Alzheimer s Disease- the spectrum of clinical presentations

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1 Alzheimer s Disease- the spectrum of clinical presentations Associate Professor Michael Woodward Chief Medical Advisor Alzheimer s Australia Vic Alzheimer s Australia National Conference 2013 Hobart

2 How do we characterize Alzheimer s disease? Age of onset Family history/genetics Initial clinical features Subsequent clinical features Pathology Neuroimaging/other biomarkers

3 Alzheimer s ain t Alzheimer s Spectrum of initial presentations and subsequent course Likely correlates with distribution and progression of pathology and development/presence of any additional pathology Reflected in neuroimaging Autopsy only shows us the final picture by then, most pathological patterns have merged

4 THE BINDING OF PIB MATCHES THE HISTOPATHOLOGY OF Aβ. Braak Stages (1997) A B C

5 Clinical presentations ( phenotypes ) of AD Amnestic Most common Language Logopenic aphasia Visuospatial Posterior cortical atrophy Behavioural Frontal variant AD

6 Amnestic AD Memory loss a prominent early feature esp episodic memory not greatly assisted by cueing Early pathology in the limbic system, including hippocampus Over time, pathology spreads, as in the Braak stagings and clinical features expand to include visuospatial, language and behavioural features more advanced stages involve executive function and eventually motor function But much variation in progression and timing of subsequent clinical features

7 Hippocampal atrophy in amnestic AD

8 Logopenic Aphasia 1 Prominent early language changes Slow speech rate Long word-finding pauses Repetition and comprehension impaired for sentences but preserved for single words Naming moderately affected Left superior and middle temporal gyri and inferior parietal lobules affected 1. Gorno-Tempini Neurology 2008;71:

9 Logopenic apahasia-mri and SPECT

10 Logopenic Aphasia: FDG-PET

11 Posterior Cortical Atrophy Early difficulties with visual and spatial functions recognizing faces working out what an object is working out how to dress/undress locating chair position when sitting Later, can develop difficulties with literacy and numeracy Memory and language preserved early on Often affects younger people (50s and 60s) Prominent atrophy of the posterior cortical regions

12 Posterior Cortical Atrophy

13 Posterior Cortical Atrophy

14 Frontal variant AD Older patient Behavioural/frontal features prominent early Amnestic disorder usually also present Clinical features suggest AD but differential diagnosis is FrontoTemporal Lobar Degeneration Neuroimaging often consistent with AD

15 Pathology in FvAD/FTLD Johnson: predominant frontal NFTs in AD with behavioural onset 1 Woodward: 37 of 45 autopsied cases from ACCORD dementia cohort had AD pathology 2 8 had coexisting FTLD-TDP43 pathology but only one had clinical diagnosis of AD + FTLD In a pathological series of 60 patients with clinically diagnosed FTLD, 7% had AD pathology alone and a further 10% had mixed AD and glial pathology 3 1. Johnson JK, Head E, Kim R, Stark A, Arnold MD, Cotman CW. Clinical and pathological evidence for a frontal variant of Alzheimer s disease. Neurology 1999: 56: Woodward M, Mackenzie I, Hsiung G-Y R, Jacova C, Feldman H. High prevalence of multiple pathologies in dementia. European Geriatric Medicine 2010; 1: Kertesz A, McMonagle P, Blair M, Davidson W, Munoz DG. The evolution and pathology of frontotemporal dementia. Brain 2005; 128:

16 Distinguishing AD with frontal features from FTLD Can be difficult if relying on diagnostic criteria NINCDS-ADRDA criteria show low specificity in distinguishing AD from FTLD most FTLD patients fulfil criteria for AD 1 Lund- Manchester criteria for FT(L)D frequently misdiagnose AD 34% of 185 community dementia cases with AD fulfilled these criteria for FTLD 2 FDG-PET scanning in a series of autopsy proven FTLD and AD cases demonstrated much overlap in patterns of hypometabolism 3 AD cases were not evaluated for frontal clinical features 1. Varma AR, Snowden JS, Lloyd JJ, Talbot PR, Mann DMA, Neary D Evaluation of the NINCDS-ADRDA Criteria in the differentiation of Alzheimer s disease and frontotemporal dementia. J Neurol Neurosurg Psychiatry 66: Ikeda M, Ishikawa T, Tanabe, H Epidemiology of frontotemporal lobar degeneration. Dement Geriatr Cogn Disord 17: Womack KB, Diaz-Arrastia R, Aizenstein HJ, et al. Temporoparietal hypometabolism in frontotemporal lobar degeneration and associated imaging diagnostic errors. Arch Neurol 68: 2011;

17 FTLD- also not a single clinical entity Rapid evolution in our understanding of FTLD Can be cut pathologically, clinically, genetically and other ways correlation not always strong Clinically, 3 main clusters: 1. Frontal/behavioural onset (sometimes called FvFTLD or BvFTLD) 2. Language onset 3. Motor onset/ features

18 Using assessment scales to distinguish AD, FvAD and FTLD Several scales suitable for assessing frontal function Frontal Assessment Battery (FAB) Assesses executive dysfunction Exit- 25 Executive, cognitive Frontal Behavioural Inventory (FBI) Behavioural Neuropsychiatric Inventory (NPI) Psychiatric features

19 Defining FvAD- ACCORD Cohort cases with dementia 71 of the AD cases (without additional clinical diagnosis of FTLD) had the FBI 36 FTLD cases- 26 had the FBI administered Baseline data utilised FBI scores for AD cases arrayed and most frontal quartile defined as FvAD. 1. Woodward M, Jacova C, Black SE, Kertesz A, Mackenzie IR, Feldman H, the ACCORD Investigators. Differentiating the frontal variant of Alzheimer s disease. Int J Geriatr Psychiatry 2010; 25: 732-8

20 Continued in Part 2

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