Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease.

The complement system constitutes a series of enzymatic steps involved in the inflammatory response and is activated in Alzheimer's disease (AD). Using Down's syndrome (DS) brains as a temporal model for the progression of AD, we examined components of the complement cascade and their relationship to other principal events in AD pathology: Abeta42 deposition, neuritic changes, neurofibrillary tangles (NFTs), and gliosis (reactive astrocytes, activated microglia). Adjacent sections of frontal cortex from 24 DS subjects ranging in age from 12 to 73 years were immunohistochemically examined for immunoreactivity (IR) of classical complement proteins (Clq and C3), markers indicating activation of complement (C4d and C5b-9), the complement inhibitor apolipoprotein J (apo J), and markers of AD neuropathology. Abeta42-labeled diffuse plaques were first detected in a 12-year-old DS subject and were not labeled by any of the complement antibodies. Colocalization of Abeta42 with Clq, C3, C4d, and/or apo J was first detected in compacted plaques in the brain of a 15-year-old DS patient with features of mature AD pathology, such as reactive astrocytes, activated microglia, dystrophic neurites, and a few NFTs. IR for C4d and C5b-9 (membrane attack complex, MAC) was observed in small numbers of plaque-associated dystrophic neurites and in focal regions of pyramidal neurons in this 15-year-old. The only other young (

Compound heterozygous genotype is associated with protracted juvenile neuronal ceroid lipofuscinosis.

We present a clinicopathological study and the first molecular genetic analysis of a family with 2 siblings affected by a rare, protracted form of juvenile neuronal ceroid lipofuscinosis (JNCL). Molecular genetic studies showed that both siblings, in addition to being heterozygous for the 1.02-kb CLN3 deletion, a common mutation in JNCL, also had a G-to-A missense mutation at nucleotide 1,020 of the CLN3 cDNA sequence on the non-1.02-kb deletion chromosomes. This point mutation resulted in a substitution of glutamic acid by lysine at position 295 of the CLN3 protein. Thus, a single point mutation at residue 295 of the CLN3 protein in protracted JNCL may underlie the phenotype in this form, which differs from that in classic JNCL.

The adult and a new late adult forms of neuronal ceroid lipofuscinosis.

Three cases of the late adult form of neuronal ceroid lipofuscinosis (NCL) are reported. Two of these are siblings with a late clinical onset at ages 26 and 44 years. The third case, sporadic, has the oldest reported age for the onset of NCL, at 63 years and may be regarded as the first example of the "presenile" form of NCL. The clinical, morphological, histochemical, ultrastructural and genetic features of these three cases are discussed. The literature of the clinicopathological NCL cases with an onset at age of 25 and older is reviewed. The clinical and morphological differences between the late adult form and the presenile form of NCL as well as the difficulties in making the diagnosis are discussed.

The dominant form of the pigmentary orthochromatic leukodystrophy.

The present report documents a family with three cases in two successive generations of pigmentary orthochromatic leukodystrophy (POLD). The clinical features of these cases and histochemical and ultrastructural investigations of two of the brains from successive generations are discussed. A review of the familial cases of POLD reported in the literature is also presented. Transmission of these cases was by a dominant inheritance. Onset of the clinical symptoms occurred at 42 to 54 years of age; duration of the disease was from 2-11 years, and death occurred at 45 to 57 years of age. Clinical manifestations of all three cases were severe headaches; bilateral pyramidal, pseudobulbar, cerebellar, and frontal release signs; gait disturbances; euphoria, or apathy; epileptic seizures; and dementia. The neuropathological pattern consists of slight cerebral atrophy, brownish discoloration of the cerebral white matter with demyelination and severe gliosis, sparing the sub-cortical U fibers; presence in the macrophages of lipid pigment granules that are sudanophilic, non metachromatic, and PAS and iron positive. The electron microscopic pattern of the lipid pigment in the macrophages is that of ceroid: electron-dense, membrane-bound intracytoplasmic lysosomes with curvilinear and/or fingerprint profiles.

Beta-protein immunoreactivity in brains of patients with neuronal ceroid lipofuscinosis: ultrastructural and biochemical demonstration.

The storage pigment in neuronal ceroid lipofuscinoses (NCL) has a close similarity to age pigment lipofuscin. We studied immunoreactivity of isolated neuronal pigments from the juvenile form of NCL and aging control, using monoclonal antibodies (mAbs) against amyloid beta-protein. Ultrastructural localization of the immunoreactivity demonstrated that in NCL the epitopes are distributed mainly in curvilinear multilamellar arrays of the storage pigments and less in fingerprint profiles, while in aging control they are more homogeneously distributed on age pigment lipofuscin. The different distribution of the epitopes may reflect some catabolic as well as morphologic differences in lysosomes. A unique 31-kDa polypeptide detected on Western blots in NCL possibly derives from the same precursor, amyloid beta-protein precursor (ABPP). ABPP processing may be aberrant in NCL brains, and this can be detected as a 31-kDa polypeptide reactive with the mAbs.