Pathological phenotype in familial neurodegenerative disease: implications for families and therapeutic constructs

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From: Therapy(Vol. 8, Issue 5)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 3,375 words
Lexile Measure: 1450L

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Author(s): Rudy J Castellani [[dagger]] 1 , Hyoung-gon Lee 2 , Robert B Petersen 2 , Xiongwei Zhu 2 , George Perry 3



Alzheimer'âs disease; familial; frontotemporal dementia; Lewy body; mutation; pathology; prion; sporadic

Since the majority of animal models for neurodegenerative diseases are based on germline mutations, and yet therapeutic constructs are ultimately aimed at treating the far more common sporadic condition, consistency of the genotype-phenotype relationship (especially pathological phenotype) between familial and sporadic disease is critical. Interestingly, however, this relationship is seldom examined. In this article, we discuss the issue of pathological phenotype and its relationship to germline mutations.

Pathology versus mutation: Alzheimer'âs disease

In the case of Alzheimer'âs disease (AD), detailed neuropathological studies of the rare familial cases have highlighted some differences from sporadic AD. Among APP mutation cases, unusually large amyloid plaques have been described in the Flemish variant (A692G ) [1] . The Iowa variant (D694N ) demonstrated an unusually heavy deposition of amyloid-[beta]β (A[beta]β)40, discrete cerebral atrophy, an abundance of cerebral amyloid angiopathy, as well as leukoencephalopathy and occipital calcifications [2] . Lewy bodies have been described in the V717I variant and other familial cases [3] . The Dutch type (E693Q ) is dominated by cerebral amyloid angiopathy and focal symptoms related to recurrent strokes, although parenchymal pathology and progressive dementia also occur in a subset [4] . Unusual 'ring-like'â amyloid plaques have been described in the Arctic variant (E693G ) [5] .

Studies on PSEN2 -linked AD are few, as are the overall number of kindreds in the population, with only 22 families described to date worldwide [101] . One study demonstrated A[beta]β40-reactive ghost tangles and ectopic white matter neurons with neurofibrillary tangles in M239V mutation cases [6] . On the other hand, a 1998 study showed a relative abundance of cerebral amyloid angiopathy with minimal neuritic pathology or rare neurofibrillary tangles (N141I ) [7] ; an earlier study of the same kindred showed neurofibrillary tangles and granulovacuolar degeneration, abundant cerebral amyloid angiopathy and rarefaction of myelin, but no neuritic plaques [8] .

The most striking differences between sporadic AD are generally seen in the PSEN1 mutation cases. In these kindreds, there is extensive amyloid burden and neurofibrillary degeneration as expected, but also abundant white matter, deep gray matter, cerebellar deposits and an abundance of the peculiar, amorphous 'cotton wool'â plaque that lacks Congo red positivity or a well developed amyloid core [9] . These patients may or may not present with focal signs including seizures, long tract signs including spastic paraparesis [10] , Parkinsonism [11] and frontotemporal symptoms [12] . The pathology variably encompasses [alpha]-synuclein-positive Lewy bodies and Lewy neurites as well [13] .

In a subset of so-called late onset familial AD linked to the ApoE εε4 allele, abundant cerebral amyloid angiopathy and a perivascular pattern of neurofibrillary degeneration was described [14] , whereas other studies have shown little impact of the ApoE genotype on pathology burden [15] .

It appears, therefore, that apart from anecdotal findings that have not been replicated, and the subset of PSEN1 cases showing extensive pathology, abundant cotton wool plaques, early age at onset and...

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Gale Document Number: GALE|A268609822