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Diagnosis made based on the results of neuropathological examination by a qualified neuropathologist. Neuropathology Diagnoses are made according to standardized diagnostic criteria. Neuropathological findings not meeting diagnostic criteria (e.g., low Braak stages, sparse senile plaques, mild atherosclerosis) are not included in the Neuropathology Diagnosis.

Diagnostic pathology not present: A neuropathological examination was carried out - the findings did not meet diagnostic criteria. Minor neuropathological findings may be present in these individuals.

Not evaluated by NP: A neuropathological examination was not carried out.

Coding pending: The neuropathological examination was carried out, but diagnostic results are currently being coded.

The neuropathology diagnosis is distinct from neuropathological findings (e.g. diffuse plaques in frontal lobe, Braak stage). Providing neuropathological findings in the NBB database is underway. However, in the meantime, neuropathological findings are available for subjects upon request.

The neuropathology metrics section describes the presence and extent of common age-related and neurodegenerative changes according to guidelines generated by experts in the field. References are provided for more information on specific staging and grading systems:

Alzheimer Disease Neuropathologic Change [ADNC]: (PMID: 22101365, PMID: 22265587, PMID: 1759558) Alzheimer disease neuropathologic change [ADNC] is the pathologic correlate of clinical Alzheimer disease. The hallmark pathologies of Alzheimer disease are beta-amyloid plaques, occurring in the extracellular space, and neurofibrillary tangles (NFTs), composed of aggregated tau protein and occurring within neurons. A subset of beta-amyloid plaques termed "neuritic plaques" is associated with underlying dystrophic neurites containing pathologic tau aggregates.

• Thal beta-amyloid phase: Describes the spread of beta-amyloid throughout the brain over the course of disease on a scale of 1 to 5. Beta amyloid deposition begins in the neocortex (Phase 1), progresses through limbic regions (Phase 2), deep gray nuclei including the basal ganglia (Phase 3), the brainstem and midbrain (Phase 4), and finally involves the cerebellum (Phase 5).
• Braak neurofibrillary tangle (NFT) stage: Describes the spread of tau neurofibrillary tangle pathology through the brain during the course of disease on a scale of I to VI. In the cerebrum, neurofibrillary tangles first involve the entorhinal cortex (Stage I), then the hippocampus (Stage II), adjacent temporal cortex and limbic cortices (stage III-VI), higher-order association cortex (Stage V), and finally primary sensory cortices such as primary visual cortex (State VI). Brainstem involvement by tau pathology precedes involvement of the cerebrum.
• CERAD age related neuritic plaque score: Semiquantitive assessment of the highest plaque density present in neocortex on a scale of absent, sparse, moderate, and frequent. Guidelines for the assessment of plaque density are provided in the references above.
• NIA-Alzheimer association score: A/B/C. A derived score on scales of 1 to 3 representing the severity of the Thal (A), Braak (B) and CERAD (C) scores.
• Level of Alzheimer's Disease Neuropathologic Change (ADNC). Based on the ABC score, a level of Alzheimer disease neuropathologic change is calculated (Not AD, Low, Intermediate, and High). This score also corresponds to the likelihood of dementia due to Alzheimer disease pathology.

Lewy Body Pathology: Lewy body pathology is the most common cause of clinical Parkinson disease and Lewy body dementia. Two common staging schemes are listed, each reflecting the typical regional progression of Lewy body pathology during the course of disease.

• Lewy Pathology (PMID: 33399945): Breaks the progression of Lewy body disease into anatomic compartments: Brainstem predominant, to reflect involvement of the brainstem, most commonly in the medulla and locus coeruleus. Limbic/transitional, to reflect involvement of limbic cortices in the temporal lobe and cingulate gyrus. Diffuse neocortical, to reflect involvement of the neocortex. In addition, Amygdala predominant Lewy body disease is included to reflect the presence of Lewy bodies in the amygdala and overlying entorhinal cortex which can occur in the setting of Alzheimer disease and may contribute to cognitive decline.
• Braak Parkinson's Disease Stage (PMID: 12498954): Breaks the progression of Lewy body disease down into 6 stages, beginning in the medulla (1 stage) and culminating in primary sensory cortices (stage 6)

Cerebrovascular disease: An umbrella term for several forms of vascular disease

• Small Vessel Disease/Arteriolar Sclerosis (center-specific criteria): Thickening and scarring in the walls of small arterioles, most commonly in the white matter. Often associated with perivascular hemosiderin and adjacent white matter rarefaction.
• Cerebral Amyloid Angiopathy (CAA), Vonsattel Grade (PMID: 9227694): CAA is a vasculopathy caused by accumulation of beta-amyloid in the walls of cortical and leptomeningeal vessels. CAA is associated with Alzheimer disease and is graded on a scale of 1 to 4 reflecting the greatest extent of vessel wall involvement on beta-amyloid stain. Grade 1 represents partial/non-circumferential wall labeling. Grade 2 represents full circumferential wall labeling on beta-amyloid stain. Grade 3 corresponds to grade 2 findings with additional vessel wall splitting. Grade 4 corresponds to additional fibrinoid vessel wall changes. This staging system does not necessarily reflect the overall density of CAA pathology and a modifier of mild/moderate/severe may be added in neuropathology reports to better convey this information.

TDP-43 Proteinopathy: An umbrella term that encompasses LATE-NC (see below) and other TDP-43 proteinopathies of the central nervous system including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis with TDP-43 pathology (ALS-TDP).

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) (PMID: 31039256, PMID: 36512061): LATE-NC is an aging-associated pathology characterized by phosphorylated TDP-43 accumulation in neurons, primarily present in the temporal lobe, that can be associated with cognitive decline. LATE-NC is thought to occur first in the amygdala, then involve the entorhinal cortex and hippocampus, and finally involve neocortex. LATE-type TDP-43 proteinopathy in neocortex can be difficult to distinguish from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP).

• Amygdala
• Entorhinal cortex
• Hippocampus
• Neocortex

Huntington Disease (HD): VonSattel grading in HD is performed on a 0 to 4 scale. 0 corresponds to a grossly normal brain. Grade 1 corresponds to an essentially normal appearing brain with moderate gliosis in the medial caudate and dorsal putamen. Grade 2 corresponds to grossly visible atrophy of the caudate head with retention of the convex outline of the caudate in the lateral ventricle. More severe neuronal loss and gliosis is present in the caudate and putamen. Grade 3 corresponds to severe caudate volume loss sufficient to cause a flat contour of the caudate in the lateral ventricle and is associated with gliosis in caudate, putamen and the globus pallidus. Grade 4 findings include very severe caudate volume loss with a concave outline in the lateral ventricle. Gliosis and atrophy of the globus pallidus is also present.

• VonSattel grade (PMID: 2932539) – HD, VonSattel

Psychiatric and neurologic diagnoses made based on review of clinical data, including medical records and/or interview or questionnaires administered to family members or other knowledgeable informants.

Refer to Basis of Clinical Brain Diagnosis for detailed information on clinical brain diagnostic categorization and formulation.

No Clinical Brain Diagnosis Found: Donors were evaluated for clinical brain diagnoses using all available sources of information, and the findings did not meet clinical brain diagnostic criteria. Minor clinical findings not meeting diagnostic criteria may be present in these individuals.

Insufficient Information for Clinical Brain Diagnosis: A diagnostic determination could not be achieved due to insufficient clinical information.

NB: The sources of information utilized to formulate Clinical Brain Diagnoses were updated in October 2021 and retroactively applied. Clinical Brain Diagnoses are formulated based on information about clinical symptoms. Neuropathology examination results, however, are not considered in the formulation of a Clinical Brain Diagnosis. For most donors, the Clinical Brain Diagnosis and Neuropathology Diagnosis are consistent with one another. However, results of the two diagnostic procedures may differ. Examples are provided below for clarification.

Diagnoses made based on genetic testing.

Diagnoses made based on the clinical records and review not primarily affecting the brain but can affect brain function.

• Normative flagged subjects could be considered representative of the expected neurodiversity across individuals without a major and persistent brain-related diagnosis.
• Normative flagged subjects may include any of the following clinical brain diagnosis (CBD) or neuropathological diagnosis (NPD) characteristics:
  • No lifetime clinical brain diagnoses identified upon evaluation (CBD label: No clinical brain diagnosis found).
  • Clinical Brain Diagnosis present at the time of death that has limited functional impact.
  • Clinical Brain Diagnosis that has met "in remission" diagnostic criteria.
  • No neuropathological diagnosis identified upon evaluation (NPD label: Diagnostic pathology not present), or neuropathological observations that reflect age-related changes or anatomically discrete events (e.g., focal ischemia).
  • Neuropathological evaluation not performed (NPD label: Not evaluated by NP), but the subject is aged 0-20 years and has no lifetime clinical brain diagnoses identified upon evaluation (CBD label: no clinical brain diagnosis found).
• Normative flagged subjects cannot have a genetic disorder diagnosis.
• Normative flagged subjects cannot have a manner of death identified as suicide.
• Subjects with a known, active COVID-19 infection at the time of death, or subjects who died due to COVID-19 related conditions, are excluded from Normative flagging.


• A common and accepted practice in postmortem brain research is to include subjects with mild CBDs, remitted CBDs, and/or NPDs as comparator (or "control") subjects.
• Normative is not a diagnostic term. As such, CBD, NPD, genetic and non-brain diagnoses are presented on the NBB portal, including for subjects with a Normative flag.
• Depending on the experimental design, it may be entirely appropriate to choose cases that are not flagged as Normative for comparison (e.g., study of the concomitants of degenerative pathology might require a comparison group where this pathology is absent, regardless of the CBD).

• Pilot Study flagged subjects are most appropriate for methodological piloting and studies to establish investigator proficiency with the methods proposed in an NBB tissue request.
• Clinical Brain Diagnosis (CBD) and/or Neuropathological Diagnosis (NPD) could not be fully determined with information available for these subjects.
• Pilot Study is not a diagnostic term. As such, CBD, NPD, genetic and non-brain diagnoses are presented on the NBB portal, including for subjects with a Pilot Study flag.
• Subjects with a known, active COVID-19 infection at the time of death, or subjects who died due to COVID-19 related conditions, are excluded from Pilot Study flagging.
• Depending on the experimental design, Pilot Study flagged subjects may be suitable for uses other than methodological piloting and proficiency studies.
  • For example, subjects with insufficient information to form the basis of a CBD may be appropriate to include in a study of the effects of Type 2 diabetes (non-brain diagnosis) on blood vessel density in the prefrontal cortex of pre-adolescent individuals.

• Not Applicable flagged subjects are those who do not meet criteria for Normative or Pilot Study flags. These subjects may have 1) exclusionary diagnoses, 2) other exclusionary factors, or 3) diagnostic coding that is pending.
• Examples of diagnostic and subject characteristics that indicate subjects as Not Applicable flagged:
  • Alzheimer's disease
  • Multiple sclerosis
  • Schizophrenia
  • Substance use disorders active at the time of death
  • Trisomy 21
  • Suicide manner of death
• Most subjects available in the NBB meet criteria for Not Applicable flagging.