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Intrinsic connectivity Networks: Neurodegenerative link

In my last 3 posts, I have talked about ICNs and how they change over developmental time-frame and how many basic ICNs we have in the adult human brain.  This post will talk about neuroegenerative diseases like Alzheimer’s and how the underlying atrophy in neurodegenrative networks closely resembles the underlying ICNs and SCNs.

But first let us brush our knowledge of neurodegenrative dementia- I will be focusing on Alzheimer’s Disease (AD) , Fronto temporal lobe degeneration related dementia ( (bv-FTD) behavioral variant Fronto-temporal dementia , (SD) Sementic dementia and  (PFNA) Progressive non-fluent Aphasia ); the cortico basal syndrome (CBS) and Amyotropic Lateral Sclerosis (ALs/Lou Gherings disease) . What all these diseases have in common is that they are progressively degenerative, related to aging, have both genetic as well as sporadic occurrence, and as we will see affect distinct dissociable brain networks (ICNs/SCNs).

These two studies for eg discuss the 3 distinct  variants of Froto temporal lobe degeneration – the bvFTD, SD and PNFA.  As per the first study:

The clinical hallmark of bv-FTD is a disturbance in the personality and behavior, with changes of mood, motivation, and inhibition, leading to profound social disruption.[1,21,22] As the initial symptoms are neuropsychiatric, without impairment on cognitive screening tests, or overt changes on structural imaging,[23,24] these patients may be inappropriately diagnosed as suffering from a psychiatric disease, usually, depression or personality disorder.[20,25]
Patients may perform normally on standard neuropsychological tests of memory, language, attention, and visual spatial ability, but more recent tests designed to assess emotion processing,[27] social cognition,[28] theory of mind,[29] and complex decision making[30] are more sensitive and may show deficits in early cases, even if standard cognitive battery are normal.[24]

Its interesting to note that bvFTD patients have intact visual-spatial abilities but show socio-emotional deficits (more on this later) .

Semantic dementia
Patients typically present with “loss of memory for words” and show impairment on tests of word comprehension, although the underlying deficit is the amodal store of semantic memory or knowledge about words, objects, people, and sounds.[7] . Patients show a gradual reduction of vocabulary and use high frequency terms (thing, boy), although speech is fluent and well articulated, without phonological or syntactic errors.[8,44,45]
A consistent feature is the impairment of naming objects or anomia. The performance is influenced by the level of familiarity and specificity of items asked. In other words, if the item is extensively encountered by the patient, it is likely to be forgotten later.[45] Likewise, the patient will tend to name objects that are prototypic of their category.[46] For instance, patients are able to name cat, dog, and horse, but not tiger or zebra, and use superordinate or general labels, calling the latter also a cat and horse, and may be just animal.[47]

Unlike SD, the presenting features of PNFA are more varied and may reflect breakdown at various stages of speech production, from alterations in lexical retrieval, misarrangements of the words according to grammatical rules, or impaired motor programming of the intended utterance.[11]
Generally speaking, there are problems with the syntactic or motor aspects of speech, causing speech to be halting, slow, and distorted.[54]
Severe agrammatism causes oversimplification of the language production, lack of function words (e.g., prepositions, auxiliary verbs, or articles), or words inflections (i.e., endings of verb or noun according to conjugation or number, respectively).[10] But in the early stages, grammatical errors are subtle and may be difficult to distinguish from common errors or detect in a short interview. Syntactic problems are usually best assessed by testing sentence comprehension.[55]

I’ll now go directly to this study by Seeley et al that shows that there are five distinct ICNs/SCNs that  closely match the underlying atrophy in five distinct such neurodegenerative diseases.  the figure below shows the atrophy maps and the ICNs and SCNs they observed for the 5 diseases they studied, viz AD, bvFTD, SD, PNFA and CBS.

The ICNs linked here to disease represent canonical findings from the ICN literature. Our AD-affected ICN (right ANG seed) corresponds to the ‘‘default mode network’’ that participates in episodic memory (Buckner et al., 2005) and became known for its task-related deactivations across fMRI studies (Fox et al., 2005; Fransson, 2005; Greicius et al., 2003). The ICN targeted in bvFTD (right FI seed) was first identified with ICA (Beckmann et al., 2005) and later linked to emotional salience processing capacities (Seeley et al., 2007) lost in early bvFTD (Seeley, 2008). SD affects an ICN (left Tpole seed) that has escaped previous detection in humans but corresponds to a Tpole-subgenual cingulate-ventral striatum-amygdala network, well-established in nonhuman primates (Mesulam and Mufson, 1982), that shows progressive atrophy in early-stage SD (Brambati et al., 2007). The PNFA-targeted ICN (left IFG seed) includes the frontal operculum, primary and supplementary motor cortices, and inferior parietal lobule bilaterally, linking the language and motor systems that enable speech fluency. This ICN, often divided into left and right hemispheric systems, has been noted in several previous studies (Beckmann et al., 2005; Damoiseaux et al., 2006; De Luca et al., 2006; van den Heuvel et al., 2008). In PNFA, asymmetric degeneration of this system may reflect its accentuated functional and connectional asymmetry in healthy humans (Stark et al., 2008). In CBS, prominent skeletal and ocular motor abnormalities result from disease within a dorsal sensorimotor association network (right PMC seed) detailed in several ICN studies (De Luca et al., 2006; Fox et al., 2005; Vincent et al., 2008) and elegantly mapped in the macaque using convergent ICN, oculomotor task-based fMRI, and axonal tracer methods (Vincent et al., 2007).

They also hypothesize about some diseases they did not study and the possible ICNs associated with them:

ICNs frequently reported (Beckmann et al., 2005; Damoiseaux et al., 2006; De Luca et al., 2006; van den Heuvel et al., 2008) but not studied here include primary and secondary visual networks that may provide substrate for the visual-spatial variant of AD known as the posterior cortical atrophy syndrome (Hof et al., 1997), a primary sensorimotor ICN that may relate to amyotrophic lateral sclerosis (Kassubek et al., 2005), and a lateral frontoparietal executivecontrol network (Seeley et al., 2007; Vincent et al., 2008) that falters in most neurodegenerative diseases as degeneration spreads beyond the sites of initial injury into widely interconnected supervisory neocortical systems.

I think of these arranged on the eight fold evo devo model as follows:

  1. posterior cortical atrophy syndrome: Visual ICN
  2. ALS /CBS : Sensorimotor ICN. (PMC seed)
  3. unknown (to me) neurodegenrative disease (ALS/CBS?) : Auditory cortex ICN
  4. PNFA : syntactic ICN (Inferior Frontal gyrus seed)
  5. Semantic Dementia : Semantic ICN (seed temporal pole)
  6. bvFTD: SALience ICN (seed Froto Insula)
  7. Alzheimer Disease : DMN ICN (seed angular gyrus)
  8. Dementia with Lewy Bodies ?? : Executive Control Network ICN.

Which brings me to the next paper by Seeley et al in which they showed that not only AD and bvFTD are respectively correlated with atrophy of DMN and SAL ICNs; but that as these networks are anti-correlated in normal control humans and as these diseases show opposite clinical profiles , the diseases are also correlated with increased connectivity in the converse network i.e AD leads to increased connectivity in SAL and bvFTD leads to increased connectivity in DMN.

This is what they hypothesized:

Behavioural variant frontotemporal dementia (bvFTD) and Alzheimer’s disease, the two most common causes of dementia among patients less than 65 years of age (Ratnavalli et al., 2002), provide a robust conceptual framework for exploring ICN fMRI applications to neurodegenerative disease. Early bvFTD disrupts complex social-emotional functions that rely on anterior peri-allocortical structures, including the anterior cingulate cortex and frontoinsula, as well as the amygdala and striatum (Rosen et al., 2002; Broe et al., 2003; Boccardi et al., 2005; Seeley et al., 2008a). These regions constitute a large-scale ICN in healthy subjects, which we have referred to as the ‘Salience Network’ due to its consistent activation in response to emotionally significant internal and external stimuli (Seeley et al., 2007b). Notably, while this anterior network degenerates, posterior cortical functions survive or even thrive, at times associated with emergent visual creativity (Miller et al., 1998; Seeley et al., 2008b). In contrast, Alzheimer’s disease often preserves social-emotional functioning, damaging instead a posterior hippocampal-cingulo-temporal-parietal network, often referred to as the ‘Default Mode Network’ (DMN) (Raichle et al., 2001; Greicius et al., 2003; Buckner et al., 2005; Seeley et al., 2009). DMN-specific functions continue to stir debate, but elements of this system, especially its posterior cortical nodes, participate in episodic memory (Zysset et al., 2002; Buckner et al., 2005) and visuospatial imagery (Cavanna and Trimble, 2006); functions lost early in Alzheimer’s disease. Just as bvFTD and Alzheimer’s disease show opposing clinical strengths and weaknesses, the Salience Network and DMN show anticorrelated ICN time series (Greicius et al., 2003; Fox et al., 2005; Fransson, 2005; Seeley et al., 2007b), suggesting a reciprocal relationship between these two neural systems. This rich clinical and neuroimaging background led us to hypothesize (as detailed in Seeley et al., 2007a) that bvFTD and Alzheimer’s disease would exert opposing influences on the Salience Network and DMN.

and this is exactly what they found. This is more than enough for today, but I cant leave without posting these two quotes from the paper:

Although patient strengths are rarely cited as important dementia diagnostic clues (Miller et al., 2000), preserved social graces and interpersonal warmth often lead experienced clinicians to suspect Alzheimer’s disease in a patient with mild memory or visuospatial complaints. Remarkably, we found that Alzheimer’s disease produces heightened Salience Network connectivity in anterior cingulate cortex and ventral striatum compared with healthy elderly controls.
Like patients with frontotemporal dementia, children with autism, who feature social-emotional and anatomical deficits akin to bvFTD (Di Martino et al., 2009a), may show superior posterior cortical functions manifesting as extraordinary artistic, arithmetic or mnestic talent (Hou et al., 2000; Treffert, 2009). In the present study, bvFTD showed increased left parietal DMN connectivity that correlated with reduced Salience Network connectivity in right frontoinsular, striatal and cingulate regions.

If you are a regular reader and know my zeal for the ‘opposites on a continuum theory’ you will be right on track as to where I am headed, but for that you have to wait for the next post.

Mathuranath, P., Aswathy, P., & Jairani, P. (2010). Genetics of frontotemporal lobar degeneration Annals of Indian Academy of Neurology, 13 (6) DOI: 10.4103/0972-2327.74246
Hodges, J., & Leyton, C. (2010). Frontotemporal dementias: Recent advances and current controversies Annals of Indian Academy of Neurology, 13 (6) DOI: 10.4103/0972-2327.74249
Zhou, J., Greicius, M., Gennatas, E., Growdon, M., Jang, J., Rabinovici, G., Kramer, J., Weiner, M., Miller, B., & Seeley, W. (2010). Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease Brain, 133 (5), 1352-1367 DOI: 10.1093/brain/awq075
Seeley, W., Crawford, R., Zhou, J., Miller, B., & Greicius, M. (2009). Neurodegenerative Diseases Target Large-Scale Human Brain Networks Neuron, 62 (1), 42-52 DOI: 10.1016/j.neuron.2009.03.024

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