Patients with Alzheimer's disease often have a mix of several different pathological processes in the brain. Besides beta-amyloid and tau pathologies, which are classic hallmarks of the disease, many patients also have a mix of different brain changes. This has been described in several autopsy based studies, for example in Schneider et al Ann Neurol 2009. It turns out that among elderly patients "pure" Alzheimer's is in fact a very rare thing. Most people have several brain problems at once rather than one isolated pathology. 

One of the most important co-pathologies in patients with Alzheimer's disease is Lewy body pathology. Lewy bodies are composed of the protein alpha-synuclein. These aggregates are key features of the synucleinopathies, which include Parkinson's disease and dementia with Lewy bodies. Dementia with Lewy bodies causes sleep and dream abnormalities, visual hallucinations  and executive dysfunction.

Click here for pictures of Lewy bodies.

Patients who have both typical Alzheimer's disease pathology and Lewy body pathology can have a mixed clinical presentation, with both memory problems and Lewy body-related problems. This continuum of pathological and clinical changes across neurodegenerative diseases has been recognized by researchers and clinicians for many years, but is only now attracting broader attention from the pharmaceutical industry. The reason for this interest is that the presence of mixed pathologies could have a critical impact on the success of therapies aimed at halting Alzheimer's disease.

So far there is no established biomarker that can reliably identify synuclein pathology in a patient with Alzheimer's disease. Such a biomarker would be very valuable, since it could be used to stratify patients with Lewy bodies to personalized treatments in clinical practice or in drug trials. Several researchers have tested cerebrospinal fluid levels of alpha-synuclein, the protein that is deposited in Lewy bodies, as a biomarker. Cerebrospinal fluid levels of this protein seem to be reduced in synucleinopathies, as shown in for example Mollenhauer et al 2011 and Hall et al 2012. 

Could cerebrospinal fluid alpha-synuclein be useful to identify Alzheimer's disease patients with Lewy body co-pathology? Very few studies have specifically tested this. One study with autopsy conformation was negative, but it included very few subjects. We selected another approach in an article that was published this summer in Journal of Alzheimer's disease (abstract available here). We tested if cerebrospinal fluid alpha-synuclein levels were related to the presence of Lewy body-like symptoms in Alzheimer's disease. 

We found that cerebrospinal fluid alpha-synuclein levels were significantly lower in Alzheimer's patients who reported hallucinations (see figure). Although this is only an indirect evidence, it may suggest that cerebrospinal fluid levels of alpha-synuclein are indeed related to Lewy bodies in patients with Alzheimer's disease. But much more work needs to be done to explore this biomarker. For example, it is possible that specific variants or oligomers of alpha-synuclein are more suitable as biomarkers than the total levels of the peptide.

We just published a paper in JAMA Neurology on emerging beta-amyloid pathology and accelerated cortical atrophy. You can read the abstract here.

We used longitudinal CSF data on β-amyloid42 (Aβ42) to identify cognitively healthy people who declined in CSF Aβ42 over time, indicating possible accumulation of β-amyloid pathology in the brain parenchyma. We then compared brain structures between people who had normal CSF Aβ42 levels at baseline and follow, people who started with normal CSF Aβ42 levels but who declined during the study, and people who had a positive CSF Aβ42 profile (reduced levels) already at baseline.

We found increased atrophy rates in people with declining CSF Aβ42 levels, suggesting that the accumulation of β-amyloid was coupled to increased atrophy rates. Surprisingly, the increased atrophy rates were not particularly pronounced in the temporal cortex or the hippocampus, which are believed to be early engaged in Alzheimer's disease. Instead, atrophy rates were increased in fronto-parietal cortical regions. These are areas where β-amyloid pathology is known to accumulate early, perhaps suggesting that the emerging β-amyloid pathology was coupled to local neurotoxicity.

AlzForum wrote about a story about the study here and MedicalResearch.com wrote about it here.

Tobias Skillbäck is the first author on a paper about cerebrospinal fluid (CSF) biomarkers for Creutzfeld-Jakob disease (CJD) that we recently published in JAMA Neurology. You can read the abstract here and interviews with Tobias here and here.

CJD is a rare rapidly progressive dementia, which often lead to death within a year from symptom onset. It is characterized by the accumulation of a specific protein, the prion protein. This protein exists normally in the brain, but in the disease it undergoes a conformational change, which makes it harmful to neurons.

Spongiform brain changes (tiny holes where nerve cells have died) in CJD

Previous studies have found that CJD patients have increased CSF levels of the neuronal protein tau, probably reflecting leakage from injured neurons. CSF tau may be increased in other dementias also, for example in Alzheimer's disease. However, in contrast to Alzheimer's disease, CJD does not increase CSF levels of phosphorylated tau. Comparing levels of CSF total tau and phosphorylated tau may therefore be used to differentiate between CJD and other dementias.

The unique approach in Tobias' study was to combine clinical CSF data with information about clinical diagnoses from the Swedish Mortality registry. This identified 9765 deceased individuals with CSF data, 93 of them with CJD as cause-of-death. The project would probably not have been possible to perform in many countries (for example the United States), since it relies on the existence of a unique personal identification number, enabling cross-reference between registries.

We found that these dementia biomarkers have very high diagnostic performance for CJD. This may be useful in clinical settings, to help diagnose this disease. If a treatment is ever developed for CJD, these biomarkers may be part of the algorithm used to determine if a patient with rapidly progressive dementia should receive CJD-specific treatment.

We have just published an article in the journal Brain on the relationship between brain  amyloid-β accumulation, cerebral blood flow and tissue loss. The abstract is available here.

Amyloid-β accumulation is a key feature of Alzheimer's disease, and is known to be related to brain tissue loss, but it is less clear how it is related to functional brain changes, including altered cerebral blood flow. Our paper is called "Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment". We used PET imaging of brain amyloid-β, combined with MRI measurements of cerebral blood flow and structural volume, in a cohort including both cognitively healthy controls and patients with different degrees of cognitive impairment.

We found that increased brain amyloid-β accumulation is associated with reduced cerebral blood flow, both in cognitively healthy controls, and patients with mild cognitive impairment or Alzheimer's disease with dementia. We also found some indications that high amyloid-β may be associated with greater cerebral blood flow reduction in controls and greater volume reduction in symptomatic disease stages, which is in line with the widely held assumption that amyloid-β accumulation leads to functional brain changes before it leads to structural changes. Naturally, longitudinal studies are needed to verify this.

The title of the book "An Anthropologist On Mars" (1995) is a quote by Temple Grandin, whose story is one of the "seven paradoxical tales" presented here. By the way, go here and here for great BrainScience podcasts with and about Temple Grandin, who is probably the worlds best known person with autism. In all of these tales, including the one about Grandin, Oliver Sacks describes his encounters with persons who have quite abnormal (acquired or innate) brain functions. The topics include color blindness, frontal lobe dysfunction, Tourette's syndrome, adult sight recovery, and variants of autism, and the tales are presented as syntheses of case studies with broader scientific and philosophical discussions.

The tales are paradoxical in the sense that the psychological-neurological conditions, which at first glance seem extremely disturbing, often are revealed as multilayered, partially recessive, or even as conveying certain strengths. A surgeon with Tourette's syndrome is jumping around in the hospital corridors, but is able to perform exquisite surgery. A painter who goes color blind enters a period of artistic creativity in his new "gray" world. But having said this, the book is not all about "feel-good" stories, some of the cases end quite tragically.

I especially enjoyed reading about Oliver Sack's personal engagement with his patients. Sometimes very outspoken, and sometimes more subtle, his own traits are exposed, reminding the reader that many (all?) psychological-neurological functions are non-discrete, and rather form a continuum, where the definitions of health and illness may be quite arbitrary.