Neurological Correlates

Brain. 2008 Jan;131(Pt 1):72-89. Epub 2007 Dec 7., “The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family,” Spina S, Farlow MR, Unverzagt FW, Kareken DA, Murrell JR, Fraser G, Epperson F,Crowther RA, Spillantini MG, Goedert M, Ghetti B., Department of Pathology and Laboratory Medicine, Indiana University School ofMedicine, Indianapolis, IN 46202, USA. (Free full publication)

In the 1990’s, families showing signs of neurodegenerative diseases were examined and found to have mutations in a particular chromosome — the chromosome was later identified to relate to neuron growth. A family with one of the specific genetic mutations was identified in 1997. This is a report of a 13 year study of over 200 of those family members.

Where the family members died, brains were removed and studied; 24 living relatives were given full clinical and neuroimaging workups; and 10 family members were studied for the full 13 years. Click and read this paper if you are at all interested in personality changes as people get older. Skim it, scroll to the results section, even if you are not a scientist.

What a study. Here’s some results:

Neurobehavioural changes
All 10 patients [who were followed for the whole 13 years] were diagnosed with frontotemporal dementia. Disinhibition, social conduct disorder, dysexecutive symptoms, memory impairment and progressive reduction of speech output were evident in patients affected for >3 years, with the exception of subject number 7, whose disease course was slower. For this individual, mild short-term memory problems and slight mental inflexibility were the only cognitive symptoms during the first 6 years of disease, with disequilibrium being the most pressing complaint. More pronounced personality changes and word-finding difficulties developed later.

Tau backgrounder:

The genetic mutation relates to a protein, called tau. It is one of those worker-bee molecules in your body — tau is essential for microtubules, and microtubules are what provides structure for neuron growth. Everyone should heart tau. Here is a video of microtubules (at 1:09 in the video). Here’s a graphic from NIH.

Click to see the NIH page describing how a neuron cytoskeleton grows. Basically, as you can see from the picture, these form layers arranged in a spiral — and the tau protein is instrumental in getting the building blocks and putting them where they belong. If tau doesn’t work properly, or it is blocked, then the neurons stop growing.

Brain. 2008 Jan;131(Pt 1):72-89. Epub 2007 Dec 7

The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family.

Spina S, Farlow MR, Unverzagt FW, Kareken DA, Murrell JR, Fraser G, Epperson F, Crowther RA, Spillantini MG, Goedert M, Ghetti B.

Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T.

PMID: 18065436 [PubMed - in process]