Chapleau M, La Joie R, Yong K, Agosta F, Allen IE, Apostolova L, Best J, Boon BD, Crutch S, Filippi M, Fumagalli GG, Galimberti D, Graff-Radford J, Grinberg LT, Irwin DJ, Josephs KA, Mendez MF, Mendez PC, Migliaccio R, Miller ZA, Montembeault M, Murray ME, Nemes S, Pelak V, Perani D, Phillips J, Pijnenburg Y, Rogalski E, Schott JM, Seeley W, Sullivan AC, Spina S, Tanner J, Walker J, Whitwell JL, Wolk DA, Ossenkoppele R, Rabinovici GD, PCA International Work Group. Demographic, clinical, biomarker, and neuropathological correlates of posterior cortical atrophy: an international cohort study and individual participant data meta-analysis. Lancet Neurol. 2024 Feb;23(2):168-177. PubMed.

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  1. This work is by far the largest study of PCA to date. It solidifies evidence from many smaller studies that PCA is a distinct syndrome, usually causes young-onset dementia, mean age at onset about 60 years, and is almost always underpinned by Alzheimer’s pathology. Patients with PCA are often mis-diagnosed, or diagnosed late, and so may not receive appropriate treatment, support, and information. This work shows that, even allowing centers to define PCA clinically using local criteria, these diagnoses closely match (and so validate) the core clinical features proposed in the PCA consensus classification framework for AD (Crutch et al, 2017).

    The very high probability that someone with PCA has underlying Alzheimer's pathology reinforces that such patients should be offered molecular diagnostic testing; and, especially as most patients are young and without other comorbidities, should not be denied access to new AD therapies and clinical trials.

    References:

    Crutch SJ, Schott JM, Rabinovici GD, Murray M, Snowden JS, van der Flier WM, Dickerson BC, Vandenberghe R, Ahmed S, Bak TH, Boeve BF, Butler C, Cappa SF, Ceccaldi M, de Souza LC, Dubois B, Felician O, Galasko D, Graff-Radford J, Graff-Radford NR, Hof PR, Krolak-Salmon P, Lehmann M, Magnin E, Mendez MF, Nestor PJ, Onyike CU, Pelak VS, Pijnenburg Y, Primativo S, Rossor MN, Ryan NS, Scheltens P, Shakespeare TJ, Suárez González A, Tang-Wai DF, Yong KX, Carrillo M, Fox NC, Alzheimer's Association ISTAART Atypical Alzheimer's Disease and Associated Syndromes Professional Interest Area. Consensus classification of posterior cortical atrophy. Alzheimers Dement. 2017 Aug;13(8):870-884. Epub 2017 Mar 2 PubMed.

    View all comments by Jonathan Schott

  2. This paper is impressive. It stands to become the pivotal reference work for the posterior cortical atrophy syndrome. It also reminds us that the mapping of syndrome to neuropathology is probabilistic rather than deterministic (Mesulam and Weintraub, 1992; Mesulam et al., 2014; Petersen et al., 2023). For example, a given neuropathologic entity (e.g., Alzheimer’s Disease Neuropathologic Change) can be associated with several syndromes, each association displaying a different probability and characteristic neuroanatomy. Conversely, each syndrome (e.g., PCA) can be associated with different neuropathologies, some more frequent (typical) than others. These two characteristics are summarized in the table below.

    A second point illustrated by this paper is relevant to the practicing clinician. While it is true that the vast majority of PCA is associated with AD, there are also definite cases of slow Creutzfeldt-Jacob, pure cortical Lewy body disease, and reportedly 4R tauopathy of the corticobasal type that can trigger the same syndrome. So, for the clinician who deals with individuals rather than groups, the value of careful differential diagnosis remains as important as ever.

    HETEROGENEOUS CLINICAL MANIFESTATIONS OF NON-DOMINANT ALZHEIMER’S DISEASE NEUROPATHOLOGIC CHANGE (AD).

    • Primarily amnestic AD (the typical form): Age- and ApoE4-related; neurofibrillary tangles (NFT) emerge and reach the highest densities in the hippocampal complex according to the Braak and Braak pattern. Known as amnestic MCI at early stages and dementia of the Alzheimer-type at later stages (DAT).
    • Primarily aphasic AD: Not age- or ApoE4-related; the ratio of language cortex to hippocampal NFT can be higher than in amnestic forms, in violation of the Braak and Braak pattern (Gefen et al., 2012). Known as primary progressive aphasia (PPA).
    • Primarily behavioral/executive AD: Relationship to age and ApoE4 to be determined; NFT can have higher density in frontal cortex than in amnestic forms (Johnson et al.,1999). Known as frontal-type dementia (FTD) or behavioral variant FTD (bvFTD).
    • Primarily visuospatial AD: Age-related but relationship to ApoE4 is not as high as in the amnestic form; NFT can have higher density in visual cortex and superior colliculus than in amnestic forms (Hof et al.,1993). Known as posterior cortical atrophy (PCA).

    References:

    Mesulam MM, Weintraub S. Spectrum of primary progressive aphasia. Baillieres Clin Neurol. 1992 Nov;1(3):583-609. PubMed.

    Mesulam MM, Weintraub S, Rogalski EJ, Wieneke C, Geula C, Bigio EH. Asymmetry and heterogeneity of Alzheimer's and frontotemporal pathology in primary progressive aphasia. Brain. 2014 Apr;137(Pt 4):1176-92. Epub 2014 Feb 25 PubMed.

    Petersen RC, Weintraub S, Sabbagh M, Karlawish J, Adler CH, Dilworth-Anderson P, Frank L, Huling Hummel C, Taylor A, Dementia Nomenclature Initiative. A New Framework for Dementia Nomenclature. JAMA Neurol. 2023 Dec 1;80(12):1364-1370. PubMed.

    Gefen T, Gasho K, Rademaker A, Lalehzari M, Weintraub S, Rogalski E, Wieneke C, Bigio E, Geula C, Mesulam MM. Clinically concordant variations of Alzheimer pathology in aphasic versus amnestic dementia. Brain. 2012 May;135(Pt 5):1554-65. PubMed.

    Johnson JK, Head E, Kim R, Starr A, Cotman CW. Clinical and pathological evidence for a frontal variant of Alzheimer disease. Arch Neurol. 1999 Oct;56(10):1233-9. PubMed.

    Hof PR, Archin N, Osmand AP, Dougherty JH, Wells C, Bouras C, Morrison JH. Posterior cortical atrophy in Alzheimer's disease: analysis of a new case and re-evaluation of a historical report. Acta Neuropathol. 1993;86(3):215-23. PubMed.

    View all comments by Marsel Mesulam

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  1. Posterior Cortical Atrophy Is a Form of Young-Onset Alzheimer’s