Distribution of Pathology in Frontal Variant Alzheimer's Disease

Abstract

Atypical presentations of Alzheimer's disease (AD) have been described, including a "frontal" variant (fvAD), which presents with personality change and executive dysfunction similar to that seen in behavioral variant frontotemporal dementia (bvFTD). This clinical variation is thought to reflect the regional distribution of pathology, although few reports include autopsy confirmation. We compared three clinicopathological groups matched for age at diagnosis and disease duration; those with possible bvFTD who at autopsy had only AD (fvAD), those with typical AD clinically and pathologically, and those with typical clinical bvFTD confirmed pathologically. The density of neurons and AD-type pathology was quantified in the frontal association, occipital association, and entorhinal cortices and hippocampal CA1 regions. Immunohistochemistry for phosphorylated tau and amyloid-β deposition was used to detect neurofibrillary tangles and plaques. Of the six core clinical features of the International Consensus Criteria, disinhibition, stereotyped behaviors, and executive dysfunction were most common, occurring in five of the six fvAD patients. Other features were rare. While there was no significant difference in neuron density between groups for any of the four regions, when the ratio of frontal:occipital pathology was examined, neuronal density in fvAD was significantly less than AD but similar to bvFTD. The frontal:occipital ratio of AD-type pathology was also greater in fvAD than AD. The findings of this study suggest a frontal variant of AD exists with features that mimic bvFTD and that this reflects a differential distribution of neurodegeneration with more marked pathology in the frontal cortex compared with the occipital cortex.

Comparison of Prefrontal Atrophy and Episodic Memory Performance in Dysexecutive Alzheimer’s Disease and Behavioral-Variant Frontotemporal Dementia

“…Furthermore, the widespread prefrontal atrophy seen in our IEF-AD group is consistent with previous reports of cortical thinning [25], AD-type pathology and neuronal loss [21,22] in the frontal lobes of dysexecutive AD patients. It is important to note, however, that PFC atrophy was more extensive in bvFTD compared to IEF-AD, despite the involvement of similar regions in these two patient groups.…”

“…Converging evidence points to an atypical, frontal distribution of neuropathology in dysexecutive AD patients [21][22][23][24][25]. One significant contribution of the present study was the comparison of PFC and MTL atrophy between bvFTD patients and AD subgroups.…”

“…Clinicopathological studies have identified pathologically confirmed cases of AD presenting with predominant executive dysfunction. The relative distribution of pathology in these cases appears to be markedly atypical, involving the frontal cortex as well as medial temporal lobe (MTL) structures [21,22]. Neuroimaging investigations further indicate that AD patients who display frontal hypoperfusion tend to show a more dysexecutive profile, as well as worse neuropsychiatric symptoms and functional impairment compared to typical AD patients [23].…”

Classification and clinicoradiologic features of primary progressive aphasia (PPA) and apraxia of speech

“…Similarly, our finding of 33% amyloid positivity among semantic dementia cases was also slightly higher than that of prior studies based on imaging (11–17%) (Leyton et al, 2011; Rabinovici et al, 2008) or pathology (10–33%) (Alladi et al, 2007; Chare et al, 2014; Hodges et al, 2010; Knibb et al, 2006; Mesulam et al, 2014), as it is well known that the majority of semantic cases have an underlying TDP-43 proteinopathy. It is possible that these patients had focal cortical presentations of Alzheimer's disease (Blennerhassett, Lillo, Halliday, Hodges, & Kril, 2014; Leyton et al, 2011; Warren, Fletcher, & Golden, 2012), as retrospective data has shown that a proportion of cases diagnosed with behavioral frontotemporal dementia, semantic variant PPA or agrammatic/nonfluent PPA according to the consensus criteria have Alzheimer's pathology at autopsy (Chare et al, 2014; Mesulam et al, 2014). However, it is likely that a large proportion of cases had codeposition of amyloid together with tau or TDP-43 (Josephs, Duffy, Strand, Machulda, Senjem, et al, 2014).…”

Typical and atypical appearance of early‐onset Alzheimer's disease: A clinical, neuroimaging and neuropathological study

“…We also observed these spongiform changes in the most severe lesions of our atypical AD patients. Blennerhassett et al . examined six patients and observed more neuronal loss and amyloid deposits in the frontal cortex than in the occipital cortex, but there were no significant changes in NFT density compared to patients with typical AD.…”