, with instructions, operational definitions, and references (Version 9.1, September 2008) NOTE: Version 9 is NOT the most current version of the NP form and is not to be used for autopsies conducted on or after January 27, 2014. For the current version of the form, please visit http://www.alz.washington.edu. This guidebook last modified August 29, 2012 Copyright © 2005-2010. University of Washington. Created and published by the ADC Clinical Task Force (John C. Morris, MD, Chair) and the National Alzheimer’s Coordinating Center (Walter A. Kukull, PhD, Director). All rights reserved. Publication funded by the National Institutes of Health through the National Institute on Aging, Cooperative Agreement #AG016976 NACC Neuropathologic Diagnosis Coding Guidebook The NACC Neuropathologic Diagnosis Coding Guidebook contains procedures to be followed when completing the NACC Neuropathology Data Form. This guidebook is authored by the members of the ADC Neuropathology Core Leaders’ Steering Committee. Typographical Conventions Instructions will appear as a sans serif font against a shaded background... sample text. General Instructions 1. Please answer all items for all subjects. 2. Explanation of allowable codes: • “Not done” and “Not assessed” – these responses are equivalent and some questions use one version or the other. • “Missing/unknown” – this response indicates the data is not available because it has been lost or is no longer retrievable. NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 1 DEMOGRAPHICS (cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13) 1. MDS/UDS Patient ID ................ (cid:13)(cid:13) (cid:13)(cid:13) (cid:13)(cid:13)(cid:13)(cid:13) 2. Date form completed ................. month day year (cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13)(cid:13) 3. Neuropath ID ............................. (cid:13) 4. Gender ........................................ (M or F) (cid:13)(cid:13)(cid:13) 5. Age at death ............................... years (cid:13)(cid:13) (cid:13)(cid:13) (cid:13)(cid:13)(cid:13)(cid:13) 6. Date of death .............................. month day year Please provide identification and demographic neuropathology information in questions 1– 6. 7. Does the brain have any gross or microscopic pathology (including any Alzheimer type pathology such as senile plaques and neurofibrillary tangles)? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (Note: For either response, items 8A through 24 must also be answered.) Answer “no” only if the brain is completely devoid of any histopathologic changes. If there are only minimal Alzheimer type changes, please indicate this in the following questions. ALZHEIMER TYPE PATHOLOGY Alzheimer’s Disease. For all brains in which there is any degree of Alzheimer type pathology (ranging from a few senile plaques and neurofibrillary tangles to advanced Alzheimer’s Disease), please indicate the nature of the pathology according to commonly used pathologic criteria. Follow the published guidelines for these entries. Answer “not done” for all criteria not used. 8A. NIA/Reagan Institute neuropathological criteria used: (mark one box) (cid:13) 1 High likelihood of dementia being due to Alzheimer’s disease (cid:13) 2 Intermediate likelihood of dementia being due to Alzheimer’s disease (cid:13) 3 Low likelihood of dementia being due to Alzheimer’s disease (cid:13) 4 Criteria not met (cid:13) 5 Not done (cid:13) 9 Missing/unknown (Hyman BT, Trojanowski JQ. Editorial on Consensus recommendations for the postmortem diagnosis of Alzheimer’s Disease from the National Institute on Aging and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. J Neuropathol Exp Neurol 1997;56:1095-1097.) NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 2 8B. CERAD neuropathological criteria used: (mark one box) (cid:13) 1 Definite Alzheimer’s disease (cid:13) 2 Probable Alzheimer’s disease (cid:13) 3 Possible Alzheimer’s disease (cid:13) 4 Criteria not met (cid:13) 5 Not done (cid:13) 9 Missing/unknown (Mirra SM, Hart MN, Terry RD. Making the diagnosis of Alzheimer's disease. A primer for practicing pathologists. Arch Pathol Lab Med 1993;117:132-144.) 8C. ADRDA/Khachaturian neuropathological criteria used: (mark one box) (cid:13) 1 Alzheimer’s disease (cid:13) 2 Criteria not met (cid:13) 3 Not done (cid:13) 9 Missing/unknown (Khachaturian S. Diagnosis of Alzheimer's disease. Arch Neurol 1985;42:1097-1105.) 8D. Other or unspecified neuropathological criteria used (e.g., Tierney, etc.): (mark one box) (cid:13) 1 Alzheimer’s disease, unspecified (cid:13) 2 Criteria not met (cid:13) 3 Not done (cid:13) 9 Missing/unknown NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 3 Neurofibrillary Pathology. For all brains in which topographic staging of neurofibrillary degeneration was done, please indicate the stage with a number from 1–7. If Braak staging was not done, use number 8. Indicate the stage according to the scheme proposed by Braak and Braak. While the original methods employed Gallyas stains, other stains for neurofibrillary pathology (e.g., tau immunostains, other silver stains or thioflavin-S) may be used. The focus is on the distribution of neurofibrillary tangles. (Nagy Z, Yilmazer-Hanke DM, Braak H, et al. Assessment of the pathological stages of Alzheimer's disease in thin paraffin sections: a comparative study. Dementia & Geriatric Cognitive Disorders 1998;9:140-144; Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 1991;82:239-259.) 9. Braak & Braak Neurofibrillary Stage. (mark one box) (cid:13) 1 Stage I (cid:13) 2 Stage II (cid:13) 3 Stage III (cid:13) 4 Stage IV (cid:13) 5 Stage V (cid:13) 6 Stage VI (cid:13) 7 Neurofibrillary degeneration not present (cid:13) 8 Not assessed (cid:13) 9 Missing/unknown Stages I–II correspond to NFT limited to the transentorhinal/entorhinal region; Stages III–IV to limbic stages; and Stages V–VI to neocortical stages. Stage VI implies involvement of primary cortices. Answer “not assessed” if topographic staging has not been done. Plaque Score. For the most severely affected cortical region, please indicate the plaque score. Please use the Consortium to Establish a Registry of Alzheimer’s Disease (CERAD) standards for sparse, moderate, and frequent. 10. Neuritic plaques (plaques with argyrophilic dystrophic neurites with or without dense amyloid cores). (mark one box) (cid:13) 1 Frequent neuritic plaques (cid:13) 2 Moderate neuritic plaques (cid:13) 3 Sparse neuritic plaques (cid:13) 4 No neuritic plaques (cid:13) 5 Not assessed (cid:13) 9 Missing/unknown Neuritic plaques are considered to be plaques with argyrophilic, thioflavin-S-positive or tau-positive dystrophic neurites with or without dense amyloid cores. Answer “not assessed” if neuritic plaques have not been specifically analyzed. NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 4 11. Diffuse plaques (plaques with non-compact amyloid and no apparent dystrophic neurites). (mark one box) (cid:13) 1 Frequent diffuse plaques (cid:13) 2 Moderate diffuse plaques (cid:13) 3 Sparse diffuse plaques (cid:13) 4 No diffuse plaques (cid:13) 5 Not assessed (cid:13) 9 Missing/unknown Diffuse plaques are considered to be plaques with non-compact amyloid and no apparent dystrophic neurites. Answer “not assessed” if diffuse plaques have not been specifically analyzed. ISCHEMIC, HEMORRHAGIC AND VASCULAR PATHOLOGY This section is meant to indicate the presence of vascular pathology, but not the absolute burden, volume, or severity of change. More detailed information about lesion distribution, burden, etc is presumed to be part of a research database. Questions about severity of vascular pathology are of necessity subjective, since current methods to easily and consistently assess severity of vascular disease have not been validated or widely implemented. Even if infarcts, focal sclerosis and hemorrhages are not present, and there is evidence of vascular pathology, be sure to answer questions 12I through 12K to record information about severity of atherosclerotic, arteriosclerotic, and amyloid vascular pathology. 12. Is ischemic, hemorrhagic or vascular pathology present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown (Note: Items 12A through 12L must also be answered.) Please include atherosclerosis, arteriosclerosis or amyloid angiopathy. 12A. Are one or more large artery cerebral infarcts present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to infarcts larger than 1 cm in diameter in the distribution of large and medium sized meningocerebral vessels rather than small parenchymal vessels. Infarcts meeting these criteria are included regardless of the histologic age and include acute lesions as well as chronic cystic lesions. NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 5 12B. Are one or more cortical microinfarcts (including “granular atrophy”) present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to infarcts that are detected microscopically and may not be grossly visible, or may appear to the naked eye as cortical granularity. Microinfarcts in non-cortical areas should not be included in this category. Infarcts meeting these criteria are included regardless of the histologic age and include acute lesions as well as chronic cystic lesions. 12C. Are one or more lacunes (small artery infarcts and/or hemorrhages) present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to cystic/old infarcts or hemorrhages 1-cm or less in diameter that are usually grossly identified and in the distribution of small parenchymal vessels, most often in basal ganglia, thalamus, pons, cerebellum and cerebral white matter. 12D. Are single or multiple hemorrhages present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to cerebral hemorrhages, regardless of size in any region of the brain. 12E. Is subcortical arteriosclerotic leukoencephalopathy present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to multifocal or diffuse white matter pathology attributable to arteriosclerotic small vessel disease and will be associated with axonal and myelin loss in the centrum ovale, often associated with brain infarcts. White matter rarefaction confined to the immediate periventricular region (so-called periventricular “capping”) should not be included. (Roman GC. Senile dementia of the Binswanger type, a vascular form of dementia in the elderly; JAMA 1987;258:1782-1788 and Caplan LR. Binswanger's disease – revisited. Neurology 1995;45:626-633.) NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 6 12F. Is cortical laminar necrosis present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to selective cortical necrosis of middle and lower cortical lamina most often associated with cerebral hypoperfusion and concentrated in border zones between major cerebral arteries. 12G. Is medial temporal lobe sclerosis (including hippocampal sclerosis) present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to selective neuronal loss and gliosis (“sclerosis”) of medial temporal lobe structures. In the hippocampus, this is often limited to CA1 and the subiculum with variable involvement of endplate and CA2. The amygdala and entorhinal cortex may also be affected. In some cases there is a clear history of cerebral hypoperfusion. In others there may be a history of epilepsy. Similar pathology can also be seen in the setting of neurodegenerative disorders (e.g., FTD). 12H. Is atherosclerotic vascular pathology (of the circle of Willis) present? (mark one box) (cid:13) 1 None (cid:13) 2 Mild (cid:13) 3 Moderate (cid:13) 4 Severe (cid:13) 5 Not assessed (cid:13) 9 Missing/unknown Use this item to indicate the severity of atherosclerotic (intimal and medial fibrofatty atheromatous plaques) disease in the large (named) arteries at the base of the brain (i.e., the circle of Willis). The assessment is qualitative and subjective and should indicate an estimate of overall severity rather than an individual vessel. NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 7 12I. Is arteriosclerosis (small parenchymal arteriolar disease) present? (mark one box) (cid:13) 1 None (cid:13) 2 Mild (cid:13) 3 Moderate (cid:13) 4 Severe (cid:13) 5 Not assessed (cid:13) 9 Missing/unknown Use this item to indicate the severity of arteriosclerosis (arteriolosclerosis) (hyalinosis of the media and adventitia) of small parenchymal and/or leptomeningeal vessels. The assessment is qualitative and subjective and should indicate an estimate of overall severity rather than an individual vessel. 12J. Is amyloid angiopathy present? (mark one box) (cid:13) 1 None (cid:13) 2 Mild (cid:13) 3 Moderate (cid:13) 4 Severe (cid:13) 5 Not assessed (cid:13) 9 Missing/unknown Use this item to indicate the severity of cerebral amyloid angiopathy as demonstrated with special stains for amyloid (e.g., Congo red, thioflavin-S, or Aβ immunostaining). The assessment is qualitative and subjective, and should indicate an estimate of overall severity rather than an individual vessel. 12K. Is another type of angiopathy (e.g., CADASIL or arteritis) present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown Use this item to indicate the presence of other forms of arteriopathy not mentioned in the above categories. 12L. Is there other pathology related to ischemic or vascular disease not previously specified present? (mark one box) (cid:13) 1 Yes (cid:13) 2 No (cid:13) 3 Not assessed (cid:13) 9 Missing/unknown This category refers to ischemic or vascular disease not specifically mentioned in the above categories. NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 8 Lewy Body Pathology. For all brains in which Lewy bodies are detected, indicate the presence and distribution of Lewy-related pathology. This classification is independent of the clinical presentation, which may be variable and include Parkinsonism, dementia, psychosis, sleep disorders, etc. 13A. Pathology is consistent with criteria of Consortium on Dementia with Lewy Bodies for: (select only one) (cid:13) 1 Lewy body pathology, brainstem predominant type (cid:13) 2 Lewy body pathology, intermediate or transitional (limbic) type (cid:13) 3 Lewy body pathology, diffuse (neocortical) type (cid:13) 4 Lewy body pathology, unspecified or not further assessed (cid:13) 5 No Lewy bodies (cid:13) 6 Not assessed (cid:13) 9 Missing/unknown 13B. Likelihood that DLB Clinical Syndrome due to DLB Pathology: (select only one) (cid:13) 1 Low (cid:13) 2 Intermediate (cid:13) 3 High (cid:13) 6 N/A (not applicable) (cid:13) 9 Missing/unknown Characterization of Lewy body pathology should use guidelines set forth by “Consortium on Dementia with Lewy bodies.” (McKeith IG, Galasko D, Kosaka K, et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): Report of the consortium on DLB international workshop. Neurology 1996;47:1113-1124 and McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and Management of Dementia with Lewy Bodies: Third report of the DLB Consortium, Neurology 2005, 65:1863-1872.) According to the 2005 guidelines, the preferred method of assessment is with immunohistochemistry for alpha-synuclein. If Lewy body pathology was assessed with ubiquitin or H&E stains (not synuclein), please specify “4 – Lewy body pathology, unspecified” as your answer. The diffuse (neocortical) type implies involvement of neocortical areas beyond the limbic lobe. The transitional (limbic) type implies cortical involvement limited to limbic lobe. Cases with Lewy bodies limited to the amygdala were not specifically addressed in the Consortium criteria, but should be included in the transitional (limbic) type for the sake of this database. The 2005 published criteria recommend semi-quantitative evaluation of Lewy bodies, similar to that used for CERAD plaque grading (absent, mild, moderate, severe, and very severe). Pathologic character- ization of Lewy body pathology is to be performed independent of Alzheimer-related pathology for the sake of this neuropathologic database. However, Alzheimer pathology as recorded in the previous section, “Alzheimer Type Pathology” (question 8A) is used to answer question 13B, the “likelihood that DLB clinical syndrome was due to DLB pathology”, by use of the following, adapted from the 2005 guidelines: Alzheimer type pathology NIA-Reagan Low NIA-Reagan Intermediate NIA-Reagan High (Braak stage 0-II) (Braak stage III-IV) (Braak stage V-VI) Lewy body type pathology Brainstem-predominant Low Low Low Limbic (transitional) High Intermediate Low Diffuse neocortical High High Intermediate NACC NP Diagnosis Coding Guidebook (version 9.1, September 2008) 9