Brain Imaging in Diagnosis of Lewy Body Dementia

Brain image highlighting right insula implicated in DLB

Recent information has emerged concerning the suicide death of the comedian/actor Robin Williams.

Autopsy results have demonstrated that Robin Williams suffered from dementia with Lewy bodies (DLB).

This public case demonstrates the difficulty in making a correct diagnosis of DLB prior to the findings at autopsy.

In a previous post I reported on a screening tool for clinicians that appears to have some promise for screening for high-risk DLB patients.

In this post, I want to follow up on this topic by reviewing a recent brain imaging study that targeted patterns of brain cortical thinning in the dementias.

The key elements in the design of this research study included the following elements:

• Subjects: 28 subjects with prodromal DLB, 27 subjects with prodromal Alzheimer's disease (AD), 31 subjects with DLB, 54 subjects with AD and cognitively normal elderly adults.
• Brain Imaging: Structural magnetic resonance imaging (MRI) with a 3 Tesla scanner
• Statistical Analysis: FreeSurfer analysis of regional cortical thickness pattern across diagnosis groups

The key findings from the study included the following:

• DLB subjects showed distinct patterns of cortical thinning compared to AD
• DLB was associated with increased thinning of the right insular cortex
• AD was associated with left parahippocampal thinning and bilateral parietal lobe thinning
• In those with full dementia, AD subjects demonstrated more thinning in the enterorhinal cortex

The authors of this study note in the discussion section of the paper that the key finding is the finding of right insular cortex thinning in DLB. This finding may allow use of brain imaging as a sensitive addition to the use of clinical and neuropsychological assessment in elderly with early and later dementia.

This study will need to be replicated in additional independent samples. Some research groups may already have scan data that may be able to be analyzed in an attempt to replicate the current study.

Readers with more interest in the study can access the free full-text manuscript by clicking on the PMID link in the citation below.

Image of the right insular cortex is from a screen shot from my iPad using the Brain Tutor app.

Follow me on Twitter @WRY999

Blanc F, Colloby SJ, Philippi N, de Pétigny X, Jung B, Demuynck C, Phillipps C, Anthony P, Thomas A, Bing F, Lamy J, Martin-Hunyadi C, O'Brien JT, Cretin B, McKeith I, Armspach JP, & Taylor JP (2015). Cortical Thickness in Dementia with Lewy Bodies and Alzheimer's Disease: A Comparison of Prodromal and Dementia Stages. PloS one, 10 (6) PMID: 26061655

Improving Diagnosis of Lewy Body Dementia

This month I have been focusing on research advances in neuropsychology in neuroscience medicine.

My daily feed screener picked up a report of a screening tool for Lewy Body Dementia (LBD) today.

LBD is often confused with Alzheimer's disease. Distinguishing the two is important for management and selection of appropriate drug treatment.

This research is not published in a free full-text manuscript format but there is a link to the scale for readers with more interest.

The research study examined the validity of a newly developed scale called the Lewy Body Composite Risk Score or LBCRS.

This score is calculated from a ten-item yes-no questionnaire that includes questions on the presence or absence of:

• Movement initiation difficulty
• Muscular rigidity
• Postural instability with frequent falls
• Tremor at rest
• Excessive daytime sleepiness
• Illogical, incoherent thought
• Staring or blank look spells
• Visual hallucinations
• Acting out dreams
• Orthostatic hypotension/autonomic insufficiency

Using a cutoff score of 3 positive responses yielded a high discrimination of LBD from Alzheimer's disease in a group of 256 patients.

The link to the scale and administration directions can be found here.

Accurate tools for identifying LBD are needed and this scale may be helpful for clinicians. It will be interesting to follow to see if this study can be replicated in another sample.

Figure of brain basal ganglia commonly affected in LBD is an iPad screenshot from the app 3D Brain from the author's files.

Follow the author on Twitter WRY999
Galvin JE (2015). IMPROVING THE CLINICAL DETECTION OF LEWY BODY DEMENTIA WITH THE LEWY BODY COMPOSITE RISK SCORE. Alzheimer's & dementia (Amsterdam, Netherlands), 1 (3), 316-324 PMID: 26405688

Bad Boy. Bad Boy. Is It Conduct Disorder?

Defining the line between normal childhood behavior and more serious problems like conduct disorder (CD) is important.

Conduct disorder is linked to a significant risk for a lifelong problem with aggression. 

Identifying CD early in life provides the hope that early intervention might reduce the later consequences of the disorder.

The American Academy of Child and Adolescent Psychiatry has an excellent online resource center to understand conduct disorder. They note the condition is characterized by four key diagnostic features with onset in childhood:

• Aggression toward people and animals
• Destruction of property
• Frequent lying/theft
• Chronic violation of rules

A recent research study by Benjamin Lahey and Irwin Waldman analyzed the validity of conduct disorder in relationship to the other common childhood forms of psychopathology.

They note a key diagnostic challenge is to differentiate conduct disorder from a similar disorder known as oppositional defiant disorder or ODD. The main conclusions from their literature review included the following:

1. CD appears distinct from ODD in many ways
2. CD more strongly predicts adult antisocial behavior compared to ODD
3. It may be of value to identify the type of aggressive behavior in cases of CD: proactive vs reactive, physical vs non-physical aggression towards other
4. Age of onset of CD may be an important signal. Early age of onset appears to have a worse prognosis
5. CD in the context of a callous, unemotional, without regret may also be an important marker for severity
6. CD is a male predominant disorder and there may be important differences in the manifestation of the disorder between boys and girls
7. Factor analysis finds CD to cluster in a broad group of externalizing disorders that includes ODD, ADHD hyperactivity and impulsivity and inattention
8. This externalizing group of disorders appears distinct from a group of childhood internalizing disorders that includes social anxiety, obsessive compulsive disorder, separation anxiety and phobias including agoraphobia
9. Externalizing disorders appear to share some distinct genetic risk
10. Although genetic factors appear key in CD and other externalizing disorders, environmental factors may interact with genetic risk to effect outcome
11. Future research implications from this review include the methods needed for refining the CD phenotype, molecular genetic studies, nonshared environmental studies and studies of the neurobiology of CD and studies of gender difference
12. It is likely that CD will share "neurobiological mechanisms with other prevalent forms of psychopathology" although is is likely there are mechanisms that will be specific or unique to CD

This review is a good place to start in understanding the phenotype of CD and how it is understood from a current research prospective.

Readers with more interest in this topic can access the free full-text manuscript by clicking on the PMID link in the citation below.

Image of toy dog is an original photo from the author's files.

Follow the author on Twitter @WRY999

Lahey BB, & Waldman ID (2012). Annual research review: phenotypic and causal structure of conduct disorder in the broader context of prevalent forms of psychopathology. Journal of child psychology and psychiatry, and allied disciplines, 53 (5), 536-57 PMID: 22211395

Brain EEG and the Genetics of ADHD

Twin studies in ADHD demonstrate a significant genetic contribution to the disorder.

Linking this genetic influence to specific biomarkers may provide a better understanding of the pathophysiology of ADHD.

Grainne McLoughlin and colleagues at the University of California San Diego and King's College London recently published a twin study of brain EEG and the genetics of ADHD.

In their study 67 twin pairs (34 monozygotic and 33 dizygotic) between the ages of 12 and 15 years completed tasks measuring brain frontocentral EEG theta patterns and reaction time.

Brain EEG frontocentral theta EEG levels increase under tasks requiring cognitive control, reaction time and handling reaction under conflict.

The authors were able to identify a specific type of EEG response in twins with ADHD compared to twins without the disorder. 

• Twins without ADHD showed changes in reaction time variability (RTV) and EEG theta performance with an attention and reaction task. 
• Twins with ADHD showed no change in these measures with the same attention and reaction task.

Of note, the authors were able to link this specific RTV and theta response to genetic features contributing to ADHD.

The authors note in their conclusion:

"This is the first finding that confirms the genetic link between frontal midline EEG activity and ADHD, as previously suggested by family studies."

This is an important finding and has significant implications in:

• Furthering understanding an EEG evoked response that may assist in the diagnosis of the ADHD phenotype
• Provide a biomarker for future family, twin and genome-wide genetic studies of ADHD
• Be helpful in teasing out environmental from genetic factors in ADHD

Readers with more interest in this study can access the free full-text manuscript by clicking on the PMID link in the citation below.

Photo of wood stork in flight is from the author's files.

Follow the author on Twitter WRY999.

McLoughlin G, Palmer JA, Rijsdijk F, & Makeig S (2014). Genetic overlap between evoked frontocentral theta-band phase variability, reaction time variability, and attention-deficit/hyperactivity disorder symptoms in a twin study. Biological psychiatry, 75 (3), 238-47 PMID: 24001472

Improving Dementia Diagnosis With a Sleep Marker

Dementia presents a growing challenge for clinicians both in the assessment as well as treatment domains.  Autopsy remains the only definitive diagnostic intervention that can confirm Alzheimer's disease and the other forms of senile dementia including vascular dementia, dementia with Lewy bodies, frontotemporal dementia and other dementia variants.

Since autopsy studies do not provide clinicians or their patients any direct benefits during the patient's lifetime, better diagnostic tests and clinical predictors are needed.

A recent study from a team of neurologists, psychiatrists, sleep medicine specialists and pathologists from the Mayo Clinic supports the potential of a sleep disorder to aid in the diagnosis of dementia with Lewy bodies.  Lewy bodies are distinct accumulations of proteins found in the brains of individuals with parkinsonism and Lewy body dementia.  They are identified at autopsy by special stains viewed under a microscope.

Dementia with Lewy bodies is often considered the second most common type of dementia.  The clinical diagnostic criteria were revised in 2005 and include core and suggestive features.  The core features include: fluctuations in cognitive abilities, parkinsonism and visual hallucinations.  The suggestive features include: sensitivity to antipsychotic drugs, reduced brain dopamine uptake on functional brain imaging and presence of the sleep disorder known as REM sleep behavior disorder (RBD).

The 2005 diagnostic guidelines for dementia with Lewy bodies can be made when patients have two of the core criteria or one of the core criteria and at least one suggestive criteria.

REM sleep behavior disorder (RBD) is a sleep disorder characterized by violent (or other dangerous) behavior during the REM or dream or nightmare phase of sleep.  This behavior can include punching, kicking, yelling, jumping out of bed often in response to specific content of the dream that is being experienced.  Individuals with RBD can physically injure themselves or their bed partners with their violent behaviors.

In normal individuals, REM sleep includes temporary muscle paralysis preventing individuals from physically responding to dreams or nightmares.  Loss of this REM sleep paralysis can lead to development of RBD.  RBD is felt to indicate disregulation of several brain neurotransmitter systems including dopamine, serotonin and acetylcholine.  This dysregulation may explain extreme sensitivity of patients with RBD to adverse effects of a variety of psychotropic drugs including antidepressants and antipsychotics.

The Mayo Clinic study included a prospective longitudinal study of a group of patients with dementia who were seen four times per year until their deaths.  Postmortem autopsies were conducted on 234 patients.  Seventy seven (33%) of the sample met pathological criteria for diffuse Lewy body disease.

The authors looked specifically at RBD as a predictor of true diagnosis of dementia with Lewy body disease.  They found that RBD was three times more powerful as a predictor of Lewy body dementia than any of the the core criteria of Lewy body dementia.

This study confirms the value of RBD in diagnosing Lewy body dementia--in fact it supports moving RBD up to a core feature rather than a suggestive feature.  A second multicenter study by Bliwise and colleagues has confirmed the high rates of RBD in Lewy body dementia compared to those with Alzheimer's disease.

These findings should encourage clinicians to aggressively look for RBD in patients with dementia to aid differential diagnosis and the treatment planning in this challenging population.

Photo of typical Santa Fe home architecture taken during sunset in Santa Fe, New Mexico from the author's collection.

Ferman TJ, Boeve BF, Smith GE, Lin SC, Silber MH, Pedraza O, Wszolek Z, Graff-Radford NR, Uitti R, Van Gerpen J, Pao W, Knopman D, Pankratz VS, Kantarci K, Boot B, Parisi JE, Dugger BN, Fujishiro H, Petersen RC, & Dickson DW (2011). Inclusion of RBD improves the diagnostic classification of dementia with Lewy bodies. Neurology, 77 (9), 875-82 PMID: 21849645

Bliwise, D., Mercaldo, N., Avidan, A., Boeve, B., Greer, S., & Kukull, W. (2011). Sleep Disturbance in Dementia with Lewy Bodies and Alzheimer’s Disease: A Multicenter Analysis Dementia and Geriatric Cognitive Disorders, 31 (3), 239-246 DOI: 10.1159/000326238

Improving Diagnostic Accuracy of Bipolar Disorder

A key clinical challenge in the mood disorders is to determine whether patients with depression actually have a diagnosis of bipolar disorder.  This can be quite difficult as patients may have limited insight while suffering a manic episode.  They may have impairments in memory during manic episodes that reduce their ability to provide an accurate psychiatric history.

The symptoms of mania are outlined in the Diagnostic and Statitistical Manual-Fourth Edition, Text Revision (DSM-IVTR) and include:

A. A distinct period of elevated, expansive or irritable mood lasting at least one week

B. Presence of three of the following symptoms or signs (four if irritable mood is assessed)

• inflated self esteem or grandiosity
• decreased need for sleep
• hypertalkative
• flight of ideas (moving quickly from one subject to another), racing thoughts
• distractibility
• increase in goal-directed activity or psychomotor agitation
• engagement in pleasurable activities with high risk for adverse out, i.e. gambling

C. Not accompanied by current symptoms of depression in which case a mixed episode is diagnosed

D. Significant impairment or psychotic symptoms or need for hospitalization

E.  Not better accounted by drug use, i.e amphetamines, a medical condition, or caused by a medical treatment for depression, i.e. antidepressants

Jules Angst and colleagues from the BRIDGE study group have recently published a study suggesting additional criteria may be helpful in diagnosing bipolar disorder in those with a history of depression.  Angst has previously proposed a bipolar specifier in depression populations that includes presence of a family history of bipolar disorder and an early-onset of illness with multiple mood episodes.

Using a international sample of over 5000 adults with ongoing major depression, Angst and his team closely examined a series of variables and determined the correlation with DSM-IV TR bipolar disorder diagnosis as well as the broader specifier criteria criteria.

The study found that a family history of mania or hypomania and multiple episodes of mood disorder did highly correlate with both DSM-IV criteria of mania.  Additionally, manic or hypomanic states during antidepressant therapy, presence of mixed mood disorder and comorbid substance abuse correlated with his bipolar specifier definition.

Using the limited DSM-IV TR mania/hypmanic criteria classifed 16% of the depressed sample as bipolar, while using the bipolar specifier increased this proportion to 47% of the sample.

The are significant clinical implications if this larger estimate of the percentage of individuals with depression meeting a bipolar variant is correct.  It would support greater use of mood stabilizers such as lithium, greater use of atypical antipsychotics such as aripiprazole and reduced use of the standard antidepressant class of drugs.  Antidepressants appear to have adverse effects on the long-term course of some individuals with the bipolar variant of mood disorder.

Dr. Gary Sachs of Harvard has also done work looking a similar expanded Bipolarity Index classification of mood disorder provided with this link.

Photo of Juno Beach sunrise using a pixelation filter from the author's collection.

Angst J, Azorin JM, Bowden CL, Perugi G, Vieta E, Gamma A, Young AH, & for the BRIDGE Study Group (2011). Prevalence and Characteristics of Undiagnosed Bipolar Disorders in Patients With a Major Depressive Episode: The BRIDGE Study. Archives of general psychiatry, 68 (8), 791-798 PMID: 21810644

Pitfalls in the Diagnosis of Adult ADHD

The diagnosis of attention-deficit/hyperactivity disorder in adults poses a challenge for patients and clinicians alike.  Hyperactivity is a less prominent sign in adults with ADHD than in children.  Attention problems may be due to a variety of conditions.  A common mistake is for a diagnosis of ADHD to be made based on a scale assessing attention problems.   This is an inappropriate diagnostic strategy unless attention symptoms can be liked specifically to an ADHD and not some other psychiatric or neurological disorder.

Kessler and colleagues recently published a study examining the current DSM-IV diagnostic criteria.  They used a sample of subjects from the National Comorbidity Survey Replication and a sample of patients from a large health plan.  The goals of the study were:

• Examine the stability of childhood ADHD symptoms to adulthood
• Examine the structure of ADHD symptoms in adults
• Find the adult symptoms most predictive of a current adult ADHD symptoms

The study found approximately 45-50% of those who met childhood ADHD diagnostic criteria met criteria as an adult.  The exact rates depended on the subtype of diagnosis in childhood, i.e. attention only, hyperactivity only, or both attention and hyperactivity.  Persistence was higher for those that met attention or attention and hyperactive subtypes as a child.

The research team found that adults with ADHD specifically endorsed ADHD symptoms tapping into brain executive function, i.e.

• “makes careless mistakes”
• “difficulty organizing tasks”
• “loses things”

The frontal lobe is the primary brain region involved in executive function and other symptoms of executive (and frontal lobe dysfunction) are available.   Kessler and colleagues recommend additional symptoms of executive function should be queried and possibly added to future versions of DSM diagnostic criteria for ADHD. These additional symptoms of executive dysfunction include problems with:

• planning
• prioritizing
• multitasking
• remembering details
• meeting deadlines
• maintaining self-discipline

Some of my own research has addressed the issue of diagnostic prevalence of ADHD in clinical populations.  We examined a series of women with eating disorders and looked for the presence of ADHD.  If just adult ADHD symptoms were assessed 21% of the sample would have been diagnosed with ADHD.  But since ADHD begins in childhood and requires childhood symptoms, we looked for presence of childhood symptoms to confirm the adult diagnosis of ADHD.  Only 5.8% of subjects had both childhood and adult symptoms.  This prevalence estimate did not appear distinctly different than the general population.

So it is important to have a comprehensive assessment when looking for the diagnosis of adult ADHD.  Executive deficits in adult ADHD appear to be a key symptom but are not adequately addressed in a DSM-IV ADHD  diagnostic assessment.

Animation of frontal lobe in red from the Wikipedia Commons file: BodyParts 3D authored by Life Sciences Data Base (LSDB).

Kessler RC, Green JG, Adler LA, Barkley RA, Chatterji S, Faraone SV, Finkelman M, Greenhill LL, Gruber MJ, Jewell M, Russo LJ, Sampson NA, & Van Brunt DL (2010). Structure and diagnosis of adult attention-deficit/hyperactivity disorder: analysis of expanded symptom criteria from the adult ADHD clinical diagnostic scale. Archives of general psychiatry, 67 (11), 1168-78 PMID: 21041618


Yates WR, Lund BC, Johnson C, Mitchell J, & McKee P (2009). Attention-deficit hyperactivity symptoms and disorder in eating disorder inpatients. The International journal of eating disorders, 42 (4), 375-8 PMID: 19040267

Google As a Medical Diagnostic Tool

My Google Reader accidentally picked up an intriguing abstract that examined a research study of resources that medical students use in solving diagnostic cases.  The abstract was picked up because it contained the word “exercise” that is one of my PubMed filter queries.  Although we often think that most diagnostic decision-making occurs from learned information stored in physician’s brains, information resources can be very helpful.  What information resources are medical students using to help them with the diagnostic process?

Graber and colleagues asked this question and designed a learning experiment.  One hundred and seventeen medical students were presented a challenging case and asked to provide their top three diagnoses as well as listing all the resources they used and the helpfulness of each resource.  This experiment occurred as part of a examination of the web-based decision support system known as Isabel.  The top six most used resources (and the percent of medical students who used the resource in the experiment) were:

• Medical books (73%)
• Google (70%)
• Other students (69%)
• Journals (49%)
• Residents and attending (29%)
• Isabel (28%)

 Of note, here were the students ratings of the top resources by usefulness (Likert Scale 1-not helpful to 5=extremely helpful:

• eMedicine (4.0)
• Medical books (3.9)
• Up-to-Date (3.8)
• Google (3.6)
• Other students (3.5)
• Journals (3.4)
• Residents and attending (3.4)

So this group of medical students reported frequently using Google to assist in a diagnostic assignment and they rate it as extremely useful.  The students also endorsed eMedicine a web-based medical information resource and the Up-to-Date subscription medical information resource.  (Disclosure: I have written two chapters published by eMedicine).  It is not clear how the students defined using “journals” in this study.  I would have thought that PubMed would be a particularly good gateway for searching for diagnostic information by finding journals relevant to a specific clinical case presentation.

The use of Google for aiding in diagnosis is not limited to medical students and physicians.  Bouwman and colleagues describe two cases where parents were able to diagnose their child’s rare lysosomal storage disorder using Google.   Both cases had received extensive evaluation by medical personnel that did not result in a correct specific diagnosis.  Both child’s parents arrived at a correct diagnosis by using Google search.  In case one, the parents searched for “unexplained recurrent fever”, “pain in feet” and “skin rash” leading them to a site describing Fabry disease.   In the second case, parents typed in a sign their son exhibited “bowed fingers” and were led to a site for their son’s correct diagnosis of mucopolysaccharidosis.

Google can also provide false, irrelevant medical information when it comes to diagnosis.  Most clinicians have experienced patient’s making an incorrect self-diagnosis from information they obtained on the web.  It is best to use multiple sources of information when puzzled by a case presentation.  However, it appears that Google Search is playing an important role in how clinicians and the general public collect diagnostic information.  We need more research examining the potential power of this tool and the limitations.

Photo of Vijay Singh practicing putting at the 2010 PGA Championship courtesy of Yates Photography

Graber ML, Tompkins D, & Holland JJ (2009). Resources medical students use to derive a differential diagnosis. Medical teacher, 31 (6), 522-7 PMID: 19811168


Bouwman MG, Teunissen QG, Wijburg FA, & Linthorst GE (2010). 'Doctor Google' ending the diagnostic odyssey in lysosomal storage disorders: parents using internet search engines as an efficient diagnostic strategy in rare diseases. Archives of disease in childhood, 95 (8), 642-4 PMID: 20418338